Aminosubstituted diaryl [a, d] cycloheptane analogues as muscarinic agonists and method of treating psychoneurological disorders

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound having the structural formula I , or its pharmaceutically acceptable salt, ester or amide, where A has the structure , where each bond in A, represented by a dotted and a solid line, represents a carbon-carbon single bond; each of a, b and c is a carbon atom; each of e, f, g and h is a carbon atom; X is nitrogen; X' is C; L is absent; each n equals 1; Y is nitrogen; W is nitrogen; R1 is hydrogen; each of R2, R3 and R4 is a hydrogen atom; each of R6, R8 and R9 is a hydrogen atom; R5 is selected from a group consisting of halogen, C1-6alkyl, optionally substituted with a hydroxy group, and C1-6alkoxy; R7 is selected from a group consisting of halogen, C1-6alkyl and perhalogenalkyl; Z is selected from a group consisting of NR11, oxygen and CH2; R11 is hydrogen; and each bond in formula I, represented by a dotted and a solid line, is a carbon-carbon double bond. The invention also relates to a method for synthesis of a formula V compound, a pharmaceutical composition based on a formula I compound, methods of treating psychoneurological disorders, a pharmaceutical composition containing a formula I compound and a psychoneurological agent.

EFFECT: obtaining novel compounds useful for modulating muscarine receptor activity.

37 cl, 1 tbl, 141 ex

 

Background of invention

The technical field to which the invention relates.

Some aspects of the present invention relate to methods for treating neuropsychiatric disorders, pain and other disorders of compounds that modulate the activity of muscarinic receptors, in particular subtypes M1, and through this modulated neuronally activity associated with the development of neuropsychiatric disorders. Aspects of the invention also relates to compounds that selectively interact with this subtype receptors, and methods of identifying such compounds.

Description of the prior art

Muscarinic cholinergic receptors mediate the action of the neurotransmitter acetylcholine in the Central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs and other tissues. Muscarinic receptors play a Central role in the Central nervous system in relation to cognitive functions, as well as in peripheral nerve parasympathetic nervous system. Identified five different subtypes of muscarinic receptors m1-m5. The m1 subtype is the predominant subtype found in the cortex of the brain believed to be involved in the regulation of cognitive functions; the m2 subtype is the predominant subtype detection is applied in heart, and believed to be involved in the regulation of heart rate; suppose that m3 is involved in the stimulation of the gastrointestinal tract and urinary tract, as well as in sweating and salivation; m4 is present in the brain and may be involved in locomotion; and m5 is present in the brain and may be involved in several functions of the Central nervous system associated with the dopaminergic system.

Conditions associated with cognitive impairment, such as Alzheimer's disease, accompanied by loss of acetylcholine in the brain. I believe that this is the result of degeneration of cholinergic neurons in the basal fore brain, which innerviews region associative areas, and the hippocampus, involved in more critical processes.

Efforts to increase levels of acetylcholine focused on increasing the levels of choline is the precursor for the synthesis of acetylcholine and blocking acetylcholinesterase (AChE) is the enzyme that metabolizes acetylcholine. Introduction choline or phosphatidylcholine was not quite successful. The AChE inhibitors show some therapeutic efficacy, but may cause cholinergic side effects due to stimulation of peripheral acetylcholine, including abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and despres is this. Side effects on the gastrointestinal tract was observed in approximately one third of patients who were treated. In addition, also found that some of the AChE inhibitors, such as takin cause significant hepatotoxicity with elevated levels of transaminase in the liver observed in approximately 30% of patients. The harmful effects of AChE inhibitors limit their clinical applicability.

Also found that the known agonists, muscarinic m1, such as arecoline are weak agonists subtype m2, and m3, and is not very effective in the treatment of cognitive impairment, most likely because of the limited dose side effects.

There is a need for compounds that enhance the transmission signal or the action of acetylcholine in the brain. Specifically, there is a need in the muscarinic agonists, active against different subtypes of muscarinic receptors in the Central and peripheral nervous system. In addition, there is a need for more selective the muscarinic agonists, such as m1 or m4-selective means, both as pharmacological tools and as therapeutic agents.

The invention

The invention relates to a compound of formula I, II, or XV

or its pharmaceutically praml is my salt complex ether, amide or prodrug, where in the above formula And selected from the group consisting of

X represents nitrogen, CH or CH2; X' represents C or CH, where when X' is, there is a double bond between X and X', when X' represents CH, there is a simple relationship between X and X'; each Y is chosen, independently, from the group consisting of nitrogen, oxygen or CH; each W is chosen individually from the group consisting of nitrogen, CH, oxygen, or sulfur; each n is chosen individually from the group consisting of 0, 1, 2 3 and 4; m is chosen from the group consisting of 1, 2 and 3; each R1separately, there is no or, individually, selected from the group consisting of hydrogen, halogen, amine, optionally substituted C1-20the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-20alkenyl, optionally substituted C2-20the quinil, optionally substituted C1-20alkoxyalkyl and optionally substituted aryl and arylalkyl; L is absent or selected from the group consisting of-NH(CH2)n- and -(CH2)n-; a, b, c and d choose, each independently, from the group consisting of carbon, nitrogen, oxygen and sulfur, or each, independently, absent, provided that there are, on ENISA least three of a, b, c or d, provided that at least one of a, b, c or d represents a carbon atom, and provided that two adjacent a, b, c or d both are oxygen atoms or sulfur atoms; e, f, g and h is chosen, each independently, from the group consisting of carbon, nitrogen, oxygen and sulfur, or each, independently, absent, provided that there are at least three of e, f, g or h, provided that at least one of e, f, g or h is a carbon atom, and provided that two neighbour of e, f, g or h both are oxygen atoms or sulfur atoms; R2, R3, R4and R5choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R2and R3or R3and R4or R4and R5taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered C is calcimine, heterocyclyl or heteroaryl ring or six-membered aryl group; R6, R7, R8and R9choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R6and R7or R7and R8or R8and R9taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group; Z is chosen from the group consisting of NR11, oxygen, sulfur and CH2; R10selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted aryl, optionally substituted arylalkyl and perhalogenated the La; and R11selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil and optionally substituted arylalkyl; R12and R13choose individually from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R12and R13taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group; and any bond represented by a dashed and solid line represents a bond selected from the group consisting of simple carbon-carbon links and double carbon-carbon link; provided that the compound of formula I or XV is not clozapine or N-desmethyl what sapina.

In some embodiments, the implementation of the compound has a structure represented by formula III or IV

.

In some embodiments, the implementation of a connection selected from the group consisting of

In some embodiments, the implementation of a connection selected from the group consisting of

In some embodiments, the exercise of none of a, b, c or d is not missing. In some embodiments, the implementation of any one of e, f, g or h is not missing. In some embodiments, the implementation of a, b, c and d are carbon atom. In some embodiments, the implementation of the e, f, g and h are carbon atom. In some embodiments, the implementation of R2selected from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl and optionally substituted C1-6alkyloxy. In some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of alkyloxy selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy. In some embodiments, the implementation of a halogen selected from the group consisting of fluorine, chlorine and the Roma. In some embodiments, the implementation of R2selected from the group consisting of hydrogen, methyl, methoxy and chlorine. In some embodiments, the implementation of R3selected from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy and NO2. In some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of alkyloxy selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy. In some embodiments, the implementation of a halogen selected from the group consisting of chlorine, bromine and iodine. In some embodiments, the implementation of R3selected from the group consisting of hydrogen, methyl, methoxy, chlorine, bromine, iodine and NO2. In some embodiments, the implementation of R4selected from the group consisting of hydrogen, halogen, optionally substituted C1-6of alkyl, perhalogenated, SO2R10and NO2. In some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of perhalogenated represents a perfluoroalkyl. In some embodiments, the implementation of p is halogenated represents trifluoromethyl. In some embodiments, the implementation of a halogen selected from the group consisting of fluorine, chlorine and bromine. In some embodiments, the implementation of R10represents hydrogen or optionally substituted C1-6alkyl, where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of R4selected from the group consisting of hydrogen, methyl, fluorine, chlorine, bromine, trifloromethyl, SO2CH3and NO2. In some embodiments, the implementation of R5selected from the group consisting of hydrogen, halogen and optionally substituted C1-6of alkyl, where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, and where in some embodiments, the implementation of a halogen selected from the group consisting of fluorine, chlorine and bromine. In some embodiments, the implementation of R5represents a hydrogen or chlorine. In some embodiments, the implementation of R6represents hydrogen or optionally substituted C1-6alkyl. In some embodiments, the implementation of R6represents hydrogen. In some embodiments, the implementation of R7selected from the group consisting of hydrogen, halogen, optional the part replaced With 1-6of alkyl, perhalogenated, CN, SO2R10and NO2where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl; where in some embodiments, the implementation of a halogen selected from the group consisting of fluorine, chlorine and bromine; where in some embodiments, the implementation of perhalogenated is a perfluoroalkyl; where in some embodiments, the implementation of perfluoroalkyl represents trifluoromethyl. In some embodiments, the implementation of R10represents hydrogen or optionally substituted C1-6alkyl, where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of R7selected from the group consisting of hydrogen, methyl, chlorine, trifloromethyl, SO2CH3CN and NO2. In some embodiments, the implementation of R8selected from the group consisting of hydrogen, halogen, optionally substituted C1-6of alkyl, where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, and where in some embodiments, the implementation of a halogen selected from the group consisting of fluorine, chlorine and bromine. is some embodiments, the implementation of R 8selected from the group consisting of hydrogen, chlorine and bromine. In some embodiments, the implementation of R9selected from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl and perhalogenated; where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl; where in some embodiments, the implementation of a halogen selected from the group consisting of fluorine, chlorine and bromine; where in some embodiments, the implementation of perhalogenated is a perfluoroalkyl; where in some embodiments, the implementation of perfluoroalkyl represents trifluoromethyl. In some embodiments, the implementation of R9selected from the group consisting of hydrogen, chlorine, methyl and trifloromethyl. In some embodiments, the implementation of R1selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl and optionally substituted aryl, where in some embodiments, the implementation of the alkyl are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of R1represents hydrogen. In some embodiments, implementation of the X represents nitrogen. In some embodiments, the realization of Y is NH. In some variants of the implementation of L is absent or selected from the group consisting of-NHCH2-, -NH - and-CH2-. In some embodiments, implementation And are selected from the group consisting of

and n are selected from the group consisting of 0, 1 and 2.

This invention also relates to a method for obtaining compounds of formula V or VI

including the interaction of the compounds of formula VII

with the compound of the formula VIII

with the formation of the condensed-cyclic compound of formula IX

and the interaction of the compounds of formula IX with the compound of the formula X

with the formation of the compounds of formula V where X is a halogen; R1selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl and optionally substituted aryl and arylalkyl; R2, R3, R4and R5choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted is 2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R2and R3or R3and R4or R4and R5taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group; R6, R7, R8and R9choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R6and R7or R7and R8or R8and R9taken together with the carbon atoms of the ring to which they are attached, form a five-membered is whether the six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group.

This invention also relates to a combinatorial library of at least 220 compounds dibenzo[b,e][1,4]diazepin[a,d]cycloheptene, which can be obtained by the coupling of compounds of formula VII

with the compound of the formula VIII

and the compound of the formula X

where X is a halogen; R1selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl and optionally substituted aryl and arylalkyl; R2, R3, R4and R5choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2 R10, heteroalkyl, NO2, NHCOR10or R2and R3or R3and R4or R4and R5taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group; R6, R7, R8and R9choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R6and R7or R7and R8or R8and R9taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group.

This invention also relates to a combinatorial library of at least 220 compounds dibenzo[b,e][1,4]diazepin[a,d]cycloheptene, which can the be obtained by the interaction of the compounds of formula VII

with the compound of the formula VIII

and the compound of the formula X

where X is a halogen; R1selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl and optionally substituted aryl and arylalkyl; R2, R3, R4and R5choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R2and R3or R3and R4or R4and R5taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or hetero is rilee ring or six-membered aryl group; R6, R7, R8and R9choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10or R6and R7or R7and R8or R8and R9taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group.

This invention also relates to a pharmaceutical composition comprising a physiologically acceptable carrier, diluent or excipient or a combination thereof and the compound of formula I, II, or XV.

This invention also relates to a method for treatment of a neuropsychiatric disorder, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I, II, or XV.

This invention also relates to a method of treatment of the neuropsychiatric disorders the STS, comprising contacting a therapeutically effective amount of the compounds of formula I, II, or XV with the patient.

