N-substituted derivatives of piperidine as serotonin receptor agents

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

 

The technical field to which the invention relates.

The present invention relates to usacycling connections with pharmacokinetic properties for the treatment of symptoms, diseases and disorders associated with monoamine receptors, including serotonin receptors.

The level of technology

Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in the functioning of the body of a mammal. In the Central nervous system 5-HT is an important neurotransmitter and neuromodulator that is involved in such diverse behaviors and reactions as sleep, nutrition, locomotion, perception of pain, cognitive ability and memory, sexual behavior, control of body temperature and blood pressure. In the spinal cord serotonin plays an important role in controlling systems afferent peripheral nociceptors (Moulignier, Rev. Neurol., 150:3-15 (1994)). 5-HT has also been attributed peripheral functions in the cardiovascular, hematological and gastrointestinal systems. It was found that 5-HT Mediaroom a variety of contractile, secretory, and electrophysiological effects, including the reduction of vascular and non-vascular smooth muscle and platelet aggregation (Fuller, Biology of Serotonergic Transmission, 1982; Boullin, Serotonin in Mental Abnormalities 1:316 (1978); Barchas et al., Serotonin and Behavior (1973)). 5-HT2A subtype of receptor (also known under what lass) wide and in addition, discretely expressed in the brain, including many cortical, limbic area and the front area of the brain that are believed to be included in the modulation of higher cognitive and affective functions. This subtype receptor is also expressed on Mature platelets, where it mediates, in turn, platelet aggregation, one of the initial stages of the process of thrombosis.

Provided a wide distribution of serotonin in the body, it is clear that there is a huge interest in drugs that affect the serotonergic system (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 huge gene family of membrane-associated human proteins that function as transductor intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where they activate the endogenous ligand serotonin or exogenous injected drugs, they change their conformational structure and then interact with the following mediators of cellular signal transmission. Many of these receptors, including the subclass of 5-HT2A, are associated with G-protein receptors (GPCR), which transmit the signal, activating proteins linking winninowie nucleotides (G-proteins), resulting in the generation or inhibition of molecules of second messengers such as cyclic AMP, inositolfosfatov and diacylglycerol. Data secondary messengers then modulate the function of various intracellular enzymes, including kinases and ion channels, which, ultimately, affect the excitability and cell function.

At least 15 genetically different subtypes of 5-HT receptors have been identified and assigned to one of seven families (5-HT1-7). Each subtype displays a unique distribution, preference to different ligands and functional correlation.

Serotonin may be an important component in various types of painful conditions such as certain psychiatric disorders (depression, aggressiveness, panic attacks, obsessive-compulsive disorder, psychosis, schizophrenia, suicidal tendency), certain neurodegenerative disorders (dementia type, Parkinson's disease, Huntington's chorea), anorexia, bulimia, disorders associated with alcoholism, stroke, and migraine (Meltzer, Neuropsychopharmacology., 21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)). Recently proven strong involvement of 5-HT2 subtype receptor in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, D. the major depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders.

Schizophrenia is a particularly devastating neuropsychiatric disorder that affects approximately 1% of the human population. It is estimated that the total financial cost of diagnosis, treatment and loss of social productivity of individuals suffering from this disease, exceeds 2% of the gross national product (GNP) of the United States. Modern therapy primarily involves pharmacotherapy using a class of drugs known as antipsychotics. Antipsychotic drugs are effective for improving the positive symptoms (e.g. hallucinations and delusions), but they often do not improve negative symptoms (e.g., social and emotional withdrawal, apathy and devirginate speech).

Currently prescribed nine major classes of antipsychotic drugs for the treatment of psychotic symptoms. However, the use of these compounds is limited by their side effects. Almost all ″typical″ connection or connections of the old generation have a material adverse effect on the motor function of the person. Data ″extrapyramidal″ side effects, so named because of its impact on modelirovanie system, can be acute (eg, dystonic reaction, a potentially life-threatening, but rare neuroleptic malignant syndrome), and chronic (eg, akathisia, tremor and late dyskinesia). Therefore, drug development focuses on new ″atypical″ substances that do not have these adverse side effects.

Antipsychotic drugs have been shown to interact with a huge number of Central monoaminergic neurotransmitter receptors, including dopaminergic, serotonergic, adrenergic, muscarinic and histaminergic receptors. It is possible that therapeutic and adverse effects of these drugs is mediated by different receptor subtypes. The high degree of genetic homology and pharmacological data subtypes of receptors makes it difficult to develop selective for subtypes of compounds, as well as the definition of normal physiological or pathophysiological role of any specific subtype of receptor. Thus, there is a need for the development of drugs that are selective with respect to individual classes and subclasses of receptors among monoaminergic neurotransmitter receptors.

The most common theory describing the mechanism of action of antipsychotic is learning about your medicine, includes antagonism of dopamine D2 receptors. Unfortunately, there is a probability that the antagonism of the dopamine D2 receptor also mediates extrapyramidal side effects. Antagonism of 5-HT2A is an alternative molecular mechanism for drugs with antipsychotic efficacy, possibly through antagonism increased or enhanced signal transduction via the serotonergic system. Therefore, antagonists of 5-HT2A are good candidates for the treatment of psychosis without extrapyramidal side effects.

Normally, these receptors, as has been suggested, are at rest, if they are not activated by the binding of agonist (a drug that activates the receptor). To the present time understood that a significant portion, if not the largest GPCR monoamine receptors, including serotonin receptors can exist in a partially activated state in the absence of their endogenous agonists. This increased basal activity (constitutive activity) can inhibit compounds called inverse agonists. Both agonists and inverse agonists have their own activity in relation to the receptor, namely, that they alone can, respectively, to activate or deactivate these molecules. The opposite is the Braz 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 basal or constitutive response of the receptor.

Applicants have recently discovered an important aspect of the functions of the 5HT2A receptor, using Technology selection and amplification of the receptor (R-SAT) (U.S. patent 5707798, 1998; Chem. Abstr. 128:111548 (1998) and included references) for the study of 5-HT2 subclass of serotonin receptors. R-SAT is a phenotypic analysis of the function of the receptor, which includes the heterologous expression of receptors in fibroblast mammals. Using this technique, the applicants were able to demonstrate that natural 5-HT2A receptors have significant constitutive, or not dependent on the agonist, receptor activity (U.S. patent 6358698; Weiner et al. J. Pharmacol. Exp. Ther. 2001, 299 (1), 268-276, which is incorporated into this description by reference in its entirety, including the drawings). Moreover, the direct testing of a huge number of centrally acting drug compounds with known clinical activity in neuropsychiatric diseases, the applicants have determined that all compounds with antipsychotic efficacy General molecular property. Almost each of the data connections used by psychiatrists to treat psychosis, as it was discovered, is a potent inverse agonist of 5-HT2A. This University is unique clinico-pharmacological correlation for one subtype of receptor is convincing evidence, the reverse agonism 5-HT2A receptor is the molecular mechanism of antipsychotic efficacy in humans.

Detailed pharmacological characterization of a large number of antipsychotic compounds showed that they have a broad activity against many related receptor subtypes. Most of these compounds shows agonistic, competitive, antagonistic or inverse agonistic activity in relation to many subtypes of monoaminergic receptors, including serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic receptors. This broad activity is probably responsible for sedative, hypotensive and motor side effects of these compounds. Therefore, it would be a huge achievement to develop compounds that are selective inverse agonists of the 5-HT2A receptor, which have little or no have activity to other subtypes monoamine receptors, especially the dopamine D2 receptors. Such compounds can be applied in the treatment of human diseases (such as antipsychotic drugs), and can avoid the adverse side effects associated with nonselective interactions with receptors.

US 4853394 describes the complex is e esters and amides of N-(hydroxyethylidene-4-yl), to enhance motor function of the stomach, have antidotnoy activity and 5-HT antagonistic activity.

EP 0260070 describes 4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-forfinal)-1-botanology ether acetic acid for relief, relief, prevention or inhibition of the manifestations of mental disorders.

The invention

Describes compounds of formula I

or their pharmaceutically acceptable salts, amides, esters, or prodrugs,

where R1selected from the group consisting of optionally substituted heterocyclyl and optionally substituted (heterocyclyl)C1-6-alkyl;

R2and R3independently selected from the group consisting of hydrogen, C1-6-alkyl and halogen, or R2together with R3form a ring;

m is selected from the group consisting of 0, 1 and 2;

n is selected from the group consisting of 1, 2 and 3;

Ar1represents optionally substituted aryl or heteroaryl;

W is selected from the group consisting of O and S;

X is selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, an optionally substituted propylene, optionally substituted vinylene and CH2N(RN), where RNselected from hydrogen and C1-6-alkyl, and

Ar2represents obazatelno substituted aryl or heteroaryl.

Also describes methods of inhibiting the activity of monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of formula I. Also describes methods of inhibiting activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of formula I. in Addition, the described methods of treatment of psychotic diseases using compounds of formula I.

Detailed description of the invention

In this specification, the following definitions will be used in their entirety for definitions of technical terms, and will be used in their entirety to determine the scope of the claims of a group of inventions for which is sought protection in the claims. The term ″constitutive activity″ is defined as the basal activity of the receptor, which does not depend on the presence of agonist. Constitutive activity of the receptor can be measured using a number of different ways, including cellular (e.g., membrane) drugs (see, e.g., Barr & Manning, J. Biol. Chem. 272:32979-87 (1997)), peeled restored receptors, with or without sod is readie associated G-protein in phospholipid vesicles (Cerione et al., Biochemistry 23:4519-25 (1984)), and functional cellular assays (U.S. patent 6358698).

The term ″agonist″ means a compound that increases the activity of the receptor when it is contact with the receptor.

The term ″antagonist″ means a compound that competes with an agonist or inverse agonist for binding to the receptor, thereby blocking the action of an agonist or inverse agonist to the receptor. However, the antagonist (also known as ″neutral″ antagonist) has no effect on constitutive receptor activity.

The term ″inverse agonist″ means a compound that reduces the basal activity of the receptor (i.e. receptor-mediated signaling). Such compounds are also known as negative antagonists. Inverse agonist is a ligand for the receptor, leading to the fact that the receptor adopts an inactive state with respect to the basal condition in the absence of any ligand. Thus, while the antagonist can inhibit the activity of the agonist, inverse agonist is a ligand that may change the conformation of the receptor in the absence of agonist. The concept of inverse agonist was introduced Bond et al. in Nature 374:272 (1995). More specifically, Bond et al. suggested that is not associated with ligand β2-adrenoceptor is there in equilibrium between an inactive conformation and spontaneously active conformation. It is assumed that agonists stabilize the receptor in an active conformation. On the contrary, inverse agonists are believed to stabilize the inactive conformation of the receptor. Thus, while the antagonist exerts its activity by inhibiting agonist, inverse agonist can further show their activity in the absence of agonist, inhibiting spontaneous conversion is not associated with the ligand of the receptor in the active conformation.

The term ″5-HT2A receptor″ means receptor with activity, the activity subtype of serotonin receptor human, which is characterized by molecular cloning and pharmacology, as described in detail Saltzman et al. in Biochem. Biophys. Res. Comm. 181:1469-78 and Julius et al. in Proc. Natl. Acad. Sci. USA 87:928-932.

The term ″subject″ refers to an animal, preferably to a mammal, most preferably to the person who is the subject of the treatment, examination or experiment.

The term ″selective″ is defined as a connection property, in accordance with which the number of connections sufficient to perform the desired response of a particular type, subtype, class, or subclass of the receptor, causes a much smaller effect or no effect on the activity of other receptor types.

Terms ″village of the activity″ or ″selective″in respect of inverse agonist, is understood as a property of the compounds according to the invention, according to which the number of connections, providing efficient exposure to the inverse agonist at the 5-HT2A receptor and, thus, reduces its activity, causes little or no causes obratnoosmoticheskiye or antagonistic activity on other, related or unrelated receptors. In particular, certain compounds according to the invention, as has been discovered that essentially do not interact with other serotonin receptors (5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6 and 7) at the concentrations at which signal transmission 5-HT2A receptor is strongly or completely suppressed. Preferred compounds according to the invention are also selective with respect to other monolingualism receptors, such as dopaminergic, histaminergic, adrenergic and muscarinic receptors. Compounds that are highly selective with respect to 5-HT2A receptors may have a curative effect in the treatment of psychosis, schizophrenia or similar mental disorders, at the same time avoiding adverse effects caused by drugs proposed for this purpose up to the present time.

EC50for agonist means the concentration needed is left to reach 50% of maximum response, visible in R-SAT. For inverse agonists EC50means the concentration of compound required to achieve 50% inhibition of R-SAT response from basal levels in the absence of a connection.

Used in this description the term ″joint introduction″ pharmacologically active compounds refers to the delivery of two or more different chemicals in vitro or in vivo. Co-administration refers to the simultaneous delivery of different substances, for simultaneous delivery of a mixture of substances, as well as delivery of one substance, followed by delivery of the second substance or additional substances. In all cases the substances that are administered together, are designed to work in conjunction with each other.

In this context, the term ″aryl″ means a carbocyclic aromatic ring or a cyclic system. In addition, the term ″aryl″ includes condensed cyclic system in which at least two aryl rings or at least one aryl and at least one C3-8-cycloalkyl have at least one common chemical bond. Some examples of ″aryl″ rings include optionally substituted phenyl, naphthalenyl, phenanthrene, anthracene, tetralinyl, fluorenyl, indenyl and indanyl. The term ″aryl″ refers to aromatic, preferably Ben is Aulnay groups, attached via one of the carbon atoms forming a ring, and optionally bearing one or more substituents selected from heterocyclyl, heteroaryl, halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. The aryl group may be substituted in the para and/or meta-position. Typical examples of aryl groups include, but are not limited to, phenyl, 3-halogenfrei, 4-halogenfrei, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-AMINOPHENYL, 4-AMINOPHENYL, 3-were, 4-were, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifloromethyl, 3-cyanophenyl, 4-cyanophenyl, dimetilfenil, naphthyl, hydroxynaphthyl, hydroxymethylene, triptoreline, alkoxyphenyl, 4-morpholine-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolidine, 4-triazolylmethyl and 4-(2-oxopyrrolidin-1-yl)phenyl.

In this context, the term ″heteroaryl″ means aromatic heterocyclic group in which one or more carbon atoms in the aromatic ring substituted by one or more heteroatoms selected from the group comprising nitrogen, sulfur, phosphorus and oxygen.

In addition, in the present context, the term ″heteroaryl″ includes con is Tserovani cyclic system, in which at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl ring, at least one heteroaryl ring and at least one heterocyclic ring or at least one heteroaryl ring and at least one C3-8-cycloalkyl ring have at least one common chemical bond.

Have in mind that the term ″heteroaryl″ refers to aromatic, C3-8-cyclic group, optionally containing one oxygen atom or sulfur, or up to four nitrogen atoms, or a combination of one oxygen atom or sulfur with one or two nitrogen atoms, and their substituted compounds, as well as benzo - and pyrido-condensed derivatives, preferably attached through one of the forming ring carbon atoms. Heteroaryl group can contain one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. In some embodiments, the implementation of the heteroaryl group may be a five - or six-membered aromatic geterotsiklicheskikh the system, containing 0, 1 or 2 substituent which may be the same or different from each other, selected from the list above. Typical examples of heteroaryl groups include, but are not limited to, unsubstituted, mono - or disubstituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazol, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, each of which is preferred, and furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazone, oxadiazole, benzopinacol, hemolysin, cinnoline, phthalazine, hinzelin and finokalia. In some embodiments, the implementation of the substituents are halogen, hydroxy, cyano, O-C1-6-alkyl, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl.

Have in mind that in the present context, the term ″alkyl″ and ″C1-6-alkyl″ means a straight or branched saturated hydrocarbon chain, the longest chain has from one to six carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Hexi is. The alkyl chain optionally may be substituted.

Have in mind that the term ″heterocyclyl″ means of three-, four-, five-, six-, seven - and eight-membered rings whose carbon atoms with 1-3 heteroatoms are specified ring. Heterocyclyl optionally may contain one or more unsaturated bonds located, however, so that aromatic π-electronic system does not occur. Heteroatoms independently selected from oxygen, sulfur and nitrogen.

Heterocyclyl may optionally contain one or more carbonyl or thiocarbonyl functional group, so that this definition is included oxo-and thio-system, such as lactams, lactones, cyclic imides, cyclic thioamide, cyclic carbamates, etc.

Heterocyclyl rings optionally may be condensed with aryl rings so that this definition includes bicyclic structure. Preferred are such condensed heterocyclyl group, which have one common link with optionally substituted benzene ring. Examples heterocyclyl group condensed with a benzene ring include, but are not limited to, benzimidazolidinone, tetrahydroquinolin and methylenedioxybenzene ring structure.

Some note the ry ″ heterocyclyl″ include, but are not limited to, tetrahydrothiopyran, 4H-Piran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-axation, 1,4-oxathiin, 1,4-axation, tetrahydro-1,4-thiazin, 2H-1,2-oxazin, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperidin, as dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolin, pyrrolidine, pyrrolidone, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiol, 1,3-ditiolan, isoxazolin, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolan. Communication with the heterocycle may be in the position of the heteroatom or via a carbon atom of the heterocycle, or, for derivatives, condensed with the benzene ring via a carbon atom of the benzene ring.

The term ″(heterocyclyl)C1-6-alkyl″ means heterocyclyl group United as a substitute through alkyl groups, each of which is such as defined in the present description. Heterocyclyl group (heterocyclyl)C1-6-alkyl groups can be substituted or unsubstituted. Have in mind that the term ″(heterocyclyl)C1-6-alkyl″ means alkyl chain, substituted, m is Nisha least once heterocyclyl group usually position of the end of the alkyl chain.

In this context, the term ″C2-8alkenyl″ means the hydrocarbon group with a straight or branched chain, having from two to eight carbon atoms and containing one or more double bonds. Some examples of C2-8-alkenyl groups include allyl, Gamaliel, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Some examples of C2-8-alkenyl groups containing more than one double bond include butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadienyl and occationally group, as well as their branched form. The position of unsaturation (double bond) can be in any position of the carbon chain.

In this context, the term ″C2-8-quinil″ means the hydrocarbon group with a straight or branched chain, having from two to eight carbon atoms and containing one or more triple bonds. Some examples of C2-8-etkinlik groups include ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl and octenyl, as well as their branched form. The position of unsaturation (triple bond) may be in any position of the chain. Unsaturated may be more than one link, so that ″C2-8-quinil″ is the FDS is th diin or endian, as is well-known specialist in this field.

In this context, the term ″C3-8-cycloalkyl″ means of three -, four-, five-, six-, seven - and eight-membered rings containing only carbon atoms. C3-8-cycloalkyl optionally may contain one or more unsaturated bonds located, however, so that aromatic π-electronic system does not occur.

Some examples of preferred ″C3-8-cycloalkyl″ are tsiklopropanovy, CYCLOBUTANE, cyclopentane, cyclopentenone, cyclopentadiene, cyclohexane, cyclohexenones, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptenyl, cycloheptenyl carbocycle.

Terms ″(aryl)C1-6-alkyl″ mean aryl group, joined as Deputy through C1-6is an alkyl group, each of which is such as defined in the present description. Aryl group (aryl)C1-6the alkyl can be substituted or unsubstituted. Examples include benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl and nafcillin.

Terms ″(cycloalkyl)C1-6-alkyl″ mean cycloalkyl group United as a substitute through an alkyl group, each of which is such as defined in the present description.

When used in this description is AI the term ″ O-C1-6-alkyl″ means C1-6-alkyloxy or alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy.

The term ″halogen″ includes fluorine, chlorine, bromine and iodine.

In the present context, i.e. in connection with the terms ″C1-6-alkyl″, ″aryl″, ″heteroaryl″, ″heterocyclyl″, ″C3-8-cycloalkyl″, ″heterocyclyl(C1-6-alkyl)″, ″(cycloalkyl)alkyl″, ″O-C1-6-alkyl″, ″C2-8alkenyl″ and ″C2-8-quinil″, the term ″optionally substituted″ means that this group may be substituted one or more times, for example 1-5 times or 1-3 times or 1-2 times, one or more groups selected from C1-6-alkyl, C1-6-alkoxy, carbonyl group (which may be represented in the tautomeric enol form), carboxyl, amino, hydroxy (which when present in an enol system may be represented in the tautomeric ketoform), nitro, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, C1-6-alkoxycarbonyl, C1-6-alkylsulphonyl, formyl, amino, mono - and di(C1-6-alkyl)amino, carbamoyl, mono - and di(C1-6-alkyl)aminocarbonyl, amino-C1-6-alkylaminocarbonyl, mono - and di(C1-6-alkyl)AMI the o-C 1-6-alkylaminocarbonyl, C1-6-alkylcarboxylic, C1-6-alkylhydroxylamines, cyano, guanidine, urea, C1-6-alkanoyloxy, C1-6-alkylsulfonate, dihalogen-C1-6-alkyl, trihalogen-C1-6-alkyl, heterocyclyl, heteroaryl and halogen. In General, the above substituents may be susceptible to additional optional substitution.

The term ″salt″ means pharmaceutically acceptable acid additive salts, obtained by processing the basic form of functional groups such as amine, with appropriate acids such as inorganic acids, for example, halogenations acid, typically hydrochloric, Hydrobromic, hydrofluoric, or idiscovered acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic, propionic, hydroxylases, 2-hydroxypropionate, 2-oxopropionate, ethandiol, propandiol, butandiol, (Z)-2-butandiol, (E)-butanediol, 2-hydroxybutanoic, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, econsultancy, benzosulfimide, 4-methylbenzenesulfonic acid, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and other acids known to the skilled in the about the Asti.

The present invention includes within the scope of its claims prodrugs of the compounds according to this invention. In General, such prodrugs are inactive derivatives of the compounds according to this invention, which are easily converted in vivo to the desired connection. Traditional methods of selecting and obtaining the appropriate proletarienne derivatives described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985). Metabolites of these compounds include active particles, which are obtained by the introduction of the compounds according to this invention in a biological environment.

When the compounds according to the invention have at least one chiral center, they may exist in the form of a racemate or enantiomer. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. Moreover, some of the crystalline forms of the compounds of the present invention may exist as polymorphs, and assumes that they as such are included in the present invention. In addition, some of the compounds of 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 claims of the present invention.

When the means of obtaining the compounds according to this invention result in a mixture of stereoisomers, such of the measures can be divided by conventional methods, such as preparative chiral chromatography. Compounds can be obtained in racemic form, or individual enantiomers can be obtained stereoselective synthesis or by separation. Compounds can be divided into the enantiomers by standard techniques, such as education diastereoisomeric couples through the formation of salts with optically active acid such as (-)-di-p-toluoyl-d-Vienna acid and/or (+)-di-p-toluoyl-l-Vienna acid, followed by fractional crystallization and regeneration of the free base. Connections can also be divided using chiral auxiliary compounds by formation of diastereoisomeric derivatives, such as esters, amides or ketals, followed by chromatographic separation and removal of the chiral auxiliary connections.

Compounds of the present invention are effective for oral administration. The in vivo experiments conducted on rodents showed that a lower dose of the compounds of the present invention leads to equal or superior to behavioral responses in animal models of psychosis. These results indicate a higher bioavailability of the compounds of the present invention compared with the compounds described in the prior art. Improved bioavailability confirm the given observation what new connections presented in the present description, are significantly more effective in the analysis of their action on serotonin receptors in vitro and, in addition, represent a significant improvement in oral introduction. Very superior efficacy observed after oral doses, probably the result of increased metabolic stability, improved physical and chemical properties such as solubility or chemical resistance, or different pharmacokinetic characteristics, such as distribution, permeability, etc. is Not associating themselves with a particular theory, it is reasonable to ascribe these differences to the presence of the heterocyclic substituent on the nitrogen atom piperidino rings of these compounds. The presence of such a heterocyclic substituent may affect the behavior of the data derived from the viewpoint of solubility and/or metabolic lability. The presence of heteroatoms in the substituents close to the nitrogen atom, as expected, also affects the basicity of the nitrogen atom, which, in turn, can affect properties such as the distribution of (LogD) or metabolism.

Usually a high degree of bioavailability of any pharmaceutical drug is very useful. This relates primarily to the ability to implement an effective and also topasna the dose for all subjects regardless of their potential susceptibility to dependent polymorphism in the metabolism of drugs. Examples of such multiple polymorphisms are well known in this field. Thus, a drug that undergoes significant metabolism during its first passage through the liver or gastrointestinal tract, will show relatively low and sometimes in a dose-dependent bioavailability, measured as plasma concentrations achieved after oral distribution. Differences between individuals in the effects of drugs, as a rule, are more severe when the drug is difficult metabolized and, as a consequence, show low oral bioavailability. Subjects with polymorphisms that lead to changes in the activity of drug metabolizing enzymes, likely to be exposed to substantially different (usually higher) levels in plasma, compared with subjects showing normal metabolic activity. Therefore, aspects of the present invention refers to new compounds, which show characteristics, leading to the idea of excellent properties of drugs compared with drugs that are known from the prior art.

In General, the compounds of formula I are active against monoamine receptors, especially serotonin receptors. Some compounds according to the invention have in common the m property, acting as inverse agonists of the 5-HT2A receptors. Thus, the experiments performed on cells transiently expressing the human phenotype of the specified receptor, showed that the compounds of General formula I weaken the transmission of signals such receptors in the absence of additional ligands acting on the receptor. Thus, we discovered that these compounds possess the inherent activity in relation to this receptor and is able to reduce basal, not stimulated by the agonist, constitutive signalling pathways, which shows the 5-HT2A receptor. The observation that compounds of General formula I are inverse agonists, also shows that these compounds have the ability to anlagenservice activation of 5-HT2A receptors, which is due to endogenous agonists or ligands, representing exogenous synthetic agonists.

In certain embodiments of the implementation of the present invention provides compounds that show a relatively high degree of selectivity towards the 5-HT2A subtype of serotonin receptors relative to other subtypes of serotonin (5-HT) family of receptors, and other receptors, most specifically monoaminergic associated with G-protein receptors such as dopamine receptors. In other variants of the Ah implementation of the compounds of the present invention act as inverse agonists of the 5-HT2A subtype of serotonin receptors.

Therefore, compounds of General formula I may be useful for the treatment or relief of symptoms of painful conditions associated with impaired function, in particular with elevated levels of activity, particularly 5-HT2A receptors, regardless of whether this dysfunction with inappropriate levels of stimulation of the receptor or phenotypic aberrations.

Other researchers have previously suggested that certain neuropsychological diseases can be caused by changing levels of constitutive activity monoamine receptors. Such constitutive activity could be modified by contact corresponding with synthetic receptor inverse agonist. Direct testing of a huge number of centrally acting drug compounds with known clinical activity in neuropsychiatric disease, the applicants have determined that all compounds with antipsychotic efficacy General molecular property. It was found that almost all of the data connections that are used by psychiatrists for the treatment of psychosis, are a strong inverse agonists 5HT2A. This correlation is strong evidence that the inverse agonism 5HT2A receptor is a molecular mechanics is the m antipsychotic efficacy in humans.

Detailed pharmacological characterization of a huge number of antipsychotic compounds in the laboratory applicants have shown that they have a broad activity against a variety of related receptor subtypes. Most of these compounds shows agonistic, competitive, antagonistic or inverse agonistic activity against multiple subtypes of monoaminergic receptors, including serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic receptors. This wide range of activity likely to be responsible for sedative, hypotensive and motor side effects of these compounds. It follows that described in the description of the compounds will be effective, for example, new antipsychotic drugs, but will have a smaller or less severe side effects compared to existing connections.

Thus, in the first aspect of the present invention relates to a compound of formula I

or its pharmaceutically acceptable salt, amide, ether complex or prodrug,

where R1selected from the group consisting of optionally substituted heterocyclyl and optionally substituted (heterocyclyl)C1-6-alkyl;

R2and R3independently researched the Simo selected from the group consisting of hydrogen, C1-6-alkyl and halogen, or R2together with R3forms a loop;

m is selected from the group consisting of 0, 1 and 2;

n is selected from the group consisting of 1, 2 and 3;

Ar1represents optionally substituted aryl or heteroaryl;

W is selected from the group consisting of O and S;

X is selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, an optionally substituted propylene, optionally substituted vinylene and CH2N(RN), where RNselected from hydrogen and C1-6-alkyl, and

Ar2represents optionally substituted aryl or heteroaryl.

As discussed above, it is believed that the presence of heterocyclic substituent on the nitrogen atom piperidino rings of these compounds improves the bioavailability of the compounds in comparison with related compounds, well-known specialist in this field.

In some embodiments, the implementation heterocyclyl or (heterocyclyl)C1-6the alkyl group, R1may be optionally substituted. The Deputy may be selected from halogen, hydroxy, alkyl, alkoxy and amino. In some embodiments, the implementation of the Deputy may be alkyl chain or a cyclic system. In further embodiments, the implementation of the Deputy is cyclic si is theme.