This invention also relates to pharmaceutical compositions containing a compound of formula I, II, or XV and neuropsychiatric tool. In some embodiments, the implementation of neuropsychiatric tool is chosen from the group consisting of a selective inhibitor of the reuptake of serotonin, an inhibitor of reuptake of norepinephrine, dopamine agonist, antagonist of muscarinic receptors, antipsychotics, antagonist of serotonin 2A and inverse agonist of the serotonin 2A. In some embodiments, the implementation of the antipsychotic agent selected from the group consisting of fenotiazina, privatelyoperated, dibenzepin, benzisoxazole and lithium salts. In some embodiments, the implementation of the phenothiazines are selected from the group consisting of chlorpromazine (Thorazine®), mezoridazina (Serentil®), prochlorperazine (Compazine®) and thioridazine (Mellaril®). In some embodiments, the implementation privatelyoperated selected from the group consisting of haloperidol (Haldol®) and pimozida (Orap®). In some embodiments, the implementation dibenzepin selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®). In some embodiments, the implementation of benzisoxazol choose the group, composed of risperidone (Resperidal®) and ziprasidone (Geodon®). In some embodiments, the implementation of the lithium salt is a lithium carbonate. In some embodiments, the implementation of the antipsychotic agent selected from the group consisting of Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Orap, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon and Zyprexa. In some embodiments, the implementation of a selective inhibitor of the reuptake of serotonin selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, ESCITALOPRAM, sibutramine, DULOXETINE, and venlafaxine, and pharmaceutically acceptable salts and prodrugs. In some embodiments, the implementation of the inhibitor of the reuptake of norepinephrine selected from the group consisting of cialisonline and reboxetine. In some embodiments, the implementation of a dopamine agonist selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zolmitriptan, cabergoline, amantadine, e.g., pergolid, ropinirole, pramipexole, and bromocriptine. In some embodiments, the implementation of the inverse agonist of the serotonin 2A is a compound of formula XIII or its related analogues.

In some embodiments, the implementation of the antagonist serotonin is a compound of formula XIV or its related analogues.

.

This invention also relates to a method for treatment of a neuropsychiatric disorder in a patient, comprising the administration to a patient a therapeutically effective amount of a pharmaceutical composition containing the compound of formula I, II, or XV and neuropsychiatric tool.

This invention also relates to a method for treatment of a neuropsychiatric disorder in a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula I, II, or XV and a therapeutically effective amount of neuropsychiatric funds. In some embodiments, the implementation stage of introducing includes introducing the compound of formula I, II, or XV and neuropsychiatric means almost simultaneously. In other embodiments, the implementation stage of introducing includes introducing the first one of the active principle from among the compounds of formula I, II, or XV and neuropsychiatric means and then the introduction of another active agent from among the compounds of formula I, II, or XV and neuropsychiatric funds. In some embodiments, the implementation of the neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, disorders of appetite, affective disorders such as major depression, bipol the RNA disorder and depression with psychotic features, and Tourette's syndrome, psychosis, caused by drugs, illness, secondary to neurological disorders such as Alzheimer's or Huntington's disease.

A detailed description of the preferred embodiments

In the first aspect of the present invention relates to a compound of formula I, II, or XV

or its pharmaceutically acceptable salt, complex ether, amide or prodrug, where in the above formulas

And are selected from the group consisting of

X represents nitrogen, CH or CH2;

X' represents C or CH, where when X' is, there is a double bond between X and X', when X' represents CH, there is a simple relationship between X and X';

each Y is chosen, independently, from the group consisting of nitrogen, oxygen, or SN;

each W is chosen individually from the group consisting of nitrogen, CH, oxygen, or sulfur;

each n choose individually from the group consisting of 0, 1, 2, 3, and 4;

m is chosen from the group consisting of 1, 2 and 3;

each R1separately, missing, or it is chosen individually from the group consisting of hydrogen, halogen, amine, optionally substituted C1-20the alkyl, optionally substituted is 3-8cycloalkyl, optionally substituted C2-20alkenyl, optionally substituted C2-20the quinil, optionally substituted C1-20alkoxyalkyl and optionally substituted aryl and arylalkyl;

L is absent or selected from the group consisting of-H(CH2)n- and -(CH2)n-;

a, b, c and d choose, each independently, from the group consisting of carbon, nitrogen, oxygen and sulfur, or each, independently, absent,

provided that there are at least three of a, b, c or d,

provided that at least one of a, b, c or d represents a carbon atom, and

provided that two adjacent a, b, c or d both are oxygen atoms or sulfur atoms;

e, f, g and h is chosen, each independently, from the group consisting of carbon, nitrogen, oxygen and sulfur, or each, independently, absent,

provided that there are at least three of e, f, g or h,

provided that at least one of e, f, g or h is a carbon atom, and

provided that two neighbour of e, f, g or h both are oxygen atoms or sulfur atoms;

R2, R3, R4and R5choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyla the si, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10,

or R2and R3or R3and R4or R4and R5taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group;

R6, R7, R8and R9choose, each independently, from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OSO2R10, heteroalkyl, NO2, NHCOR10,

or R6and R7or R7and R8or R8and R9taken together with the carbon atoms of the ring, the cat is the ring they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group;

Z is chosen from the group consisting of NR11, oxygen, sulfur and CH2;

R10selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted aryl, optionally substituted arylalkyl and perhalogenated;

R11selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil and optionally substituted arylalkyl;

R12and R13choose individually from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy, optionally substituted C2-6alkenyl, optionally substituted C2-6the quinil, optionally substituted C1-6alkoxyalkyl, optionally substituted C1-6alkylthio, perhalogenated, CN, COR10, CONHR10, NHCONHR10, SO2Other10, SO2R10, OO 2R10, heteroalkyl, NO2, NHCOR10,

or R12and R13taken together with the carbon atoms of the ring to which they are attached, form a five-membered or six-membered cycloalkyl, heterocyclyl or heteroaryl ring or six-membered aryl group.

Communication presented by a dashed and solid line represent the relationship selected from the group consisting of simple carbon-carbon links and double carbon-carbon linkages. The dotted connection between X and X' in formulas I, II and XV indicates that X and X' can connect to either a simple or a double bond.

In some embodiments, the implementation of the compound of the formula I and XV does not include clozapine or N-desmethylclozapine, the structure of which is shown below

In some embodiments, implementation of the compounds of formula I and XV Y represents nitrogen or CH. In other embodiments, implementation of the compounds of formula II, Y is nitrogen, oxygen or CH.

The term "pharmaceutically acceptable salt" refers to a form of connection, which does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by the interaction of the compounds of the invention with inorganic acids such as chlorine is standardna acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc. Pharmaceutical salts can also be obtained by the interaction of the compounds of the invention with the base with the formation of a salt such as ammonium salt, a salt of an alkali metal such as sodium or potassium salt, a salt of alkaline earth metal such as calcium or magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, Tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine etc.

The term "ester" refers to a chemical group of the formula -(R)n-COOR', where R and R' chosen, independently, from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (related through a cyclic carbon atom) and heteroalicyclic group (linked via a cyclic carbon atom), and where n is 0 or 1.

"Amide" is a chemical group of the formula -(R)n-C(O)other' or -(R)n-NHC(O)R', where R and R', independently, are selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (related through a cyclic carbon atom) and heteroalicyclic group (linked via a cyclic carbon atom), and where n is 0 or 1. Amide may also be Soboh the residue of the amino acid or peptide molecules, attached to a molecule of the present invention, and through this formed the prodrug.

Any side chain of the compounds of the present invention containing the amino, hydroxy or carboxyl group, can be atrificial or lidirovat. Methods and specific groups that are used to achieve the end result, well-known experts in this field and can be easily found in literary sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, included in this description by reference.

The term "prodrug" refers to a vehicle that turns into the original drug in vivo. Prodrugs are often used because, in some cases, they can be easier to implement than the original drug. They can be, for example, bioavailable when administered orally, while the original tool is not available. The prodrug may also have improved solubility in pharmaceutical compositions compared to the original drug. Examples of prodrugs, without limitation, may be the compound of the present invention that is administered in the form of ester (the"prodrug") to facilitate the passage of the cell membrane where water solubility is detrimental to mobility but which then metabol the Cesky hydrolyzed to the carboxylic acid - active start immediately inside the cell where water solubility is favorable. Another example of a prodrug may be a short peptide (polyaminoamide)associated with an acid group where the peptide is metabolized to form the active start.

The term "aromatic" refers to an aromatic group containing at least one ring with a system of conjugated PI-electrons, and includes both carbocyclic aryl (e.g. phenyl)and heterocyclic aryl group (e.g., pyridine). The term includes monocyclic or condensed polycyclic (i.e. cycles that share a pair of carbon atoms) groups. The term "carbocyclic" refers to a compound containing one or more covalently closed circular structures and the atoms which form the basis of the ring are all carbon atoms. Thus, the term sets the difference carbocyclic rings from heterocyclic, in which the base ring contains at least one atom different from carbon atom. The term "heteroaromatic" refers to an aromatic group that contains at least one heterocyclic ring.

Used in this description, the term "alkyl" refers to aliphatic hydrocarbon group. The alkyl group may be saturated with the Oh alkyl" group, which means that it does not contain any of alkinoos or alkyne group. An alkyl group may also be an "unsaturated alkyl" group, which means that it contains at least one alanovoy or alginovu group. The definition of "Allenova" refers to a group containing at least two carbon atoms and at least one double carbon-carbon bond, and the definition of "alkyne" refers to a group containing at least two carbon atoms and at least one triple carbon-carbon bond. Alkyl group, saturated or unsaturated, may be branched, linear or cyclic.

An alkyl group can contain 1 to 20 carbon atoms (whenever the appearance of a numeric interval, such as "1 to 20"refers to any integer in the given range; e.g., "1-20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms, although this definition also includes the introduction of the term "alkyl"where a numeric interval not specified). An alkyl group may also be an alkyl medium size with 1-10 carbon atoms. The alkyl group can also represent a lower alkyl with 1-5 carbon atoms. The alkyl group in the compounds of the invention may be referred to the AK "( 1-C4)alkyl" or similar. Just as an example, the designation "(1-C4)alkyl" indicates that the alkyl chain contains from one to four carbon atoms, i.e. an alkyl chain selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The alkyl group may be substituted or unsubstituted. When an alkyl group is substituted, the substitute(s) group(s) is(are) one or more groups selected individually and independently from cycloalkyl, aryl, heteroaryl, heteroalicyclic group, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen, carbonyl, thiocarbonyl, carbamyl, N-carbamyl, thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, Silla, trihalomethane and amino, including mono-, di - and tizanidine amino groups, and their derivatives containing protective groups. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethynyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. When the Deputy described as "optional samewe the s'", such Deputy may be substituted for one of the above substituents.

Deputy "R"appearing as such and without a numerical designation refers to the Deputy selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked via a carbon atom of the ring) and heteroalicyclic group (linked via carbon atom ring).

Group "O-carboxy" refers to the group RC(=O)O-, where R has the values specified in this specification.

Group "C-carboxy" refers to the group-C(=O)OR where R has the values specified in this specification.

"Acetyl" group is a group-C(=O)CH3.

"Trihalogenmenthanes" group is a group of X3CS(=O)2-where X is a halogen.

Group "cyano" refers to the group-CN.

Group isocyanate" is a group-NCO.

Group thiocyanato" is a group-NS.

Group isothiocyanato" is a group-NS.

"Sulfanilic" group is a group-S(=O)-R, where R has the values specified in this specification.

The group "S-sulfonamide" refers to the group-S(=O)2NR, where R has the values specified in this specification.

Group N-sulfonamide" is a group RS(=O)2NH-, where R has the values specified in this specification.

Group "trihalomethane" is a group of X3 CS(=O)2NR-, where X and R have the meanings specified in this specification.

"Karbonilnoj" group is a group-OC(=O)-NR, where R has the values specified in this specification.

"N-karbonilnoj" group is a group R(=O)NH-, where R has the values specified in this specification.

"Thiocarbamyl" group is a group-OC(=S)-NR, where R has the values specified in this specification.

"N-thiocarbamyl" group is a group R(=S)NH-, where R has the values specified in this specification.

Group "C-amido" refers to the group-C(=O)-NR2where R has the values specified in this specification.

Group "N-amido" refers to the group RC(=O)-NH-, where R has the values specified in this specification.

The term "perhalogenated" refers to an alkyl group where all hydrogen atoms are replaced by halogen atoms.

The term "arylalkyl" refers to the group RC(=O)R', where R has the values specified herein, and R' represents a divalent alkylenes group. Examples of arylalkyl, without limitation, may include CH3C(=O)CH2-, CH3C(=O)CH2CH2-, CH3CH2C(=O)CH2CH2-, CH3C(=O)CH2CH2CH2and similar groups.

Unless otherwise noted, when I assume that the Deputy is "optionally substituted"means that the Deputy PR is dstanley a group, which may be substituted by one or more groups, separately and independently, selected from among cycloalkyl, aryl, heteroaryl, heteroalicyclic group, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen, carbonyl, thiocarbonyl, carbamyl, N-carbamyl, thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, Silla, trihalomethane and amino, including mono - and disubstituted amino groups, and their derivatives containing protective groups. The protective group that can form a protected derivatives of the above substituents are known to specialists in this field, and they can be found in references such as the above-cited Greene and Wuts.

In this context it is assumed that the term "cycloalkyl" covers a three-, four-, five-, six-, seven - and eight-membered or with a large number of members ring containing only carbon atoms. Cycloalkyl optionally may contain one or more unsaturated bonds, however, arranged in such a way that the system is aromatic PI-electrons does not occur. A few examples of "cycloalkyl are carbocycle of cyclopropane, CYCLOBUTANE, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1-cyclohexadiene, 1,4-cyclohexadiene, Cycloheptane or Cycloheptane.

It is implied that the term "heterocyclyl" means three-, four-, five-, six-, seven - and eight-membered or with a large number of ring members, where the specified ring are carbon atoms with 1-3 heteroatoms. Heterocyclyl optionally may contain one or more unsaturated bonds, however, arranged in such a way that the system is aromatic PI-electrons does not occur. Heteroatoms chosen independently of the number of atoms of oxygen, sulfur and nitrogen.

Heterocyclyl may also contain one or more carbonyl or thiocarbonyl functional group, so that this definition includes exosystem and tosystem, such as lactams, lactones, cyclic imides, cyclic thioamide, cyclic carbamates, and similar systems.

Heterocyclyl ring can optionally be condensed with aryl rings, so this definition includes bicyclic structure. Specifically these condensed heterocyclyl groups have one common link with optionally substituted benzene ring. Examples benzododecinium heterocyclyl groups include, but are not limited to, cyclic patterns of benzimidazolidinone, tetrahydroquinoline and methylenedioxybenzene.

Some instances "heterocyclyl" include, but 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, pyrrolidin, 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 be through a carbon atom of the heterocycle or, in the case benzododecinium derivatives, via the carbon atom of the benzene ring.

In the present context is understood that the term "aryl" means a carbocyclic aromatic ring or rings. In addition, the term "aryl" includes condensed cyclic system where at least two aryl rings or at least one aryl and at least one3-8cycloalkyl have in common includes at least one chemical bond. Some examples of "aryl" rings include optionally alseny phenyl, naphthalenyl, phenanthrene, anthracene, tetralinyl, fluorenyl, indenyl and indanyl. The term "aryl" refers to aromatic, including, for example, a benzene group, attached through one of the forming ring carbon atoms and optionally containing one or more substituents selected from heterocyclyl, heteroaryl, halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, C1-6alkoxy, C1-6of alkyl, C1-6-hydroxyalkyl,1-6-aminoalkyl,1-6alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. The aryl group may be substituted in the para - and/or metabolite. In other embodiments, implementation of the aryl group may be substituted in anthopology. 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 the context of the present invention assumes that the term "heteroaryl" means hetero is clichesque aromatic group, where one or more carbon atoms in the aromatic ring substituted by one or more heteroatoms selected from the group consisting of nitrogen atoms, sulfur, phosphorus and oxygen.

In addition, in the context of the present invention, the term "heteroaryl" refers to a condensed cyclic systems, where 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 heterocyclyl ring or at least one heteroaryl ring and at least one cycloalkane ring have in common includes at least one chemical bond.

It is implied that the term "heteroaryl" refers to aromatic C3-8cyclic groups containing one oxygen atom or sulfur, or up to four nitrogen atoms, or a combination of one atom of oxygen or sulfur, and up to two nitrogen atoms, and their substituted and benzo - and pyridinediamine derived, for example, connected via one of the carbon atoms forming the ring. Heteroaryl group can contain one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, C1-6alkoxy, C1-6of alkyl, C1-6hydroxyalkyl,1-6aminoach the La, With1-6alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. In some embodiments, the implementation of the heteroaryl group may be a five - and six-membered aromatic heterocyclic system containing 0, 1 or 2 substituent which may be the same or different from one another, selected from the substituents listed above. Typical examples of heteroaryl groups include, but are not limited to, groups formed from unsubstituted and mono - or disubstituted furan derivatives, 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, furazane, 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-C1-6alkyl, C1-6alkyl, hydroxys1-6alkyl and amino1-6alkyl.

In some embodiments, the implementation disclosed herein, the compound is chosen from the trail of the affected structures

where R1-R9, W, Y and Z have the values listed in this description.

In some other embodiments, the implementation disclosed herein, the compound selected from the following structures

where R1, W, Y and Z have the values listed in this description.

In some embodiments, the implementation disclosed herein, the compound has a structure represented by formula III or formula IV

where R1-R5, W, X, X', Y and Z have the values listed in this description.

In some embodiments, the exercise of none of a, b, c or d is not missing, and formed in this ring is six-membered ring. In other embodiments, implementation of any one of e, f, g or h is not absent, and, therefore, formed when this ring is six-membered ring. In some embodiments, the implementation of a, b, c and d are carbon atoms, and formed when the ring is optionally substituted phenyl ring. In other embodiments, implementation of the e, f, g and h are carbon atoms, which, likewise, form a optionally substituted phenyl ring.

In some embodiments, the implementation of R2can be selected from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl and optionally substituted C1-6alkyloxy. In some embodiments, the implementation of the alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In other embodiments, implementation of alkyloxy can be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy. In other embodiments, implementation of the halogen may be selected from the group consisting of fluorine, chlorine and bromine. In some embodiments, the implementation of R2can be selected from the group consisting of hydrogen, methyl, methoxy and chlorine.

In some embodiments, the implementation of R3can be selected from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl, optionally substituted C1-6alkyloxy and NO2. The alkyl group can be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, while the alkoxy may be selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy. In other embodiments, implementation of the halogen may be selected from the group consisting of chlorine, bromine and iodine. In other embodiments, implementation of R3may be in the bran from the group consisting of hydrogen, methyl, methoxy, chlorine, bromine, iodine and NO2.

In some embodiments, the implementation of R4can be selected from the group consisting of hydrogen, halogen, optionally substituted C1-6of alkyl, perhalogenated, SO2R10and NO2. In some embodiments, the implementation of the alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In other embodiments, implementation of perhalogenated can be a perfluoroalkyl, which in some embodiments may not represent trifluoromethyl. In other embodiments, implementation of the halogen may be selected from the group consisting of fluorine, chlorine and bromine. When R4represents the SO2R10, R10can represent hydrogen or optionally substituted C1-6alkyl, which may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of R4can be selected from the group consisting of hydrogen, methyl, fluorine, chlorine, bromine, trifloromethyl, SO2CH3and NO2.

In some embodiments, the implementation of R5can be selected from the group consisting of hydrogen, halogen and optionally substituted C1-6the alkyl. Alkyl may betweren from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, while the halogen may be selected from the group consisting of fluorine, chlorine and bromine. In some embodiments, the implementation of R5can be a hydrogen or chlorine.

In some embodiments, the implementation of R6can represent hydrogen or optionally substituted C1-6alkyl. The alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of R6may represent hydrogen.

In some embodiments, the implementation of R7can be selected from the group consisting of hydrogen, halogen, optionally substituted C1-6of alkyl, perhalogenated, CN, SO2R10and NO2. The alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, while the halogen may be selected from the group consisting of fluorine, chlorine and bromine. In some embodiments, the implementation of perhalogenated represents a perfluoroalkyl, which in some embodiments may not represent trifluoromethyl. In the variants of implementation, in which R7can be a SO2R10, R10can represent hydrogen or long is Ino substituted C 1-6alkyl, which may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In some embodiments, the implementation of R7can be selected from the group consisting of hydrogen, methyl, chlorine, trifloromethyl, SO2CH3CN and NO2.

In some embodiments, the implementation of R8can be selected from the group consisting of hydrogen, halogen and optionally substituted C1-6of alkyl, where alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. The halogen may be selected from the group consisting of fluorine, chlorine and bromine. In some embodiments, the implementation of R8can be selected from the group consisting of hydrogen, chlorine and bromine.

Embodiments of the present invention include variants in which R9can be selected from the group consisting of hydrogen, halogen, optionally substituted C1-6the alkyl and perhalogenated. The alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. The halogen may be selected from the group consisting of fluorine, chlorine and bromine. Perhalogenated can be a perfluoroalkyl, which in some embodiments may not represent trifluoromethyl. In some variations the tah implementation of R 9can be selected from the group consisting of hydrogen, chlorine, methyl and trifloromethyl.

In some embodiments, the implementation of R1can be selected from the group consisting of hydrogen, optionally substituted C1-6the alkyl and optionally substituted aryl. The alkyl may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, while the aryl may be phenyl or naphthyl. In other embodiments, implementation of R1can be heteroaryl. In some embodiments, the implementation of R1may represent hydrogen. In some embodiments, the implementation of R1is missing.

In some embodiments, the realization of X can be nitrogen. In other embodiments, the realization of Y can represent NH, and W may represent a nitrogen or CH.

In some embodiments, the implementation of the compounds of formula I or formula XV L is absent or selected from the group consisting of-NHCH2-, -NH - and-CH2-. In some embodiments, the implementation of the compounds of formula I or formula XV And are selected from the group consisting of

where n is chosen from the group consisting of 0, 1 and 2.

Some of the options for the implementation of the compounds of formula I, formula II or formula XV are:

2,7-dichloro-11-(piperazin-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2,8-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-bromo-2-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin,

6-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin,

7-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-bromo-1-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-bromo-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

4,8-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-2-fluoro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

3,8-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-bromo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

3,7-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-bromo-3-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

3-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

3-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin,

7-chloro-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-methyl-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-4-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

1,8-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-bromo-5-methyl-11-(peep the Razin-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

7,8-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin,

11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-fluoro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin-8-carbonitrile,

8-bromo-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

3-fluoro-6-piperazine-1-yl-11N-dibenzo[b,e]azepin,

2-(tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-(tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]oxazepine,

8-chloro-2-(tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-(tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

11-(piperazine-1-yl)dibenzo[b,f][1,4]diazepin,

11-(piperazine-1-yl)-2,3-dihydro-1,4-benzodioxin[6,7-b][1,4]benzodiazepin,

8-chloro-11-[1,4]diazepin-1-yl-5H-dibenzo[b,e][1,4]diazepin,

N'-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine,

N'-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-diethylether-1,2-diamine,

8-chloro-11-(4-methyl[1,4]diazepam-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-2-methoxy-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

N'-(5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine,

11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepin,

N'-(8-fluoro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-NN-dimethylated-1,2-diamine,

8-fluoro-11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepin,

N'-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-mutilate-1,2-diamine,

8-chloro-11-(TRANS-2,5-dimethylpiperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(3,5-dimethylpiperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(3-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(3-phenylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-5-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-5-benzyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-iodine-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

2-iodine-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-phenyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(piperidine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(morpholine-4-yl)-5H-dibenzo[b,e][1,4]diazepin,

5-allyl-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

6-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-5-piperazine-1-yl-11N-benzo[b]pyrido[2,3-e][1,4]diazepin,

2-chloro-10-piperazine-1-yl-5H-dibenzo[b,f]azepin,

8-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]diazepin,

8-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine,

3-chloro-6-piperazine-1-yl-11N-dibenzo[b,e]azepin,

8-bromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

7-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxa who EPIN,

8-chloro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-bromo-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

7-chloro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-bromo-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

2-bromo-8-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

2,8-dibromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

2-bromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

2-bromo-7-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine,

4-methyl-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine,

8-fluoro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-fluoro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-fluoro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

2-bromo-8-fluoro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

3-methoxy-8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

4,8-dimethyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

3-methoxy-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine,

2-bromo-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine,

6-chloro-11-(piperazine-1-yl)dibenzo[b,f][,4]oxazepine,

2-bromo-8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

7-chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-phenyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,

8-chloro-11-(piperidine-4-yl)-5H-dibenzo[b,e][1,4]diazepin,

5-benzyl-8-chloro-11-(piperidine-4-yl)-5H-dibenzo[b,e][1,4]diazepin,

8-bromo-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he,

5,10-dihydrobenzo[b,e][1,4]diazepin-11-he,

8-fluoro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he,

8,5-dichloro-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin,

(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(S)-1-pyrrolidin-2-ylmethylamino,

1-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperidine-4-ylamine,

1-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)pyrrolidin-3-ylamine,

(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(R)-1-pyrrolidin-2-ylmethylamino,

(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)pyrrolidin-3-ylamine,

8-chloro-11-(2,5-diazabicyclo[2,2,1]hept-2-yl)-5H-dibenzo[b,e][1,4]diazepin,

azetidin-3-yl-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)amine,

7-bromo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin,

7-bromo-2-methyl - (piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin,

7-bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin,

7-bromo-10-(piperazine-1-yl)-1,2,3,3A,4,10A-hexahydrobenzo[b]cyclopent[e][1,4]diazepin,

8-chloro-11-(4-terbisil)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(4-forfinal)-5H-di is Enzo[b,e][1,4]diazepin,

8-chloro-11-(4-nonylphenyl)-5H-dibenzo[b,e][1,4]diazepin,

8-chloro-11-(pyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepin and

8-chloro-11-(1H-pyrazole-4-yl)-5H-dibenzo[b,e][1,4]diazepin.