In certain embodiments of the implementation of the ring heterocyclyl in R1you can choose from a group consisting of tetrahydrothiopyran, 4H-Piran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazinyl, as dihydrouracil, research, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidinone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. In some embodiments, the implementation of a heterocyclic ring selected from 1,3-dioxane, 1,3-dioxolane and tetrahydropyran.

Azollaceae ring may be a 5-, 6 - or 7-membered ring, when m is selected from 0, 1 and 2. However, in certain embodiments of the implementation azollaceae ring is a 6-membered ring, in which m is 1.

In addition to the substitution at the nitrogen atom, azollaceae ring may be substituted by R2and R3. R2and R3can be independently selected from the group consisting of hydrogen, C 1-6-alkyl and halogen, or so that R2together with R3form a ring. That is, R2and R3can be a diradicals, which are combined to form a 3-, 4-, 5-, 6 - or 7-membered cyclic system with atoms usacycling rings.

In some embodiments, the implementation azollaceae ring system selected from the

in which R7and R8independently selected from the group consisting of hydrogen, halogen, hydroxyl and C1-6-alkyl. In certain embodiments of the implementation of R7and R8represent hydrogen.

In other embodiments, implementation of R2and R3represent hydrogen.

In some embodiments, the implementation of R1represents an optionally substituted (heterocyclyl)C1-6-alkyl. In specific cases of these embodiments, R1represents an optionally substituted (heterocyclyl)methyl, optionally substituted (heterocyclyl)ethyl or optionally substituted (heterocyclyl)propyl. In other embodiments, implementation of R1represents an optionally substituted (heterocyclyl)ethyl.

Ar1associated with the Central nitrogen atom through a short aliphatic chain containing 1, 2 or 3 carbon atoms. In certain embodiments domestic which n is 1, the resulting methylene bridge between the Central nitrogen atom and Ar1. Ar1can be an optionally substituted aryl or heteroaryl. In some embodiments, the implementation of Ar1represents optionally substituted aryl. In some embodiments, the implementation of the Central nitrogen atom is linked to optionally substituted benzyl group.

In certain embodiments implement Ar1represents an optionally substituted aryl, which may be a 4-substituted aryl. 4-Deputy 4-substituted aryl may be any Deputy, known to the person skilled in the art, for example, C1-6-alkyl, C1-6-alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano, guanidine, urea and halogen. In some embodiments, the implementation of the halogen represents fluorine, while in other embodiments, implementation of the halogen represents chlorine.

In other embodiments, the implementation of Ar1selected from the group consisting of alkyl substituted phenyl, alkoxysilanes phenyl, halogen-substituted phenyl, replacement of the phenyl and aminosilanes phenyl. In some embodiments, the implementation of the Deputy may attend 0-5 times or 0-4 times or 0-3 times, such as 0, 1, 2 or 3 times. In certain embodiments implement Deputy presets is there 1-2 times. In some embodiments, the implementation of Ar1represents a 4-substituted aryl selected from the group consisting of 4-halogenfree and 4-alkylphenyl. In some embodiments, the implementation of the phenyl group is a 4-forfinal.

In other embodiments, the implementation of Ar1represents an optionally substituted heteroaryl. Heteroaryl may contain substituents known to the person skilled in the art, such as C1-6-alkyl, C1-6-alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano, guanidine, urea and halogen.

Besides usacycling ring and Ar1by short aliphatic chain, the Central nitrogen atom is linked to Ar2through a bridge containing 2-4 carbon atoms. This bridge includes a carbonyl or thiocarbonyl functional group W is selected from the group consisting of oxygen and sulfur. In some embodiments, the implementation of W represents oxygen.

In certain embodiments of the realization of X can be selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, an optionally substituted propylene, optionally substituted vinylene and CH2N(RN). Thus, X can be extended bridge control group 1-3 atom between the Central nitrogen atom and Ar2and share the ü Central nitrogen part of the amide or urea. In some embodiments, implementation of the X selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, and CH2N(RN). In some embodiments, implementation of the X represents an optionally substituted methylene or-CH2N(RN), where RNmay be hydrogen.

In certain embodiments implement Ar2can be an optionally substituted aryl or heteroaryl. In certain embodiments implement Ar2represents optionally substituted aryl. In some embodiments, the implementation of Ar2represents a 4-substituted aryl.

In a further embodiment, Ar2can be selected from the group consisting of alkoxy-substituted phenyl, halogen-substituted phenyl, replacement of phenyl, aminosilanes phenyl and heterocyclization phenyl.

In certain embodiments implement Ar2represents a 4-substituted aryl, in which the Deputy is selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, heterocyclyl and heteroaryl. In some embodiments, the implementation of the substituents on Ar2selected from chlorine, fluorine, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, triptoreline, N-morpholinyl, N-pyrrolidine is a, N-pyrazolyl, N-triazolyl and 2-oxopyrrolidin.

In another aspect, the present invention relates to a compound selected from the group including

the hydrochloride of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-salutogenesis)urea;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]ndimethylacetamide;

N-(4-terbisil)-N-(piperidine-4-yl)-2-(4-isobutoxide)ndimethylacetamide;

the dihydrochloride of N-{1-[3-(3,5-dimethylpiperidin-1-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

the methyl ester dihydrochloride of 1-[3-(4-{(4-terbisil)-[2-(4-isobutoxide)acetyl]amino}piperidine-1-yl)propyl]piperidine-4-carboxylic acid;

dioxalate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(1-methylpyrrolidine-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

dioxalate N-{1-[3-(2,6-dimethylmorpholine-4-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

dioxalate N-(4-terbisil)-N-{1-[3-(3-hydroxypiperidine-1-yl)propyl]piperidine-4-yl}-2-(4-isobutoxide)ndimethylacetamide;

dioxalate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-methylpiperidin-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;

dioxalate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(3-pyrrolidin-1-ylpropyl)piperidine-4-yl]ndimethylacetamide;

dioxalate N-{1-[3-(2,5-dimethylpiperidin-1-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-of butoxyphenyl)ndimethylacetamide;

dioxalate N-(4-terbisil)-N-{1-[3-(3-hydroxyethylpiperazine-1-yl)propyl]piperidine-4-yl}-2-(4-isobutoxide)ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-[2-(4-forfinal)ethyl]-2-(4-isobutoxy)-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-[2-(4-forfinal)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}-2-(4-propoxyphenyl)ndimethylacetamide;

oxalate of N-(4-terbisil)-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}-2-(4-propoxyphenyl)ndimethylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-[2-(4-forfinal)ethyl]-2-(4-isobutoxide)ndimethylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-[2-(4-forfinal)ethyl]-2-(4-propoxyphenyl)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propoxyphenyl)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-salutogenesis)urea;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-forfinal)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-p-tolylacetate;

tartrate 2-benzofuran-5-yl-N-{1-[2-(1,3-dio the San-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

tartrate 2-(2,3-dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

tartrate N-{1-[2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)amine;

tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-triptoreline)ndimethylacetamide;

tartrate 2-(4-cyanophenyl)-N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

the hydrochloride of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(2-Oxymetazoline-1-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

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

the hydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-{1-[2-(2-Oxymetazoline-1-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

the hydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;

the hydrochloride of N-{1-[2-(2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)ethyl]piperidine-4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)ndimethylacetamide;

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

the hydrochloride of N-(4-terbisil)-2-(4-isopropoxy enyl)-N-{1-[4-(2-oxo-2,3-dihydrobenzoic-1-yl)butyl]piperidine-4-yl}ndimethylacetamide;

the hydrochloride of N-{1-[2-(2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropoxyphenyl)ndimethylacetamide;

benzyl ether of 4-(4-forbindelsen)piperidine-1-carboxylic acid;

N-(1-benzyloxycarbonylamino-4-yl)-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea;

oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-piperidine-4-ylcarbamate;

oxalate of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea;

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

the hydrochloride of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

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

tartrate N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propoxyphenyl)ndimethylacetamide;

oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}urea;

oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]urea;

the dihydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholine-4-retil)piperidine-4-yl]ndimethylacetamide;

the dihydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]ndimethylacetamide;

the dihydrochloride of N-(4-forbesi is)-2-(4-isobutoxy)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]ndimethylacetamide;

the dihydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]ndimethylacetamide;

oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-[1-(3-piperidine-1-ylpropyl)piperidine-4-yl]urea;

tartrate N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-[1-(3-((S)-4-isopropyl-2-oxazolidinone-1-ylpropyl)piperidine-4-yl]urea;

oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethyl]}piperidine-4-yl]urea;

oxalate of N-{1-[3-(1,3-dioxolane-2-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea;

oxalate of N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea;

oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-{[2-(1-methylpyrrolidine-2-yl)ethyl]piperidine-4-yl}urea;

oxalate of N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide oxalate;

tartrate N-[1-(1,3-dioxane-5-yl)piperidine-4-yl)-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

tartrate N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-forfinal)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-forfinal)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-trifloromethyl)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-ProPak iphenyl)ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(tetrahydropyran-4-yl)piperidine-4-yl]ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(tetrahydropyran-4-ylmethyl)piperidine-4-yl]ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(tetrahydropyran-4-yl)ethyl]piperidine-4-yl]ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-forfinal)-N-[1-(tetrahydropyran-4-yl)piperidine-4-yl]ndimethylacetamide;

tartrate N-[1-((S) - for 3,5-dihydroxyphenyl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

tartrate N-{1-[2-((4S)-1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)amine;

tartrate 2-(4-benzyloxyphenyl)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-hydroxyphenyl)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-methoxyphenyl)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropylphenyl)ndimethylacetamide;

tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-trifloromethyl)ndimethylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-ethoxyphenyl)ndimethylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropoxyphenyl the l)ndimethylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-phenylacetamide;

oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(2-floratone)phenyl]ndimethylacetamide;

oxalate of N-{1-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-((R)-4-methyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-{1-[2-(4,6-dimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

oxalate of N-(4-terbisil)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-2-(4-trifloromethyl)ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isopropylphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-N-{1-[2-((R)-4-methyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-2-(4-trifloromethyl)ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(2-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(1,3-dioxolane-2-yl)propyl]piperidine-4-yl}ndimethylacetamide;

the dihydrochloride of N-(4-terbisil)-2-(4-isobutoxide)N-{1-(3-piperidine-1-ylpropyl)piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(tetrahydropyran-2-yloxy)ethyl]piperidine-4-yl}ndimethylacetamide;

N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-oxopiperidin-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;

the hydrochloride of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-oxopyrrolidin-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-((R)-4-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-((S)-4-methyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide;

oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-((S)-4-ethyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide;

L-tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(1,3-oxathiolan-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

L-tartrate 2-(4-bromophenyl)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutylphenyl)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propylaminoethyl)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(1-nitropropyl)phenyl)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidin-yl}-N-(4-terbisil)-2-[4-(2-oxopyrrolidin-1-yl)phenyl]ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutylphenyl)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-itfeel)ndimethylacetamide;

L-tartrate 2-(4-acetogenin)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

L-tartrate 2-[4-(1-hydroxyimino)phenyl]-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(morpholine-4-ylphenyl)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(pyrazole-1-ylphenyl)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)-1-methylethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

L-tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(pyrazole-1-ylphenyl)ndimethylacetamide;

tartrate N-[1-((R) - for 3,5-dihydroxyphenyl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

tartrate N-{1-[2-((4R)-1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide and

L-tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(1,2,4-triazole-4-yl)phenyl]ndimethylacetamide.

As indicated, applicants have discovered that compounds of formula I are effective modulators of 5-HT2A subtype of serotonin receptors person. Thus, the invention further relates to a method of Engibarov is of the activity of monoamine receptor, comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds, as described in the present description. Monoamine receptor may be a serotonin receptor, usually 5-HT2A subclass.

Serotonin receptor may alternatively be located in the Central nervous system or peripheral nervous system. Usually serotonin receptor may be in the blood cells or platelets. In certain embodiments of the implementation of the serotonin receptor may be mutated or modified.

The activity of a monoamine receptor, which is modulated, usually can be a signal activity. In addition, the activity can usually be constitutive. Activity associated with serotonin receptor, usually can be activated.

In another aspect, the present invention relates to a method of inhibiting activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds, as described in the present description. Activation, which can inhibit the method according to the present invention, Oba is but may represent activation, resulting from exposure to agonist. Substance-agonist may be exogenous or endogenous. In addition, the activation can be constitutive.

Another aspect of the present invention relates to the treatment of painful conditions associated with dysfunction of monoamine receptor, and to the use of compounds of formula I to obtain drugs for the treatment of painful conditions associated with monoamine receptor. Painful condition may be associated with activation of a monoamine receptor, for example with increased activity of monoamine receptor.

In another aspect the present invention relates to a method of treating schizophrenia, comprising introducing to a subject in need of such treatment, a therapeutically effective amount of the compounds of formula I, which is described in the present description. Alternative invention relates, in particular, to the use of compounds of formula I to obtain drugs for the treatment of schizophrenia. A further aspect relates to a method of treatment of migraine comprising the administration to a subject in need of such treatment, a therapeutically effective amount of the compounds of formula I. an Alternative invention relates, in particular, to the use of compounds of formula I to obtain drugs for the treatment of the migration is I. A further aspect of the invention relates to a method of treating psychosis comprising introducing to a subject in need of such treatment, a therapeutically effective amount of the compounds of formula I. an Alternative invention relates, in particular, to the use of compounds of formula I to obtain drugs for the treatment of psychosis. One additional aspect of the invention relates to a method of treatment of psychotic symptoms such as hallucinations resulting from the introduction of dopamine agonists such as L-dopa, individuals in need of treatment, such as people suffering from Parkinson's disease, comprising introducing the compound of formula I. an Alternative invention relates, at least in part, to the use of compounds of formula I to obtain drugs for the treatment of psychotic symptoms such as hallucinations resulting from the introduction of dopamine agonists such as L-dopa, individuals in need of treatment, such as people suffering from Parkinson's disease.

Another aspect of the present invention relates to a method of treatment of a pathological state associated with monoamine receptor comprising the administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of the formula I, which charact is characterized in the present description. Painful condition can be selected from the group consisting of schizophrenia, schizoaffective disorders; psychosis and related behavioral normalista observed in neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, dementia with calves Levi, fronto-temporal dementia, Huntington's disease and spinocerebellar atrophy; caused by drug psychosis, including side effects observed in the treatment of chronic neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease, using a selective inhibitor of serotonin reuptake (SSRIs); Raynaud's syndrome; migraine headaches; hypertension; thrombosis; vascular spasm; ischemia; depression; anxiety; engine tick; Tourette syndrome; psoriasis; motor fluctuations; tremor; rigidity; bradykinesia; psychomotor slowing; addiction, including alcoholism, opium addiction and nicotine addiction; sleep disorders; disorders of appetite; decreased libido and problems with ejaculation. Thus, the invention relates to the use of compounds of formula I, which is described in the present description, to obtain drugs for the treatment of diseases and conditions selected from the group consisting of schizophrenia, schizoaffective disorders; psychosis and related to the x behavioral anormality, observed in neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, dementia with calves Levi, fronto-temporal dementia, Huntington's disease and spinocerebellar atrophy; caused by drug psychosis, including side effects observed with SSRI therapy in chronic neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease; Raynaud's syndrome; migraine headaches; hypertension; thrombosis; vascular spasm; ischemia; depression; anxiety; motor TIC; Tourette syndrome; psoriasis; motor fluctuations; tremor; rigidity; bradykinesia; psychomotor slowing; addiction, including alcoholism, opium addiction and nicotine addiction; sleep disorders; disorders of appetite; decreased libido and problems with ejaculation.

Another aspect of the present invention relates to the treatment caused by drugs psychosis and treatment of adverse effects observed with SSRI therapy behavioral aspects of chronic neurodegenerative diseases, usually for the treatment of psychotic symptoms such as hallucinations, after administration of dopamine agonists such as L-dopa, patients in need of such treatment, for example, people suffering from Parkinson's disease.

Similarly, aspects of the present invention relate to a method of treatment of illness is any and conditions as described herein, including the introduction of additional or therapeutic amount of one or more compounds of formula I. Thus, the invention relates to the use of compounds of formula I to obtain drugs for the treatment of diseases and conditions, as described herein, where the compound of formula I is the only active agent in medicine or is optional, where the medicinal product further includes an agent known to the person skilled in the art for the treatment of specified diseases or conditions.

Other aspects of the invention relate to pharmaceutical compositions containing an effective amount of the compounds of General formula I. the Compounds of the present invention can be introduced in the form of any of the foregoing compositions and according to the dosing regimens adopted in this area, whenever you want specific pharmacological modification of the activity of monoamine receptor.

Aspects of the present invention also offer pharmaceutical compositions containing one or more compounds according to the invention together with a pharmaceutically acceptable diluent or excipient. Preferably these compositions are in unit dosage forms such as tablet and, pills, capsules (including songs extended release or delayed release), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosols or liquid sprayable solutions, drops, ampoules, auto device for injection or suppositories, for oral, parenteral (e.g. intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal introduction or for introduction of inhalation or insufflate, and can be made appropriately and in accordance with accepted practice, for example, as described in Remington''s Pharmaceutical Sciences, (Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, included in this description by reference). An alternative composition may constitute a form of long-term release, suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as a salt of Caproic acid, may be adapted to provide a depot preparation for intramuscular injection. The aim of the present invention is also to offer the appropriate local composition for administration, e.g., eyes, or skin or mucous membrane.

A further aspect of the invention relates to a method for identifying genetic polymorphism, prednesol is suggesting the subject to be sensitive to one or more compounds of the formula I, as described in the present description, including:

introduction to the subject therapeutically effective amounts of compounds;

determination of the reaction of the specified entity on the specified connection, thus placing sensitive subject that has an improved disease state associated with monoamine receptor, and the establishment of genetic polymorphism in the subject with sensitivity, where the genetic polymorphism predisposes a subject to be sensitive to the compound. Superior painful condition generally associated with 5-HT class or 5-HT2A subclass of monoaminergic receptors.

A further aspect of the invention relates to a method for establishing a subject suitable for treatment of one or more compounds of formula I, including the presence of the polymorphism in the subject, where the polymorphism predisposes a subject to be sensitive to the connection and where the presence of the polymorphism indicates that the subject is suitable for treatment of one or more compounds of formula I.

Ways to get

Compounds of the present invention can be synthesized following methods or by modifications of these methods. Ways of modifying this methodology include, among others, temperature, solvent, reagents, etc. and are obvious to a person skilled in this field.

For example, the compounds of formula C can be synthesized from the corresponding ketone A by reductive amination using any primary amine. The reaction is easily carried out, 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 reagent, including deposited on a solid support reagents. The reaction is usually carried out at room temperature. Ketone A, an example of which is piperidone, you can choose from a list of compounds corresponding to the Z-group is specified for the compounds of formula (I). Ketones can be commercially available or can be synthesized by the method described by Lowe et al. in J. Med. Chem. 37: 2831-40 (1994); Carroll et al. in J. Med. Chem. 35: 2184-91 (1992) or Rubiralta et al. in Piperidine - Structure, Preparation, Reactivity and Synthetic Applications of Piperidine and its Derivatives. (Studies in Organic Chemistry 43, Elsevier, Amsterdam, 1991). The protective group P includes such groups as described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 3 Ed. John Wiley & Sons, 1999, and must be chosen in such a way that they are sustainable in the used reaction conditions and is easily removed at a convenient stage, using famous in this field techniques. Typical protective groups which are N-Boc, N-Cbz, N-Bn.

Alternatively, Amin C can be synthesized from primary amine B by reductive amination with the aldehyde. The reaction is easily carried out, 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 reagent, including deposited on a solid support reagents. The reaction is usually carried out at room temperature. Primary amine B, an example of which is 4-aminopiperidin, you can choose from a list of compounds corresponding to the Z-group is specified for the compounds of formula I. Amines may be commercially available or can be synthesized from the corresponding ketones. The protective group P can be selected, as described above.

Alternatively, Amin C can be synthesized from primary amine B alkylation with alkylating agent (R-L1). Leaving group L1represents, respectively, a halogen atom, such as bromine or iodine, or a sulfonate, such as toluensulfonate or methanesulfonate, or another leaving group, favoring the reaction. The reaction is easily carried out, mixing the reagents in the basic conditions in an inert solvent, for example, diisopropylethylamine in acetonitrile or K2CO3in N,N-dimethyl who formamide. The reaction is usually carried out at temperatures from room temperature up to 80°C. Primary amine B, an example of which is 4-aminopiperidin, you can choose from a list of compounds corresponding to the Z-group is specified for the compounds of formula I. Amines may be commercially available or can be synthesized from the corresponding ketones. The protective group P can be selected, as described above.

In this diagram, R and R* are defined in accordance with formula I, P represents a suitable protective group, and L1represents a suitable leaving group.

Secondary amine C can be allievate using any isocyanate or isothiocyanate (Q1-N=C=W), getting the corresponding urea or thiourea D. the Reaction is usually carried out, stirring the reagents using an excess of isocyanate or isothiocyanate in an inert solvent, for example dichloromethane, at temperatures between 0°C and room temperature and anhydrous conditions. Amin C can also be allievate using gelegenheid carboxylic acid (Q2COX, for example an acid chloride or anhydride of carboxylic acid (Q2C=O)2O)receiving amide of the General structure E. the Reaction is usually carried out using an excess of Alliluyeva agent and an appropriate base, such as triethylamine or Diisopropylamine is in, in an inert solvent, for example dichloromethane, at a temperature of from 0°to room temperature and anhydrous conditions. Alternatively, the carboxylic acid halides or anhydrides of carboxylic acid, amine C can be allievate using carboxylic acid (Q2COOH) and a suitable binder, such as PyBroP, DCC or EDCI. The reaction is usually carried out using an excess of Alliluyeva agent and binding agent in an inert solvent, for example dichloromethane, at a temperature of from 0°to room temperature and anhydrous conditions. Compounds of General formula (E) can be transformed into the corresponding thioamides, using the technique described by Varma et al. in Org. Lett. 1: 697-700 (1999), Cherkasov et al. in Tetrahedron 41:2567 (1985) or Scheibye et al. in Bull. Soc. Chim. Belg. 87:229 (1978).

In this diagram, R, Q1, Q2and W are defined in accordance with formula (I), P represents a suitable protective group, and X represents halogen.

Deputy T on the cyclic nitrogen atom in the compounds F or G you can enter the two-stage method. First, the protective group on the urea D or amide E removed using well known methods. For example, N-Boc group is removed by treatment of the protected compound 4M HCl in dioxane or triperoxonane acid in dichloromethane. Then secondary amines derived from D and E, can alkiline the step by reductive amination using an aldehyde (T-CHO) or ketone (T=O). The reaction is easily carried out, stirring the reactants in an inert solvent, such as methanol or ethanol. As a reducing agent can be used borohydride deposited on a solid carrier, NaBH4, NaCNBH3, BH3·pyridine, H2/Pd-C or any related reagent, including deposited on a solid support reagents. The reaction is usually carried out at room temperature.

Alternatively, compounds F and G can be synthesized from secondary amine, obtained from D or E, as described above, the alkylation with alkylating agent (T-L1). Leaving group L1accordingly, represents a halogen atom such as bromine or iodine, or a sulfonate, such as toluensulfonate or methanesulfonate, or another leaving group, favoring the reaction. The reaction is easily carried out, mixing the reagents in the basic conditions in an inert solvent, such as diisopropylethylamine in acetonitrile or K2CO3in N,N-dimethylformamide. The reaction is usually carried out at temperatures from room temperature up to 80°C.

Alternatively, the T-group can be introduced at the first stage of the synthetic sequence leading to the compounds of the present invention N-alkylation of compound H any alkylating agent (T-L1). Leaving group L1accordingly, the present is the focus of a halogen atom, for example bromine or iodine, or a sulfonate, such as toluensulfonate or methanesulfonate, or another leaving group, favoring the reaction. The reaction is easily carried out, mixing the reagents in the basic conditions in an inert solvent, such as diisopropylethylamine in acetonitrile or K2CO3in N,N-dimethylformamide. The reaction is usually carried out at temperatures from room temperature up to 80°C. alternatively, the T-group can be introduced at the first stage by reductive amination using an aldehyde (T-CHO) or ketone (T=O) and suitably secured connection H', an example of which is 4-piperidinylmethyl. The reaction is easily carried out, stirring the reactants in an inert solvent, such as methanol or ethanol. As a reducing agent can be used borohydride deposited on a solid carrier, NaBH4, NaCNBH3, BH3·pyridine, H2/Pd-C or any related reagent, including deposited on a solid support reagents. The reaction is usually carried out at room temperature, but less reactive carbonyl compounds may require higher temperatures and/or preliminary formation of the corresponding imine with the removal of water before adding the reducing agent. The removal of the protective group to give the desired compound J. Deut is CNY Amin H and H', an example of which is 4-piperidone and its protected derivative, you can choose from a list of compounds corresponding to the Z-groups listed for the compounds of formula (I). Amines may be commercially available or can be synthesized by the method described by Lowe et al. in J. Med. Chem. 37: 2831-40 (1994) and Carroll et al. in J. Med. Chem. 35: 2184-91 (1992).

Alternatively, compounds of General formula J can be synthesized, using as starting compound K, using the method described Kuehne et al. in J. Org. Chem. 56:2701 (1991) and Kuehne et al. in J. Org. Chem. (1991) 56:513.

In this diagram, R, Q1, Q2, W, and T are defined in accordance with formula (I), and L1represents a suitable protective group.

Heterocyclisation alkylating agents, such as T-L1may be commercially available or usually they can be obtained by alkylation of the heterocycle bifunctional alkyl linker, as shown below. Leaving group L1and L2accordingly, represent a halogen atom, for example chlorine, bromine or iodine, or a sulfonate, such as toluensulfonate or methanesulfonate, or another leaving group, favoring the reaction. The reaction is easily carried out, stirring REAG the options in the basic conditions in an inert solvent, for example, diisopropylethylamine in acetonitrile, or K2CO3in N,N-dimethylformamide. The reaction is usually carried out at temperatures from room temperature up to 80°C. Obtained at this stage of the alkylating agent can interact in situ at the next stage, with a secondary amine (i.e. D/E is removed from protection or H) or it can be isolated from the reaction mixture prior to further use. Heterocyclisation alcohols, such as T*-CH2OH or T-OH, can be converted into the corresponding alkylating agents T-L1, conversion of the hydroxyl to a leaving group, for example, toluensulfonate, methanesulfonamido or halogenoalkanes. Alternatively, T*-CH2OH or T-OH can oxidize to the corresponding aldehydes or ketones T*-CHO or T=O, for example, chlorbromuron pyridinium, CrO3-H2SO4or methods Swarna or dess-Martin, for use on stage reductive amination with secondary amines, as described above.

In this diagram, Y, p and T are defined in accordance with formula (I), and L1and L2represents a suitable protective group.

The functional blocks comprising the aromatic group Ar1and Ar2may be commercially available or can be synthesized by methods described in literature dealing with the E. The introduction of substituents on Ar1and Ar2can be made from a suitable precursor at any appropriate stage of the receive data connections.

For example, compounds containing alkoxysubstituted, you can usually get a synthesis of ethers by the Williamson from the respective hydroxyaryl derivatives.

Structure containing the amine substituents on Ar1or Ar2can be obtained from the appropriate halogen and pseudohalogen predecessors (for example, Br-, I-, Cl-, triflate, nonflat-, toiletcleaner aryl derivatives) aminating catalyzed by metals such as Pd or Ni (Hartwig, Angew. Chem. Int. Ed., 1998, 37, 2046-2067; Yang & Buchwald, J. Organometallic Chem., 1999, 576, 125-146; Hartwig in Modern Amination Methods; Ricci Ed.; Wiley-VCH: Weinheim, Germany, 2000) or aminating catalyzed by Cu (Buchwald et al. Org. Lett., 2002, 4, 581-584; Kwong & Buchwald, Org. Lett., 2003, 5, 793-796). Alternatively, these compounds can be obtained by alkylation of precursors on the basis of aniline (Hickinbottom, J. Chem. Soc. 1930, 992) or by reductive amination (Emerson & Walters, J. Amer. Chem. Soc., 1938, 60, 2023; Milovic et al. Synthesis, 1991, 11, 1043-1045), or dehydrating alkylation (Rice & Kohn, J. Amer. Chem. Soc., 1955, 77, 4052; Brown & Reid, J. Amer. Chem. Soc., 1924, 46, 1838). In addition, compounds of this type also can be synthesized from the corresponding Baranovich acids catalyzed by Cu combination (Antilla & Buchwald, Org. Lett., 2001, 3, 2077-2079).

Art is ucture, containing amide substituents on Ar1or Ar2can be obtained from the appropriate halogen and pseudohalogen predecessors catalyzed amidation using Pd (Yin & Buchwald, J. Amer. Chem. Soc., 2002, 124, 6043-6048) or Cu (Buchwald et al. J. Amer. Chem. Soc., 2002, 124, 7421-7428). Alternatively, these compounds can also be obtained from the appropriate aniline precursors by acylation (Wolf, Liebigs Ann. Chem., 1952, 576, 35; Yasukara et al. J. Chem. Soc. Perkin Trans. 1, 2000, 17, 2901-2902; Nigam & Weedon, J. Chem. Soc., 1957, 2000) or formirovanie (Hirst & Cohen, J. Chem. Soc., 1895, 67, 830; Olah & Kuhn, Chem. Ber. 1956, 89, 2211; Guthrie et al. Can. J. Chem., 1993, 71, 2109-2122).

Compounds containing alkylsulfanyl Deputy at Ar1or Ar2can be obtained from the appropriate halogen or pseudohalogen precursors catalyzed by diatrypaceae using as the catalyst Pd (Li, J. Org. Chem., 2002, 67, 3643-3650) or Cu (Kwong & Buchwald, Org. Lett., 2002, 4, 3517-3520). Alternatively, these compounds can be obtained by alkylation of the corresponding benzothiophene predecessors (Vogel, J. Chem. Soc., 1948, 1809; Landini & Rocca, Synthesis, 1974, 565-566; Bun-Hoi et al. J. Org. Chem., 1951, 16, 988). Alternatively, alkylarylsulfonate can be obtained by irradiation of bentolila and alkenes (Screttas & Micha-Screttas, J. Org. Chem., 1978, 43, 1064-1071).

Compounds according to the invention, containing acyl group in Ar1or Ar2can be obtained from the relevant arily the Idov-catalyzed acylation using Pd as a catalyst (Cacchi et al. Org. Lett., 2003, 5, 289-293). Alternatively, these compounds can be obtained from the corresponding benzene reaction Friedel-(Read, J. Amer. Chem. Soc., 1922, 44, 1746-1755) or attachment of aryl Grignard reagent to a nitrile (Whitmore et al. J. Amer. Chem. Soc., 1947, 69, 235-237) or acylchlorides (Whitmore & Lester, J. Amer. Chem. Soc., 1942, 64, 1247)or catalyzed acylation arylboronic acids using as the catalyst Pd (Gooβen & Ghosh, Angew. Chem. Int. Ed. Engl., 2001, 40, 3458-3460) or Rh.

Compounds according to the invention, which are N-containing aromatic heterocycle at Ar1or Ar2you can get catalyzed by metal cross combination (Buchwald et al. Org. Lett., 2002, 2, 1403-1406; Buchwald et al. J. Amer. Chem. Soc., 2001, 123, 7727-7729; Buchwald et al. J. Amer. Chem. Soc., 2002, 124, 11684-11688). Alternatively, these compounds can be obtained from suitable precursors, such as arylhydrazines, arylamine or arylnitrenes known from the literature (for example, Alvisi, Gazz. Chem. Ital., 1892, 22, 159; Finar, Godfrey, J. Chem. Soc., 1954, 2293; Muri et al. Synth. Commun., 1998, 28, 1299-1321; Artico et al. Europ. J. Med. Chem. Chim. Ther., 1992, 27, 219-228; Biagi et al. Farmaco Ed. Sci. 1988, 43, 597-612; Stefancich et al. Farmaco Ed. Sci. 1984, 39, 752-764).

As a rule, in the course of any method of obtaining compounds of the present invention may be necessary and/or desirable to protect sensitive or reactive groups on any of the examined molecules. This can be achieved using traditional the protective groups, such as described in 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. The protective group can be removed at a suitable subsequent stage using methods known in this field.

EXAMPLES

The following examples are not limiting and are only an illustration of some embodiments of the present invention.

Chemical synthesis

Common procedures

The NMR spectra of1H recorded on the spectrometer Varian Mercury-VX400MHz at 400 MHz and chemical shifts are given in units δ [ppm] relative to the residual peak of chloroform (CDCl3in 7,26 ppm and methanol (CD3OD) of 3.31 ppm as solvent. Constant interaction, J are given in Hertz. Unless otherwise stated, NMR spectra of compounds provided for their free amine form. Due to the presence of rotamers, as a rule, there are two groups of signals and is given by the ratio of rotamers. When it is possible to accurately identify the appropriate signals for each of the two rotamers, they are given together [for example, 4,66-4,58 and 3.76-3,68 (2m, 1H)]. Cartridges acidic ion-exchange solid-phase extraction (SPE) is a MEGA BE-SCX company Varian.

Substances and solvents were of the highest purity available from commercial sources, and ispolzovalis is without further purification.

Method HPLC/JHMS

The analysis carried out on the combined preparative/analytical system Waters/Micromass, consisting of ZMD single quadrupole mass spectrometer equipped with an interface with electrospray ionization. The HPLC system consists of a gradient pump Waters 600 degassing in the online management system 2700 sample and detector 996 PDA. The separation is performed on column X-Terra MS C18, 5 μm 4,6×50 mm, Buffer A: 10 mm ammonium acetate in water, buffer B: 10 mm ammonium acetate in a mixture of acetonitrile/water 95/5. The gradient from 30% B to 100% B for 7 min, hold at 100% B for 1 min and re-balance for 5.5 minutes, the System operates at 1 ml/min

Obtaining cleaners containing hydrochloride salts

Typically tertiary amines dissolved in dichloromethane, treated with excess 1M HCl in diethyl ether and precipitated from n-heptane. The solvent is removed in vacuum and after drying cleaners containing hydrochloride salt obtained as colorless solids.

Getting oxalate or tartrate salts

Typically tertiary amines dissolved in methanol, treated with 1 EQ. the appropriate acid, removing the solvent, salt again dissolved in dichloromethane and precipitated from n-heptane. The solvent is removed in vacuum, obtaining salt as colorless solids.

Deriving phenylacetyl orida

A derivative of phenylacetic acid (15 mmol) dissolved in dichloromethane (100 ml) and slowly add oxalicacid (45 mmol). The reaction mixture is stirred for 4 hours and then evaporated to dryness. The product is obtained as a colourless oil and used directly after receipt at the stage of acylation.

4-Solutocapillary acid (128NLS28)

Methyl(4-hydroxyphenyl)acetate (14.6 g, 0,0885 mol) is dissolved in DMF (200 ml), add potassium carbonate (31.0 g, 0,224 mmol) and the mixture stirred for 1 h at room temperature (RT). Add 1-bromo-2-methylpropan (19.2 ml, 0,177 mol) and the mixture is heated at 80°C for 3 days with vigorous stirring. The mixture is cooled to CT, filter, remove the solvent and the residue partitioned between 1,5M NaOH and ethyl acetate. The organic layer is evaporated, the residue dissolved in a mixture of methanol (100 ml) and water (100 ml), add KOH (10 g, 0,178 mol) and the mixture is stirred over night at RT. The methanol is removed by evaporation and the mixture is extracted with dichloromethane. The organic layer is poured, the aqueous layer was acidified with 4M HCl to pH 2-3 and extracted twice with dichloromethane. The combined organic layers dried over Na2SO4, filtered and evaporated, getting mentioned in the title compound (16,9 g, 92%) as a colourless solid.

4-Propoxybenzene acid (98AF7-66)

Receive, as described for 128NLS28 using propyl bromide as the alkylating agent.

4-Isopropoxyphenoxy acid (130AF24-163)

Receive, as described for 128NLS28 using Isopropylamine as alkylating agent.

The hydrochloride of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-salutogenesis)urea (80MBT86-2C)

Monohydrate hydrochloride 4-piperidone (4.0 g, 26.0 mmol) dissolved in dichloromethane (130 ml). After adding triethylamine (8,66 g, to 85.8 mmol) the mixture is stirred for 10 min and then cooled to 0°C. dropwise with stirring anhydride triperoxonane acid (12.0 g, 57,2 mmol). After 2 h at room temperature the reaction is stopped by adding water (100 ml) and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic phases are dried over Na2SO4, filtered and concentrated, obtaining 1-(TRIFLUOROACETYL)-4-piperidone (5,07 g, 100%).

4-Forbindelsen (3,14 g of 25.9 mmol) was dissolved in methanol (150 ml). Add 1-(TRIFLUOROACETYL)-4-piperidone (5,07 g of 25.9 mmol) and the pH adjusted to about 5 with acetic acid. The reaction mixture was stirred for 5 min and slowly added with stirring NaBH3CN (2,46 g of 38.9 mmol). After 20 h at room temperature, the reaction mixture was concentrated. Added 2M NaOH (100 ml) and the aqueous phase extragere the t dichloromethane (2× 100 ml). The combined organic phases are dried over Na2SO4, filtered and concentrated, obtaining N-(4-terbisil)-1-(TRIFLUOROACETYL)piperidine-4-amine (50ELH85, only 2.91 g, 37%).

4-Solutocapillary acid (7.6 g, of 36.5 mmol) dissolved in THF (50 ml). Added Proton SpongeTM(of 8.2 g, 38 mmol) and the mixture is stirred for 15 minutes added dropwise diphenylphosphoryl (10.6 g, 38 mmol) and the mixture refluxed for 4 hours the Mixture is cooled to room temperature and placed in the freezer at -18°20 hours resulting white precipitate vigorously stirred with diethyl ether (250 ml) for 15 min and filtered. The filtrate is evaporated, obtaining the crude 4-solutionsolution (1.97 g, 9.6 mmol)which is dissolved in dichloromethane (50 ml) and added to a solution 50ELH85 (2.91 in g, 9.6 mmol) in dichloromethane (50 ml). The reaction mixture is stirred for 20 h and concentrated. The crude product is purified flash chromatography (0-5% methanol in dichloromethane)to give N-(4-terbisil)-N-[1-(TRIFLUOROACETYL)piperidine-4-yl]-N'-(4-salutogenesis)urea (76ELH17, 3,90 g, 91%).

Connection 76ELH17 (3,90 g, 8,7 mmol) dissolved in methanol (12 ml) and added dropwise to a 2M solution of potassium carbonate in methanol (100 ml) under stirring. After 4 h, the methanol is evaporated and the aqueous phase extracted with dichloromethane (2×100 ml). The joint body is ical phases are dried over Na 2SO4filter and concentrate, receiving semifinished solid (2,95 g), which was purified flash chromatography (10% methanol in dichloromethane with 1% triethylamine)to give N-(4-terbisil)-N-(piperidine-4-yl)-N'-(4-isobutylbenzene)urea (76ELH18, 1.40 g, 39%) as a colourless solid.

IHMS m/z 414 [M+H]+.1H-NMR (CDCl3): δ 7,21 to 6.75 (m, 8H), 4,47 was 4.42 (m, 1H), 4,39 (t, J=5 Hz, 1H), 4,35 (s, 2H), 4,27 (d, J=5 Hz, 2H), 3,68 (d, J=6 Hz, 2H), 3,13-of 3.06 (m, 2H), 2,74-of 2.66 (m, 2H), 2,11 of 1.99 (m, 1H), 1,78-1,71 (m, 3H), 1,58 of 1.46 (m, 2H), and 1.00 (d, J=6 Hz, 6H).

Connection 76ELH18 (200 mg, 0,484 mmol) dissolved in acetonitrile (20 ml). Add potassium carbonate (74 mg, 0,553 mmol) and sodium iodide (80 mg, 0,553 mmol), then added 2-(2-bromacil)-1,3-dioxolane (100 mg, 0,553 mmol). The reaction mixture is refluxed for 20 hours the Mixture is concentrated, water is added (50 ml) and the aqueous phase extracted with dichloromethane (2×50 ml). The combined organic phases are dried over Na2SO4, filtered and evaporated. The resulting oil twice purified flash chromatography (5% methanol in dichloromethane)to give a colorless oil (50 mg, 20%).

Rf=0,70 (MeOH/CH2Cl2, 1:9). IHMS m/z 514 [M+H]+.1H-NMR (CDCl3): δ 7,21 to 6.75 (m, 8H), 4,94 (t, J=4.5 Hz, 1H), 4,73-to 4.62 (m, 1H), 4,58 (t, J=5.5 Hz, 1H), to 4.41 (s, 2H), 4.26 deaths (d, J=5.5 Hz, 2H), 4,00-of 3.80 (m, 4H), 3,68 (d, J=6.0 Hz, 2H), 3.43 points-to 3.35 (m, 2H), 2,94-2,87 (m, 2H), 2,68-to 2.57 (m, 2H), 2,45 of-2.32 (m, 2H), 2,20-to 2.13 (m, 2H), 2,10-2,00 (m, 1H) 1,88-of 1.81 (m, 2H), and 1.00 (d, J=6.0 Hz, 6H). HPLC tR=8,1 minutes

The compound obtained is transformed into its cleaners containing hydrochloride salt, which is obtained as a colourless solid (80MBT86-2C).

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]ndimethylacetamide (106MBT54-D)

Methyl(4-hydroxyphenyl)acetate (500 mg, 3.0 mmol) dissolved in DMF (3 ml). Add K2CO3(829 mg, 6.0 mmol), and then add isobutylene (800 μl, 9.0 mmol). The mixture is heated to 150°With microwave radiation for 30 min and concentrated. The residue is dissolved in a mixture of methanol and water, 1:1 (20 ml). Add NaOH (1 g) and the mixture is stirred for 30 minutes, the Methanol is removed on a rotary evaporator. The aqueous phase is acidified with 4M HCl and extracted with dichloromethane (2×50 ml). The combined organic phases are extracted with 2M NaOH (2×50 ml). Then the combined aqueous phases are acidified with 4M HCl and extracted with dichloromethane (2×50 ml). The combined organic phases are dried over Na2SO4, filtered and evaporated, receiving [4-(2-hydroxy-2-methylpropoxy)phenyl]acetic acid (106MBT52-D, 470 mg, 70%) as a colourless solid.

1H-NMR (CDCl3): δ 7,19 (m, 2H), to 6.88 (m, 2H), of 3.78 (s, 2H), only 3.57 (s, 2H), of 1.34 (s, 6H).

Acid 106MBT52-D (150 mg, 0.67 mmol) dissolved in dichloromethane (10 ml). Add N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-forbe the ZIL)Amin (118AF52-95, 180 mg of 0.56 mmol), and then add triethylamine (235 μl, 0.84 mmol). Add hexaphosphate bromo-Tris-pyrrolidinone (PyBroP, 392 mg, 0.84 mmol) and the mixture is stirred at room temperature for 2 hours the Mixture is concentrated and passed through 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 to elute from the column with 10% NH4OH in methanol (2×4 ml) and evaporated. The resulting oil was dissolved in dichloromethane (20 ml) and washed with saturated aqueous NaHCO3(5×20 ml). The organic phase is dried over Na2SO4, filtered and evaporated. The resulting oil purified flash chromatography (0-5% methanol in dichloromethane)to give a colourless oil (110 mg, 31%).

Rf=0,64 (MeOH/CH2Cl2, 1:9). IHMS m/z 529 [M+H]+.1H-NMR (CDCl3, rotamer of 0.4:0.6 to): δ 7,25-PC 6.82 (m, 8H), with 4.64-4,48 (m, 2,4H), of 4.44 (s, 1,2H), 4,10-a 4.03 (m, 2H), 3,79-to 3.67 (m, 5,2H), 3,50 (s, 1,2H), 2,90-of 2.81 (m, 2H), 2,42-3,95 (m, 2H), 2,12-to 1.98 (m, 2,2H), 1,87-to 1.79 (m, 0,8H), 1,76 is 1.48 (m, 5,2H), 1,36-of 1.27 (m, 7,8H). HPLC tR=6,1 minutes

The assembled connection turn in his tartrate salt, which is obtained as a colourless solid (106MBT54-D).

N-(4-Terbisil)-N-(piperidine-4-yl)-2-(4-isobutoxide)ndimethylacetamide (103NLS56)

To a solution of amine 118AF93-51 (10,37 g, 30.3 mmol) and triethylamine (9,36 ml, about 60.6 mmol) in dichloromethane (200 ml) the aqueous phase in 0° To add a solution of 4-solutocapillary 128NLS28 (8,93 g, to 39.4 mmol) in dichloromethane (100 ml). The solution is stirred at RT for 3 h, and then water is added and the mixture washed with saturated aqueous NaHCO3. The organic layer was washed with 5% HCl, water and saturated salt solution, dried over sodium sulfate, filtered and evaporated in vacuum. The residue is purified column chromatography on silica gel, elwira speed gradient mixture of 0-50% ethyl acetate in n-heptane, receiving N-(4-terbisil)-N-[1-(benzyloxycarbonyl)piperidine-4-yl]-2-(4-isobutoxide)ndimethylacetamide in the form of a colorless oil.

This compound is dissolved in absolute ethanol (200 ml) and hydronaut over night at RT using Pd/C (10%, 1 g) as a catalyst. The mixture is filtered through Celite, the solvent removed and the residue is dried in vacuum, obtaining a colorless oil (7,02 g, 58% over two stages). This compound is used without further purification.

IHMS m/z 399 [M+H]+. HPLC tR=8,8 minutes

The dihydrochloride of N-{1-[3-(3,5-dimethylpiperidin-1-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (103NLS45-B)

To 3,5-dimethylpiperidine (43 μl, 0.33 mmol) in DMF (1 ml) is added potassium carbonate (132 mg, 1.0 mmol)then was added 1-chloro-3-iodopropane (32 mmol, 0.30 mmol) and the mixture was stirred at 50°C for 2 hours After cooling to CT add races the thief 103NLS56 (100 mg, 0.25 mmol) in DMF (0.5 ml), and then add sodium iodide (45 mg, 0.30 mmol). The mixture is shaken for 20 h at 60°C, filtered, evaporated to dryness and purified column chromatography on silica gel, elwira speed gradient mixture of 0-10% methanol in dichloromethane. Next, the residue is purified by passing through the SPE cartridge with reversed phase With18getting the desired compound (35 mg, 25%), which make it dihydrochloride salt.

Rf=0,61 (MeOH/CH2Cl2, 1:9). IHMS m/z 552 [M+H]+. HPLC tR=8,7 minutes

The methyl ester dihydrochloride of 1-[3-(4-{(4-terbisil)-[2-(4-isobutoxide)acetyl]amino}piperidine-1-yl)propyl]piperidine-4-carboxylic acid (103NLS45-E)

Get a way that is described for 103NLS45-IN, using methyl ether piperidine-4-carboxylic acid (44 μl, 0.33 mmol). Exit 7 mg, 5%.

IHMS m/z 582 [M+H]+. HPLC tR=7,8 minutes

Dioxalate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(1-methylpyrrolidine-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (103NLS63-G)

To a solution of amine 103NLS56 (15 mg, of 0.038 mmol) in DMF (0.3 ml) add a solution of the hydrochloride of 2-(2-chloroethyl)-1-methylpyrrolidine (8,4 mg, 0.045 mmol) in DMF (0.1 ml), and then add cesium carbonate (50 mg, 0.15 mmol) and sodium iodide (6.8 mg, 0.045 mmol). The mixture is stirred over night at 60°S, partitioned between dichloromethane and saturated aqueous NaHCO . The organic layer is dried over sodium sulfate, filtered and evaporated. The residue is purified preparative HPLC with reversed phase (C18) and the obtained compound (10.5 mg, 54%) turned in his dioxalate salt.

IHMS m/z 510 [M+H]+. HPLC tR=8,1 minutes

Dioxalate N-{1-[3-(2,6-dimethylmorpholine-4-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide dioxalate (103NLS69-A)

To a solution of 2,6-dimethylmorpholine (6,1 μl, 49 µmol) in DMF (0.3 ml) was added 1-chloro-3-iodopropane (4,9 μl, 45 μmol) in DMF (0.05 ml), then added cesium carbonate (50 mg, 0.15 mmol). The mixture was shaken at 50°C for 3 hours After cooling to CT type piperidine derivative 103NLS56 (15 mg, 38 μmol) in DMF (0.1 ml) and sodium iodide (6.8 mg, 45 μmol) and stirred over night at 60°C. the Mixture is partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer is dried over sodium sulfate, filtered and evaporated. The residue is purified preparative HPLC with reversed phase (C18) and the obtained compound (6.3 mg, 30%) turn his dioxalate salt.

IHMS m/z 554 [M+H]+. HPLC tR=8,7 minutes

Dioxalate N-(4-terbisil)-N-{1-[3-(3-hydroxypiperidine-1-yl)propyl]piperidine-4-yl}-2-(4-isobutoxide)ndimethylacetamide (103NLS69-B)

Get a way that is described for 103NLS69-A, using the hydrochloride of 3-hydroxypiperidine is on (6,8 mg, 49 µmol). The output of 7.9 mg, 30%.

IHMS m/z 540 [M+H]+. HPLC tR=8,1 minutes

Dioxalate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-methylpiperidin-1-yl)propyl]piperidine-4-yl}ndimethylacetamide (103NLS69-C)

Get a way that is described for 103NLS69-A, using 2-methylpiperidin (5,8 μl, 49 µmol). Output 5.2 mg, 26%.

IHMS m/z 538 [M+H]+. HPLC tR=8,7 minutes

Dioxalate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(3-pyrrolidin-1-ylpropyl)piperidine-4-yl]ndimethylacetamide (103NLS69-D)

Get a way that is described for 103NLS69-A, using pyrrolidine (5,0 ál, 49 µmol). The output of 4.6 mg, 24%.

IHMS m/z 510 [M+H]+. HPLC tR=8,4 minutes

Dioxalate N-{1-[3-(2,5-dimethylpiperidin-1-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (103NLS69-E)

Get a way that is described for 103NLS69-A, using 2,5-dimethylpyrrole (6,0 μl, 49 µmol). Output 3.4 mg, 17%.

IHMS m/z 538 [M+H]+. HPLC tR=8,7 minutes

Dioxalate N-(4-terbisil)-N-{1-[3-(3-hydroxyethylpiperazine-1-yl)propyl]piperidine-4-yl}-2-(4-isobutoxide)ndimethylacetamide (103NLS69-F)

Get a way that is described for 103NLS69-A, using 3-hydroxyethylpiperazine (5,5 μl, 49 µmol). The output of 5.5 mg, 26%.

IHMS m/z 554 [M+H]+. HPLC tR=8,0 minutes

(4S)-3-(3-Chloropropyl)-4-isopropylacetanilide-2-he (103NLS94)

Sodium hydride (60% suspension in oil, 288 mg, 7.2 mmol) are added to a solution of ()-4-isopropyl-2-oxazolidinone (775 mg, 6.0 mmol) in dry tetrahydrofuran (50 ml) in an argon atmosphere. The suspension is stirred for 15 min at RT, then added dropwise within 30 min was added 1-bromo-3-chloropropane (1,18 ml of 12.0 mmol). The mixture is refluxed overnight, filtered and the filtrate is evaporated in vacuum. The residue purified column chromatography on silica gel, elwira speed gradient mixture of 0-4% methanol in dichloromethane, receiving (4S)-3-(3-chloropropyl)-4-isopropylacetanilide-2-he (824 mg, 67%) as a colourless oil.

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide (117NLS01)

To a solution of 103NLS56 (207 mg, 0.52 mmol) is added potassium carbonate (215 mg, 1.56 mmol) followed by addition of an alkylating agent 103NLS94 (127 mg, of 0.62 mmol) and sodium iodide (93 mg, of 0.62 mmol). The mixture was stirred at 65°during the night, the solvent is removed and the residue distributed between ethyl acetate and water. The organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified column chromatography on silica gel, elwira speed gradient mixture of 0-4% methanol in dichloromethane. Further purification fulfil passing through the acidic ion-exchange SPE cartridge, getting the desired compound (209 mg, 71%) as a colourless oil, which was converted into its oxalate is ol.

Rf=0,35 (MeOH/CH2Cl2with 5:95). IHMS m/z 568 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,21-to 6.80 (m, 8H, Ar-H), 4,60-a 4.53 (m, 0,6H, PIP-H), 4,49 and 4,43 (2s, 2H, benzyl-H), 4,19-to 4.14 (m, 1H, oxa-CH2), 4,06-4,01 (m, 1H, oxa-CH2), of 3.77-to 3.67 (m, 4,2H, PIP-H, oxa-NCH, CH2OiBu, benzyl-H), 3,53-of 3.46 (m, 2,2H, benzyl-N, OCONCH2), 2,98-to 2.85 (m, 3H, PIP-H, OCONCH2), 2,39 was 2.25 (m, 2H, NCH2), 2,10-2,00 (m, 3,2H, CH(CH3)2, PIP-H, CHOiBu), 1,85 of 1.50 (m, 6H, PIP-H, NCH2CH2), 1-29 (m, 0,8H, PIP-H), 1,01 is 0.99 (m, 6H, CH3OiBu), 0,89-of 0.83 (m, 6H, CH(CH3)2). HPLC tR=8,9 minutes

Oxalate of N-[2-(4-Porvenir)ethyl]-2-(4-isobutoxy)-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide (117NLS03-A)

Get a way that is described for 117NLS01, using N-[2-(4-forfinal)ethyl]-2-(4-isobutoxy)-N-(piperidine-4-yl)ndimethylacetamide (111 mg, 0.27 mmol, obtained according to the method described for 103NLS56). Yield 90 mg, 57%.

Rf=0,30 (MeOH/CH2Cl2with 5:95). IHMS m/z 582 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,18-to 6.80 (m, 8H, Ar-H), 4,40-of 4.35 (m, 0,4H, PIP-H), 4,20-to 4.15 (m, 1H, oxa-CH2), 4,05-4,01 (m, 1H, oxa-CH2in ), 3.75-of 3.46 (m, 6,6H, PIP-H, oxa-NCH, CH2OiBu, benzyl-N, OCONCH2), to 3.36 (m, 2H, ArCH2CH2N)3,02-2,84 (m, 3H, PIP-H, OCONCH2), 2,81 is 2.75 (m, 2H, ArCH2), 2,37 was 2.25 (m, 2H, NCH2), 2,09-to 1.98 (m, 2,8H, CH(CH3)2, PIP-H, CHOiBu), 1,85-of 1.62 (m, 6H, PIP-H, NCH2CH2), to 1.31 (m, 1,2H, PIP-H), 1.00 and is-0.97 (m, 6H, CH ), 0,89 is 0.84 (m, 6H, CH(CH3)2). HPLC tR=9,1 minutes

Oxalate of N-[2-(4-forfinal)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}-2-(4-propoxyphenyl)ndimethylacetamide (117NLS03-IN)

Get a way that is described for 117NLS01, using N-[2-(4-forfinal)ethyl]-N-(piperidine-4-yl)-2-(4-propoxyphenyl)ndimethylacetamide (108 mg, 0.27 mmol, obtained according to the method described for 103NLS56). Yield 76 mg, 50%.

Rf=0,33 (MeOH/CH2Cl2,5:95). IHMS m/z 568 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,17-for 6.81 (m, 8H, Ar-H), 4,40-of 4.35 (m, 0,4H, PIP-H), 4,20-to 4.15 (m, 1H, oxa-CH2), 4,05-4,01 (m, 1H, oxa-CH2), 3,90-of 3.85 (m, 2H, OCH2OPr), and 3.72-of 3.48 (m, 4,6H, PIP-H, oxa-NCH, benzyl-N, OCONCH2), 3,36-3,30 (m, 2H, ArCH2CH2N), 2,99-of 2.86 (m, 3H, PIP-H, OCONCH2), 2,80-to 2.74 (m, 2H, Ai-CH2), 2,38-of 2.26 (m, 2H, NCH2), 2,11-2,03 (m, 1,8H, CH(CH3)2, PIP-H), 1,87-of 1.64 (m, 8H, PIP-H, CH2OPr, NCH2CH2), to 1.31 (m, 1,2H, PIP-H), 1,03-0,98 (m, 3H, CH3OPr), 0.88 to 0,83 (m, 6H, CH(CH3)2). HPLC tR=8,5 minutes

Oxalate of N-(4-terbisil)-N-{1-[3-(4-(S)-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}-2-(4-propoxyphenyl)ndimethylacetamide (117NLS03-C)

Get a way that is described for 117NLS01 using N-(4-terbisil)-N-(piperidine-4-yl)-2-(4-propoxyphenyl)ndimethylacetamide (104 mg, 0.27 mmol, obtained according to the method described for 103NLS56). The output 120 mg, 80%.

Rf=0,36 (MeOH/CH2Cl25:95). IHMS m/z 554 [M+H]+.1 H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,19-of 6.78 (m, 8H, Ar-H), 4,57-4,48 (m, 0,6H, PIP-H), 4,48, and was 4.42 (2c, 2H, benzyl-H), 4,18-4,12 (m, 1H, oxa-CH2), Android 4.04-4.00 points (m, 1H, oxa-CH2), 3,91-of 3.85 (m, 2H, OCH20Prin ), 3.75-3,66 (m, 2,2H, PIP-H, oxa-NCH, benzyl-H), 3,49-of 3.43 (m, 2,2H, benzyl-N, OCONCH2), 2,98 is 2.80 (m, 3H, PIP-H, OCONCH2), 2,33 was 2.25 (m, 2H, NCH2), 2,05-1,50 (m, 10,2H, CH(CH3)2, NCH2CH2, PIP-H, CH20Pr), 1.27mm (m, 0,8H, PIP-H), 1.18 to 0,98 (m, 3H, CHOrg), 0,87 is 0.81 (m, 6H, CH(CH3)2). HPLC tR=8,3 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (103NLS63-F)

Get a way that is described for 117NLS01 using 103NLS56 (262 mg, 0,657 mmol) and 2-(2-bromacil)-1,3-dioxane as an alkylating agent. Iodide of sodium is not required. The output 152 mg, 45%.