In another aspect, the present invention relates to a method for obtaining compounds of formula V or formula VI

including

the interaction of the compounds of formula VII

with the compound of the formula VIII

with the formation of the condensed-cyclic compound of formula IX

and the interaction of the compounds of formula IX with the compound of the formula X

with the formation of the compounds of formula V or VI;

where X represents halogen, and R1-R9have the meanings specified in the description. In some embodiments, the implementation of the compound of formula V, synthesized according to the described method represents clozapine, while in other embodiments, the implementation of connection is a N-desmethylclozapine. In some other embodiments, the implementation of the compound of formula V, synthesized according to the described method, is not clozapine or N-desmethylclozapine.

According to this aspect of the scheme 1 and 2 depict the synthesis of certain compounds disclosed in this description is the AI. The first several stages of obtaining the intermediate lactam described, inter alia, Liao et al., in J. Med. Chem., 1997, 40, 4146-4153. The last stage is described, for example, Liao et al., in J. Med. Chem., 1999, 42, 2235-2244. Both of these references are included in this description by reference, including the drawings.

Scheme 1

Scheme 2

In some embodiments of the invention, the building blocks of a and b choose, but are not limited to specified, from among:

In another aspect, the present invention relates to a combinatorial library of at least 10, or at least 30, or at least 50 or at least 100 or at least 200, or at least 220 compounds dibenzo[b,e][1,4]diazepine, which can be obtained by the coupling of compounds of formula VII

with the compound of the formula VIII

and the compound of the formula XI

where X represents a halogen; W represents a nitrogen, CH, oxygen, or sulfur; n is 1, 2, 3 or 4, and R1-R9have the meanings specified in the description. In some embodiments, the implementation of a combinatorial library includes clozapine and/or N-desmethylclozapine. Some one is x variants of implementation of the combinatorial library does not include clozapine or N-desmethylclozapine.

In another aspect, the present invention relates to a combinatorial library of at least 10, or at least 30, or at least 50 or at least 100 or at least 200, or at least 220 compounds dibenzo[b,e][1,4]diazepine, which can be obtained by the coupling of compounds of formula VII

with the compound of the formula VIII

and the compound of the formula XII

where X represents a halogen; W represents a nitrogen, CH, oxygen, or sulfur; n is 1, 2, 3 or 4, and R1-R9have the meanings specified in this specification.

Used in this description, the term "combinatorial library" refers to all compounds obtained by the interaction between each connection of one group connection in each of the other groups in the set of several groups of compounds. In the context of the present invention, the set consists of three groups, where one group represents all of the compounds of formula VII, the second group represents all of the compounds of formula VIII and the third group represents all of the compounds of formula X. Each compound of formula VII can be subjected to interaction with any and every compound of the formula VIII and any and every compound of formula X to obtain the substituted compound form is s, V or VI. All connections included in the scope of formula V or VI, thus obtained, are included in the scope of the present invention. Also in the scope of the present invention includes combinatorial libraries smaller, obtained by the interaction of some or all of the compounds of formula VII with some or all of the compounds of formula VIII and some or all of the compounds of formula X.

In some embodiments, the implementation of the compounds of formulas I, II, or XV disclosed and described herein, may have the ability to modulate the activity of a muscarinic receptor.

The term "modulate" refers to the ability of a compound disclosed herein to alter the function of muscarinic receptor. A modulator may activate the muscarinic receptor, may activate or inhibit the activity of muscarinic receptor depending on the concentration of the compound acting on muscarinic receptor, or may inhibit the activity of the muscarinic receptor. The term "modulate" also refers to the change in the function of muscarinic receptor by increasing or decreasing the probability that between muscarinic receptor and the natural binding partner complex is formed. The modulator may increase the probability that such a complex between muscarinic receptor and a natural partner is about bonding is formed, can increase or decrease the probability that a complex is formed between the muscarinic receptor and the natural binding partner depending on the concentration of the compound acting on muscarinic receptor, and can reduce the probability that between muscarinic receptor and the natural binding partner complex is formed. In some embodiments, the implementation of the modulation of muscarinic receptor can be assessed using the technology selection and amplification of receptors (Receptor Selection and Amplification) (R-SAT), as described in U.S. patent No. 5707798 included in this description by reference.

The term "activate" refers to the increased cellular functions muscarinic receptor. The term "inhibit" refers to the weakening of the cellular function of the muscarinic receptor. The function of muscarinic receptor may be an interaction with the natural partner for the binding or catalytic activity.

The term "introduction of contact", as used herein, refers to the conversion of a compound disclosed herein, and muscarinic receptor target in such a state that the compound can affect the activity of the muscarinic receptor or directly, i.e. by interacting with muscarinic receptor, or indirectly, i.e. interacting with on the natives molecule, depends on the activity of the muscarinic receptor. Such "contacting" can be done in a test tube, Petri dish or similar. In vitro in contacting can only participate connection and interest muscarinic receptor or may participate in whole cells. Cells can also be maintained or grow in the cups for the cultivation of cells is contacted with the compound in such an environment. In this context, the ability of a compound to act on muscarinic receptor-related disorder, i.e. IC50connection, you can define up to attempt to use the compounds in vivo with more complex living organisms. For cells outside the organism, there are several well-known specialists in the field of methods contact muscarinic receptors with compounds, including direct microinjection of cells and several methods transmembrane transfer, and other methods. The term "contacting" can also refer to the conversion of a compound disclosed herein, in contact with the muscarinic receptor-targeted in vivo. Thus, if a compound disclosed herein, or a prodrug is injected into the body and the connection connects to the muscarinic receptor in the body, such contacting is included in this volume is the first invention.

In some embodiments, the implementation of the compound of formulas I, II, or XV may be an agonist of the specified receptor, while in other embodiments, implementation of the compound may be an antagonist of the specified receptor. Connection, which is a partial agonist, in some cases, it may be a partial activator of the receptor, while in other cases there may be a partial inhibitor of receptor function. In some circumstances, the connection may be a tissue-specific modulator, while in other conditions, the connection can be especificacion modulator.

Some compounds disclosed herein may exist as stereoisomers including optical isomers. In the scope of the present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers, which can be divided according to methods well known to specialists in this field.

In another aspect, the present invention relates to a pharmaceutical composition comprising a physiologically acceptable carrier, diluent or excipient or a combination thereof and the compound of formula I, II, or XV.

The term "pharmaceutical composition" refers to a mixture of compounds of the invention with other chemical components, such as dilute is whether or media. The pharmaceutical composition facilitates the introduction of the compound into the body. In this area there are many methods of introducing compounds such as oral administration, injection, aerosol, parenteral and local introduction, and other methods. The pharmaceutical composition can also be obtained by the interaction of the compounds with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc.

The term "carrier" refers to a chemical compound that facilitates the introduction of the compound into cells or tissues. For example, dimethylsulfoxide (DMSO) is the most commonly used media, as it facilitates the absorption of many organic compounds in cells or tissues of an organism.

The term "diluent" refers to a chemical compound, diluted in water that will dissolve the desired connection, as well as stabilize the biologically active form of connection. In this area as diluents use salts dissolved in buffered solutions. One of the commonly used buffered solutions is phosphate buffered saline, because of the mimics salt state human blood. As the buffer salt can adjust the pH of the solution at low concentrations, buffered diluent rarely alters the biological activity of the compounds.

The term "physiologically acceptable" refers to a carrier or diluent, which does not prevent the biological activity and properties of the connection.

The pharmaceutical compositions described in this description, you can enter the patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(AMI). The methods of preparation and administration of the compounds of the present invention can be found in "Remington''s Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, 18thedition, 1990.

Suitable routes of administration may include, for example, oral, rectal, transmucosal or putting in the introduction; parenteral delivery, including intramuscular, subcutaneous, intravenous and intramedullary injections as well as intrathecal, direct intraventricular, intraperitoneally, intranasal, or intraocular injections.

Alternatively, the connection can be entered locally and not systemically, for example, by injection of the compound directly into the renal or cardiac area, often in composition depot or slow release. In addition, medicine is a authorized tool can be entered in the targeted delivery system of the medicinal product, for example, in a liposome coated with tissue-specific antibodies. Liposomes will be directed and selectively absorbed by a particular organ.

The pharmaceutical compositions of the present invention can be obtained by a method known per se, for example, conventional methods of mixing, dissolving, granulation, production drops, grinding into powder, emulsification, encapsulation, capture and tableting.

Thus, pharmaceutical compositions for use according to the present invention can be obtained by conventional means using one or more physiologically acceptable carriers contain excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. The specific composition depends on the method of introduction. Any of the well known methods, carriers and excipients can be used as suitable and as is common in this area, see, for example, Remington's Pharmaceutical Sciences, CIT. above.

For injection means according to the invention can be obtained in the form of aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, ringer's solution, or buffered saline. For transmucosal introduction in compositions used smash the living substance, corresponding to the barrier through which penetration occurs. Such wetting agents generally known in this field.

For oral administration the compounds can be entered in the composition, simply by combining the active compounds with pharmaceutically acceptable carriers well known in this field. Such carriers contribute to the introduction of the compounds in the composition in the form of tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral administration by the patient, which is subjected to treatment. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with the pharmaceutical combination of the invention, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if necessary, to obtain core tablets or pills. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hypromellose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP). If necessary, the can is about to add dezintegriruetsja substances, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

The kernel is applied a suitable coating. For this purpose you can use concentrated sugar solutions, which optionally can contain the Arabian gum, talc, polyvinylpyrrolidone, carbopol, polyethylene glycol and/or titanium dioxide, solutions glaze and suitable organic solvents or solvent mixtures. In the coating of tablets or pills, you can add dyes or pigments to identify or characterize different combinations of doses of active compounds.

Pharmaceutical preparations which can be used orally include composite capsules made of gelatin, and also soft solid capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Composite capsules can contain the active ingredients in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricating agents such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, can be added stabilizers. All HDMI is tion for oral administration should be in dosages, suitable for such an introduction.

For transbukkalno the introduction of the compositions can take the form of tablets or pellets obtained in the usual way.

For administration by inhalation, the compounds for use according to the present invention are usually delivered in the form of an aerosol spray coming from the packages under pressure or nebulizer with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure, the unit dose can be determined by using the valve for delivering metered quantities. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator can be obtained in compositions containing a mixture of a powder of the compound and a suitable powder base, such as lactose or starch.

Connection, you can enter in the composition for parenteral administration by injection, for example by injection of a test dose of a substance, or by continuous infusion. Compositions for injection can be presented in unit dosage form, e.g., in ampoules or mnogochasovykh containers with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous medium, and may contain substances to obtain the omposite, such as suspendida, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, it is possible to obtain suspensions of the active compounds as appropriate oily suspensions for injection. Suitable lipophilic solvents or environment include fatty oils such as sesame oil, or synthetic fatty acid esters, such as etiloleat or triglycerides, or liposomes. Aqueous suspension for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or substances that increase the solubility of the compounds, to produce highly concentrated solutions.

Alternatively, the active ingredient may be in powder form to obtain a composition with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

Connections can also be entered in the composition of the rectal compositions such as suppositories or retention enemas, e.g. containing conventional bases for suppositories, such as cocoa butter or other glycerides.