Rf=0,35 (MeOH/CH2Cl21:9). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,26-to 6.80 (m, 8H, Ar-H), 4.63 to-4,39 (m, 3,6H, PIP-H, dioxane-H, benzyl-H), 4.09 to 4,01 (m, 2H, dioxane-H), 3,78-to 3.64 (m, 5,2H, PIP-H, dioxane-H, CH2OiBu, benzyl-H), 3,50 (s, 1,2H, benzyl-H), 2,92-and 2.79 (m, 2H, PIP-H), 2,43-of 2.34 (m, 2H, NCH2), 2,10 is 1.96 (m, 3,2H, dioxane-H, PIP-H, CHOiBu), 1,88 is 1.48 (m, 6H, PIP-H, NCH2CH2), 1,35-1,24 (m, 1,8H, dioxane-H, PIP-H), 1,01 (m, 6H, CH3OiBu). HPLC tR=8,8 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-[2-(4-forfinal)ethyl]-2-(4-isobutoxide)ndimethylacetamide (117NLS03-D)

Get method, which is described DL is 117NLS03, using 2-(2-bromacil)-1,3-dioxane as an alkylating agent. Iodide of sodium is not required. Exit 99 mg, 70%.

Rf=0,35 (MeOH/CH2Cl25:95). IHMS m/z 527 [M+H]+.1H-NMR (CDCl3, rotamer 0,7:0,3) δ 7,18-to 6.80 (m, 8H, Ar-H), 4,58-of 4.54 (m, 1H, dioxane-H), 4,48-to 4.41 (m, 0,3H, PIP-H), 4,10-4,06 (m, 2H, dioxane-H), of 3.77-3,66 (m, 5,4H, dioxane-H, benzyl-N, CH2OiBu), 3,64-to 3.52 (m, 1,3H, benzyl-N, PIP-H), 3,37-of 3.32 (m, 2H, CH2NCO), 2.99 and 2,89 (2m, 2H, PIP-H), 2,82 was 2.76 (m, 2H, ArCH2), 2,49-2,39 (m, 2H, NCH2), 2,12-2,00 (m, 2,6H, dioxane-H, PIP-H, CHOiBu), a 1.88-to 1.67 (m, 6H, PIP-H, CH2OiBu, NCH2CH2), 1,35 to 1.31 (m, 2,4H, dioxane-H, PIP-H), and 1.00 (t, 6H, J=6,6, CH3OiBu). HPLC tR=8,8 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-[2-(4-forfinal)ethyl]-2-(4-propoxyphenyl)ndimethylacetamide (117NLS03-E)

Get a way that is described for 117NLS03-IN, using 2-(2-bromacil)-1,3-dioxane as an alkylating agent. Iodide of sodium is not required. Yield 90 mg, 65%.

Rf=0,23 (MeOH/CH2Cl25:95). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3, rotamer 0,7:0,3) δ 7,21-for 6.81 (m, 8H, Ar-H), 4,58-of 4.54 (m, 1H, dioxane-H), 4,48 was 4.42 (m, 0,3H, PIP-H), 4,10-4,06 (m, 2H, dioxane-H), 3,91-3,86 (m, 2H, CHOrg), of 3.77 at 3.69 (m, 3,4H, dioxane-H, benzyl-H), 3,63 of 3.56 (m, 1,3H, benzyl-N, PIP-H), 3,38-of 3.31 (m, 2H, CH2NCO), 2.99 and 2,89 (2m, 2H, PIP-H), 2,82 was 2.76 (m, 2H, ArCH2), 2,49-2,39 (m, 2H, NCH2), 2,12-2,00 (m, 1,6H, dioxane-H, PIP-H), 1,87-of 1.65 (m, 8H, PIP-H, CH2OPr, NCH2CH2), 1,35 to 1.31 (m, 2,4H, diox is n-N, PIP-H), of 1.05 to 1.00 (m, 3H, CHOrg). HPLC tR=8,0 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propoxyphenyl)ndimethylacetamide (117NLS03-F)

Get a way that is described for 117NLS03, using 2-(2-bromacil)-1,3-dioxane as an alkylating agent. Iodide of sodium is not required. The output 107 mg, 79%.

Rf=0,41 (MeOH/CH2Cl25:95). IHMS m/z 499 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,20-to 6.80 (m, 8H, Ar-H), 4,62-4,56 (m, 0,6H, PIP-H), 4,54-4,51 (m, 1H, dioxane-H), 4,49 and 4,43 (2s, 2H, benzyl-H), 4,08-Android 4.04 (m, 2H, dioxane-H), 3,92-a 3.87 (m, 2H, OCH2OPr), 3,76-3,68 (m, 3,2H, PIP-H, dioxane-H, benzyl-H), 3,50 (s, 1,2H, benzyl-H), 2,90-and 2.83 (m, 2H, PIP-H), 2,43-of 2.36 (m, 2H, NCH2), 2,10-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1,86-is 1.51 (m, 8H, PIP-H, CHOrg, NCH2CH2), 1,32-of 1.27 (m, 1,8H, dioxane-H, PIP-H), 1,05 is 0.99 (m, 3H, CH3). HPLC tR=7,6 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-salutogenesis)urea (117NLS25)

Get a way that is described for 117NLS01, using 2-(2-bromacil)-1,3-dioxane (24 μl, 0.18 mmol) as the alkylating agent N-(4-terbisil)-N'-(4-salutogenesis)-N-(piperidine-4-yl)urea (76ELH18, 50 mg, 0.12 mmol). Iodide of sodium is not required. Yield 38 mg, 60%.

Rf=0,32 (MeOH/CH2Cl21:9). IHMS m/z 528 [M+H]+.1H-NMR (CDCl3) δ 7,18-6,74 (m, 8H, Ar-H), a 4.53 (t, 1H, J= 5,1, dioxane-H), to 4.46 (t, 1H, J=5,3, NH), 4,33-of 4.25 (m, 5H, PIP-H, benzyl-H), 4,08-Android 4.04 (m, 2H dioxane-H), 3,75-3,68 (m, 2H, dioxane-H), 3,66 (d, 2H, J=6,6, CH2OiBu), 2,93-is 2.88 (m, 2H, PIP-H), 2,43-2,39 (m, 2H, NCH2), 2,09-to 1.98 (m, 4H, CHOiBudioxane-H, PIP-H), 1,77-of 1.56 (m, 6H, PIP-H, NCH2CH2), 1,32 of 1.28 (m, 1H, dioxane-H)0,99 (d, 6H, J= 6,6, CH3OiBu). HPLC tR=8,7 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-forfinal)ndimethylacetamide (117NLS87-A)

To a solution of 118AF52-95 (300 mg, of 0.93 mmol) and triethylamine (0.52 in ml, 3.72 mmol) in dry THF (10 ml) at 0°With added dropwise a solution of 4-perforazione (0,19 ml of 1.39 mmol) in THF (5 ml) and stirred at RT for 3 h, the Reaction mixture was filtered and the filtrate is evaporated to dryness. The residue is distributed between ethyl acetate and 1M NaOH, the organic layer was washed with saturated salt solution, dried over Na2SO4, filtered and evaporated. Purification of column chromatography on silica gel with elution step gradient mixture of 0-8% methanol in dichloromethane followed by purification of the compounds passing through the acidic ion-exchange SPE cartridge, gives the desired compound (131 mg, 31%), which make it tartrate salt, as described above.

Rf=0,39 (MeOH/CH2Cl21:9). IHMS m/z 459 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,25-to 6.88 (m, 8H, Ar-H), 4,58-to 4.52 (m, 0,6H, PIP-H), 4,50 (t, 1H, J=5,1, dioxane-H), 4,48, and of 4.44 (2s, 2H, benzyl-H), 4,06-was 4.02 (m, 2H, dioxane-H)of 3.78 and a 3.50 (2s, 2H, benzyl-H), 3.72 points-to 3.64 (m, 2,4H, PIP-H, dioxane-is), 2,84 (m, 2H, PIP-H), is 2.40 to 2.35 (m, 2H, NCH2), 2,07 of 1.99 (m, 2,2H, dioxane-H, PIP-H), 1.85 to 1,50 (m, 6H, PIP-H, NCH2CH2), 1,30-1,25 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=6,9 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-p-tolylacetate (117NLS87-IN)

Get a way that is described for 117NLS87-A, using 4-methylphenylacetic and 118AF52-95 (300 mg, of 0.93 mmol). Exit 119 mg, 28%.

Rf=0,43 (MeOH/CH2Cl21:9). IHMS m/z 455 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,17-6,87 (m, 8H, Ar-H), 4,60-a 4.53 (m, 0,5H, PIP-H), 4,50 (t, 1H, J=5,1, dioxane-H), 4,48, and to 4.41 (2s, 2H, benzyl-H), 4,05-4,01 (m, 2H, dioxane-H), of 3.77-3,66 (m, 3,5H, PIP-H, benzyl-N, dioxane-H), 3,50 (s, 1H, benzyl-H), 2,87 is 2.80 (m, 2H, PIR, N, 2,40-of 2.34 (m, 2H, NCH2), 2,30, and of 2.28 (2s, 3H, CH3), 2,07-of 1.95 (m, 2H, dioxane-H, PIP-H), 1,83 of 1.50 (m, 6H, PIP-H, NCH2CH2), 1,29-1,25 (m, 2H, dioxane-H, PIP-H). HPLC tR=7,7 minutes

Tartrate 2-benzofuran-5-yl-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (128NLS22-A)

Benzofuran-5-luksusowe acid is obtained by adapting the method described by Dunn et al. (J. Med. Chem., 1986, 29, 2326), and her turn in the appropriate acetylchloride treatment oxalylamino. Specified in the title compound is obtained from 118AF52-95 (58 mg, 0.18 mmol) by the method described for 117NLS87-A. Yield 27 mg, 43%.

Rf=0,52 (MeOH/CH2Cl21:9). IHMS m/z 481 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ to 7.64-6,68 m, 9H, Ar-H), 4,62-of 4.54 (m, 0,6H, PIP-H) 4,53-of 4.44 (m, 3H, dioxane-H, benzyl-H), 4,07-a 4.03 (m, 2H, dioxane-H), 3,82-3,61 (m, 3,2H, PIP-H, benzyl-N, dioxane-H), of 3.45 (s, 1,2H, benzyl-H), 2.91 in is 2.80 (m, 2H, PIP-H), 2,44 to 2.35 (m, 2H, NCH2), 2,08-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1.85 to and 1.56 (m, 6H, PIP-H, NCH2CH2), 1,32-of 1.27 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=6,6 minutes

Tartrate 2-(2,3-dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (128NLS22-IN)

Connection (2,3-dihydrobenzofuran-5-yl)acetic acid is obtained by adapting the method described by Dunn et al. (J. Med. Chem., 1986, 29, 2326), and turn in the appropriate acetylchloride treatment oxalylamino. Specified in the title compound is obtained from 118AF52-95 (58 mg, 0.18 mmol) by the method described for 117NLS87-A. Yield 27 mg, 31%.

Rf=0,50 (MeOH/CH2Cl21:9). IHMS m/z 483 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,10-6,60 (m, 7H, Ar-H), 4,55-and 4.40 (m, 5,6H, PIP-H, dioxane-H, benzyl-N', ArOCH2), 4,01-of 3.97 (m, 2H, dioxane-H), 3.72 points-3,62 (m, 3,2H, PIP-H, benzyl-N, dioxane-H)to 3.41 (s, 1,2H, benzyl-H), 3,14-of 3.06 (m, 2H, OCH2CH2), 2,80 (m, 2H, PIP-H), 2,35-of 2.30 (m, 2H, NCH2), 1,99-of 1.93 (m, 2,2H, dioxane-H, PIP-H), 1,80-of 1.44 (m, 6H, PIP-H, NCH2CH2), 1,27-1,22 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=6,9 minutes

Tartrate N-{1-[2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (117NLS37)

1-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)ethanol with the according methods described in the literature (R. Carman et al. Aust. J. Chem., 1998, 51, 955), and oxidized to the aldehyde by treatment with chlorbromuron pyridinium. The crude aldehyde (80 mg, 0.55 mmol) are added to a solution 103NLS56 (184 mg, 0.46 mmol) in methanol (5 ml). Add acetic acid (0.05 ml), and then add lambrogini sodium (58 mg, of 0.92 mmol) and the mixture is stirred over night at RT. The solvent is removed and the residue partitioned between dichloromethane and 1M NaOH. The organic layer was washed with saturated NH4Cl, dried over Na2SO4, filtered and evaporated. Purification of column chromatography on silica gel with elution with a mixture of 0-5% methanol in dichloromethane gives the desired compound (50 mg, 21%), which make it tartrate salt.

Rf=0,39 (MeOH/CH2Cl21:9). IHMS m/z 527 [M+H]+.1H-NMR (CDCl3,rotamer 0,6:0,4) δ 7,22-6,79 (m, 8H, Ar-H), 4,62-of 4.54 (m, 0,6H, PIP-H), 4,49 and 4,42 (2s, 2H, benzyl-H), 4,06-3,98 (m, 1H, dioxolan-H), 3.75 to 3,66 (m, 4,4H, PIP-H, CH2OiBu, benzyl-H), of 3.48 (m, 2H, dioxolan-N), 2,89-and 2.83 (m, 2H, PIP-H), 2,45 was 2.25 (m, 2H, NCH2), 2,07 of 1.99 (m, 2,2H, PIP-H, CHOiBu), 1.85 to a rate of 1.51 (m, 6H, PIP-H, NCH2CH2), 1,36 of 1.28 (m, 6,8H, C(CH3)2, PIP-H), 1,02 is 0.99 (m, 6H, CH3OiBu). HPLC tR=9,3 minutes

4-[2-(Toluensulfonate)ethyl]-1,3-dioxane (128NLS46-B)

Suspension of 1,3,5-pentandiol (1.01 g, with 8.33 mmol), paraformaldehyde (0,46 g) and methanesulfonate (0.33 ml) in DMF (3 ml) is heated for 10 is in at 130° With microwave radiation. The mixture is distributed between ethyl acetate and water, the organic layer dried over Na2SO4, filtered and evaporated. The residue is dissolved in methanol (3 ml), add concentrated HCl (0,09 ml) and the mixture is heated at 80°C for 10 min by microwave radiation. Add ethyl acetate and 2M NaOH, the aqueous layer was extracted twice with ethyl acetate and the combined organic layers washed with saturated salt solution, dried over Na2SO4, filtered and evaporated. The crude product is treated with p-toluensulfonate and DMAP, following the techniques described in the literature (Moune et al. J. Org. Chem., 1997, 62, 3332). Specified in the title compound (1.18 g, 49% of the total yield of the crude substances) are obtained in the form of a yellowish oil which is used without purification.

N-{1-[2-(1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)Amin (128NLS52)

To a suspension of the hydrochloride monohydrate of 4-piperidone (1.26 g, 8,23 mmol) in acetonitrile (100 ml) is added potassium carbonate (3.4 g, 24.6 mmol), and then add toluensulfonate 128NLS46 (3,54 g, 12,36 mmol) and sodium iodide (1.85 g, 12,35 mmol) and stirred overnight at 60°C. the Mixture is filtered, the filtrate is evaporated in vacuo and the residue partitioned between 1M NaOH and ethyl acetate. The organic layer is separated, the aqueous layer was extracted twice with ethyl acetate and the combined organic with the ois dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution step gradient mixture of 0-4% methanol in dichloromethane gives 1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-one (128NLS50, 1.73 g, 98%).

To a solution of 128NLS50 (1.73 g, 8,13 mmol) in methanol (100 ml) was added dropwise 4-forbindelsen (0,93 ml, 8,13 mmol) and acetic acid. To the mixture at 0°slowly add lambrogini sodium (2.15 g, 40 mmol) and stirred at RT over night. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and 1M NaOH, the aqueous layer was twice extracted with dichloromethane and the combined organic layers dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of 0-30% methanol in dichloromethane gives specified in the title compound (1.51 g, 58%) as a colourless solid.

Tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (128NLS62)

Get a way that is described for 117NLS87-A, using 4-solutocapillary and 128NLS52 (480 mg, 1,49 mmol). Output 458 mg, 60%.

Rf=0,36 (MeOH/CH2Cl21:9). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3,rotamer 0,6:0,4) δ 7,21-to 6.80 (m, 8H, Ar-H), free 5.01 (d, 1H, J=6,1, dioxane-H), 4,66-4,56 (m, 1,6H, PIP-H, dioxane-H) 4,51 and of 4.44 (2c, 2H, benzyl-H), 4.09 to 405 (m, 1H, dioxane-H), of 3.77 and 3,51 (2c, 2H, benzyl-H), 3,70 is 3.57 (m, 4,4H, PIP-H, dioxane-H, CH2OiBu), 2,91-and 2.83 (m, 2H, PIP-H), 2,45-of 2.34 (m, 2H, NCH2), 2,10-2,00 (m, 2,2H, PIP-H, CHOiBu), 1,85-of 1.26 (m, 8,8H, PIP-H, dioxane-H, NCH2CH2), of 1.03 to 1.00 (m, 6H, CH3OiBu). HPLC tR=8,8 minutes

Tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-triptoreline)ndimethylacetamide (128NLS54-A)

Get a way that is described for 117NLS87-A, using 4-tryptophansynthroid and 128NLS52 (116 mg, 0.32 mmol). Yield 52 mg, 32%.

Rf=0,42 (MeOH/CH2Cl21:9). IHMS m/z 509 [M+H]+.1H-NMR (CDCl3,rotamer 0,6:0,4) δ 7,60-of 6.90 (m, 8H, Ar-H), 4,99 (d, 1H, J=6,1, dioxane-H), 4,65-of 4.54 (m, 1,6H, PIP-H, dioxane-H), to 4.52 and 4,47 (2s, 2H, benzyl-H), 4,07-Android 4.04 (m, 1H, dioxane-H), 3,88 (s, 0,8H, benzyl-H), 3,69 of 3.56 (m, 3,6H, benzyl-N, PIP-H, dioxane-H), 2,89 (m, 2H, PIP-H), 2,49-2,31 (m, 2H, NCH2), 2,07 of 1.99 (m, 1,2H, PIP-H), 1,89-of 1.36 (m, 8,8H, PIP-H, dioxane-H, NCH2CH2). HPLC tR=7,3 minutes

Tartrate 2-(4-cyanophenyl)-N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (128NLS54-C)

4-Cyanophenylacetic acid synthesized according to the method described by Jaeger et al. (J. Chem. Soc., 1941, 744-747), and turn in the appropriate acetylchloride treatment oxalylamino. Specified in the header of the connection are described for 117NLS87-A, using 4-cyanophenylacetic and 128NLS52 (116 mg, 0.32 mmol). The output 60 mg, 40%.

Rf=0,40 (MeOH/CH2 Cl21:9). IHMS m/z 466 [M+H]+.1H-NMR (CDCl3, rotamer 0,7:0,3) δ a 7.62 6.89 in (m, 8H, Ar-H), equal to 4.97 (d, 1H, J=6,1, dioxane-H), 4,63 (m, 1H, dioxane-H), 4,59-4,47 (m, 2,7H, PIP-H, benzyl-H), 4,06-was 4.02 (m, 1H, dioxane-H), 3,86 (s, 0,6H, benzyl-H), 3,69-3,55 (m, 3,7H, benzyl-N, PIP-H, dioxane-H), 2.91 in-2,86 (m, 2H, PIP-H), 2,47-of 2.30 (m, 2H, NCH2), 2,05-of 1.39 (m, 10H, PIP-H, dioxane-H, NCH2CH2). HPLC tR=4,3 minutes

The hydrochloride of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(2-Oxymetazoline-1-yl)ethyl]piperidine-4-yl}ndimethylacetamide (69NLS97)

Get a way that is described for 117NLS01 using 103NLS56 (240 mg, of 0.60 mmol) and 1-(2-toluensulfonate)-2-imidazolidinone as alkylating agent. Yield 95 mg, 31%.

IHMS m/z 511 [M+H]+.1H-NMR (CD3OD, rotamer 0,6:0,4) δ 7,24-for 6.81 (m, 8H, Ar-H), 4,56, and to 4.52 (2s, 2H, benzyl-H), to 4.41-4,37 and 3,93-3,88 (m, 1H, PIP-H), 3,84, and of 3.56 (2s, 2H, benzyl-H), to 3.73 at 3.69 (m, 2H, CH2OiBu), 3.46 in-3,20 (m, 6H, imide-CH2, NCH2CH2), 2,99-to 2.85 (m, 2H, PIP-H), 2,44 (m, 2H, NCH2), 2,10 is 1.96 (m, 3,2H, PIP-H, CHOiBu), 1,67-of 1.62 (m, 3H, PIP-H), of 1.30 (m, 0,8H, PIP-H), 1,03 is 0.99 (m, 6H, J=6,6, CH3OiBu). HPLC tR=9,5 minutes

Choosing suitable secondary amines (obtained by analogy with the method described for 103NLS56), the following compound is obtained using similar methods.

Hydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-Oxymetazoline-1-yl)ethyl]piperidine-4-yl}ndimethylacetamide (63ELH39-B)

IHMS m/z 465 [M+H]+ .1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,30-to 6.80 (m, 8H), 4,60-a 4.53 (m, 0,6H), 4,50 and 4,43 (2s, 2H), 3,78 (m, 4,2H), 3,51 (s, 1,2H), 3.46 in-3,24 (m, 6H), 2,92-and 2.79 (m, 2H), 2,46-to 2.40 (m, 2H), 2.35 and to 2.29 (2s, 3H), 2,11-2,05 (m, 1,2H), 1,92 is 1.86 (m, 0,8H), 1,65 of 1.50 (m, 3,2H, partially covered by the HDO signal), to 1.31 (m, 0,8H).

The hydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-{1-[2-(2-Oxymetazoline-1-yl)ethyl]piperidine-4-yl}ndimethylacetamide (63ELH87)

The hydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)propyl]piperidine-4-yl}ndimethylacetamide (103NLS39)

Get a way that is described for 117NLS01 using N-(4-terbisil)-N-(piperidine-4-yl)-2-(4-isoproterenol)ndimethylacetamide (229 mg, 0.59 mmol) and 1-(3-chlorpropyl)-3-methyl-1,3-dehydrobenzperidol-2-alkylating agent. Exit 205 mg, 61%.

Rf=0,29 (MeOH/CH2Cl25:95). IHMS m/z 573 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,18-of 6.78 (m, 12H, Ar-H), 4,59-4,43 (m, 3,5H, PIP-H, OCH, benzyl-H), 3,88 (t, 2H, J=6,8, NCONCH2), 3,74 (m, 1,5H, PIP-H, benzyl-H), 3,49 (s, 1H, benzyl-H), 3,38 and 3,37 (2s, 3H, NCH3), 2,93-and 2.79 (m, 2H, PIP-H), a 2.36-to 2.29 (m, 2H, NCH2), 2,02-of 1.95 (m, 1H, PIP-H), 1,90 of 1.46 (m, 6H, PIP-H, NCH2CH2), 1,31-1,25 (m, 7H, PIP-H, CH(CH3)2). HPLC tR=8,0 minutes

Choosing suitable secondary amines (obtained by analogy with the method described for 103NLS56) and alkylating agents, the following compounds of gain, using a similar method:

the hydrochloride of N-{1-[2-(2-dioxo-1,4-dihydro-2H-hinzelin-3-yl)ethyl]piperidine-4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)ndimethylacetamide (63ELH29A),

hydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(2-oxo-2,3-dihydrobenzoic-1-yl)propyl]piperidine-4-yl}ndimethylacetamide (50ELH89),

the hydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-{1-[4-(2-oxo-2,3-dihydrobenzoic-1-yl)butyl]piperidine-4-yl}ndimethylacetamide (63ELH91),

the hydrochloride of N-{1-[2-(2,4-dioxo-1,4-dihydro-2H-hinzelin-3-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropoxyphenyl)ndimethylacetamide (63ELH89).

Benzyl ether of 4-(4-forbindelsen)piperidine-1-carboxylic acid (118AF93-51)

To a solution of benzyl 4-oxo-1-piperidinecarboxylate (10.2 g, while 43.8 mmol) in methanol (150 ml) at room temperature is added dropwise a solution of 4-forbindelsen (5,48 g that 43.8 mmol) in a mixture of methanol and acetic acid (5:1, 60 ml). To this mixture, slowly add lambrogini sodium (5.5 g, of 87.5 mmol). After 20 hours of stirring at RT the reaction mixture is neutralized and the solvent is removed by evaporation under reduced pressure. The residue is partitioned between dichloromethane and water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of 7% methanol in dichloromethane gives the desired compound (9.0 g, 60%).

Rf=0,56 (MeOH/CH2Cl25:95). IHMS m/z 343 [M+H]+. HPLC tR=6,2 minutes

N-(1-Benzyloxycarbonylamino-4-yl)-N-(4-terbisil)-N'-(4-isopropoxy ensil)urea (118AF97-120)

To a solution of 4-(isopropoxy)phenylacetic acid (2,89 g, 14.9 mmol) in dry tetrahydrofuran (18 ml) at RT in the atmosphere of argon added 1,8-bis(dimethylamino)naphthalene (3,19 g, 14.9 mmol). After 25 minutes of stirring at RT are added dropwise diphenylphosphoryl (4,10 g, 14.9 mmol) and the mixture refluxed for 6 hours. The mixture is cooled to CT and then incubated at -20°during the night, precipitating salt is ammonium phosphate. To the cold reaction mixture is added a mixture of diethyl ether and ethyl acetate (1:1 vol./about., 25 ml). The precipitate was filtered from the reaction mixture and washed with a mixture of diethyl ether : ethyl acetate (1:1 vol./about., 20 ml). The filtrate is evaporated to dryness, obtaining 1-isocyanatomethyl-4-isopropoxybenzoic in the form of an oil (3.2 g), which is used in the next stage without further purification.

To a solution of benzyl ester of 4-(4-forbindelsen)piperidine-1-carboxylic acid 118AF93-51 (5.7 g, and 16.7 mmol) in dry tetrahydrofuran (20 ml) is added sodium carbonate (3.5 g, to 25.3 mmol). To this suspension is added a solution of 1-isocyanatomethyl-4-isopropoxybenzoic (3.2 g, and 16.7 mmol) in dry tetrahydrofuran (10 ml) in an argon atmosphere. The reaction mixture was stirred over night at RT. Then this mixture is partitioned between dichloromethane and water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Cleaning OST the TKA column chromatography on silica gel with elution with a mixture of 8% methanol in dichloromethane gives the desired compound (2.0 g, 22%).

Rf=0,36 (MeOH/CH2Cl2,5:95). IHMS m/z 534 [M+H]+. HPLC tR=10,2 minutes

Oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-piperidine-4-ylcarbamate (118AF99-121)

The desired compound is obtained by hydrogenation 118AF97-120 (2.0 g, 3.75 mmol) in absolute ethanol (100 ml)using palladium on coal as a catalyst. The product was then purified column chromatography on silica gel, elwira speed gradient mixture of 5-10% methanol in dichloromethane. The output of 1.16 g, 77%.

Rf=0,10 (MeOH/CH2Cl2, 10:90). IHMS m/z 400 [M+H]+.1H-NMR (CDCl3) δ 7,19 (m, 2H, Ar-H), 7,01-6,69 (m, 4H, Ar-H), 6,76 (m, 2H, Ar-H), 4,51-and 4.40 (m, 3H, PIP-H, OCH(CH3), NH), 4,35 (s, 2H, benzyl-H), 4,28 (s, 1H, benzyl-H), 4,27 (s, 1H, benzyl-H), 3,14-of 3.07 (m, 2H, PIP-H), 2,74 of 2.68 (m, 2H, PIP-H), 2,10 (broadened s, 1H, NH), 1,78 is 1.70 (m, 2H, PIP-H), 1,58 is 1.48 (m, 2H, PIP-H), of 1.31 (d, 6H, J=6,0, OCH(CH3)). HPLC tR=5,9 min

Oxalate of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea (130AF10-147)

To a solution of 118AF99-121 (0.3 g, 0.75 mmol) in dry N,N-dimethylformamide (2 ml) is added potassium carbonate (0.21 g, 1.50 mmol). The suspension is shaken for 30 minutes at 58°C. To the warm suspension is added dropwise a solution of 2-(2-bromacil)-1,3-dioxolane (0,163 g, 0.90 mmol) in dry N,N-dimethylformamide (0.4 ml) and heating continued overnight. The mixture is cooled to CT, then filtered and partitioned between water is the first and dichloromethane. The organic layer was washed with aqueous solution of 4% of magnesium sulfate and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of 4% methanol in dichloromethane gives the desired compound (197 mg, 53%). The product is converted into its oxalate form, as described above.