In addition to the compositions described above, the connection can also be entered in the composition of the prep is the ATA-depot. These drugs for long periods can be entered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. So, for example, the compounds can enter into composition with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system containing benzyl alcohol, a nonpolar surfactant, miscible with water, the organic polymer and aqueous phase. Commonly used of the cosolvent system is a system of co-solvents VPD, which represents 3%, wt./about., a solution of benzyl alcohol, 8%, wt./about., a solution of nonpolar surfactant Polysorbate 80™ and 65%, wt./about., a solution of polyethylene glycol 300, obtained in absolute ethanol. Naturally, the proportions in the system of co-solvents may vary significantly without breaking its characteristics of solubility and toxicity. In addition, the identity of the co-solvent components may vary: for example, instead of Polysorbate 80™, you can use other low-toxicity nonpolar surfactants; may vary R is setting the log file name fraction of polyethylene glycol; the polyethylene glycol can be substituted by other biocompatible polymers such as polyvinylpyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

Alternatively, you can use other delivery systems for hydrophobic pharmaceutical compounds. Liposomes and emulsions are well known examples of media or carriers for hydrophobic drugs. You can also use some organic solvents, such as dimethylsulfoxide, although, as a rule, a possible consequence is the greater toxicity. In addition, the compounds can be delivered using systems with a slow release, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agent. A variety of materials for systems with slow release developed and well-known specialists in this field. Capsule delayed release may, depending on their chemical nature, release the compounds for a few weeks for more than 100 days. Depending on the chemical nature and the biological stability of therapeutic reagent, you can use other strategies for protein stabilization.

Many of the compounds used in the pharmaceutical combinations of the invention may be provided as salts with f is rmaceuticals compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic acid and other acids. Salts tend to be more soluble in aqueous or other protonic solvents than the corresponding form of free acids or bases.

Pharmaceutical compositions suitable for use in the present invention include compositions where the active ingredients are contained in amounts effective to achieve this goal. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or eliminate symptoms of disease or prolong the viability of the subject, which they were treated. Determination of a therapeutically effective amount may be experts in this field, particularly in the light of this detailed description.

The specific composition, the route of administration and dosage of the pharmaceutical compositions of the present invention, each physician may be selected taking into account the patient's condition (see, e.g., Fingl et al., 1975, "The Pharmacological Basis of Therapeutics", Ch. 1, p.1). Specifically, the range of doses of the composition introduced to the patient can be from about 0.5 to 1000 mg/kg of body weight of the patient. The dosage may be ADNOC atoi or entered two or more times in the course of one or several days, as required by a given patient. It should be noted that almost all of the specific compounds mentioned in the present description, set the dosage for people to ensure at least a certain state. So, in most cases, in the present invention will be used in the same dosages, or dosages that are in the range of from about 0.1% to 500%, preferably from about 25% to about 250%, from the dosage prescribed for people. If the dosage for humans is not established, as is in the case of newly developed pharmaceutical compounds, a suitable dosage can be derived from the values of the ED50or ID50or other corresponding values obtained in the in vitro or in vivo, established by studies of toxicity and efficacy in animals.

Although the exact dosage will be determined on the basis of drug action, in most cases, you can make a generalization regarding the dosage. The scheme of daily intake for an adult can be, for example, an oral dose of from 0.1 mg to 500 mg of each ingredient, preferably from 1 mg to 250 mg, for example 5 to 200 mg or an intravenous, subcutaneous or intramuscular dose of each ingredient is from 0.01 mg to 100 mg, preferably from 0.1 mg to 60 mg, for example 1-40 mg of each ingredient pharmacist is ical compositions of the present invention or its pharmaceutically acceptable salt in the calculation of the free base moreover, the composition is administered 1-4 times per day. Alternatively, compositions of the invention it is possible to introduce a continuous intravenous infusion, preferably at a dose of each ingredient to 400 mg per day. Thus, the total daily dosage by oral administration of each ingredient specifically will be in the range from 1 to 2000 mg, and the total daily dosage parenteral specifically will be in the range from 0.1 to 400 mg Appropriate will be the introduction connections for continuous treatment, for example, in the course of a week or more, or for months or years.

The number of doses and interval can be selected individually to provide plasma levels of the active agent that is sufficient to maintain the modulating action or minimal effective concentration (MONTHS). MONTHS will vary for each compound but can be estimated from data obtained in vitro. The dosage required to achieve MONTHS, will depend on individual characteristics and route of administration. However, for determination of the concentration in plasma can be used analyses by HPLC or biological analyses.

Dosing intervals can also be determined using the value of MONTHS. The composition should be entered using the scheme, which maintains plasma levels above ME is within 10-90% of the time preferably 30-90% and most preferably 50-90%.

In cases of local injection or selective absorption of the effective local concentration of the medication could not be correlated with plasma concentration.

Enter the amount of the composition will, of course, depend on characteristics of the subject, which is subjected to treatment, the mass of the subject, the severity of the disease, the route of administration and prescription of the doctor.

The composition, if necessary, can be provided on the packaging or distribution device, which may contain one or more unit dosage forms containing the active ingredient. Packaging, for example, may consist of metal foil or plastic film, such as blister packaging. Packaging or distribution device can be accompanied by instructions for administration. Packaging or distribution device may also be accompanied by a notice pinned on the packaging, in the form prescribed by the state Agency regulating the manufacture, use or sale of pharmaceuticals, which reflects the approval of the authority form of the medicinal product for use in human or veterinary medicine. Such notice, for example, can be a label containing the approval of the Management U.S. Food and Drug in addition to the public funds or on the attached product. The compositions containing the compound of the invention together with a compatible pharmaceutical carrier may also be obtained, placed in appropriately packaged and labeled for treatment of the specified condition.

In another aspect, the present invention relates to a method for treatment of a neuropsychiatric disorder in a patient, including the introduction of the indicated patient a therapeutically effective amount of the compounds of formula I or II. In some embodiments, the implementation of the neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, disorders of appetite, affective disorders such as major depression, bipolar disorder and depression with psychotic features, and Tourette's syndrome, psychosis, caused by drugs, illness, secondary to neurological disorders such as Alzheimer's or Huntington's disease.

In some embodiments, the implementation of the compound of formula I or XV represents clozapine, while in other embodiments, the implementation of connection is a N-desmethylclozapine. In some other embodiments, the implementation of the compound of formula I or XV is not clozapine or N-desmethylclozapine.

In yet another TSA is those present invention relates to a method for treatment of a neuropsychiatric disorder in a patient, comprising contacting a therapeutically effective amount of the compounds of formula I, II, or XV with the specified patient.

In some embodiments implementing the present invention relates to pharmaceutical compositions containing a compound of formula I, II, or XV and neuropsychiatric tool. Used in this description, the term "mental tool" refers to a compound or combination of compounds that affect the neurons in the brain either directly or indirectly, or acting on the signal from the neurons in the brain. Therefore, neuropsychiatric tools can affect a person's mental state, such as a person's mood, perception, nociception, cognition, mental alertness, memory, etc. In some embodiments, the implementation of neuropsychiatric tool can be selected from the group consisting of a selective inhibitor of the reuptake of serotonin, an inhibitor of reuptake of norepinephrine, dopamine agonist, antipsychotics, antagonist of serotonin 2A and inverse agonist of the serotonin 2A.

In some embodiments, the implementation of the antipsychotic agent can be selected from the group consisting of fenotiazina, privatelyoperated, dibenzepin, benzisoxazole and lithium salts. Phenothiazine group link which can be selected from the group consisting of chlorpromazine (Thorazine®), mezoridazina (Serentil®), prochlorperazine (Compazine®) and thioridazine (Mellaril®). Privatelyoperated group of compounds can be selected from the group consisting of haloperidol (Haldol®) and pimozida (Orap®). Dibenzepin group of compounds can be selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®). Benzisoxazole group of compounds can be selected from the group consisting of risperidone (Resperidal®) and ziprasidone (Geodon®). The lithium salt may be a lithium carbonate. In some embodiments, the implementation of the antipsychotic agent can be selected from the group consisting of aripiprazole (Abilify), clozapine, Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, olanzapine (Zyprexa), Orap, Permitil, Prolixin, Phenergan, quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Triaflon and Zyprexa or their pharmaceutically acceptable salts.

In some embodiments, the implementation of a selective inhibitor of the reuptake of serotonin selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, ESCITALOPRAM, sibutramine, DULOXETINE, and venlafaxine, and their pharmaceutically acceptable salts and prodrugs.

In some embodiments, the implementation of the inhibitor of the reuptake of norepinephrine selected from the group consisting of tions Cetina and reboxetine.

In other embodiments, the implementation of a dopamine agonist selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zolmitriptan, cabergoline, amantadine, e.g., pergolid, ropinirole, pramipexole and bromocriptine.

In another embodiment, the inverse agonist of the serotonin 2A is an ACP-103 or equivalent. ACP-103 is the designation of the compounds of formula XIII

In another embodiment the antagonist of the serotonin 2A is a M 110907 or equivalent. M 110907 is the designation of the compounds of formula XIV

In another aspect, the present invention relates to a method for treatment of a neuropsychiatric disorder in a patient, including the introduction of the indicated patient a therapeutically effective amount of a pharmaceutical composition containing the compounds of formula I, II, or XV and neuropsychiatric tool. In another aspect the present invention relates to a method for treatment of a neuropsychiatric disorder in a patient, including the introduction of the indicated patient a therapeutically effective amount of the compounds of formula I, II, or XV and a therapeutically effective amount of neuropsychiatric tools.

In some embodiments, the implementation of the patient is the milk of causee. The mammal may be selected from the group consisting of mice, rats, rabbits, Guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans. In some embodiments, the implementation of the patient is the man.

In some embodiments, the implementation stage of the introduction of the above methods includes the introduction of the compounds of formula I, II, or XV and specified neuropsychiatric means almost simultaneously. These implementation options are options in which the compound of formula I or II and neuropsychiatric tool are the same intended for the introduction of the composition, i.e. in a single tablet, pill or capsule, or in a single solution for intravenous injection, or in the same solution, which you can drink, or in the same drug pills or patch containing both compounds. Options for implementation include embodiments in which each connection is a separate intended for the introduction of the song, but the patient an appointment of such individual songs almost simultaneously, i.e. one pill take immediately after another, or one injection one connection do immediately after injection of another connection, etc.

In other embodiments, the implementation stage of introducing includes introducing the first one and is effective beginning from among the compounds of formula I, II, or XV and neuropsychiatric tools, and then the introduction of another active agent from among the compounds of formula I, II, or XV and neuropsychiatric funds. In such scenarios, the implementation of the patient can be entered composition containing one of the compounds, and then after some time, in a few minutes or a few hours entered another composition comprising one another connection. These implementation options also include variants in which a composition containing one of the compounds, the patient is given a regular or continuous manner, and at the same time, he occasionally gets a composition comprising another connection.

In some embodiments, the implementation of the neuropsychiatric disorder, which is subjected to treatment by the methods and compounds of the present invention, are selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, disorders of appetite, affective disorders such as major depression, bipolar disorder and depression with psychotic features, and Tourette's syndrome, psychosis, caused by drugs and psychosis secondary to neurological disorders such as Alzheimer's or Huntington's disease.

Examples

Example 1. General method 1 (A)

The mixture AMI what obenteni acid (1 EQ.), 2-peritrabecular (3 EQ.) and Cs2CO3(3 equiv.) in DMF is heated at 140aboutC for 1 hour and then left at room temperature. The mixture is diluted with water and washed with EtOAc (2×).

To the aqueous phase add EtOH and Na2S2O4(5 EQ.) and the resulting mixture is stirred for 1 hour. To the mixture of hydrochloric acid (2M), then the aqueous phase is extracted with EtOAc (3×) and the combined organic phases are concentrated.

The residue is dissolved in CH2Cl2add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3 equiv.) the resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was diluted with EtOAc, washed with aqueous solution of NaOH (2M) and concentrate.

The residue is dissolved in dioxane and 50°C is added to a mixture of TiCl4(1.1 EQ., 1M solution in toluene) and piperazine (5 EQ.) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (2M) up until the solution is acidic, and then the aqueous phase is extracted with EtOAc (2×). To the aqueous phase add an aqueous solution of NaOH (2M) up until the solution is alkaline, and the resulting suspension extracted with EtOAc (3×). The combined organic phases are concentrated and the residue purified HPLC.

Example 2. 2,dichlor-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F1)

4-Chloro-2-ftorirovannom (263 mg, 1.5 mmol) and 2-amino-5-chlorobenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and get 6,1 mg specified in the connection header (166JO85F1). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 100/85.

Example 3. 2-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F6)

2-Ftorirovannom (212 mg, 1.5 mmol) and 2-amino-5-chlorobenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and get 5.3 mg specified in the connection header (166JO85F6). MS (ESI) 313 (MH+). Purity for MN+(UV/MS) 100/95.

Example 4. 2,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F2)

5-Chloro-2-ftorirovannom (263 mg, 1.5 mmol) and 2-amino-5-chlorobenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according ON and get to 4.8 mg specified in the connection header (166JO85F2). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 99/99.

Example 5. 8-Bromo-2-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F3)

5-Bromo-2-ftorirovannom (330 mg, 1.5 mmol) and 2-amino-5-chlorobenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and get 8.0 mg specified in the connection header (166JO85F3). MS (ESI) 391 (MH+). Purity for MN+(UV/MS) 100/96.

Example 6. 2-Chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (166JO85F7)

4-Fluoro-3-nitrobenzotrifluoride (314 mg, 1.5 mmol) and 2-amino-5-chlorobenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and receive 0.3 mg specified in the connection header (166JO85F7). MS (ESI) 381 (MH+). Purity for MN+(UV/MS) 100/95.

Example 7. 6-Chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (189JO77)

3-Chloro-4-fluoro-5-nitrobenzotrifluoride (366 mg, 1.5 mmol) and 2-aminobenzoic acid (69 mg, 0.5 mmol) is subjected to interaction according OM and get 28 mg specified in the connection header (189JO77). MS (ESI) 381 (MH+). Purity for MN+(UV/MS) 99/100.

Example 8. 7-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE35)

4-Chloro-2-ftorirovannom (528 mg, 3.0 mmol) and 2-aminobenzoic acid (138 mg, 1.0 mmol) is subjected to interaction according ON and get a 5.0 mg specified in the connection header (160FE35). MS (ESI) 313 (MH+). Purity for MN+(UV/MS) 99/86.

Example 9. 8-Bromo-1-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE36)

5-Bromo-2-ftorirovannom (660 mg, 3.0 mmol) and 2-amino-6-chlorobenzoyl acid (172 mg, 1.0 mmol) is subjected to interaction according OM and produces the t 5.0 mg specified in the connection header (160FE36). MS (ESI) 391 (MH+). Purity for MN+(UV/MS) 94/87.

Example 10. 8-Bromo-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE40)

5-Bromo-2-ftorirovannom (660 mg, 3.0 mmol) and 2-amino-5-methylbenzoic acid (152 mg, 1.0 mmol) is subjected to interaction according OM and get 7.9 mg specified in the connection header (160FE40). MS (ESI) 371 (MH+). Purity for MN+(UV/MS) 100/100.

Example 11. 4,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE41)

5-Chloro-2-ftorirovannom (527 mg, 3.0 mmol) and 2-amino-3-chlorbenzoyl acid (172 mg, 1.0 mmol) is subjected to interaction according ON and get to 4.6 mg specified in the connection header (160FE41). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 95/70.

Example 12. 8-Chloro-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE41)

5-Chloro-2-ftorirovannom (527 mg, 3.0 mmol) and 2-amino-5-methylbenzoic acid (151 mg, 1.0 mmol) is subjected to interaction according OM and get 7,1 mg specified in the connection header (160FE41). MS (ESI) 327 (MH+). Purity for MN+(UV/MS) 100/94.

Example 13. 8-Chloro-2-fluoro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE42-F3)

5-Chloro-2-ftorirovannom (264 mg, 1.5 mmol) and 2-amino-5-fermenting acid (78 mg, 0.5 mmol)is subjected to interaction according OM and get 21 mg specified in the connection header (160FE42-F3). MS (ESI) 331 (MH+). Purity for MN+(UV/MS) 99/98.

Example 14. 3,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE42-F4)

5-Chloro-2-ftorirovannom (264 mg, 1.5 mmol) and 2-amino-4-chlorbenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and get 9,4 mg specified in the connection header (160FE42-F4). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 99/97.

Example 15. 2-Bromo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE43-F6)

5-Chloro-2-ftorirovannom (528 mg, 3.0 mmol) and 2-amino-5-bromobenzoyl acid (216 mg, 1.0 mmol) is subjected to interaction according OM and receive 20 mg specified in the connection header (160FE43-F6). MS (ESI) 391 (MH+). Purity for MN+(UV/MS) 100/100.

Example 16. 3,7-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE58D1)

4-Chloro-2-ftorirovannom (263 mg, 1.5 mmol) and 2-amino-4-chlorbenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and get 3,1 mg specified in the connection header (160FE58D1). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 63/83.

Example 17. 8-Bromo-3-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE58D3)

5-Bromo-2-ftorirovannom (330 mg, 1.5 mmol) and 2-amino-4-chlorbenzoyl acid (86 mg, 0.5 mmol) under the will eraut interaction according OM and get 1.1 mg specified in the connection header (160FE58D3). MS (ESI) 391 (MH+). Purity for MN+(UV/MS) 90/85.

Example 18. 3-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE58D6)

2-Ftorirovannom (212 mg, 1.5 mmol) and 2-amino-4-chlorbenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and get 2.2 mg specified in the connection header (160FE58D6). MS (ESI) 313 (MH+). Purity for MN+(UV/MS) 90/100.

Example 19. 3-Chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (160FE58D7)

4-Fluoro-3-nitrobenzotrifluoride (314 mg, 1.5 mmol) and 2-amino-4-chlorbenzoyl acid (86 mg, 0.5 mmol) is subjected to interaction according OM and receive 2.0 mg specified in the connection header (160FE58D7). MS (ESI) 313 (MH+). Purity for MN+(UV/MS) 100/100.

Example 20. 7-Chloro-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE581)

4-Chloro-2-ftorirovannom (263 mg, 1.5 mmol) and 2-amino-5-methylbenzoic acid (76 mg, 0.5 mmol) is subjected to interaction according OM and get 1.1 mg specified in the connection header (160FE581). MS (ESI) 327 (MH+). Purity for MN+(UV/MS) 100/90.

Example 21. 2-Methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE586)

4-Ftorirovannom (212 mg, 1.5 mmol) and 2-amino-5-methylbenzoic acid (76 mg, 0.5 mmol) experience the t interaction according ON and get to 6.8 mg specified in the connection header (160FE586). MS (ESI) 293 (MH+). Purity for MN+(UV/MS) 100/100.

Example 22. 2-Methyl-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (160FE587)

4-Fluoro-3-nitrobenzotrifluoride (314 mg, 1.5 mmol) and 2-amino-5-methylbenzoic acid (76 mg, 0.5 mmol) is subjected to interaction according OM and get 1.2 mg specified in the connection header (160FE587). MS (ESI) 361 (MH+). Purity for MN+(UV/MS) 100/85.

Example 23. 8-Chloro-4-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE74)

5-Chloro-2-ftorirovannom (1.06 g, 6.0 mmol) and 2-amino-3-methylbenzoic acid (302 mg, 2.0 mmol) is subjected to interaction according ON and get to 4.8 mg specified in the connection header (160FE74). MS (ESI) 327 (MH+). Purity for MN+(UV/MS) 97/90.

Example 24. 1,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (203FE03)

5-Chloro-2-ftorirovannom (1.06 g, 6.0 mmol) and 2-amino-6-chlorobenzoyl acid (343 mg, 2.0 mmol) is subjected to interaction according OM and get 3,1 mg specified in the connection header (203FE03). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 100/99.

Example 25. 8-Bromo-5-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO32)

5-Bromo-2-ftorirovannom (580 mg, 2.6 mmol) and N-methylanthranilic acid (200 mg, 1 mmol) is subjected to interaction according OM and get 1.6 mg specified in the connection header (166JO32). MS (ESI) 371 (MH+). Purity for MN+(UV/MS) 90/74.

Example 26. General method 2 (A)

The mixture aminobenzoic acid (1 EQ.), 2-peritrabecular (3 EQ.) or 2-chloronitrobenzene (3 EQ.) and Cs2CO3(3 equiv.) in DMF is heated at 140°C for 1 hour and then left at room temperature. The mixture is diluted with water and washed with EtOAc (2×).

To the aqueous phase add EtOH and Na2S2O4(5 EQ.) and the resulting mixture is stirred for 1 hour. To the mixture of hydrochloric acid (2M), then the aqueous phase is extracted with EtOAc (3×) and the combined organic phases are concentrated.

The residue is dissolved in xylene and the mixture was stirred at 130°C during the night. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrate.

The residue is dissolved in dioxane and 50°C is added to a mixture of TiCl4(1.1 EQ., 1M solution in toluene) and piperazine (5 EQ.) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (2M) up until the solution is acidic, and then the aqueous phase is extracted with EtOAc (2×). To the aqueous phase add an aqueous solution of NaOH (2M) up until the solution is alkaline, and the resulting suspension extracted with EtOAc (3×). United'or is adicheskie phase is concentrated and the residue purified HPLC.

Example 27. 7,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO28)

1,2-Dichloro-4-fluoro-5-nitrobenzene (1.26 g, 6.0 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according OM and receive 16 mg specified in the connection header (166JO28). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 99/96.

Example 28. 11-(Piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (166JO23)

4-Fluoro-3-nitrobenzotrifluoride (1,25 g, 6 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according OM and receive 12 mg specified in the connection header (166JO23). MS (ESI) 347 (MH+). Purity for MN+(UV/MS) 81/98.

Example 29. 11-(Piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19)

2-Ftorirovannom (847 mg, 6.0 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according OM and receive 16 mg specified in the connection header (160FE19). MS (ESI) 279 (MH+). Purity for MN+(UV/MS) 100/100.

Example 30. 8-Fluoro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19)

2.5-Diplomarbeit (955 mg, 6.0 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according ON and get a 8.9 mg specified in the connection header (160FE19). MS (ESI) 297 (MH+ ). Purity for MN+(UV/MS) 99/97.

Example 31. 11-(Piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin-8-carbonitrile (160FE19D)

4-Chloro-3-nitrobenzene (1.10 g, 6.0 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according OM and get 4,7 mg specified in the connection header (160FE19D). MS (ESI) 304 (MH+). Purity for MN+(UV/MS) 100/86.

Example 32. 8-Bromo-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19)

5-Bromo-2-ftorirovannom (1,32 g, 6.0 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according OM and receive 15 mg specified in the connection header (160FE19). MS (ESI) 357 (MH+). Purity for MN+(UV/MS) 100/100.

Example 33. 8-Methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19F)

4-Chloro-3-nitrotoluene (1,03 g, 6.0 mmol) and 2-aminobenzoic acid (274 mg, 2 mmol) is subjected to interaction according OM and get 1.6 mg specified in the connection header (160FE19F). MS (ESI) 293 (MH+). Purity for MN+(UV/MS) 70/70.

Example 34. General method 3 (A)

To the derived N-methylpiperazine (0.1 mmol)dissolved in THF (2 ml)at 10°C was added 1-chloroethylphosphonic (17 mg, 0.12 mmol). Then the mixture is refluxed for 18 hours. The temperature decrease is remove the THF under reduced pressure. Then the remaining oil is added methanol and the mixture is shaken at 65°C for 2 hours. The methanol is removed under reduced pressure and the remaining crude reaction product is purified HPLC.

Example 35. 3-Fluoro-6-piperazine-1-yl-11N-dibenzo[b,e]azepin (160FE02)

3-Fluoro-6-(4-methylpiperazin-1-yl)-11N-dibenzo[b,e]azepin (31 mg, 0.1 mmol) is subjected to interaction according OM and receive 8 mg specified in the title compound, isolated as a salt of oxalate (160FE02). MS (ESI) 296 (MH+). Purity for MN+(UV/MS) 99/100.

Example 36. 2-(Tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE13)

2-(Tripterocalyx)-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (39 mg, 0.1 mmol) is subjected to interaction according OM and receive 3.0 mg specified in the connection header (160FE13). MS (ESI) 427 (MH+). Purity for MN+(UV/MS) 95/98.

Example 37. 2-(Tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]oxazepine (160FE13)

2-(Tripterocalyx)-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]oxazepine (39 mg, 0.1 mmol) is subjected to interaction according OM and get 11 mg specified in the connection header (160FE13). MS (ESI) 428 (MH+). Purity for MN+(UV/MS) 98/100.

Example 38. 8-Chloro-2-(who referenceservice)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE13)

8-Chloro-2-(tripterocalyx)-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (42 mg, 0.1 mmol) is subjected to interaction according OM and get 3.2 mg specified in the connection header (160FE13). MS (ESI) 461 (MH+). Purity for MN+(UV/MS) 100/100.