Rf=0,39 (MeOH/CH2Cl2, 4:94). IHMS m/z 500 [M+H]+.1H-NMR (CDCl3) δ 7,17 (m, 2H, Ar-H), 7,00-to 6.95 (m, 4H, Ar-H), 6,76 (m, 2H, Ar-H), 4,88 (t, 1H, J=4,8, dioxolan-N), 4,51-of 4.44 (m, 2H, NH, CH(CH3)2), 4,36-4.26 deaths (m, 5H, benzyl-N, PIP-H), 3.95 to of 3.80 (m, 4H, dioxolan-N), 2,98-only 2.91 (m, 2H, PIP-H), 2,48 is 2.43 (m, 2H, NCH2), 2,10-a 2.01 (m, 2H, PIP-H), 1.85 to to 1.79 (m, 2H, NCH2CH2), 1,76 is 1.58 (m, 4H, PIP-H), of 1.30 (d, 6H, J=6,0, CH(CH3)2). HPLC tR=6,9 minutes

Choosing suitable secondary amines (obtained by analogy with the method described for 103NLS56), the following compound is obtained using similar methods:

the hydrochloride of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)ndimethylacetamide (63ELH29),

the hydrochloride of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (74AKU06-2),

the hydrochloride of N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-2-(4-isopropoxyphenyl)-N-(4-methylbenzyl)ndimethylacetamide (76ELH07),

tartrate N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propoxyphenyl)ndimethylacetamide (38PH50).

Oxalate of N-(4-terbisil)-N'-4-isopropoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}urea (130AF12-148)

To a solution of 130AF10-147 (50 mg, 0.10 mmol) in 1,4-dioxane (1 ml) is added 4M HCl (0.5 ml) and water (0.5 ml). The mixture is stirred in a sealed flask for 10 minutes under microwave radiation at 120°C. the mixture is Then partitioned between dichloromethane and water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. The residue is dissolved in 1,4-dioxane (1 ml) and add a solution of (S)-(+)-propylene glycol (39 mg, 0.51 mmol) in 1,4-dioxane (0.5 ml). After addition of HCl (4M in dioxane, 0.5 ml) the mixture is stirred in a sealed flask for 20 minutes under microwave radiation at 120°C. the Mixture was partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic layer is evaporated to dryness. Purification of the residue column chromatography on silica gel with elution step gradient mixture of 4-8% methanol in dichloromethane gives the desired compound (2.1 mg, 4%). The product is converted into its oxalate form, as described above.

Rf=0,36 (MeOH/CH2Cl2, 4:94). IHMS m/z 514 [M+H]+. HPLC tR=7,2 minutes

Oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]urea (130AF09-145)

To a cold suspension of the research (200 mg, to 2.29 mmol) and sodium carbonate (0,63 g, 4,56 mmol) in dry tetrahydrofuran (8 ml) at 0°add a solution of 1-chloro-3-bromopropane in dry tetrahydrofuran (2 ml)SMEs stirred at 45° With during the night. The mixture is cooled to CT, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of ethyl acetate and n-heptane (70:30) gives 3-chloro-1-morpholine-4-improper (156 mg, 42%).

A solution of 3-chloro-1-morpholine-4-isprobana (7,6 mg, 0.046 mmol) in dry N,N-dimethylformamide (0.10 ml) are added to a solution 118AF99-121 (15 mg, 0,037 mmol) and cesium carbonate (40 mg, 0,123 mmol) in a mixture of dry N,N-dimethylformamide and acetonitrile (1:2, 0,30 ml). After adding sodium iodide (7.0 mg, 0,047 mmol) the mixture is shaken overnight at 60°C. the Mixture is cooled to CT. The acetonitrile is removed by evaporation under reduced pressure and the residue partitioned between dichloromethane (2 ml) and water (1 ml). The organic layer is evaporated to dryness. Purification of the residue preparative HPLC with reversed phase (C18) gives the desired compound (6,1 mg, 32%).

IHMS m/z 527 [M+H]+. HPLC tR=6,2 minutes

Choosing suitable secondary amines (obtained by analogy with the method described for 103NLS56), the following compound is obtained using similar methods:

the dihydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholine-4-retil)piperidine-4-yl]ndimethylacetamide (63ELH40-2),

the dihydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]ndimethylacetamide (63ELH41-2),

the dihydrochloride of N-(4-terbisil)-2-(4-isobutoxy)-N-[1-3-morpholine-4-ylpropyl)piperidine-4-yl]ndimethylacetamide (74AKU07-2),

the dihydrochloride of N-(4-terbisil)-2-(4-isopropoxyphenyl)-N-[1-(3-morpholine-4-ylpropyl)piperidine-4-yl]ndimethylacetamide (76ELH14-A).

Oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-[1-(3-piperidine-1-ylpropyl)piperidine-4-yl]urea (130AF09-146)

The desired compound is synthetized from piperidine, 1-chloro-3-bromopropane and 118AF99-121 (15 mg, 0,037 mmol), using the same way to obtain 130AF09-145. The output of 5.8 mg, 30%.

IHMS m/z 525 [M+H]+. HPLC tR=6,8 minutes

Tartrate N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-[1-(3-((S)-4-isopropyl-2-oxazolidinone-ylpropyl)piperidine-4-yl]urea (130AF14-152)

The desired compound synthesized from (4S)-3-(3-chloropropyl)-4-isopropylacetanilide-2-it 103NLS94 (7.4 mg, 0.045 mmol) and 118AF99-121 (15 mg, 0,037 mmol), using the same way to obtain 130AF09-145. The output of 3.3 mg, 16%.

IHMS m/z 569 [M+H]+. HPLC tR=8,2 minutes

Oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}urea (130AF07-143)

The desired compound is synthesized from 2-bromo-1-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethane (10,7 mg, 0.045 mmol) and 118AF99-121 (15 mg, 0,037 mmol), using the same way to obtain 130AF09-145. The output of 8.3 mg, 15%.

IHMS m/z 556 [M+H]+. HPLC tR=9,6 minutes

Oxalate of N-{1-[3-(1,3-dioxolane-2-yl)propyl]piperidine-4-yl}-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea (130AF07-131)

The desired connection Sintesi the comfort of 3-chloro-1-(1,3-dioxolane-2-yl)propane (6,79 mg, 0.045 mmol) and 118AF99-121 (15 mg, 0,037 mmol), using the same way to obtain 130AF09-145. The output of 5.6 mg, 11%.

IHMS m/z 514 [M+H]+. HPLC tR=8,3 minutes

Oxalate of N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-N'-(4-isopropoxyphenyl)urea (130AF05-129)

A solution of 2,2-dimethyl-1,3-dioxane-5-it (9.75 mg, of 0.075 mmol) in methanol (0.10 ml) are added to a solution 118AF99-121 (15 mg, 0,037 mmol) in methanol (0.10 ml). The reaction mixture was stirred at RT after addition of acetic acid (60 μl of 1M solution in methanol). After 2 h stirring the solution lamborginid sodium (5 mg, 0,079 mmol) in methanol (0.10 ml) and stirring is continued overnight at RT. The solvent is removed by evaporation under reduced pressure and the residue partitioned between 2M aqueous sodium hydroxide and dichloromethane. Layers separated by filtration through a PTFE filter. The organic layer is evaporated to dryness. Purification of the residue preparative HPLC with reversed phase (C18) gives the desired compound (2.3 mg, 12%).

IHMS m/z 514 [M+H]+. HPLC tR=9,0 minutes

Oxalate of N-(4-terbisil)-N'-(4-isopropoxyphenyl)-N-{[2-(1-methylpyrrolidine-2-yl)ethyl]piperidine-4-yl}urea (130AF07-135)

The desired compound is synthesized from 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (7.7 mg, 0,041 mmol) and 118AF99-121 (15 mg, 0,037 mmol), using the same way to obtain 130AF09-145. Output is 4.4 mg, 23%.

IHMS m/z 511 [M+H]+. HPLC tR=7,0 minutes

Oxalate of N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (130AF22-105)

To a solution of 103NLS56 (179 mg, 0.45 mmol) in methanol (10 ml) added dropwise a solution of 2,2-dimethyl-1,3-dioxane-5-it (81 mg, of 0.62 mmol) in methanol (10 ml). The reaction mixture was stirred at RT after addition of acetic acid (200 μl). After 2 hours, slowly add lambrogini sodium (56 mg, 0.90 mmol) and stirring is continued overnight at RT. The mixture is neutralized with a few drops of 2M aqueous sodium hydroxide. The solvent is removed by evaporation under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of 6% methanol in dichloromethane gives the desired compound (98 mg, 43%).

Rf=0,32 (MeOH/CH2Cl26:94). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,26-6,79 (m, 8H, Ar-H), 4,63-of 4.54 (m, 0,6H, PIP-H), 4,50 and 4,43 (2s, 2H, benzyl-H), 3,91 and 3,88 (2D, 1H, J=5.6, dioxane-H), 3,79-to 3.67 (m, 6,2H, dioxane-H, benzyl-N, PIP-H, CH2OiBu), 3,51 (s, 1,2H, benzyl-H), 2,98-is 2.88 (m, 2H, PIP-H), 2,64-2,52 (m, 1H, dioxane-H), 2,38-of 2.28 (m, 1,2H, PIP-H), 2,17-2,00 (m, 1,8H, CH(CH3)2, PIP-H), 1,72 to 1.47 (m, 3,2H, PIP-H), USD 1.43 (m, 0,8H, PIP-H), 1,38-1,22 (m, 6H, dioxane-CH3), ,01 (m, 6H, CH(CH3)2). HPLC tR=10,0 minutes

Tartrate N-[1-(1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (130AF26-164)

To a solution of 130AF22-105 (level 98.2 mg, 0,19 mmol) in 1,4-dioxane (2 ml) was added 3M aqueous HCl (1 ml) and water (1 ml) and the mixture is stirred in a sealed flask under microwave radiation for 10 minutes at 120°C. the Mixture is partitioned between water and dichloromethane and the organic layer dried over sodium sulfate, filtered and evaporated to dryness. The residue is dissolved in 1,4-dioxane (2 ml). To this solution add a solution of formaldehyde (37% aqueous solution of 101 mg of 1.16 mmol) in 1,4-dioxane (0.5 ml). The reaction mixture was stirred in a sealed flask for 30 minutes under microwave radiation at 120°C. To the reaction mixture at room temperature is added molecular sieves (4Å) and removed after 24 hours. The mixture is heated for an additional 20 minutes at 120°under microwave radiation and partitioned between dichloromethane and sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of 6% methanol in dichloromethane gives the desired compound (17 mg, 18%). The product is converted into its tartrate form, as described above.

Rf=0,30 (MeOH/CH2Cl26:94). IHMS m/z 485 [MH] +.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-to 6.80 (m, 8H, Ar-H), 4,88 (m, 1H, dioxane-H), br4.61-4,56 (m, 1,6H, dioxane-H, PIP-H), 4,50 and 4,43 (2s, 2H, benzyl-H), 4,12-4,06 (m, 2H, dioxane-H) 3,85-of 3.60 (m, 5,2H, dioxane-H, benzyl-N, PIP-H, CH2OiBu), 3,51 (s, 1,2H, benzyl-H), 2,94-of 2.86 (m, 2H, PIP-H), 2,59-2,48 (m, 1H, dioxane-H), 2,37-of 2.28 (m, 1,2H, PIP-H), 2,17 is 2.01 (m, 1,8H, CH(CH3)2, PIP-H), 1,68 of 1.46 (m, 3,2H, PIP-H), 1,46-of 1.30 (m, 0,8H, PIP-H), of 1.02 (m, 6H, CH(CH3)2). HPLC tR=9,5 minutes

Tartrate N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-forfinal)ndimethylacetamide (130AF35-168)

The desired compound synthesized from 2,2-dimethyl-1,3-dioxane-5-it (59 mg, 0.45 mmol) and N-(4-terbisil)-2-(4-forfinal)-N-piperidine-4-ylacetamide (83 mg, 0.24 mmol)using the same way to obtain 130AF22-105. Starting material N-(4-terbisil)-2-(4-forfinal)-N-piperidine-4-ylacetamide get as 103NLS56.

Rf=0,26 (MeOH/CH2Cl25:95). IHMS m/z 459 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,28-6,91 (m, 8H, Ar-H), 4.63 to-to 4.52 (m, 0,6H, PIP-H), 4,51 and 4,46 (2s, 2H, benzyl-H), 3,92-3,88 (m, 2H, dioxane-H), 3,82 at 3.69 (m, 3,2H, dioxane-H, benzyl-N, PIP-H), 3,54 (s, 1,2H, benzyl-H), 2,99-2,90 (m, 2H, PIP-H), 2,62 is 2.51 (m, 1H, dioxane-H), 2,39-of 2.28 (m, 1,2H, PIP-H), 2,18 is 2.10 (m, 0,8H, PIP-H), 1,72 of 1.50 (m, 3,2H, PIP-H), 1,42 to 1.31 (m, 6,8H, PIP-H, dioxane-CH3). HPLC tR=7,9 minutes

Tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-forfinal)ndimethylacetamide (130AF41-171)

The original prophetic the creation of N-(4-terbisil)-2-(4-forfinal)-N-piperidine-4-ylacetamide get the same way as 103NLS56.

To a solution of N-(4-terbisil)-2-(4-forfinal)-N-piperidine-4-ylacetamide (79,4 mg, 0.23 mmol) in dry N,N-dimethylformamide (3 ml) is added potassium carbonate (64 mg, 0.46 mmol). To this suspension is added dropwise at room temperature, add a solution of 4-[2-(tosyloxy)ethyl]-1,3-dioxane 128NLS46 (99 mg, 0.35 mmol) in dry N,N-dimethylformamide (1 ml). The reaction mixture was stirred over night at 60°and partitioned between dichloromethane and water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution step gradient mixture of 2-5% methanol in dichloromethane gives the desired product (71 mg, 67%). The product is converted into its tartrate form, as described above.

Rf=0,41 (MeOH/CH2Cl26:96). IHMS m/z 459 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,28-of 6.90 (m, 8H, Ar-H), 4,99 (m, 1H, dioxane-H), 4,77 with 4.64 (m, 1,6H, PIP-H, dioxane-H)to 4.52 (s, 2H, benzyl-H), 3,80 of 3.56 (m, 4,4H, dioxane-H, benzyl-N, PIP-H), 3,21-is 3.08 (m, 1,2H, PIP-H), 2,96-is 2.88 (m, 0,8H, PIP-H), 2,75-of 2.56 (m, 1,2H, NCH2), 2,52-of 2.24 (m, 2H, PIP-H, NCH2), 2,04-of 1.30 (m, 9,8H, PIP-H, NCH2CH2, dioxane-H). HPLC tR=6,4 minutes

Tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-trifloromethyl)ndimethylacetamide (130AF80-186)

To a solution of N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)amine 128NLS52 (96 mg, 0.30 mmol) Vahom dichloromethane (5 ml) at RT add triethylamine (125 μl, 0.89 mmol). The solution is cooled to -10°and added dropwise a solution of (4-trifloromethyl)acetylchloride (71 mg, 0.30 mmol) in dry dichloromethane (1 ml). The reaction mixture was stirred over night at RT. The solvent is removed by evaporation under reduced pressure. The residue is suspended in tetrahydrofuran and filtered. The filtrate is evaporated to dryness and the residue purified column chromatography on silica gel, elwira a mixture of 4% methanol in dichloromethane, getting the desired compound (46 mg, 30%). Connection make it tartrate form, as described above.

Rf=0,33 (MeOH/CH2Cl26:94). IHMS m/z 459 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,34-6,91 (m, 8H, Ar-H), free 5.01 (d, 1H, J=6,0, dioxane-H), 4,66-of 4.54 (m, 1,6H, PIP-H, dioxane-H), to 4.52 and 4,49 (2s, 2H, benzyl-H), 4.09 to of 4.05 (m, 1H, dioxane-H), 3,83 (s, 0,8H, benzyl-H), 3.72 points of 3.56 (m, 3,6N, dioxane-H, benzyl-N, PIP-H), 2,94-of 2.86 (m, 2H, PIP-H), 2,50 of-2.32 (m, 2H, NCH2), 2,11-2,00 (m, 1,2H, PIP-H), 1,90-of 1.52 (m, 8,8H, PIP-H, NCH2CH2, dioxane-H). HPLC tR=7,6 minutes

Tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propoxyphenyl)ndimethylacetamide (130AF71-184)

To a solution of N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)amine 128NLS52 (126 mg, 0,39 mmol) in dry dichloromethane (5 ml) at RT add triethylamine (163 μl, of 1.17 mmol). The solution is cooled to -15°and added dropwise a solution of (4-propoxyphenyl)acetylchloride (92 m is, 0.43 mmol) in dry dichloromethane (2 ml). The reaction mixture is stirred for 2 hours at RT. The solvent is removed by evaporation under reduced pressure. The residue is suspended in tetrahydrofuran and filtered. The filtrate is evaporated to dryness and the residue purified column chromatography on silica gel, elwira speed gradient mixture of 0-4% methanol in dichloromethane, getting the desired compound (66 mg, 34%). The product is converted into its tartrate form, as described above.

Rf=0,16 (MeOH/CH2Cl24:96). IHMS m/z 499 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-of 6.78 (m, 8H, Ar-H), to 5.00 (m, 1H, dioxane-H), 4,66-of 4.54 (m, 1,6H, PIP-H, dioxane-H), 4,50, and of 4.44 (2s, 2H, benzyl-H), 4,10-a 4.03 (m, 1H, dioxane-H), 3,92-a 3.87 (m, 2H, OCHOrg), 3,78-to 3.50 (m, 4,4H, dioxane-H, benzyl-N, PIP-H), 2,92-2,82 (m, 2H, PIP-H), 2,50-to 2.29 (m, 2H, NCH2), 2,09-to 1.98 (m, 1,2H, PIP-H), 1,88-of 1.27 (m, 10,8H, PIP-H, NCH2CH2, dioxane-H, CHOrg), 1,05-099 (m, 3H, CHOrg). HPLC tR=7,6 minutes

Tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(tetrahydropyran-4-yl)piperidine-4-yl]ndimethylacetamide (130AF33-166)

To a solution of 103NLS56 (57 mg, 0.14 mmol) in methanol (2 ml) add a solution of tetrahydro-4H-Piran-4-it (43 mg, 0.42 mmol) in methanol (1 ml). After adding acetic acid (100 μl), the reaction mixture is stirred for 15 minutes in a sealed flask under microwave radiation at 100°C. Then added to the mixture of cianbro igrid sodium (26 mg, 0.42 mmol) and stirring is continued for an additional 60 min under microwave radiation at 80°C. the Mixture is passed through an acidic ion-exchange SPE cartridge. Further purification of the product column chromatography on silica gel with elution step gradient mixture of 2-5% methanol in dichloromethane gives the desired compound (19.2 mg, 28%). Connection make it tartrate form, as described above.

Rf=0,18 (MeOH/CH2Cl25:95). IHMS m/z 483 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-to 6.80 (m, 8H, Ar-H), with 4.64-4,56 (m, 0,6H, PIP-H), 4,51 and 4.45 (2s, 2H, benzyl-H), was 4.02-of 3.96 (m, 2H, Tgp-H), of 3.77-3,68 (m, 3,2H, benzyl-H, CH2OiBu, PIP-H), 3,51 (s, 1,2H, benzyl-H), 3,30 (t, 2H, J=12,0, Tgp-H), 2,98-is 2.88 (m, 2H, PIP-H), 2,46-of 2.34 (m, 1H, Tgp-H), 2,28-2,19 (m, 1,2H, PIP-H), 2,10-1,99 (m, 1,8H, CHOiBu, PIP-H), 1,73 to 1.47 (m, 7,2H, PIP-H, Tgp-H)of 1.39 and 1.33 (m, 0,8H, PIP-H), 1,01 (m, 6H, CH3OiBu). HPLC tR=8,0 minutes

Tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(tetrahydropyran-4-ylmethyl)piperidine-4-yl]ndimethylacetamide (130AF82-187)

Specified in the title compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (110 mg, 0.27 mmol) and tetrahydro-2H-Piran-4-yorbalinda (63 mg, 0.55 mmol), using the same way to obtain 130AF33-166. Yield 18 mg, 13%.

Rf=0,30 (MeOH/CH2Cl2with 5:95). IHMS m/z 497 [M+H]+. HPLC tR=8,4 minutes

Tartrate N-(4-terbisil)-2-(4-shall isobutoxide)-N-{1-[2-(tetrahydropyran-4-yl)ethyl]piperidine-4-yl}ndimethylacetamide (130AF83-188)

Specified in the title compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (110 mg, 0.27 mmol) and tetrahydro-2H-Piran-4-ilaterally (and 70.5 mg, 0.55 mmol), using the same way to obtain 130AF33-166. Yield 40 mg, 29%.

Rf=0,30 (MeOH/CH2Cl2with 5:95). IHMS m/z 511 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-to 6.80 (m, 8H, Ar-H), 4,65-4,55 (m, 0,6H, PIP-H), 4,51, and of 4.44 (2s, 2H, benzyl-H), 3.95 to the 3.89 (m, 2H, Tgp-H), 3,78-3,66 (m, 3,2H, benzyl-H, CH2OiBu, PIP-H), 3,51 (s, 1,2H, benzyl-H), to 3.34 (t, 2H, J=12,0, Tgp-H), 2,92-2,82 (m, 2H, PIP-H), 2,34-of 2.26 (m, 2H, NCH2CH2), 2,11 is 1.96 (m, 2,2H, PIP-H, CHOiBu), 1,84-1,20 (m, 11,8H, PIP-H, Tgp-H, CH2CH2N)of 1.02 (m, 6H, CH3OiBu). HPLC tR=8,2 minutes

Tartrate N-(4-terbisil)-2-(4-forfinal)-N-[1-(tetrahydropyran-4-yl)piperidine-4-yl]ndimethylacetamide (130AF37-169)

The desired compound synthesized from tetrahydro-4H-Piran-4-it N-(4-terbisil)-2-(4-forfinal)-N-piperidine-4-ylacetamide, using the same way to obtain 130AF33-166. Starting material N-(4-terbisil)-2-(4-forfinal)-N-piperidine-4-ylacetamide get as 103NLS56.

Rf=0,29 (MeOH/CH2Cl2with 5:95). IHMS m/z 429 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,29-6,91 (m, 8H, Ar-H), with 4.64-4,55 (m, 0,6H, PIP-H), to 4.52 and 4,48 (2s, 2H, benzyl-H), was 4.02-3,95 (m, 2H, Tgp-H), 3,80 (s, 0,8H, benzyl-H), 3.75 to to 3.64 (m, 0,4H, PIP-H), 3,54 (s, 1,2H, benzyl-N)to 3.34 (t, 2H, J=12,0, Tgp-H), 2,99-2,90 (m, 2H, PIP-H) 2,48-of 2.36 (m, 1H, Tgp-H), 2.26 and-of 2.20 (m, 1,2H, PIP-H), 2,08 is 2.00 (m, 0,8H, PIP-H), 1,76 to 1.47 (m, 7,2H, PIP-H, Tgp-H), 1.41 to of 1.34 (m, 0,8H, PIP-H). HPLC tR=5,6 minutes

Tartrate N-[1-((S) - for 3,5-dihydroxyphenyl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (130AF65-182)

The compound (R)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol synthesized in accordance with methods Moune et al. (J. Org. Chem., 1997, 62, 3332-3339). To a solution of 103NLS56 (94 mg, 0.24 mmol) in dry N,N-dimethylformamide (3 ml) is added potassium carbonate (83 mg, of 0.60 mmol). To this suspension is added a solution of (R)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol (82 mg, 0.28 mmol) in dry N,N-dimethylformamide (1 ml), and then add sodium iodide (43 mg, 0.29 mmol). The reaction mixture was stirred over night at 60°With. Then she is allowed to cool to CT, filtered and evaporated to dryness. The residue is partitioned between dichloromethane and 2M aqueous sodium hydroxide. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution step gradient mixture 6-10% methanol in dichloromethane gives the desired compound (35 mg, 29%), which make it tartrate form, as described above.

Rf=0,48 (MeOH/CH2Cl2, 10:90). IHMS m/z 501 [M+H]+. HPLC tR=7,4 minutes

Tartrate N-{1-[2-((4S)-1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)AC is tumida (130AF67-183)

To a solution of the tartrate salt 130AF65-182 (37 mg, 0,056 mmol) in 1,4-dioxane added paraformaldehyde (9 mg, 0.28 mmol) and hydrochloric acid (4M in 1,4-dioxane, 0.5 ml). The reaction mixture is stirred for 2 hours in a sealed flask under microwave irradiation at 120°and partitioned between dichloromethane and sodium bicarbonate. The organic layer was washed with saturated salt solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue acidic ion-exchange SPE cartridge gives the desired compound (9.0 mg, 31%), which make it tartrate form, as described above. Determine that the enantiomeric excess (ee) is 94%, using the analysis of chiral HPLC (column Chiralpak AD, 4,6×250 mm; heptane/isopropanol, 50:50, by 0.3% DEA; 0.5 ml/min; tR20,5 min).

Rf=0,41 (MeOH/CH2Cl2, 8:92). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-to 6.80 (m, 8H, Ar-H), to 5.00 (m, 1H, dioxane-H), 4,68-of 4.54 (m, 1,6H, PIP-H, dioxane-H), 4,51 and 4.45 (2s, 2H, benzyl-H)4,06 (m, 1H, dioxane-H), of 3.77-of 3.48 (m, 6,4H, dioxane-H, benzyl-N, CH20iBu, PIP-H), 2,98-and 2.79 (m, 2H, PIP-H), 2,50-of 2.58 (m, 2HNCH2), and 2.14 of 1.99 (m, 2,2H, CHOiBu, PIP-H), 1,90-1,25 (m, 8,8H, PIP-H, NCH2CH2, dioxane-H)of 1.02 (m, 6H, CH3OiBu). HPLC tR=8,7 minutes

N-{1-[2-(1,3-Dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)Amin (118AF52-95).

To a solution of the hydrochloride monohydrate 4-PIP is redone (6,45 g, 42.0 mmol) in acetonitrile (200 ml) is added sodium carbonate (17,4 g, 125,9 mmol). After 30 minutes stirring at RT for reaction mixture was added dropwise a solution of 2-(2-bromacil)-1,3-dioxane (8,45 g, a 43.3 mmol) in acetonitrile (50 ml), stirring is continued overnight at RT and refluxed for an additional 2 hours. The solvent is removed by evaporation under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of 7% methanol in dichloromethane gives 1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-one (to 6.19 g, 69%).

To a solution of 4-forbindelsen (3.9 ml, 34 mmol) in methanol (100 ml) in an argon atmosphere at RT add a solution of 1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-it (to 6.19 g, 29 mmol) in methanol (80 ml). After 30 minutes of stirring at RT, the reaction mixture is acidified (pH=5) with acetic acid and cooled to 0°C. To the cold mixture, slowly add lambrogini sodium (2.15 g, 40 mmol) and stirring is continued at RT overnight. The reaction mixture is alkalinized 2M NaOH and concentrated in vacuo. The residue is distributed between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. The residue is dissolved in absolute is ethanol (57 ml). To this solution was added a solution of maleic acid (and 3.31 g, 28.5 mmol) in absolute ethanol (60 ml), resulting in precipitate formation. The precipitate is collected by filtration and converted into the free base primary extraction. Yield 8.5 g, 91%.

Rf=0,29 (MeOH/CH2Cl2, 7:93). IHMS m/z 323 [M+H]+.1H-NMR (CDCl3) δ 7,25 (m, 2H, Ar-H), to 6.95 (m, 2H, Ar-H), of 4.54 (t, 1H, J=5.6, dioxane-H), 4,07-was 4.02 (m, 2H, dioxane-H), to 3.73-to 3.67 (m, 4H, dioxane-H, benzyl-H), 2,85-and 2.79 (m, 2H, PIP-H), 2,49-is 2.37 (m, 3H, NCH2, PIP-H), 2,05-1,72 (m, 7H, PIP-H, NCH2CH2, dioxane-H), 1,44-1,25 (m, 4H, dioxane-H, PIP-H, NH). HPLC tR=1,4 minutes

Tartrate 2-(4-benzyloxyphenyl)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (118AF66-102)

A solution of triethylamine (0,89 ml, 6.38 mmol) and 118AF52-95 (0,80 g, 2.48 mmol) in dry THF (10 ml) cooled to 0°C. To the cold reaction mixture is added dropwise a solution of 4-benzyloxybenzaldehyde (0,72 g, was 2.76 mmol) and stirring is continued at RT for 2 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. Purification of the residue column chromatography on silica gel with elution step gradient of 0-6% methanol in dichloromethane gives the desired compound (0,53 g, 39%), which make it tartrate form, as described above.