Example 39. 8-(Tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE13D)

8-(Tripterocalyx)-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (39 mg, 0.1 mmol) is subjected to interaction according OM and get 2.2 mg specified in the connection header (160FE13D). MS (ESI) 427 (MH+). Purity for MN+(UV/MS) 100/100.

Example 40. General method 4 (OM4)

To a mixture of TiCl4(1.1 EQ., 1M solution in toluene) and amine (0.5 mmol) in dioxane at 50°C or to a mixture of TiCl4(2.2 EQ., 1M solution in toluene) and amine (1.0 mmol) in dioxane at 50°C, add a mixture of the corresponding lactam (0.1 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the aqueous mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases are concentrated and the residue purified HPLC.

<> Example 41. 11-(Piperazine-1-yl)-dibenzo[b,f][1,4]diazepin (160FE17)

10H-Dibenzo[b,f][1,4]diazepin-11-he (23 mg, 0.1 mmol) and piperazine (43 mg, 0.5 mmol) is subjected to interaction according OM4 and get 3,1 mg specified in the connection header (160FE17). MS (ESI) 296 (MH+). Purity for MN+(UV/MS) 97/90.

Example 42. 11-(Piperazine-1-yl)-2,3-dihydro-1,4-benzodioxin[6,7-b][1,4]benzodiazepin (160FE17)

2,3-Dihydro-1,4-benzodioxin[6,7-b][1,4]benzodiazepin-11(N)-(29 mg, 0.1 mmol) and piperazine (43 mg, 0.5 mmol) is subjected to interaction according OM4 and get 1.9 mg specified in the connection header (160FE17). MS (ESI) 354 (MH+). Purity for MN+(UV/MS) 99/95.

Example 43. 8-Chloro-11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepin (160FE16)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and homopiperazine (50 mg, 0.5 mmol) is subjected to interaction according OM4 and receive 12 mg specified in the connection header (160FE16). MS (ESI) 327 (MH+). Purity for MN+(UV/MS) 99/93.

Example 44. N'-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine (160FE16D)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and N,N-dimethylethylenediamine (44 mg, 0.5 mmol) is subjected to interaction according OM4 and receive a 20 mg is shown in the connection header (160FE16D). MS (ESI) 315 (MH+). Purity for MN+(UV/MS) 100/100.

Example 45. N'-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-diethylether-1,2-diamine (160FE16)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and N,N-diethylethylenediamine (58 mg, 0.5 mmol) is subjected to interaction according OM4 and get 3.9 mg specified in the connection header (160FE16). MS (ESI) 343 (MH+). Purity for MN+(UV/MS) 99/94.

Example 46. 8-Chloro-11-(4-methyl[1,4]diazepam-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE16F)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and 1-methylhomopiperazine (57 mg, 0.5 mmol) is subjected to interaction according OM4 and get 5,7 mg specified in the connection header (160FE16F). MS (ESI) 341 (MH+). Purity for MN+(UV/MS) 100/100.

Example 47. 8-Chloro-2-methoxy-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE20)

8-Chloro-2-methoxy-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (28 mg, 0.1 mmol) and piperazine (86 mg, 1.0 mmol) is subjected to interaction according OM4 and obtain 19 mg specified in the connection header (160FE20). MS (ESI) 342 (MH+). Purity for MN+(UV/MS) 99/100.

Example 48. N'-(5H-Dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine (160FE20)

5,10-Dihydrobenzo[b,e][1,4]diazepin-11-he (160FE15A) (21 mg, 0,mmol) and N,N-dimethylethylenediamine (88 mg, 1.0 mmol) is subjected to interaction according OM4 and get to 7.6 mg specified in the connection header (160FE20). MS (ESI) 281 (MH+). Purity for MN+(UV/MS) 100/100.

Example 49. 11-[1,4]Diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepin (160FE20)

5,10-Dihydrobenzo[b,e][1,4]diazepin-11-he (160FE15A) (21 mg, 0.1 mmol) and homopiperazine (100 mg, 1.0 mmol) is subjected to interaction according OM4 and receive 12 mg specified in the connection header (160FE20). MS (ESI) 293 (MH+). Purity for MN+(UV/MS) 95/95.

Example 50. N'-(8-Fluoro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine (160FE20D)

8-Fluoro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (160FE15) (23 mg, 0.1 mmol) and N,N-dimethylethylenediamine (88 mg, 1.0 mmol) is subjected to interaction according OM4 and get 11 mg specified in the connection header (160FE20D). MS (ESI) 299 (MH+). Purity for MN+(UV/MS) 100/100.

Example 51. 8-Fluoro-11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepin (160FE20)

8-Fluoro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (160FE15) (23 mg, 0.1 mmol) and homopiperazine (100 mg, 1.0 mmol) is subjected to interaction according OM4 and obtain 19 mg specified in the connection header (160FE20). MS (ESI) 311 (MH+). Purity for MN+(UV/MS) 100/100.

Example 52. N'-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-mutilate-1,2-diamine (160FE22)/u>

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and N-methylethylenediamine (74 mg, 1.0 mmol) is subjected to interaction according OM4 and get to 7.6 mg specified in the connection header (160FE22). MS (ESI) 301 (MH+). Purity for MN+(UV/MS) 92/83.

Example 53. 8-Chloro-11-(TRANS-2,5-dimethylpiperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE33)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and TRANS-2,5-dimethylpiperazine (114 mg, 1.0 mmol) is subjected to interaction according OM4 and get 1.9 mg specified in the connection header (160FE33). MS (ESI) 341 (MH+). Purity for MN+(UV/MS) 100/100.

Example 54. 8-Chloro-11-(3,5-dimethylpiperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE33)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and 2,6-dimethylpiperazine (114 mg, 1.0 mmol) is subjected to interaction according OM4 and get 18 mg specified in the connection header (160FE33). MS (ESI) 341 (MH+). Purity for MN+(UV/MS) 100/100.

Example 55. 8-Chloro-11-(3-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE38)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and 2-methylpiperazine (100 mg, 1.0 mmol) is subjected to interaction according OM4 and receive 30 mg specified in the header is connected to the I (160FE38). MS (ESI) 327 (MH+). Purity for MN+(UV/MS) 100/89.

Example 56. 8-Chloro-11-(3-phenylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE45)

8-Chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (25 mg, 0.1 mmol) and 2-phenylpiperazin (162 mg, 1.0 mmol) is subjected to interaction according OM4 and get 27 mg specified in the connection header (160FE45). MS (ESI) 389 (MH+). Purity for MN+(UV/MS) 100/89.

Example 57. 8-Chloro-5-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (189JO25)

To a mixture of 8.5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160F64) (50 mg, 0,19 mmol) and toluene (1.5 ml) in DMF (0.5 ml) is added NaH (12 mg, 0.29 mmol, 60% in mineral oil). Then add MeI (24 μl, 0.38 mmol). The resulting mixture was stirred for 1 hour and then the reaction quenched by adding saturated aqueous solution of NaHCO3(2 ml). The mixture is extracted with diethyl ether, the combined organic phases are dried (Na2SO4) and concentrate. The residue is dissolved in toluene (2.0 ml), added piperazine (98 mg, 1.1 mmol) and the resulting mixture was stirred at 100°C for 1 hour. Then added to the mixture of hydrochloric acid (1 ml, 2M) and EtOAc (2 ml). The phases are separated, the aqueous phase is extracted with EtOAc (2 ml) and then added an aqueous solution of NaOH (2 ml, 2M). The alkaline aqueous phase is extracted with EtOAc (3×2 ml), the combined organic phases are dried(Na 2SO4) and concentrate. The residue is dissolved in DMF, purified HPLC and get 34 mg specified in the connection header (189JO25). MS (ESI) 327 (MH+). Purity for MN+(UV/MS) 100/100.

Example 58. 8-Chloro-5-benzyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE46-PIPBN)

8,5-Dichloro-5H-dibenzo[b,e][1,4]diazepin (160F46) (51 mg, 0.20 mmol) and benzylbromide (68 mg, 0.4 mmol) is subjected to interaction as described in example 57, and get to 8.4 mg specified in the connection header (160FE46-PIPBN). MS (ESI) 403 (MH+). Purity for MN+(UV/MS) 100/100.

Example 59. 8-Iodine-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO38)

A mixture of 8-bromo-5,10-dihydrobenzo[b,e][1,4]diazepin-11-she (166JO31) (60 mg, 0.21 mmol), NaI (62 mg, 0.42 mmol), N,N-dimethylethylenediamine (2,2 μl, 0,021 mmol) and CuI (2 mg, 0.42 mmol) in dioxane (1 ml) is heated in a sealed tube for 3 days. The reaction mixture is cooled to room temperature, the mixture is then contribute in a column of ion exchange resin SCX-2, the reaction product elute CH2Cl2and obtain 49 mg of the intermediate 8-idletime. Intermediate intacta (20 mg, to 0.060 mmol) in dioxane (1 ml) at 50°C is added to a mixture of TiCl4(of 0.13 ml, 0.13 mmol, 1M solution in toluene) and piperazine (0,051 g to 0.60 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave is at room temperature. To the mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases are concentrated. The residue is purified HPLC and get to 4.1 mg specified in the connection header (166JO38). MS (ESI) 405 (MH+). Purity for MN+(UV/MS) 100/100.

Example 60. 2-Iodine-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO54)

2-Bromo-8-chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (intermediate compound according to the method A) (30 mg, 0.09 mmol) is subjected to interaction as described in example 59, and get 7,0 mg specified in the connection header (166JO54). MS (ESI) 439 (MH+). Purity for MN+(UV/MS) 100/100.

Example 61. 8-Phenyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (189JO53)

To a mixture of 8-bromo-5,10-dihydrobenzo[b,e][1,4]diazepin-11-she (166JO31) (30 mg, 0.12 mmol), benthivorous acid (18 mg, 0.15 mmol) and K2CO3(34 mg, 0.24 mmol) in obeskislorozhennaja a mixture of toluene/EtOH/H2O (1.5 ml) is added tetrakis(triphenylphosphine)palladium(0) (catalytic amount) and the resulting mixture was stirred at 80°C during the night. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrate the receive crude 8-vanillacream. Intermediate vanillacream in dioxane (1 ml) at 50°C is added to a mixture of TiCl4(of 0.24 ml, 0.24 mmol, 1M solution in toluene) and piperazine (0,103 g, 1.2 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases contribute in a column of ion exchange resin SCX-2. The column was washed with Meon, then the reaction product elute NH3(7h. the solution in the Meon), concentrated and the residue purified HPLC and receive 16 mg specified in the connection header (189JO53). MS (ESI) 355 (MH+). Purity for MN+(UV/MS) 100/100.

Example 62. 8-Chloro-11-(piperidine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO69)

To the crude 8-chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (90 mg, purity 50%, 0,218 mmol) in pyridine (2 ml) is added piperidine (37 mg, 0.44 mmol) and the resulting mixture heated in a sealed tube at 160°C for 10 hours the Mixture is concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc, 8:1-6:1) and receive 12 mg specified in the connection header (166JO69). MS (ESI) 312 (MH+). Purity for MN+(UV/MS) 100/100.

Example 63. 8-Chloro-11-(morpho is in-4-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO69)

The crude 8-chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (90 mg, purity 50%, 0,218 mmol) and morpholine are interaction, as described in example 62, and get 11 mg specified in the connection header (166JO69). MS (ESI) 314 (MH+). Purity for MN+(UV/MS) 100/98.

Example 64. 5-Allyl-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO68)

To a mixture of 8-chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-she (500 mg, 2.0 mmol) and dioxane (10 ml) is added To tert-Ovi (343 mg, 3.1 mmol), the mixture was stirred at 60°C for 1 hour, then cooled to room temperature, add p-methoxybenzylamine (0,42 ml, 3.1 mmol) and the resulting mixture was stirred at 40°C for 2 h the Reaction is quenched by adding Meon (2 ml). The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc, 4:1-3:1) and receive the intermediate p-methoxybenzylidene lactam (732 mg), purity 85%, which is used in the next stage without additional purification.