Rf=0,27 (MeOH/CH2Cl2, 7:93). IHMS m/z 547 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,6-6,86 (m, 13H, Ar-H), 5.08 to 5,02 (m, 2H, PhCH2O), with 4.64 was 4.42 (m, 3,6H, PIP-H, benzyl-N, dioxane-H), 4,11-was 4.02 (m, 2H, dioxane-H), 3,79-to 3.67 (m, 3,2H, dioxane-H, benzyl-N, PIP-H), 3,50 (s, 1,2H, benzyl-H), 2,94 is 2.80 (m, 2H, PIP-H), 2,46-of 2.34 (m, 2H, NCH2), 2,12-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1,87 of 1.50 (m, 6H, PIP-H, NCH2CH2), 1,36-1,24 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=8,9 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-hydroxyphenyl)ndimethylacetamide (118AF67-103)

The desired compound is obtained by hydrogenation 118AF66-102 (0.50 g, to 0.92 mmol) in absolute ethanol (200 ml)using palladium on coal as a catalyst. The product was then purified column chromatography on silica gel, elwira speed gradient 3-6% methanol in dichloromethane. The desired compound (0,22 g, 53%) turn his tartrato form, as described above.

Rf=0,30 (MeOH/CH2Cl2, 6:94). IHMS m/z 457 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,13-6,86 (m, 6H, Ar-H), 6,72-only 6.64 (m, 2H, Ar-H), 4,66-of 4.57 (m, 0,6H, PIP-H), of 4.54 (m, 1H, dioxane-H), 4,48, and 4,37 (2s, 2H, benzyl-H), 4,08-4,01 (m, 2H, dioxane-H), 3,80-3,66 (m, 3,2H, dioxane-H, benzyl-N, PIP-H), 3,47 (m, 1,2H, benzyl-H), 2,94-2,82 (m, 2H, PIP-H), 2,47-2,39 (m, 2H, NCH2), 2,10-of 1.97 (m, 2,2H, dioxane-H, PIP-H), 1,88-of 1.53 (m, 6H, PIP-H, NCH2CH2), 1,34-1,25 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=3,0 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-methoxyphenyl)ndimethylacetamide (118AF60-96)

A solution of triethylamine (0,57 ml 4.09 to mmol) and 118AF52-95 (328 mg, of 1.02 mmol) in dry THF (5 ml) cooled to 0°C. To the cold reaction mixture is added dropwise a solution of 4-methoxyphenylacetylene (376 mg, 2.04 mmol) and stirring is continued at RT for 20 hours. The reaction mixture was partitioned between 2M NaOH and water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. The residue is purified column chromatography on silica gel, elwira speed gradient mixture of 0-6% methanol in dichloromethane. Final purification of the product acidic ion-exchange SPE cartridge gives the desired compound (153 mg, 33%), which make it tartrate form, as described above.

Rf=0,40 (MeOH/CH2Cl2, 4:96). IHMS m/z 471 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,24-6,79 (m, 8H, Ar-H), 4,63-of 4.54 (m, 0,6H, PIP-H), to 4.52 (t, 1H, J=5,2, dioxane-H), 4,49 of 4.44 and (2s, 2H, benzyl-H), 4.09 to 4,01 (m, 2H, dioxane-H), 3,79-3,68 (m, 6,2H, dioxane-H, benzyl-N, PIP-H, OCH3), a 3.50 (m, 1,2H, benzyl-H), 2.91 in is 2.80 (m, 2H, PIP-H), 2,43-of 2.36 (m, 2H, NCH2), 2,10-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1,86-is 1.51 (m, 6H, PIP-H, HCH2CH2), 1,34-of 1.26 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=7,0 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropylphenyl)ndimethylacetamide (118AF63-100)

The desired compound synthesized from 118AF52-95 (400 mg, 1,24 mmol) and 4-isopropylacetanilide (340 mg, at 1.73 mmol), using the same way to obtain 118AF66-102. D. linaluu cleaning is performed acidic ion-exchange SPE cartridge. Exit 273 mg, 46%.

Rf=0,34 (MeOH/CH2Cl2, 7:93). IHMS m/z 483 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,22-6,89 (m, 8H, Ar-H), with 4.64-4,43 (m, 3,6H, PIP-H, dioxane-H, benzyl-H), 4.09 to as 4.02 (m, 2H, dioxane-H), 3,79 (s, 0,8H, benzyl-H), 3,76-3,66 (m, 2,4H, dioxane-H, PIP-H), of 3.54 (m, 1,2H, benzyl-N), 2,92-and 2.79 (m, 3H, PIP-H, CH(CH3)2), 2,41 to 2.35 (m, 2H, NCH2), 2,12-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1.85 to for 1.49 (m, 6H, PIP-H, NCH2CH2), 1,34-1,19 (m, 7,8H, PIP-H, dioxane-H, CH(CH3)2). HPLC tR=8,6 minutes

Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-trifloromethyl)ndimethylacetamide (118AF58-98)

The desired compound synthesized from 118AF52-95 (328 mg, of 1.02 mmol) and 4-triftormetilfullerenov (345 mg, 1.44 mmol), using the same way to obtain 118AF66-102. Exit 267 mg, 49%.

Rf=0,31 (MeOH/CH2Cl2, 4:96). IHMS m/z 525 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,30-of 6.90 (m, 8H, Ar-H), 4.63 to-4,48 (m, 3,6H, PIP-H, dioxane-H, benzyl-H), of 4.05 (m, 2H, dioxane-H), 3,82 (s, 0,8H, benzyl-H), 3,76-3,62 (m, 2,4H, dioxane-H, PIP-H), 3,55 (m, 1,2H, benzyl-H), 2,92-2,84 (m, 2H, PIP-H), 2,43-of 2.36 (m, 2H, NCH2), 2,10 is 1.96 (m, 2,2H, dioxane-H, PIP-H), 1,88-to 1.79 (m, 0,8H, PIP-H), 1,76-of 1.52 (m, 5,2H, PIP-H, NCH2CH2), 1,38-of 1.26 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=8,4 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-ethoxyphenyl)ndimethylacetamide (118AF68-104)

The desired compound synthesized from 118AF52-95 (400 m is, to 1.24 mmol) and 4-ethoxyphenylacetic (300 mg and 1.51 mmol), using the same way to obtain 118AF66-102. Further cleaning is performed acidic ion-exchange SPE cartridge. Yield 0.15 g, 25%.

Rf=0,26 (MeOH/CH2Cl2, 6:94). IHMS m/z 485 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-6,79 (m, 8H, Ar-H), with 4.64-of 4.54 (m, 0,6H, PIP-H), to 4.52 (t, 1H, J=5,2, dioxane-H), 4,49 and 4,43 (2s, 2H, benzyl-H), 4,07-of 3.97 (m, 4H, dioxane-H, OCH2), 3,76-3,66 (m, 3,2H, dioxane-H, PIP-H, benzyl-H), 3,49 (s, 1,2H, benzyl-H), 2.91 in is 2.80 (m, 2H, PIP-H), 2,42 of-2.32 (m, 2H, NCH2), 2,10-of 1.97 (m, 2,2H, dioxane-H, PIP-H), 1,86 is 1.48 (m, 6H, PIP-H, NCH2CH2), 1,42-of 1.36 (m, 3H, CH3), 1,34-1,24 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=7,6 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropoxyphenyl)ndimethylacetamide (118AF73-107)

The desired compound synthesized from 118AF52-95 (400 mg, 1,24 mmol) and 4-isopropoxybenzonitrile (340 mg, 1,60 mmol), using the same way to obtain 118AF66-102. Further cleaning is performed acidic ion-exchange SPE cartridge. Yield 91 mg, 15%.

Rf=0,58 (MeOH/CH2Cl2, 8:92). IHMS m/z 499 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,19-of 6.78 (m, 8H, Ar-H), with 4.64 was 4.42 (m, 4,6H, PIP-H, dioxane-H, benzyl-N, CHOiPr), 4,07 (m, 2H, dioxane-H), 3,76-3,68 (m, 3,2H, dioxane-H, PIP-H, benzyl-H), 3,49 (s, 1,2H, benzyl-H), 2.91 in is 2.80 (m, 2H, PIP-H), 2,42 to 2.35 (m, 2H, NCH2), 2,10 of 1.99 (m, 2,2H, dioxane-H, PIP-H), 1.85 to a rate of 1.51 (m, 6H, peep the, NCH2C2), to 1.31 (m, 7,8H, OCH(CH3)2, PIP-H, dioxane-H). HPLC tR=8,1 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-phenylacetamide (118AF77-109)

The desired compound synthesized from 118AF52-95 (300 mg, of 0.93 mmol) and phenylacetylene (197 mg, of 1.27 mmol), using the same way to obtain 118AF66-102. Further cleaning is performed acidic ion-exchange SPE cartridge. The yield 68 mg, 17%.

Rf=0,28 (MeOH/CH2Cl2with 5:95). IHMS m/z 441 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,33-6,89 (m, 9H, Ar-H), 4,65-of 4.44 (m, 3,6H, PIP-H, dioxane-H, benzyl-H), 4.09 to a 4.03 (m, 2H, dioxane-H), of 3.84 (s, 0,8H, benzyl-H), 3,76-to 3.67 (m, 2,4H, dioxane-H, PIP-H), 3,57 (s, 1,2H, benzyl-N), 2,92-and 2.79 (m, 2H, PIP-H), 2,44-of 2.34 (m, 2H, NCH2), 2,10-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1,86-is 1.51 (m, 6H, PIP-H, NCH2CH2), 1,34 is 1.23 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=6,1 minutes

Oxalate of N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(2-floratone)phenyl]ndimethylacetamide (118AF85-113)

The desired compound synthesized from 118AF52-95 (360 mg, 1.11 mmol) and 4-(2-floratone)phenylacetylide (282 mg, of 1.30 mmol), using the same way to obtain 118AF66-102. Further cleaning is performed acidic ion-exchange SPE cartridge. Yield 84 mg, 15%.

Rf=0,36 (MeOH/CH2Cl2with 5:95). IHMS m/z 503 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,27-6,84 (m, 8H, Ar-H), 4,80 (m, 1H, OCH2CH2), and 4.68 (m, 1H, OCH2CH2F), 4,65 is 4.45 (m, 3,6H, PIP-H, dioxane-H, benzyl-H), 4,22 (m, 1H, OCH2CH2F)to 4.16 (m, 1H, OCH2CH2F), 4,10-a 4.03 (m, 2H, dioxane-H), 3,79-3,68 (m, 3,2H, dioxane-H, PIP-H, benzyl-H), 3,51 (s, 1,2H, benzyl-H), 2,92-2,82 (m, 2H, PIP-H), 2,44-of 2.36 (m, 2H, NCH2), 2,12 of 1.99 (m, 2,2H, dioxane-H, PIP-H), 1,88-is 1.51 (m, 6H, PIP-H, NCH2CH2), 1,35-of 1.26 (m, 1,8H, PIP-H, dioxane-H). HPLC tR=7,0 minutes

Oxalate of N-{1-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (118AF27-83)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide 103NLS63F (22 mg, 0,042 mmol) and 2,2-dimethyl-1,3-propane diol (33 mg, 0.38 mmol)using the same way to obtain 130AF12-148. Product cleaning HPLC with reversed phase (C18gives specified in the title compound (2.8 mg, 12%). IHMS m/z 541 [M+H]+. HPLC tR=9,9 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-((R)-4-methyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (118AF29-84)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide 103NLS63F (38 mg, 0,074 mmol) and (R)-(-)-1,3-butanediol (33 mg, 0.38 mmol)using the same way to obtain 130AF12-148. Product cleaning HPLC with reversed phase (C18gives specified in the title compound (11.6 mg, 28%). IHMS m/z 527 [M+H]sup> +. HPLC tR=8,7 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (118AF31-85)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide 103NLS63F (40 mg, 0,078 mmol) and (S)-(+)-propylene glycol (30 mg, 0,39 mmol), using the same way to obtain 130AF12-148. Product cleaning HPLC with reversed phase (C18gives specified in the title compound (21 mg, 53%). IHMS m/z 513 [M+H]+. HPLC tR=9,9 minutes

Oxalate of N-{1-[2-(4,6-dimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (118AF37-88)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide 103NLS63F (40 mg, 0,078 mmol) and 2,4-pentanediol (41 mg, 0,39 mmol), using the same way to obtain 130AF12-148. Product cleaning HPLC with reversed phase (C18gives specified in the title compound (9 mg, 21%). IHMS m/z 541 [M+H]+. HPLC tR=10,5 minutes

Oxalate of N-(4-terbisil)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}-2-(4-trifloromethyl)ndimethylacetamide (118AF87-114)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-trifloromethyl)ndimethylacetamide 118AF58-98 (70 mg, 0.13 mmol) and (S)-(+)-propylene glycol (53 mg ,69 mmol), using the same way to obtain 130AF12-148. Product cleaning column chromatography on silica gel with elution step gradient mixture of 0-4% methanol in dichloromethane gives specified in the title compound (31 mg, 46%). Rf=0,17 (MeOH/CH2Cl2, 4:96). IHMS m/z 525 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,34-6,91 (m, 8H, Ar-H), 5.03 and 4,92 (2T, 1H, J=4,8, dioxolan-N), 4,66-4,56 (m, 0,6H, PIP-H), to 4.52 and 4,49 (2s, 2H, benzyl-H), 4,22-4,07 (m, 1,4H, dioxolan-H), 3.95 to the 3.89 (m, 0,6H, dioxolan-N), 3,84 (C, 0,8H, benzyl-H), 3,74-to 3.64 (m, 0,4H, PIP-H), 3,57 (s, 1,2H, benzyl-H), 3,40-to 3.33 (m, 1H, dioxolan-N), 2,78-of 2.86 (m, 2H, PIP-H), 2,49-of 2.38 (m, 2H, NCH2), 2,10-a 2.01 (m, 1,2H, PIP-H), 1.70 to of 1.53 (m, 6H, PIP-H, NCH2CH2), 1,40-1,22 (m, 3,8H, PIP-H, CH3). HPLC tR=8,7 minutes

Oxalate of N-(4-terbisil)-2-(4-isopropylphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (118AF91-117)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isopropylphenyl)ndimethylacetamide 118AF63-100 (150 mg, 0.31 mmol) and (S)-(+)-propylene glycol (95 mg, 1,24 mmol), using the same way to obtain 130AF12-148. Product cleaning column chromatography on silica gel with elution step gradient mixture of 0-4% methanol in dichloromethane gives specified in the header of the connection (of 51.2 mg, 34%).

Rf=0,19 (MeOH/CH2Cl2, 4:96). IHMS m/z 483 [M+H]+.1H-NMR (CDCl3, retama the s 0,4:0,6) δ 7.24 to make 6.90 (m, 8H, Ar-H), 5.03 and 4,92 (2T, 1H, J=4,8, dioxolan-N), 4,67-4,55 (m, 0,6H, PIP-H), 4,51 and 4,47 (2s, 2H, benzyl-H), 4,21-4,07 (m, 1,4H, dioxolan-N), 3,94-to 3.89 (m, 0,6H, dioxolan-N), 4,81-to 3.50 (m, 1,2H, benzyl-N, PIP-H), 3,55 (s, 1,2H, benzyl-H), 3,40-to 3.33 (m, 1H, dioxolan-N), 2,94-and 2.83 (m, 3H, PIP-H, CH(CH3)2), 2,47-of 2.38 (m, 2H, NCH2), 2,09 is 2.01 (m, 1,2, PIP-H), 1,86-of 1.52 (m, 6H, PIP-H, NCH2CH2), 1,31-1,19 (m, 9,8H, PIP-H, CH3CH(CH3)2). HPLC tR=8,6 minutes

Oxalate of N-(4-terbisil)-N-{1-[2-((R)-4-methyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-2-(4-trifloromethyl)ndimethylacetamide (118AF75-108)

The desired compound synthesized from N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-trifloromethyl)ndimethylacetamide 118AF58-98 (70 mg, 0.13 mmol) and (R)-(-)-1,3-butanediol (60 mg, 0.66 mmol), using the same way to obtain 130AF12-148. Product cleaning column chromatography on silica gel with elution step gradient mixture of 0-4% methanol in dichloromethane gives specified in the title compound (28 mg, 40%).

Rf=0,24 (MeOH/CH2Cl2with 5:95). IHMS m/z 539 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,33-6,91 (m, 8H, Ar-H), with 4.64-4,48 (m, 3,6H, benzyl-N, dioxane-H, PIP-H), Android 4.04 (m, 1H, dioxane-H), 3,83 (s, 0,8H, benzyl-H), 3.75 to 3,63 (m, 2,4H, dioxane-H, PIP-H), of 3.56 (s, 1,2H, benzyl-H), 2,92-and 2.83 (m, 2H, PIP-H), 2,44-of 2.38 (m, 2H, NCH2), 2,09 is 2.01 (m, 1,2 PIP-H), 1,89-of 1.53 (m, 7H, dioxane-H, PIP-H, NCH2CH2), 1,44 to 1.31 (m, 1,8H, dioxane-H, PIP-H), 1,19 (m, 3H, CH3). In the LC t R=9,0 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (118AF33-86)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (145 mg, 0.36 mmol) and 2-(2-bromacil)-2,5,5-trimethyl-1,3-dioxane (104,5 mg, 0.44 mmol)using the same method as for the synthesis of 130AF65-182. Product cleaning column chromatography on silica gel with elution with a mixture of 5% methanol in dichloromethane gives specified in the title compound (119 mg, 58%).

Rf=0,15 (MeOH/CH2Cl2with 5:95). IHMS m/z 555 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-6,79 (m, 8H, Ar-H), 4,66-4,56 (m, 0,6H, PIP-H), 4,49 and 4,43 (2s, 2H, benzyl-H), 3,76-3,68 (m, 3,2H, PIP-H, benzyl-N, CH2OiBu), 3,52-3,47 (m, 4H, dioxane-H)to 3.41 (m, 1,2H, benzyl-H), 2,93-2,84 (m, 2H, PIP-H), 2,48-to 2.40 (m, 2H, NCH2), 2,11-2,00 (m, 2,2H, CHOiBu, PIP-H), 1,87 and 1.80 (m, 2,8H, PIP-H, NCH2CH2), 1,72 of 1.50 (m, 3,2H, PIP-H)of 1.33 (s, 3,8H, CH3, PIP-H), of 1.02-0.87 (m, 12H, CH3). HPLC tR=9,8 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(2-methyl-1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (118AF35-87)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (311 mg, 0.78 mmol) and 2-(2-bromacil)-2-methyl-1,3-dioxolane (188 mg, 0.96 mmol), using the same method as for the synthesis of 130AF65-182. Cleaning the speaker chromatogr is via on silica gel with elution with a mixture of 5% methanol in dichloromethane gives specified in the title compound (61 mg, 15%).

Rf=0,20 (MeOH/CH2Cl2with 5:95). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,17-6,76 (m, 8H, Ar-H), with 4.64-to 4.52 (m, 0,6H, PIP-H), 4,47, and to 4.41 (2s, 2H, benzyl-H), 3,93-3,82 (m, 4H, dioxolan-N), 3,76-3,63 (m, 3,2H, benzyl-H, CH2OiBu, PIP-H), 3,47 (s, 1,2H, benzyl-H), 2,94 of 4.83 (m, 2H, PIP-H), 2,43 of-2.32 (m, 2H, NCH2), 2,12-of 1.97 (m, 2,2H, CHOiBu, PIP-H), 1,84-1,72 (m, 2,8H, PIP-H, NCH2CH2), 1.70 to 1,50 (m, 3,2H, PIP-H), 1.27mm (C, 3,8H, CH3, PIP-H), and 0.98 (m, 6H, CH3OiBu). HPLC tR=8,8 minutes

Tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(1,3-dioxolane-2-yl)propyl]piperidine-4-yl}ndimethylacetamide (118AF79-39)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (156 mg, 0,39 mmol) and 2-(3-chloropropyl)-1,3-dioxolane (62 μl, 0.47 mmol), using the same method as for the synthesis of 130AF65-182. Purification of column chromatography on silica gel with elution step gradient mixture of 0-4% methanol in dichloromethane gives specified in the title compound (49 mg, 25%).

Rf=0,45 (MeOH/CH2Cl2, 7:93). IHMS m/z 513 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-6,79 (m, 8H, Ar-H), 4,84 (t, 1H, J=4,4, dioxolan-N), 4,66-4,56 (m, 0,6H, PIP-H), 4,50, and of 4.44 (2s, 2H, benzyl-H), 3.95 to 3,90 (m, 2H, dioxolan-N), 3,84-to 3.67 (m, 5,2H, benzyl-H, CH2OiBu, PIP-H, dioxolan-N), 3,50 (s, 1,2H, benzyl-H), 2,94-2,84 (m, 2H, PIP-H), 2,34-of 2.27 (m, 2H, NCH2), 2,10-to 1.98 (m, 2,2H, CHOiBu, PIP-H), 1,84-of 1.78 (m, 0,8H, PIP-H), 1,71-1,50 (m, 7,2H, PI is-H, NCH2CH2), 1,34-1,25 (m, 0,8H, PIP-H), 1,01 (m, 6H, CH3OiBu). HPLC tR=8,0 minutes

The dihydrochloride of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-(3-piperidine-1-ylpropyl)piperidine-4-yl}ndimethylacetamide (98AF36-43)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (189 mg, 0.47 mmol), 1-piperidine (61 μl, 0.61 mmol) and 1-chloro-3-iodopropane (61 μl, or 0.57 mmol), using the same method as for the synthesis of 130AF09-145. Product cleaning column chromatography on silica gel with elution with a mixture of 10% methanol in dichloromethane gives the specified header connection (75,6 mg, 31%).

Rf=0,13 (MeOH/CH2Cl2, 1:4). IHMS m/z 524 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-for 6.81 (m, 8H, Ar-H), 4,66-of 4.54 (m, 0,6H, PIP-H), 4,51 and 4.45 (2s 2H, benzyl-H), 3,78-3,68 (m, 3,2H, benzyl-H, CH2OiBu, PIP-H), 3,52 (s, 1,2H, benzyl-H), 2,93-and 2.83 (m, 2H, PIP-H), 2,40-of 2.23 (m, 8H, NCH2), 2,15-of 1.26 (m, 15H, PIP-H, CH(CH3)2CH2), of 1.02 (m, 6H, CH(CH3)2). HPLC tR=8,0 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(tetrahydropyran-2-yloxy)ethyl]piperidine-4-yl}ndimethylacetamide (98AF41-44)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (185 mg, 0.46 mmol) and 2-(2-chloroethoxy)tetrahydro-2H-Piran (75 μl, 0.51 mmol), using the same method as for the synthesis of 130AF09-145. Product cleaning chrome column is cografya on silica gel with elution with a mixture of 4.5% methanol in dichloromethane gives specified in the title compound (96 mg, 40%).

Rf=0,18 (MeOH/CH2Cl2, 4:96). IHMS m/z 527 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,21-of 6.78 (m, 8H, Ar-H), 4,67-4,56 (m, 0,6H, PIP-H), of 4.54 (m, 1H, THP), 4,49 of 4.44 and (2s, 2H, benzyl-H), 3,86-3,66 (m, 5,2H, benzyl-H, CH2OiBu, PIP-H, CHO), to 3.58-3.43 points (m, 3,2H, benzyl-H, CHO), 3,01-2,89 (m, 2H, PIP-H), 2,62, and 2,55 (2T, 2H, J=6,0, NCH2CH2O), and 2.26-2,17 (m, 1,2H, PIP-H), 2,12 is 1.96 (m, 1,8H, CHOiBu, PIP-H), 1,82-of 1.44 (m, 9,2H, PIP-H, THP), 1,33-of 1.26 (m, 0,8H, PIP-H), 1,01 (m, 6H, CH(CH3)2). HPLC tR=7,2 minutes

N-(4-Terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-oxopiperidin-1-yl)propyl]piperidine-4-yl}ndimethylacetamide (98AF73-64)

To a solution of 2-piperidone (54 mg, 0.54 mmol) in dry THF (2 ml) in an atmosphere of argon is added sodium hydride (60% suspension in oil, 26 mg, of 0.65 mmol). After 15 minutes of stirring at RT, the reaction mixture was cooled to 0°C for 15 minutes. To the cold mixture is added dropwise 1-bromo-3-chloropropane (160 μl, of 1.62 mmol) and stirring is continued overnight at RT. The mixture is partitioned between water and ethyl acetate, the organic layer dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue column chromatography on silica gel with elution step gradient mixture of 60-80% ethyl acetate in n-heptane gives 1-(3-chloropropyl)piperidine-2-he (33 mg, 35%).

Rf=0,22 (ethyl acetate/n-heptane, 8:2). IHMS m/z 176 [M+H]+. HPLC tR=1,8 minutes

A solution of 1-(3-chloropropyl)piperidine-2-it (32 is g, 0.18 mmol) in dry DMF (2 ml) are added to a suspension of potassium carbonate (52 mg, 0.38 mmol) and N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (62 mg, 0.15 mmol) in dry DMF (2 ml). After adding sodium iodide (25 mg, 0,17 mmol) the mixture is stirred overnight at 48°C. Then partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue HPLC with reversed phase (C18) gives the desired compound (2.6 mg, 3%).

Rf=0,11 (MeOH/CH2Cl2with 5:95). IHMS m/z 538 [M+H]+. HPLC tR=8,2 minutes

The hydrochloride of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-oxopyrrolidin-1-yl)propyl]piperidine-4-yl}ndimethylacetamide (98AF76-65)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (107 mg, 0.27 mmol), 2-pyrrolidone and 1-bromo-3-chloropropane, using the same method as for the synthesis of 98AF73-64. Product cleaning column chromatography on silica gel with elution step gradient mixture of 4-8% methanol in dichloromethane gives specified in the title compound (15 mg, 11%).

Rf=0,39 (MeOH/CH2Cl2, 1:9). IHMS m/z 524 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-to 6.80 (m, 8H), 4,65-a 4.53 (m, 0,6H), 4,50, and of 4.44 (2s, 2H), 3,76-to 3.67 (m, 3,2H), 3,51 (m, 1,2H), 3,34 (t, 2H, J=7,2), 3,26 (t, 2H, J=7,2), 2,95-2,82 (m, 2H), 2,38 was 2.25 (m, 4H), 2,12 is 1.96 (m, 4,2H), 1,86-of 1.56 (m, 6H), of 1.29 (m ,8H), a 1.01 (m, 6H). HPLC tR=7,6 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-((R)-4-isopropyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide (98AF100-73)

To a solution of (R)-4-isopropyl-2-oxazolidinone (356 mg, of 2.75 mmol) in dry tetrahydrofuran (17 ml) in an atmosphere of argon is added sodium hydride (55% suspension in oil, 144 mg, of 3.31 mmol). The suspension is stirred for 1 hour at RT, then cooled to 0°and added dropwise a solution of 1-bromo-3-chloropropane in dry tetrahydrofuran (3 ml). After 48 hours stirring at 58°the mixture is quenched with water. The solvent is removed by evaporation under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer is evaporated to dryness. Purification of the residue column chromatography on silica gel with elution with a mixture of ethyl acetate and n-heptane (70:30) gives (4R)-3-(3-chloropropyl)-4-isopropylacetanilide-2-he (401 mg, 71%).

To a suspension of potassium carbonate (217 mg, 1.57 mmol) and N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (250 mg, to 0.63 mmol) in dry DMF (6 ml) add a solution of (4R)-3-(3-chloropropyl)-4-isopropylacetanilide-2-she (160 mg, 0.78 mmol) in dry DMF (2 ml). After adding sodium iodide (113 mg, 0.75 mmol) the mixture is stirred overnight at 62°and partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and you arevut dry. Purification of the residue column chromatography on silica gel with elution with a mixture of 5% methanol in dichloromethane gives the desired compound (143 mg, 40%).

Rf=0,28 (MeOH/CH2Cl2, 6:96). IHMS m/z 568 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-of 6.78 (m, 8H, Ar-H), br4.61-4,51 (m, 0,6H, PIP-H), 4,48, and was 4.42 (2s, 2H, benzyl-H), to 4.15 (t, 1H, J=8,8, oxa-N)to 4.01 (m, 1H, oxa-H), 3,78-to 3.64 (m, 4,2H, PIP-H, benzyl-N, oxa-H, CH2OiBu), of 3.48 (m, 2,2H, benzyl-N, CONCHCH2), 2,92-and 2.79 (m, 3H, PIP-H, CONCHCH2), 2,34-2,22 (m, 2H, NCH2CH2CH2), 2,10 is 1.96 (m, 3,2H, PIP-H, CHiPrCHOiBu), 1,76 of 1.50 (m, 6H, PIP-H, NCH2CH2), 1,32-of 1.26 (m, 0,8H, PIP-H), 0,99 (m, 6H, CH3OiBu), 0,81-0.87 (m, 6H, CH3iPr). HPLC tR=9,1 minutes

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-(2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide (98AF94-71)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (298 mg, 0.75 mmol), 2-oxazolidone and 1-bromo-3-chloropropane, using the same method as for the synthesis of 98AF100-73. Product cleaning column chromatography on silica gel with elution with a mixture of 5% methanol in dichloromethane gives specified in the title compound (157 mg, 40%).

Rf=0,23 (MeOH/CH2Cl2with 5:95). IHMS m/z 526 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-of 6.78 (m, 8H, Ar-H), br4.61-4,50 (m, 0,6H, PIP-H), 4,48, and was 4.42 (2s, 2H, benzyl-H), 4,29-4-24 (m, 2H, oxa-OCH2), 3,78-3,65 (who, 3,2H, PIP-H, benzyl-N, CH2OiBu), 3,52-of 3.48 (m, 3,2H, benzyl-N, oxa-NCH2)at 3.25 (t, 2H, J=7,2, CONCH2CH2CH2N), 2,89 is 2.80 (m, 2H, PIP-H), 2,33-of 2.26 (m, 2H, NCH2CH2CH2NCO), 2,09 to 1.76 (m, 3H, PIP-H, CHOiBu), 1,71-1,49 (m, 5,2H, PIP-H, NCH2CH2CH2), 1,33-of 1.27 (m, 0,8H, PIP-H), and 1.00 (m, 6H, CH3OiBu). HPLC tR=7,8 minutes

(S)-4-Methyloxazolidine-2-he (118AF10-77)

To a solution of L-alaninol (500 mg, of 6.65 mmol) and 1,1-carbonyldiimidazole (1.29 g, 7,98 mmol) in dry THF (10 ml) at RT in the atmosphere of argon dropwise added triethylamine (0,94 ml of 6.65 mmol). The reaction mixture was stirred over night at 60°C. the Solvent is removed by evaporation under reduced pressure. Purification of the residue column chromatography on silica gel with elution with a mixture of 6% methanol in dichloromethane gives the desired compound (450 mg, 67%).

Rf=0,39 (MeOH/CH2Cl2, 6:94).1H-NMR (CDCl3) δ 6,74 (m, 1H), 4,45-4,34 (m, 1H), 4,98-of 4.77 (m, 2H), 1,17 (m, 3H).

Tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-((S)-4-methyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide (118AF18-81)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (205 mg, 0.52 mmol), (S)-4-methyloxazolidine-2-it (118AF10-77) and 1-bromo-3-chloropropane, using the same method as for the synthesis of 98AF100-73. Next do the cleaning acidic ion-exchange SPE cartridge. Output mg, 38%.

Rf=0,22 (MeOH/CH2Cl2, 6:94). IHMS m/z 540 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-of 6.78 (m, 8H, Ar-H), br4.61-4,50 (m, 0,6H, PIP-H), 4,48, and was 4.42 (2s, 2H, benzyl-H), 4,34 (m, 1H, oxa-H), 3,84-3,66 (m, 5,2H, PIP-H, benzyl-N, oxa-H, CH2OiBu), 3,49 (s, 1,2H, benzyl-H), 3,42-to 3.34 (m, 1H, CONCH2), 3,09-3,00 (m, 1H, CONCH2), 2,92-and 2.79 (m, 2H, PIP-H), 2,33-of 2.26 (m, 2H, NCH2), 2,10-to 1.98 (m, 2,2H, PIP-H, CHOiBu,), 1,86 to 1.76 (m, 0,8H, PIP-H), 1,72 is 1.48 (m, 5,2H, PIP-H, NCH2CH2), of 1.29 (m, 0,8H, PIP-H), 1,22 (m, 3H, oxa-CH3), 0,99 (m, 6H, CH3OiBu). HPLC tR=8,4 minutes

(S)-4-Ethyloxazole-2-he (118AF08-76)

To a solution of (S)-(+)-2-amino-1-butanol (515 mg, 5,77 mmol) and 1,1-carbonyldiimidazole (1.10 g, is 6.78 mmol) in dry THF (10 ml) at RT in the atmosphere of argon dropwise added triethylamine (0,80 ml, 5,74 mmol). The reaction mixture was stirred over night at RT. The solvent is removed by evaporation under reduced pressure. Purification of the residue column chromatography on silica gel with elution with a mixture of 6% methanol in dichloromethane gives the desired compound (485 mg, 73%).

Rf=0,42 (MeOH/CH2Cl2, 6:94).

Oxalate of N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[3-((S)-4-ethyl-2-oxoacridine-3-yl)propyl]piperidine-4-yl}ndimethylacetamide (118AF16-80)

The desired compound synthesized from N-(4-terbisil)-2-(4-isobutoxy)-N-piperidine-4-ylacetamide 103NLS56 (202 mg, 0.51 mmol), (S)-4-ethyloxazole-2-it (118AF08-76) and 1-bromo-3-chlorpropyl is a, using the same method as for the synthesis of 98AF100-73. Product cleaning acidic ion-exchange SPE cartridge gives specified in the title compound (126 mg, 44%).

Rf=0,28 (MeOH/CH2Cl2, 6:94). IHMS m/z 554 [M+H]+.1H-NMR (CDCl3, rotamer 0,4:0,6) δ 7,20-of 6.78 (m, 8H, Ar-H), br4.61-to 4.52 (m, 0,6H, PIP-H), 4,48, and was 4.42 (2s, 2H, benzyl-H), 4,32-4.26 deaths (m, 1H, oxa-H), 3,94-3,88 (m, 1H, oxa-H), 3,76-3,66 (m, 4,2H, PIP-H, benzyl-N, oxa-H, CH2OiBu), 3,49 (s, 1,2H, benzyl-H), 3.46 in-3,37 (m, 1H, CONCH2), 3.04 from-2,96 (m, 1H, CONCH2), 2,90-2,78 (m, 2H, PIP-H), 2,33-of 2.24 (m, 2H, NCH2), 2,11 is 1.96 (m, 2,2H, PIP-H, CHOiBu), 1,82 is 1.75 (m, 0,8H, PIP-H), 1,74-of 1.42 (m, 7,2H, PIP-H, NCH2CH2CH2CH3), of 1.29 (m, 0,8H, PIP-H), and 1.00 (m, 6H, CH3OiBu)to 0.85 (m, 3H, CH2CH3). HPLC tR=8,7 minutes

2-(2-Bromacil)-1,3-oxathiolan (121JP11)

Adapting the method of Yamada et al. (Tetrahedron Lett., 1998, 39, 7709-7712), to a mixture of 2-(2-bromacil)-1,3-dioxolane (1.45 g, 8.0 mmol) and 2-mercaptoethanol (2,81 ml, 40 mmol) in dichloromethane (15 ml) at RT in the atmosphere of Ar added dropwise ether complex of boron TRIFLUORIDE (5 ml, 40 mmol) and stirred at RT over night. To the crude mixture is added saturated aqueous NaHCO3(100 ml), then extracted using Et2O (3×100 ml), dried (Na2SO4) and evaporated in vacuo. Purification by vacuum distillation (90°C, 1 mm RT. Art.) gives 1,08 g specified in the title compound as a yellow oil. The purity of this in the society after distillation is 71% (according to GC analysis) and use it on stage alkylation (121JP12) without additional purification.

L-Tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-{1-[2-(1,3-oxathiolan-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide (121JP12)

Specified in the header connection get the General procedure described above for 103NLS63-F using 103NLS56 (130 mg, 0.33 mmol) and 121JP11 (85 mg, 0.43 mmol) as the alkylating agent. Processing, as for 121JP11, subsequent vacuum filtration chromatography on silica gel (WFH, ethyl acetate/n-heptane 0:1→ethyl acetate/n-heptane 1:0→ethyl acetate/MeOH 4:1) to give 85 mg (51%) 121JP12 in the form of a colorless thick oil. L-Tartrate Sol receive, as described above.

Rf=0,57 (MeOH/CH2Cl2, 1:10). IHMS m/z 515 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,20-6,76 (m, 8H), 5,10-5,00 (m, 1H, oxathiolan-N), 4,66-of 4.54 (m, 0,5H, PIP-H), 4,48, and was 4.42 (2s, 2H, benzyl-H), 4,30-4,22 (m, 1H, oxathiolan-N), 3,78-to 3.64 (m, 4,5H, PIP-H, benzyl-N, oxathiolan-H, OCH2OiBu), 3,48 (s, 1H, benzyl-H), 3,01-2,82 (m, 4H, PIP-H, oxathiolan-N), 2,60-of 2.34 (m, 2H, NCH2), 2.21 are of 1.56 (m, 8H, PIP-H, NCH2CH2CHOiBu), 1,32-1,22 (m, 1H, PIP-H), 1.04 million-to 0.96 (m, 6H, CH3OiBu). HPLC tR=10,1 minutes

L-Tartrate 2-(4-bromophenyl)-N-{1-[2-(1,3-dioxane-2-yl)ethyl)piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (121JP13)

Specified in the header connection receive according to the method described above for 117NLS87-A using 118AF52-95 (200 mg, of 0.62 mmol) and 4-bromoferrocene acid (500 mg, 2.32 mmol). To the crude mixture is added saturated NaHCO 3(100 ml), then extracted with CH2Cl2(3×100 ml), dried (Na2SO4) and evaporated in vacuo. WFH on silica gel (ethyl acetate/n-heptane 1:1→ethyl acetate/n-heptane 1:0→ethyl acetate/MeOH 2:1) to give 250 mg (78%) 121JP13 in the form of a thick oil. L-Tartrate Sol receive, as described above.

Rf=0,49 (MeOH/CH2Cl2, 1:10). IHMS m/z 521 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,50-to 6.88 (m, 8H), 4,62-of 4.57 (m, 0,4H, PIP-H), 4,50 (t, 1H, J=4,9, dioxane-H) 4,48 and 4,42 (2s, 2H, benzyl-H), 4,06-4,00 (m, 2H, dioxane-H), 3,76, and a 3.50 (2s, 2H, benzyl-H), 3.75 to of 3.60 (m, 2,6H, PIP-H, dioxane-H), 3,01 and 2,90 (2D, 2H, J=10,5, PIP-H), 2.52 and 2,41 (2T, 2H, J=8,0, NCH2), 2,10-to 1.98 (m, 2,2N, dioxane-H, PIP-H), 1,97 is 1.58 (m, 6H, PIP-H, NCH2CH2), 1,38-1,20 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=8,3 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutylphenyl)ndimethylacetamide (121JP27)

Adapting the methodology Buchwald et al. (J. Amer. Chem. Soc., 1996, 118, 7215-7216), 121JP13 (100 mg, 192 μmol), isobutylamine (17 mg, 230 μmol), Pd2dba3(11.6 mg, 19.2 mmol), BINAP (12.0 mg, 38.4 mmol) and NaOtBu (from 25.8 mg, 269 μmol) was placed in the flask, add toluene (2 ml) and the resulting mixture was stirred at 80°C for 18 hours. Processing, as for 121JP13, subsequent preparative HPLC with reversed phase (C18give of 25.7 mg (27,0%) 121JP27 as a thick colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,30 MeOH/CH 2Cl2, 1:10). IHMS m/z 512 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,10-for 6.81 (m, 6H), 6,59-of 6.49 (m, 2H), 4,65-4,55 (m, 0,5H, PIP-H), 4,55-4,50 (m, 1H, dioxane-H), 4,50 and 4,43 (2s, 2H, benzyl-H), 4,10-was 4.02 (m, 2H, dioxane-H), 3,80-to 3.67 (m, 3,5H, PIP-H, benzyl-N, dioxane-H) to 3.45 (s, 1H, benzyl-H), 2,95-to 2.85 (m, 4H, PIP-H, NHCH2CH(CH3)2)), 2,45 to 2.35 (m, 2H, NCH2), 2,09 of 1.99 (m, 2H, dioxane-H, PIP-H), 1,91 of 1.50 (m, 7H, NCH2CH2, PIP-H, NHCH2CH(CH3)2), 1,38-1,25 (m, 2H, dioxane-H, PIP-H), and 0.98 (m, 6H, NHCH2CH(CH3)2). HPLC tR=8,2 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-propylaminoethyl)ndimethylacetamide (121JP28)

Get in the same way as described in the method of synthesis 121JP27, using Propylamine (16 mg, 230 μmol) instead of isobutylamine, receiving 24 mg (25%) 121JP28 in the form of a thick oil. L-Tartrate Sol receive, as described above.

Rf=0,33 (MeOH/CH2Cl2, 1:10). IHMS m/z 498 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,11-PC 6.82 (m, 6H), 6,53-to 6.43 (m, 2H), 4,58 figure-4.49 (m, 0,5H, PIP-H), 4,48 is 4.45 (m, 1H, dioxane-H), 4,42 and 4.35 (2s, 2H, benzyl-H), 4,05-3,95 (m, 2H, dioxane-H), 3,70-of 3.60 (m, 3,5H, PIP-H, benzyl-N, dioxane-H), 3,40 (s, 1H, benzyl-H), 3,05-2,95 (m, 2H, PIP-H), 2,85-2,70 (m, 2H, NHCH2CH2CH3), 2,48-of 2.38 (m, 2H, NCH2), 2,05-1,90 (m, 2H, dioxane-H, PIP-H), 1,92-of 1.40 (m, 8H, NCH2CH2, PIP-H, NHCH2CH2CH3), 1,40 of 1.28 (m, 2H, dioxane-H, PIP-H), and 0.98 (m, 3H, NHCH2CH2CH3). HPLC R=7,3 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(1-nitropropyl)phenyl)ndimethylacetamide (121JP34)

Adapting the methodology Vogl & Buchwald (J. Org. Chem., 2002, 67, 106-111), 121JP13 (135 mg, 0.26 mmol), 1-nitropropane (47 mg, 0.52 mmol), Cs2CO3(95 mg, 0.29 mmol), 2-di-tert-butylphosphine (15,5 mg, 52 μmol) and Pd2dba3(to 11.9 mg, 13 μmol) was placed in the flask, add DME (2 ml) and the reaction mixture stirred at 60°C for 20 hours. Treatment for 121JP13, subsequent preparative TLC (CH2Cl2/MeOH, 15:1, 10× elution) to give 22 mg (16%) 121JP34 as a thick colorless oil. L-Tartrate salt specified in the connection header receive, as described above.

Rf=0,58 (MeOH/CH2Cl2, 1:10). IHMS m/z 528 [M+H]+. HPLC tR=8,1 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(2-oxopyrrolidin-1-yl)phenyl]ndimethylacetamide (121JP31)

Adapting the methodology Yin & Buchwald (J. Amer. Chem. Soc., 2002, 124, 6043-6048), 121JP13 (124 mg, 0.24 mmol), pyrrolidone (24,7 mg, 0.29 mmol), Cs2CO3(111 mg, 0.34 mmol), Xantphos (20,8 mg, being 0.036 mmol) and Pd2dba3(11.0 mg, 0.012 mmol) is placed in a flask, add dioxane (2 ml) and the reaction mixture stirred at 90°C for 70 hours. Processing, as for 121JP13, follow-up, as for 121JP27, give 8 mg (7%) 121JP31 as a thick colorless oil. L-Tartrate Sol receive, as is isano above.

Rf=0,31 (MeOH/CH2Cl2, 1:10). IHMS m/z 524 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,60-to 6.80 (m, 8H), 4,60-4,50 (m, 0,4H, PIP-H), 4,47 (t, 1H, J=5,1, dioxane-H) 4,42 of 4.38 and (2s, 2H, benzyl-H), 4.04 the-of 3.97 (m, 2H, dioxane-H), 3,82-of 3.60 (m, 5,4H, PIP-H, dioxane-H, benzyl-H, pyrrole-H)at 3.25 (s, 1,2H, benzyl-H), 2,90-of 2.72 (m, 2H, PIP-H), 2,60-of 2.50 (m, 2H, pyrrole-H), 2,39 of-2.32 (m, 2H, NCH2) 2,18-1,90 (m, 4,2N, dioxane-H, PIP-H, pyrrole-H), 1,81-of 1.40 (m, 6H, PIP-H, NCH2CH2), 1,32-of 1.18 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=4,9 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutylphenyl)ndimethylacetamide (121JP33)

Adapting the method of Li (J. Org. Chem., 2002, 67, 3643-3650), 121JP13 (120 mg, 0,231 mmol), 2-methyl-1-propanethiol (25 mg, 0.28 mmol), [(tBu)2P(OH)]2PdCl2(11.6 mg, 0,0231 mmol) and NaOtBu (44 mg, 0.46 mmol) is placed in a flask, add toluene (2 ml) and the reaction mixture is stirred at 110°C for 16 hours. Processing, as for 121JP13, and purification, as for 121JP27, give 1.7 mg (1.4 percent) 121JP33 as a thick colorless oil. L-Tartrate salt specified in the connection header receive, as described above.

Rf=0,46 (MeOH/CH2Cl2, 1:10). IHMS m/z 529 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,24-PC 6.82 (m, 8H), 4,57-4,48 (m, 0,4H, PIP-H), 4,47 (t, 1H, J=5,1, dioxane-H), 4,45, and to 4.38 (2s, 2H, benzyl-H), 4,05-3,95 (m, 2H, dioxane-H), and 3.72 (s, 0,8H, benzyl-H), 3,70-of 3.60 (m, 2,6H, peep N, dioxane-H) 3,44 (s, 1,2H, benzyl-H), 2,87 is 2.75 (m, 2H, PIP-H), of 2.72 (t, 2H, J=6,5, SCH2 CH(CH3)2)), 2,38-of 2.28 (m, 2H, NCH2), 2,05-of 1.88 (m, 2,2H, dioxane-H, PIP-H), 1,81 is 1.48 (m, 7H, NCH2CH2, PIP-H, SCH2CH(CH3)2), 1,30-1,20 (m, 1,8H, dioxane-H, PIP-H), and 0.98 (t, 6H,J=6,7, SCH2CH(CH3)2). HPLC tR=8,8 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-itfeel)ndimethylacetamide (121JP40)

Specified in the header connection receive according to the method described above for 117NLS87-A, using 118AF52-95 (400 mg, 1,24 mmol) and 4-iodiferous acid (1.22 g, with 4.64 mmol). Processing, as for 121JP13, and purification, as for 121JP34, give 320 mg (46%) 121JP40 as a thick colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,52 (MeOH/CH2Cl2, 1:10). IHMS m/z 567 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ the 7.65 at 7.55 (m, 2H), 7,16-6,85 (m, 6H), 4,59-4,50 (m, 0,6H, PIP-H), 4,51 (t, 1H, J=5.0, dioxane-H), 4,50, and was 4.42 (2s, 2H, benzyl-H), 4.09 to 4,00 (m, 2H, dioxane-H), 3.75 to and 3,49 (2s, 2H, benzyl-H), 3,74-3,54 (m, 2,4H, PIP-H, dioxane-H), 2,85 (d, 2H, J=10,6, PIP-H), 2,41 to 2.35 (m, 2H, NCH2), 2,08-of 1.95 (m, 2,2H, dioxane-H, PIP-H), 1,88 of 1.50 (m, 6H, PIP-H, NCH2CH2), 1,39-of 1.27 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=8,6 minutes

L-Tartrate 2-(4-acetogenin)-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (121JP44)

Adapting the methodology Cacchi et al. (Org. Lett., 2003, 5, 289-293), 121JP40 (68 mg, 0.12 mmol), acetic anhydride (61 mg, 0.6 mmol), Pd2dba3(1.4 mg, 1.5 mmol), litigare (26 mg, 0.6 mmol and EtNiPr 2(31 mg, 0.24 mmol) is placed in a flask, add DMF (0.9 ml) and the resulting mixture was stirred at 100°C for 18 hours. Processing, as for 121JP13, and purification, as for 121JP34 give 19 mg (33%) 121JP44 as a thick colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,50 (MeOH/CH2Cl2, 1:10). IHMS m/z 483 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,88 for 7.78 (m, 2H), was 7.36-6,84 (m, 6H), 4,58 figure-4.49 (m, 0,4H, PIP-H), 4,48-to 4.46 (m, 1H, dioxane-H), 4,45, and to 4.38 (2s, 2H, benzyl-H), 4,05-3,95 (m, 2H, dioxane-H), 3,81, and 3,55 (2s, 2H, benzyl-H), 3,70-of 3.60 (m, 2,6H, PIP-H, dioxane-H), 2,85 is 2.75 (m, 2H, PIP-H), and 2.52 to 2.54 (2s, 3H, CH3), 2,38-of 2.27 (m, 2H, NCH2), 2,05-of 1.92 (m, 2,2H, dioxane-H, PIP-H), 1,81-of 1.45 (m, 6H, NCH2CH2, PIP-H), 1.32 to-1,22 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=5,5 minutes

L-Tartrate 2-[4-(1-hydroxyimino)phenyl]-N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)ndimethylacetamide (121JP48)

121JP44 (14 mg, 29 μmol), pyridine (4.6 mg, 58 mmol) and ethanol (5 ml) is placed in a flask, to which is added hydroxide, hydroxylamine (4,1 mg, 58 μmol)and the resulting mixture is stirred at RT for 5 hours. Processing, as for 121JP13, and purification, as for 121JP34 give 7 mg (49%) 121JP48 as a thick colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,40 (MeOH/CH2Cl2, 1:10). IHMS m/z 498 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,63-7,51 (m, 2H), 7,33-to 6.88 (m, 6H), 4,66-4,58 (who, 0,4H, PIP-H), 4,56-a 4.53 (m, 1H, dioxane-H), 4,51, and 4,40 (2s, 2H, benzyl-H), 4,10-Android 4.04 (m, 2H, dioxane-H), 3,85, and to 3.58 (2s, 2H, benzyl-H), 3,78-to 3.67 (m, 2,6H, PIP-H, dioxane-H) 2,97-and 2.83 (m, 2H, PIP-H), 2,47-is 2.37 (m, 2H, NCH2), and 2.26 2.24 (2s, 3H, CH3), 2,12-to 1.98 (m, 2,2H, dioxane-H, PIP-H), 1,88 is 1.58 (m, 6H, NCH2CH2, PIP-H), 1,37-of 1.29 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=4,0 minutes

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(morpholine-4-ylphenyl)ndimethylacetamide (121JP49)

Adapting the methodology Buchwald et al. (Org. Lett., 2002, 4, 581-584), 121JP40 (50 mg, 88 μmol), morpholine (9,2 mg, 106 μmol), CuI (1.7 mg, 8,8 mmol) and K3PO4(37.6 mg, 177 μmol) was placed in a flask in an atmosphere of air, add ethylene glycol (2 ml) and the resulting mixture was stirred at 80°C for 16 h in air atmosphere. Processing, as for 121JP13, and purification, as for 121JP34, give 4,7 mg (10%) 121JP49 as a thick colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,33 (MeOH/CH2Cl2, 1:10). IHMS m/z 526 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,18-6,72 (m, 8H), 4.62, and 4,37 (2s, 2H, benzyl-H), 4,57-4,50 (m, 0,4H, PIP-H), 4,50 was 4.42 (m, 1H, dioxane-H), 4,05-3,95 (m, 2H, dioxane-H), 3,82 of 3.75 (m, 4H, morph-N), and 3,69 3,43 (2s, 2H, benzyl-H), 3,68-3,61 (m, 2,6H, PIP-H, dioxane-H), 3,12-3,03 (m, 4H, morph-N), 2,85 is 2.75 (m, 2H, PIP-H), 2,38-of 2.27 (m, 2H, NCH2), 2,07-1,90 (m, 2,2H, dioxane-H, PIP-H), 1,82-of 1.45 (m, 6H, NCH2CH2, PIP-H), 1,30-1,22 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=6,2 minutes

L-Tartra Is N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(pyrazole-1-ylphenyl)ndimethylacetamide (121JP56)

Adapting the methodology Buchwald et al. (J. Amer. Chem. Soc., 2001, 123, 7727-7729), 121JP40 (48 mg, 85 mmol), pyrazole (7 mg, 102 μmol), CuI (0.4 mg, 1.7 mmol), racemic TRANS-1,2-cyclohexanediamine (1.0 mg, 8.5 μmol) and K2CO3(25 mg, 181 μmol) was placed in the flask, add dioxane (1.5 ml) and the resulting mixture was stirred at 110°C for 60 h of the Treatment, as for 121JP13, and purification, as for 121JP34, give 3.9 mg (9%) 121JP56 as a thick colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,27 (MeOH/CH2Cl2, 1:10). IHMS m/z 507 [M+H]+.1H-NMR (CDCl3, rotamer 0,6:0,4) δ 7,86 and of 7.82 (2D, 1H, J=2,2, Piras-N), to 7.64 (d, 1H, J=4,4, Piras-N), a 7.62-6,83 (m, 8H), 6.42 per-6,36 (m, 1H, Piras-N), 4,60 figure-4.49 (m, 0,6H, PIP-H), 4,48 (t, 1H, J=5,1, dioxane-H), 4,45, and to 4.38 (2C, 2H, benzyl-H), 4,05-3,95 (m, 2H, dioxane-H), 3,80, and 3,54 (2s, 2H, benzyl-H), 3,70-3,61 (m, 2,4H, PIP-H, dioxane-H), 2,85 is 2.75 (m, 2H, PIP-H), 2,38-of 2.28 (m, 2H, NCH2), 2,07-1,90 (m, 2,2H, dioxane-H, PIP-H), 1,82-of 1.45 (m, 6H, NCH2CH2, PIP-H), 1,35-1,22 (m, 1,8H, dioxane-H, PIP-H). HPLC tR=6,4 minutes

2-(2-Bromopropyl)-1,3-dioxane (121JP80)

Adapting the methodology Büchi and Wüest (J. Org. Chem., 1969, 34, 1122-1123), concentrated aqueous HBr (5,2 g, 64 mmol) dropwise over 5 min at 5°in an atmosphere of air added CROTONALDEHYDE (3 g, 43 mmol). After 15 min stirring at 5°With, resulting colorless mixture becomes brown, add 1,3-propandiol (8,1 g, 107 m is ol) and the reaction mixture is stirred at 5° C for an additional 0.5 h, then allowed to warm her up to CT and finally stirred at RT for 2 h and Then the crude reaction mixture is extracted with n-heptane (2×200 ml), the combined extracts n-heptane dried over Na2SO4that is evaporated in vacuum and 121JP80 allocate by vacuum distillation (75°C, 0.18 mm Hg)to give 124 mg (1.4 per cent) indicated in the title compounds as a colorless liquid.

Research data:1H-NMR (CDCl3) δ to 4.73 (DD, 1H, J=7,2, 3,4), 4,26-4,18 (m, 1H), 4,15-4,06 (m, 2H), 3,83 of 3.75 (m, 2H), 2,15-of 1.97 (m, 3H), 1,71 (d, 3H, J=6,6), 1,38-1,32 (m, 1H).

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)-1-methylethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (121JP84)

Specified in the header connection receive according to the method described above for 103NLS63-F, using 103NLS56 (202 mg, 0.51 mmol) and 121JP80 (124 mg, 0.59 mmol) as the alkylating agent. Processing, as for 121JP13, and purification, as for 121JP34, give 1.9 mg (0.7 percent) 121JP84 in the form of a thick oil. L-Tartrate Sol receive, as described above.

Rf=0,43 (MeOH/CH2Cl2, 1:10). IHMS m/z 527 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,19-to 6.80 (m, 8H), 4,50-to 4.33 (m, 3,5H, dioxane-H, benzyl-N, PIP-H), 4.04 the-3,93 (m, 2H, dioxane-H), 3.72 points-3,55 (m, 5,5H, dioxane-H, benzyl-N, PIP-H, OCH2OiBu), 3,42 (s, 1H, benzyl-H), 2,78 at 2.59 (m, 2H, PIP-H), 2,34-of 2.16 (m, 1H, NCH), 2,08-1,89 (m, 2H, PIP-H, CHOiBu), 1,79 of 0.77 (m, 17H, CH3OiBu, NCHCH3, NCHCH2, PIP-H, d is oxan-N). HPLC tR=8,5 minutes

Ethyl ester of 4-IOpenRowset acid (121JP58)

4-Iodiferous acid (3 g), ethanol (20 ml) and concentrated H2SO4(5 ml) is refluxed overnight. Then is evaporated, about 15 ml of ethanol, the residue is extracted with dichloromethane (3×100 ml), the combined organic extracts washed with saturated aqueous NaHCO3, dried over Na2SO4and evaporated in vacuum, obtaining of 2.97 g (90%) 121JP58 in the form of a yellow oil.

Research data:1H-NMR (CDCl3) δ a 7.62 (d, 2H, J=8,4), 7,02 (d, 2H, J=8,4), 4,07 (q, 2H, J=7,0)and 3.59 (s, 2H), 1,12 (t, 3H, J=7,0).

Ethyl ester of 4-pyrazole-1-altenroxel acid (121JP64)

121JP58 (290 mg, 1.0 mmol) is treated in the same way as 121JP40 for synthesis 121JP56. After heating the reaction mixture at 110°C for 72 h and processed as 121JP13 the crude mixture purified WFH (CH2Cl2/MeOH 1:0→20:1)to give 180 mg (78%) 121JP64 in the form of a yellow oil.

Research data:1H-NMR (CDCl3) δ a 7.92 (DD, 1H, J=2,3, 1,0), 7,72 (d, 1H, J=1,3), a 7.62 (d, 2H, J=8,7), 7,39 (d, 2H, J=8,7), 6.42 per (DD, 1H, J=2.5 a, 1,9), 4,18 (q, 2H, J=7,0), 3,61 (s, 2H), 1,22 (t, 3H, J=7,1).

4-Pyrazole-1-ilinishna acid (121JP68, 87)

121JP64 (180 mg, 0.78 mmol), monohydrate of lithium hydroxide (164 mg, 3.9 mmol), H2O (10 ml) and THF (10 ml) is stirred overnight at RT. Then the crude substance is extracted with dihormati is ω (3× 150 ml), the pH of the aqueous phase was adjusted to about 3 using 4M HCl, and extracted with dichloromethane (3×150 ml). The combined organic layers dried over Na2SO4, filtered and evaporated in a vacuum, getting 128 mg (81%) 121JP68 in the form of a yellow solid substance.

Research data:1H-NMR (CDCl3) δ of 7.90 (m, 1H), to 7.75 (m, 1H), 7,63 (d, 2H, J=8,6), 7,38 (d, 2H, J=8,6), of 6.45 (m, 1H), 3,68 (s, 2H).

L-Tartrate N-{1-[2-(1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-(pyrazole-1-ylphenyl)ndimethylacetamide (121JP91)

Specified in the header connection get the General procedure described above for 117NLS87-A, using 128NLS52 (87 mg, 0.27 mmol) and 121JP87 (60 mg, 0.27 mmol). Processing, as for 121JP13, and purification, as for 121JP34, give 25 mg (18%) 121JP91 in the form of a colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,34 (MeOH/CH2Cl2, 1:10). IHMS m/z 507 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ 7,92 and 7,88 (2D, 1H, J=2,2, Piras-N), 7,71 (d, 1H, J=4,7, Piras-N), 7,69-of 6.90 (m, 8H), 6,48-6.42 per (m, 1H, Piras-N)to 5.00 (d, 1H, J=6,3, dioxane-H)and 4.65 (d, 1H, J=6,4, dioxane-H), 4.63 to-4,55 (m, 0,5H, PIP-H), to 4.52 and 4,46 (2s, 2H, benzyl-H), 4,10-was 4.02 (m, 1H, dioxane-H), 3,86 and 3.57 (2s, 2H, benzyl-H), 3,78-3,55 (m, 2,5H, PIP-H, dioxane-H) 2,93-2,82 (m, 2H, PIP-H), 2,49-of 2.30 (m, 2H, NCH2), 2,10-to 1.98 (m, 1H, PIP-H), 1,90-of 1.33 (m, 9H, NCH2CH2, PIP-H, dioxane-H). HPLC tR=5,2 minutes

Tartrate N-[1-((R) - for 3,5-dihydroxyphenyl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (130AF93-18)

The desired compound synthesized from (S)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol (Moune et al. J. Org. Chem., 1997, 62, 3332-3339) and 103NLS56, using the same method as described for obtaining 130AF65-182.

Rf=0,48 (MeOH/CH2Cl2, 10:90). IHMS m/z 501 [M+H]+. HPLC tR=7,4 minutes

Tartrate N-{1-[2-((4R)-1,3-dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide (130AF95-190)

The desired compound (7.9 mg, 55%) are synthesized from 130AF93-189 (18.6 mg, 0,028 mmol), using the same method as described for obtaining 130AF67-183. Using analysis of chiral HPLC (column Chiralpak AD, 4,6×250 mm; heptane/i-D 50:50, by 0.3% DEA; 0.5 ml/min; tR=22,7 min) determines that the enantiomeric excess of 99%. Data1H-NMR and IHMS identical 130AF67-183.

4-(1,2,4-Triazole-4-yl)phenylacetic acid (141JP01)

Adapting the methodology Catarzi et al. (J. Med. Chem., 2001, 44, 3157-3165), to a suspension of 4-aminophenylarsonic acid (201 mg, of 1.33 mmol) in anhydrous pyridine add deformalization (352 mg, 4.0 mmol) and then dropwise trimethylsilane (2,53 ml, 20 mmol) and Et3N (1,30 ml, 9.3 mmol). The mixture is heated at 100°during the night, volatile components are removed under reduced pressure and the resulting solid is treated with water (6 ml), collected, washed with H2O and dried in vacuum, obtaining 251 mg (93%) 141JP01 in the form of a solid light brown substance. W is MS m/z 204 [M+H] +.1H-NMR (DMSO-d6) δ 9,05 (s, 2H), a 7.62 (d, 1H, J=8,6), 7,40 (d, 1H, J=8,2), 3,61 (s, 2H).

L-Tartrate N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)-2-[4-(1,2,4-triazole-4-yl)phenyl]ndimethylacetamide (141JP13)

Acid 141JP01 (35 mg, 0,17 mmol), N-{1-[2-(1,3-dioxane-2-yl)ethyl]piperidine-4-yl}-N-(4-terbisil)Amin (118AF52-95, 55 mg, 0,17 mmol) and diisopropylethylamine (52 mg, 0.51 mmol) dissolved in DMF (5 ml). Add hexaphosphate bromo-Tris-pyrrolidinone (PyBroP, 119 mg, 0.25 mmol) and the mixture is stirred at RT for 2 h the Mixture was concentrated and passed through an acidic ion-exchange SPE cartridge. The cartridge was washed with methanol (8×4 ml) and the remaining product to elute from the column with 10% NH4OH in methanol (2×4 ml) and evaporated. The resulting oil purified as 121JP34, receiving 47 mg (54%) 141JP13 in the form of a colorless oil. L-Tartrate Sol receive, as described above.

Rf=0,26 (MeOH/CH2Cl2, 1:10). IHMS m/z 508 [M+H]+.1H-NMR (CDCl3, rotamer 0,5:0,5) δ of 8.47 and 8.41 (2s, 1H, -H)of 7.48-6,89 (m, 8H, Ar-H), 4,62-4,56 (m, 0,6H, PIP-H), 4,56 figure-4.49 (m, 3H, dioxane-H, benzyl-H), 4,10-4,01 (m, 2H, dioxane-H), 3,79 and 3,61 (2s, 2H, benzyl-H), of 3.77-to 3.67 (m, 2,4H, PIP-H, dioxane-H), 2,94-2,84 (m, 2H, PIP-H), 2,45 to 2.35 (m, 2H, NCH2), 2,10 was 1.43 (m, 9H, dioxane-H, NCH2CH2, PIP-H), 1,37-of 1.27 (m, 1H, dioxane-H).

Determination of receptor activity in vitro

Analysis of the selection and amplification of the receptor (R-SAT)

Functionalizations analysis, Technology selection and amplification of the receptor (R-SAT™), use (with minor modifications of the methods described previously (Brann, M.R., U.S. patent 5707798, 1998; Chem. Abstr. 1998, 128, 111548), for screening compounds for efficacy in relation to 5-HT2Athe receptor. Briefly, NIH3T3 cells grown in 96-well tablets for growing tissue cultures to 70-80% confluence. Cells transferout 12-16 hours of plasmid DNA using SuperFect (Qiagen Inc.) according to the manufacturer's protocols. Usually R-SAT performed with 50 ng/well of receptor and 20 ng/well of plasmid DNA β-galactosidase. All of the receptors and G-proteins are found in the pSI, the expression vector for mammalian cells (Promega Inc.), as described previously. Gene 5-HT2Areceptor is subjected to additional internal amplification primers from cDNA brain using oligodeoxynucleotide, based on the published sequence (Saltzman et al. Biochim. Biophys Res. Comm. 1991, 181, 1469). For large-scale transpency cells transferout for 12-16 hours, then trypsinized and frozen in DMSO. Then the frozen cells are thawed, seeded capabilities from 10,000 to 40,000 cells per well in 96-well plate that contains the medicine. Then in both the way the cells are grown in a humidified atmosphere containing 5% CO2within five days. Then the medium is removed from the of lanslow and activity of the marker gene is measured, adding substrate β-galactosidase o-nitrophenyl-β-D galactopyranoside (ONPG, in PBS with 5% NP-40). The resulting colorimetric reaction was measured by spectrophotometric tablet reader (Titertek Inc.) at 420 nm. All data analyzed using the computer program XLFit (IDBSm). Efficiency is the percentage of maximum repression compared to the repression of the control connection (ritanserin in the case of 5-HT2A). pIC50represents the negative log(IC50), where IC50is the calculated molar concentration that produces 50% of maximum repression.

Definition of behavioral effects in vivo

Animals and equipment

As subjects using male mice NSA (Harlan; San Diego, Ca). The weight of mice is 20-30 Animals, placed 8/to a cell in One Cage (One Cage; Lab Products, Inc., Seaford, DE) c-litter (1/8 inch Bed ″O″ Cob; Harlan Teklad, Madison, WI) in a room with controlled temperature of 22±3°and 12-hour cycle of light : dark (light from 6 o'clock until noon). Water and standard food for rodents (Harlan Teklad) in the home cage was constantly available. For testing plastic cells to determine locomotor activity (20×20×30 cm; AccuScan Instruments, Columbus, OH) equipped with a photocell for measuring horizontal activity. Dan is haunted collect, using a computer program System (AccuScan Instruments).

Method

To determine the spontaneous activity of the tested compounds administered separately (subcutaneously for 10 minutes or orally 30 min before the session). For the experiments on hyperactivity in mice injected with injection of 0.3 mg/kg MK-801 VB. 15 minutes before the session (maximum dose to get hyperactive on inverted U-shaped dose-effect, as determined in pilot experiments) in combination with the solvent or the test compound. Data on motor activity collected within 15 min session in a lit room. Mice not subjected to testing in the cells for studies of motor activity. Each dose or combination doses tested for a separate group of mice (n=8).

Data analysis

Calculate distance traveled (cm) and average animal in the group. Analysis of variance (ANOVA) and subsequent t-test Dunnet compared with the control, representing a solvent, is carried out for each function, the dose-response. The lowest dose, which detect significantly different from the control, representing a solvent is defined as the minimum effective dose (MED).

Active connections

1. The compound of the formula I

or its pharmaceutically acceptable salt, amide or ester,

where R1represents unsubstituted heterocyclyl or heterocyclyl substituted by one or more alkyl groups, where the specified heterocyclyl selected from the group comprising tetrahydrothiopyran, tetrahydropyran, piperidine, 1,3-dioxane, 1,4-dioxane, piperazine, 1,3-axation, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazolidine, 1,3-dioxolane, 1,3-ditiolan, isoxazolidine, oxazolidine, thiazolidine and 1,3-oxathiolan;

R2and R3represent hydrogen;

m is equal to 1;

n is equal to 1;

Ar1represents unsubstituted phenyl or phenyl substituted by halogen;

W is selected from the group consisting of oxygen and sulfur;

X is selected from the group consisting of methylene and CH2N(RN), where RNrepresents hydrogen; and

Ar2represents unsubstituted phenyl or phenyl substituted by a Deputy selected from the group comprising halogen, alkyl and alkoxy;

2. The compound according to claim 1, wherein said heterocyclyl is unsubstituted.

3. The compound according to claim 1, wherein said g is eroticly selected from the group consisting of 1,3-dioxane and tetrahydropyran.

4. The compound according to claim 1, in which W represents oxygen.

5. The compound according to claim 1, in which Ar1represents a 4-substituted phenyl.

6. The compound according to claim 5, in which Ar1is a fluoro-substituted phenyl.

7. The compound according to claim 1, in which X represents methylene.

8. The compound according to claim 1, in which X represents CH2N(RN).

9. The compound according to claim 1, in which Ar2represents a 4-substituted phenyl.

10. The compound according to claim 1, in which the halogen at Ar2selected from the group consisting of bromine, chlorine, fluorine and iodine, and where the alkoxy at Ar2selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tributoxy.

11. A compound selected from the group including

oxalate of N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-N′-(4-isopropoxyphenyl)urea;

oxalate of N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

tartrate N-[1-(1,3-dioxane-5-yl)piperidine-4-yl)-N-(4-terbisil)-2-(4-isobutoxide)ndimethylacetamide;

tartrate N-[1-(2,2-dimethyl-1,3-dioxane-5-yl)piperidine-4-yl]-N-(4-terbisil)-2-(4-forfinal) ndimethylacetamide;

tartrate N-(4-terbisil)-2-(4-isobutoxy)-N-[1-(tetrahydropyran-4-yl)piperidine-4-yl]ndimethylacetamide and

tarte is at N-(4-terbisil)-2-(4-forfinal)-N-[1-(tetrahydropyran-4-yl)piperidine-4-yl]ndimethylacetamide.

12. A method of inhibiting the activity of 5-NTA serotonin receptor, comprising contacting a 5-NTA serotonin receptor with a compound according to claim 1.

13. Method of inhibiting activation of 5-NTA serotonin receptor, comprising contacting a 5-NTA serotonin receptor with a compound according to claim 1.

14. The use of the compounds of formula (I) to obtain drugs for the treatment of painful conditions associated with 5-NTA receptor.

15. The application 14, in which the disease state is selected from the group consisting of schizophrenia, schizoaffective disorder, psychosis, drug psychosis and side effects observed in the treatment of chronic neurodegenerative disorders selective inhibitor of serotonin reuptake (SSRIs).

16. The application indicated in paragraph 15, in which the specified neurodegenerative disorder selected from Alzheimer's disease, Parkinson's disease, dementia with calves Levi, fronto-temporal dementia, spinocerebellar atrophy, and Huntington disease.

17. The application 14, in which the disease state is selected from the group consisting of Raynaud's syndrome, migraine, hypertension, thrombosis, vascular spasm, ischemia, depression, anxiety, motor TIC, Tourette syndrome, dyskinesias, motor fluctuations, tremor, rigidity, bradykinesia, psychomotor process plants is to be placed, addiction, including alcoholism, opium addiction and nicotine addiction, sleep disorders, disorders of appetite, decreased libido and problems with ejaculation.

18. The application 14, which is a painful condition associated with a dysfunction of 5-NTA receptor.

19. The application 14, in which the disease state is associated with activation of 5-NTA receptor.

20. The application 14, in which the disease state is associated with increased activity of 5-NTA receptor.

21. The method according to item 12, where 5-NTA receptor is located in the Central nervous system.

22. The method according to item 12, where 5-NTA receptor is located in the peripheral nervous system.

23. The method according to item 12, where 5-NTA receptor is in the blood cells or platelets.

24. The method according to item 12, where 5-NTA receptor mutated or modified.

25. The method according to item 12, where the activity is a signaling activity.

26. The method according to item 12, where the activity is a constitutive activity.

27. The method according to item 12, where the activity associated with activation of 5-NTA receptor.

28. The method according to item 13, where the activation is performed agonistic agent.

29. The method according to p where agonistic agent is exogenous.

30. The method according to p where agonistic agent is endogenous.

31. The method according to item 13, where activation is constitutive.

32. The method according to item 13, gde-NTA receptor is located in the Central nervous system.

33. The method according to item 13, where 5-NTA receptor is located in the peripheral nervous system.

34. The method according to item 13, where 5-NTA receptor is in the blood cells or platelets.

35. The method according to item 13, where 5-NTA receptor mutated or modified.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to phthalimido-derivatives of the general formula (I): wherein X means -N= or -CH=; R1 means -CO-NR5R6, -CHR7-(CH2)n-CO-NR5R6, -(CH2)n-NR5R6, -(CH2)n-COOR8, -(CH2)n-CN, -CHR7-(CH2)n-CF3, -(CH2)n-NH-COR9, -(CH2)n-NH-COOR8, -(CH2)n-piperidinyl, -(CH2)n-morpholinyl, -(CH2)n-tetrahydrofuranyl, -(CH2)n-thiophenyl or -(CH2)n-isoxazolyl wherein a heterocyclic ring can be substituted with (C1-C6)-alkyl; -(CH2)n-phenyl wherein phenyl ring can be substituted with halogen atom or halogen-(C1-C6)-alkyl; -(CH2)p-OR8, -(CH2)p-SR8, -(CH2)p-SO-R9 or -(CH2)n-CS-NR5R6; R2 means hydrogen atom (H), (C1-C6)-alkyl, -(CH2)p-OR10, -(CH2)p-SR or benzyl; R3 means H, (C1-C6)-alkyl; R4 means halogen atom, halogen-(C1-C6)-alkyl, cyano-, (C1-C6)-alkoxy- or halogen-(C1-C6)-alkoxy-group; Each R5 and R6 means independently of one another H, (C1-C6)-alkyl; R7 means H, -OH, (C1-C6)-alkoxy-group; R8 means H, (C1-C6)-alkyl; R9 means (C1-C6)-alkyl; R10 means H, (C1-C6)-alkyl; m = 1, 2 or 3; n = 0, 1 or 2; p = 1 or 2, and their pharmaceutically acceptable salts. Compounds of the formula (I) inhibit activity of monoamine oxidase B (MAO B) that allows their using as a drug.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 4 sch, 1 tbl, 53 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel indolyl-derivatives of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkyl substituted with from one to three halogen atoms; R2 means hydrogen atom, (C1-C8)-alkyl; R3 means (C1-C8)-alkoxy-group; R4 means hydrogen atom; A means oxygen atom or sulfur atom; n = 1,2 or 3. Synthesized compounds possess agonistic activity with respect to PPARα- and/or PPARγ-receptors. Also, invention relates to methods for their synthesis, a pharmaceutical composition based on thereof and their using for preparing medicinal agents, and to a method for treatment and/or prophylaxis of diseases.

EFFECT: improved method of synthesis and treatment, valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 7 sch, 17 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means substituted or unsubstituted thiazolinyl or oxazolinyl residue; each R5 and R6 means independently hydrogen atom or protective group; X means oxygen (O), sulfur atom (S) or -NR7 wherein in each case R7 means hydrogen atom or lower alkyl; RB means in each case independently hydrogen atom, (C1-C6)-alkyl, -CY3, -CHY2 or -CH2Y wherein Y means F, Br, Cl or J. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I) and possessing cytotoxic activity, and using this compound in treatment of malignant tumor with multiple drug resistance.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R means -C(O)R1 wherein R1 is chosen from the series: (C1-C6)-alkyl, -C=CH-COOH, -NHCH2-CH2R2, -N(CH2-CH2OH)CH2-CH2OH, -N(CH3)CH2-CH2-NHCH3, -N(CH3)CH2-CH2N(CH3)CH3, saturated 4-, 5- and 6-membered cycles and saturated and unsaturated 5- and 5-membered cycles comprising at least one heteroatom from a series sulfur (S), nitrogen (N) and oxygen (O), and optionally substituted with a group chosen from the series: (C1-C6)-alkyl, -C=O-R5, -OH, (C1-C6)-alkyl substituted with hydroxy-group optionally, (C1-C6)-alkyl substituted optionally with a group of the series: -NH2, -N-(C1-C6)-alkyl, -SO2CH3, =O, and 5- and 6-membered saturated cycles comprising at least one heteroatom chosen from N and O, and wherein R5 is chosen from the series: hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkyl substituted with hydroxy-group optionally, and (C1-C6)-alkyl substituted with NH2-group optionally; R2 is chosen from the series: -N(CH3)CH3, -NH2, morpholinyl and piperazinyl; X1, X2 and X3 are chosen independently from the series: -OH, (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CH2OCH3 and -CH2OCH2CH3, or one among X1, X2 or X3 means hydrogen atom, and two others are chosen independently from the series: hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2-CH2R3, -OCH2-CF3 and -OR4, morpholylmethyl, -N(CH3)CH3, -CH2OH, -COOH, or one among X1, X2 or X3 means hydrogen atom, and two others in common with two carbon atoms including bonds between them in benzene cycle to which they are bound optionally form 5- or 6-membered saturated cycle comprising at least one heteroatom chosen from S, N and O, and wherein R3 is chosen from the series: -F, -OCH3, -N(CH3)CH3, saturated 5-membered cycle comprising at least one heteroatom N; R4 means 3-5-membered saturated cycle, and each Y1 and Y2 is chosen independently from the series: -Cl, -Br, -NO2,-C≡N and C≡N, and compound of the formula (II) also given in the invention description. Also, invention relates to a pharmaceutical composition possessing anti-proliferative activity and based on these compounds. Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 39 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 4-(phenylpiperazinylmethyl)-benzamide of the general formula (I): or their salt, or separate enantiomers and their salts wherein R1 means phenyl, pyridinyl, thienyl, furanyl, imidazolyl that can be substituted possibly; R2 means ethyl and isopropyl; R3 means hydrogen, fluorine atom; R4 means -NH2, -NHSO2R5 wherein R5 means (C1-C6)-alkyl. Compounds are useful in therapy, in particular, in treatment of pain. Also, invention describes methods for synthesis of compounds of the formula (I) and a pharmaceutical composition based on thereof.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

12 cl, 1 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel benzofuran derivatives comprising group of carbamoyl type of the formula [1]: wherein cycle Z represents group of the formula or A represents a simple bond or group of the formula -NH-; Y represents lower alkylene group, cycloalkanediyl group, phenyl group or piperidyl group; R4 and R5 are similar or different, and each represents hydrogen atom, unsubstituted lower alkyl group, lower alkyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, lower alkyl group substituted with hydroxyl group, lower alkyl group substituted with lower alkoxy group, or lower alkyl group substituted with pyridyl group; or R4 and R5 represent tetrahydropyranyl; or R4 and R are bound by ends to form in common with adjacent nitrogen atom and represent pyrrolidinyl group, morpholinyl group, pyrrolidinyl group substituted with (hydroxy)(lower alkyl) group, pyrrolidinyl group substituted with hydroxyl group, thiomorpholinyl group, piperidinyl group, piperdinyl group substituted with hydroxyl group, piperazinyl group substituted with (hydroxy)(lower alkyl) group, piperidinyl group substituted with (hydroxy)(lower alkyl) group, piperazinyl group substituted with lower alkyl group, pyrrolidinyl group substituted with lower alkoxycarbonylamino group, piperidinyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, or piperidinyl group substituted with lower alkoxycarbonyl group; R1 represents hydrogen atom, halogen atom or lower alkyl group; cycle B of the formula: represents benzene cycle optionally substituted with one or two groups chosen independently from halogen atom, optionally substituted lower alkyl group, hydroxy group, lower alkoxy group optionally substituted with alkoxycarbonyl group or amino group; carbonyl group optionally substituted with lower alkoxy group, hydroxyl group, amino group optionally substituted with 1-2 alkyl groups, morpholinyl or pyrrolidyl group; optionally substituted amino group; R3 represents hydrogen atom or lower alkyl group. Also, invention relates to it's a pharmaceutically acceptable salt that are useful as Fxa inhibitors. Also, invention relates to a pharmaceutical composition based on these compounds and their using in treatment of thrombosis.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

18 cl, 22 tbl, 143 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention proposes a method for synthesis of derivatives of piperazine, namely, N-arylpiperazines of the formula (VI): wherein R, Ar and Aryl are given in the invention claim. Method involves interaction of compound of the formula (I) with NH2R' and the following conversion of synthesized intermediate substance of the formula (II) to the end compound. Except for, invention proposes a method for synthesis of intermediate substance N1-(2'-pyridyl)-1,2-alkanediaminesulfamic acid of the formula (II) wherein R and R' have values given in the invention claim by above given the reaction scheme. Also, invention involves compound of the formula (II) and its optical isomers. Except for, invention relates to a method for synthesis of intermediate compound of the formula (V) from intermediate substance of the formula (II) and to a method for synthesis of N-arylpiperazines of the formula (VI) from intermediate compound of the formula (V). Invention provides using intermediate substance of the formula (II) for synthesis of chiral piperazine derivatives that display activity with respect to 5-HT1A receptors by the stereoselective and convergent manner.

EFFECT: improved methods of synthesis, valuable biological property of compounds.

11 cl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method for treatment.

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of nicotinamide of the general formula (I): wherein R1 is chosen from hydrogen atom, unsubstituted or substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl or heteroaryl; R2 is chosen from hydrogen atom, (C1-C6)-alkyl and group -(CH2)q-(C3-C7)-cycloalkyl, or -(CH2)mR1 and R2 in common with nitrogen atom to which they are bound form (four-six)-membered heterocyclic ring; R3 represents chlorine atom or methyl group; R4 represents group -NH-CO-R7 or -CO-NH-(CH2)q-R8; R7 is chosen from hydrogen atom, (C1-C6)-alkyl, group -(CH2)q-(C3-C7)-cycloalkyl and others; R8 is chosen from hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl and others; each X and Y is chosen independently from hydrogen atom, methyl group and halogen atom; Z represents halogen atom; m is chosen from 0,1, 2, 3 and 4; n and q are chosen from 0, 1 and 2, and to pharmaceutically acceptable salts or their solvates. Indicated compounds possess inhibitory activity with respect to p38 kinase and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 127 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes novel derivatives of the formula (I): wherein R1 are similar or different and mean hydrogen atom (H),-CN, (C1-C8)-alkyl, (C1-C8)-alkoxy-group; A means phenyl, pyrazolyl wherein each of them is bound to X through carbon atom and substituted with one or two radicals comprising (C1-C8)-alkyl, (C1-C8)-halogenalkyl; X means oxygen atom (O); R2 and R3 mean H; m means O; R6 means H, (C1-C8)-alkyl, (C1-C8)-alkylsulfonyl substituted with halogen atom; B means [(C1-C8)-alkyl]-carbonyl, [(C3-C6)-cycloalkyl]-carbonyl wherein each radical is not substituted or substituted with one or some radicals chosen from a row comprising halogen atom, (C1-C8)-alkoxy-group and [(C1-C8)-alkoxy]-carbonyl, (C1-C8)-alkylsulfonyl substituted with halogen atom, [(C2-C8)-alkenyl]-carbonyl, phenylcarbonyl substituted with one some radicals chosen from a row comprising halogen atom, (C1-C8)-alkyl and -NO2, or di-[(C1-C8)-alkyl]-aminosulfonyl, formyl or group of the formula -CO-CO-R1 wherein R1 means (C1-C8)-alkyl or phenyl-substituted [(C2-C8)-alkenyl]-carbonyl, furancarbonyl, thienylcarbonyl, halogen-substituted phenylaminocarbonyl, dimethylaminosulfonyl or group of the formula: or wherein W means oxygen or sulfur atom; T means O; R11 means unsubstituted (C1-C8)-alkyl or substituted with halogen atom; R12 and R13 are similar or different and mean H, unsubstituted (C1-C8)-alkyl, with exception for N-hydroxy-N-[(6-phenoxy-2-pyridyl)methyl]-acetamide, and a herbicide agent comprising compound of the formula (I) and accessory substances used usually in preparing agents for plants protection. Proposed compounds possess the herbicide activity and therefore they can be used agriculture.

EFFECT: valuable properties of compounds and agents.

3 cl, 2 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved preparing method.

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinoline that can be used as ligands of neuropeptide Y (NPY) receptors and being first of all as neuropeptide Y (NPY) antagonists. Invention describes compounds of the formula (I): wherein R1 means -O-R4 or -NR5R6; R2 means hydrogen atom, alkyl, alkoxy-group or halogen atom; R3 means alkyl or halogen atom; R means hydrogen atom, alkyl, phenyl, phenyl substituted with 1-3 substitutes chosen independently of one another from group comprising alkyl, cyano-group, trifluoromethyl, alkoxy-group, halogen atom, pyrrolidinylcarbonyl and nitro-group, alkoxyalkyl or heterocyclyl that means saturated or aromatic 4-10-membered heterocycle comprising one heteroatom chosen from nitrogen, oxygen atoms; R5 and R6 are chosen independently of one another from group comprising hydrogen atom, alkyl or phenyl; or R5 and R6 in common with nitrogen atom (N) to which they are added form 5-10-membered heterocyclic ring comprising nitrogen atom optionally; A1 means 5-7-membered saturated heterocyclic ring comprising nitrogen atom added to quinoline ring and the second nitrogen atom optionally and wherein ring is substituted optionally with 1-3 substitutes chosen independently of one another from group comprising alkyl, alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, tetrahydropyranyloxyalkyl and cycloalkylalkoxy-group; A2 means -CH2- or -C(O)- wherein alkyl individually or in combination means alkyl group with a direct chain that comprises 1-8 carbon atoms; and their pharmaceutically acceptable salts and alkyl esters. Also, invention describes methods for synthesis of compounds of the formula (I) and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 117 ex

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