To a mixture of p-methoxybenzylidene of lactam (100 mg, 0.27 mmol) and DMF (2 ml) is added NaH (16 mg, 0.41 mmol, 60% in mineral oil), the mixture was heated to 60°C. and then left at room temperature the re. Add allylbromide (36 μl, 0.41 mmol), the mixture was stirred at room temperature for 3 hours, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc, 8:1-4:1) and concentrate. The residue is dissolved in triperoxonane acid (4 ml), the mixture was stirred at room temperature overnight and then at 45°C for 2 hours. The mixture is concentrated and the residue is subjected to chromatography (SiO2, heptane:EtOAc, 8:1-4:1) and concentrate. The residue is dissolved in toluene (2 ml) and add N,N-dimethylaniline (48 μl, 0.38 mmol) and POCl3(35 μl, 0.38 mmol). The resulting mixture was stirred at 100°C for 2 hours and then concentrated. The residue is dissolved in dioxane, added piperazine (65 mg, from 0.76 mmol) and the resulting mixture was stirred at 100°C for 3 hours. To the mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases are concentrated. The residue is purified HPLC and get 17 mg specified in the connection header (166JO68). MS (ESI) 353 (MH+). Purity for MN+(UV/MS) 99/88.

Example 65. 6-Chloro-11-(piperazine-1-yl)-5H-DIB is the site, located between[b,e][1,4]diazepin (189JO68)

A mixture of methyl-2-aminobenzoate (454 mg, 3.0 mmol), 3-chloro-2-peritrabecular (352 mg, 2 mmol) and Cs2CO3(0,78 g, 2.4 mmol) in DMF (4 ml) was stirred at 140°C for 2 hours.

The mixture is diluted with EtOAc, washed with 2M aqueous solution NaH (2×5 ml), dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2the system toluene:heptane:EtOAc) and concentrated. The residue is dissolved in THF (10 ml), add 1M aqueous LiOH solution (5 ml), the mixture was stirred at 80°C for 1 hour and then left at room temperature. Add 2M hydrochloric acid to pH 2. The aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×). The combined organic phases are dried (Na2SO4) and concentrate. The residue is dissolved in EtOH, add the mixture To a2CO3(to 1.38 g, 10 mmol) and Na2S2O4(1,74 g, 10 mmol) in water and the resulting mixture is stirred for 1 hour. The mixture is diluted with water, washed with 2M aqueous solution NaH (2×5 ml), then dried (Na2SO4) and concentrate.

The residue is dissolved in CH2Cl2and add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (307 mg, 1.6 mmol). The resulting mixture was stirred at room temperature for 1 hour. CME is ü diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc, 2:1) and receive the intermediate lactam.

Intermediate lactam is dissolved in dioxane and 50°C is added to a mixture of TiCl4(0,19 ml to 0.19 mmol, 1M solution in toluene) and piperazine (73 mg, 0.85 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture add hydrochloric acid (1 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×1 ml). To the aqueous phase add an aqueous solution of NaOH (2 ml, 2M) and the resulting suspension extracted with EtOAc (3×1 ml). The combined organic phases are concentrated and the residue purified HPLC and get 9,8 mg specified in the connection header (189JO68). MS (ESI) 313 (MH+). Purity for MN+(UV/MS) 100/98.

Example 66. 8-Chloro-5-piperazine-1-yl-11N-benzo[b]pyrido[2,3-e][1,4]diazepin (166JO63)

To a mixture of 5-chloro-2-nitroaniline (345 mg, 2 mmol) and pyridine (162 μl, 2 mmol) in dioxane was added 1-chloronicotinamide (352 mg, 2 mmol) and the resulting mixture was stirred at room temperature for 2 hours the Mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue crystallized from Meon and receive 271 mg p is Megalochori of diarylamino. To a mixture of intermediate diarylamino (100 mg, 0.32 mmol) and EtOH (0.5 ml) is added the mixture To a2CO3(220 mg, 1.6 mmol) and Na2S2O4(278 mg, 1.6 mmol) in water (0.5 ml) and the resulting mixture is stirred for 1 hour at room temperature. The mixture is concentrated and the residue is dissolved in EtOAc/H2O and the layers separated. The organic phase is dried (Na2SO4) and concentrate. The residue is dissolved in xylene and heated at 130°C. overnight, then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc) and receive the intermediate lactam. Intermediate lactam is dissolved in dioxane and 50°C is added to a mixture of TiCl4(187 μl, 0,187 mmol, 1M solution in toluene) and piperazine (73 mg, 0.85 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture add hydrochloric acid (1 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×2 ml). To the aqueous phase add an aqueous solution of NaOH (2 ml, 2M) and the resulting suspension extracted with EtOAc (3×1 ml). The combined organic phases are concentrated and the residue purified HPLC and receive 20 mg specified in the connection header (166JO63). MS (ESI) 314 (MH+). Purity for MN+(UV/MS) 100/99.

Example 67. 2-Chloro-10-piperaz the n-1-yl-5H-dibenzo[b,f]azepin (189JO39)

To a mixture of 2-chloro-5-(4-methoxybenzyl)-5,11-dihydrobenzo[b,f]azepin-11-she (189JO27) (150 mg, 0.41 mmol) and CH2Cl2(10 ml) in an atmosphere of Ar at -75°C add TiCl4(of 0.60 ml of 0.60 mmol, 1M solution in toluene) and the resulting mixture is stirred for 1 hour. The mixture is diluted with saturated aqueous NH4Cl and CH2Cl2leave at room temperature and separated phases. The aqueous phase is extracted with CH2Cl2(1×10 ml), the combined organic phases are dried (Na2SO4) and concentrate and get the crude reaction product containing a protective group (90 mg, 90%), which is used in the next stage without additional purification.

To a solution of TiCl4(of 0.18 ml, 0.18 mmol, 1M solution in toluene) and piperazine (283 mg, 3.3 mmol) in dioxane (4 ml) at 50°C add the crude product containing a protective group (80 mg, 0.33 mmol)and the resulting suspension stirred at 100°C for 1.5 hours. The mixture is left at room temperature, then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (Al2About3CH2Cl2:MeOH, 1:0-25:1) and obtain 64 mg (63%) specified in the connection header (189JO39). MS (ESI) 312 (MH+). Purity for MN+(UV/MS) 97/95.

Example 68. 8-Chloro-11-(p is perazin-1-yl)dibenzo[b,f][1,4]diazepin (189JO16)

To a mixture of 8-chloro-10H-dibenzo[b,f][1,4]diazepin-11-she (189JO13) (38 mg, 0.15 mmol) and N,N-dimethylaniline (46 μl, 0.36 mmol) in toluene added POCl3(27 μl, 0.29 mmol), the mixture is stirred for 2 hours at 100°C and then concentrated. Add toluene (2 ml) and piperazine (62 mg, 0.73 mmol), the mixture was stirred at 100°C for 3 hours and then left at room temperature. To the mixture add hydrochloric acid (1 ml, 2M) and then the aqueous phase is extracted with EtOA (2×2 ml). To the aqueous phase add an aqueous solution of NaOH (3 ml, 2M) and the mixture was extracted with EtOAc (3×3 ml). The combined organic phases are concentrated and the residue purified HPLC and get 6.6 mg specified in the connection header (189JO16). MS (ESI) 330 (MH+). Purity for MN+(UV/MS) 99/98.

Example 69. 8-Chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO31)

A mixture of 8-chloro-10H-dibenzo[b,f][1,4]oxazepine-11-she (189JO29) (17 mg, 0,069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (16 mg, 0.040 mmol) in toluene (2 ml) is heated in a sealed tube using a microwave oven (130°C, 20 minutes). The reaction mixture is cooled to room temperature, add MeI (18 μl, 0.29 mmol) and the resulting mixture heated in a sealed tube using a microwave oven (120°C, 20 minutes). mesh concentrate, the residue is dissolved in pyridine (2 ml) and added piperazine (25 mg, 0.29 mmol). The resulting mixture was heated in a sealed tube at 130°C overnight and then using a microwave oven (160°C, 30 minutes). The mixture is concentrated, diluted with EtOAc and washed with water. The organic phase contribute in a column of ion exchange resin SCX-2. The column was washed with Meon, then the reaction product elute NH3(7h. the solution in the Meon) and get 9.0 mg (57%) specified in the connection header (189JO31). MS (ESI) 314 (MH+). Purity for MN+(UV/MS) 92/100.

Example 70. 8-Chloro-11-(4-methylpiperidin-1-yl)dibenzo[b,f][1,4]oxazepine (189JO47)

A mixture of 8-chloro-10H-dibenzo[b,f][1,4]oxazepine-11-she (189JO29) (30 mg, 0,069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (29 mg, 0.040 mmol) in toluene (2 ml) is heated in a sealed tube using a microwave oven (130°C, 20 minutes). The reaction mixture is cooled to room temperature, add MeI (38 μl, 0.29 mmol) and the resulting mixture heated in a sealed tube using a microwave oven (120°C, 20 minutes). The mixture is concentrated and the residue is dissolved in pyridine (2 ml) and added piperazine (24 mg, 0.29 mmol). The resulting mixture was heated in a sealed tube at 130°C overnight and then heated using a microwave oven (160°C, 30 minutes). The mixture is concentrated, Rabba is given in EtOAc and washed with water. The organic phase is dried (Na2SO4), concentrated and subjected to flash chromatography (SiO2, toluene:EtOAc:MeOH, 4:2:0 - 2:2:1) and get a 8.9 mg specified in the connection header (189JO47). MS (ESI) 328 (MH+). Purity for MN+(UV/MS) 98/93.

Example 71. 3-Chloro-6-piperazine-1-yl-11N-dibenzo[b,e]azepin (189JO60)

3-Chloro-5,11-dihydrobenzo[b,e]azepin-6-he (189JO59) (25 mg, 0.1 mmol) and piperazine are interacting according OM4 and get 2.2 mg specified in the connection header (189JO60). MS (ESI) 312 (MH+). Purity for MN+(UV/MS) 100/100.

Example 72. General method 5 (A)

A mixture of methyl ester of aminobenzoic acid (2.0 mmol), 2-peritrabecular (1.0 mmol) and Cs2CO3(0.65 g, 2.0 mmol) in DMF (4 ml) was stirred at 40°C for 2 hours the Mixture is diluted with EtOAc (10 ml) and washed with 2M aqueous NaOH solution (2×5 ml).

The EtOAc phase add EtOH, N2A, C2CO3(0,69 g, 5 mmol) and Na2S2O4(0.87 g, 5 mmol) and the resulting mixture was vigorously stirred for 1 hour. The aqueous phase is removed, the organic phase is washed with 1M aqueous NaOH solution (2×5 ml) and then concentrated.

The residue is dissolved in DMF (1 ml), add toluene (4 ml) and NaH (60 mg, 1.5 mmol, 60% in mineral oil), the mixture was stirred at 80°C overnight and then the reaction quenched by adding saturated aqueous races the thief NH 4Cl. The resulting mixture was diluted with EtOAc, washed with 2M aqueous NaOH solution (2×5 ml), dried (Na2SO4) and concentrate. The residue is dissolved in dioxane and 50°C is added to a mixture of TiCl4(1.1 ml, 1.1 mmol, 1M solution in toluene) and piperazine (0,41 g, 5 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases are dried (Na2SO4), concentrated and the residue purified HPLC.

Example 73. 8-Bromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO48)

5-Bromo-2-ftorirovannom (220 mg, 1 mmol) and methyl-2-hydroxybenzoate (304 mg, 2 mmol) is subjected to interaction according OM and receive 36 mg specified in the connection header (189JO48). MS (ESI) 358 (MH+). Purity for MN+(UV/MS) 96/82.

Example 74. 11-(Piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO48)

2-Ftorirovannom (141 mg, 1 mmol) and methyl-2-hydroxybenzoate (304 mg, 2 mmol) is subjected to interaction according OM and get 5.2 mg specified in the connection header (189JO48). MS (ESI) 280 (MH+). Purity for MN+(UV/MS) 99/99.

Example 75. 7-Chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)

4-Chloro-2-ftorirovannom (175 mg, 1 mmol) and methyl-2-hydroxybenzoate (304 mg, 2 mmol) is subjected to interaction according OM and get 17 mg specified in the connection header (189JO50). MS (ESI) 314 (MH+). Purity for MN+(UV/MS) 100/100.

Example 76. 8-Chloro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)

5-Chloro-2-ftorirovannom (175 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) is subjected to interaction according ON and get to 6.8 mg specified in the connection header (189JO50). MS (ESI) 344 (MH+). Purity for MN+(UV/MS) 94/86.

Example 77. 8-Bromo-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50D)

5-Bromo-2-ftorirovannom (220 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) is subjected to interaction according OM and get 14 mg specified in the connection header (189JO50D). MS (ESI) 388 (MH+). Purity for MN+(UV/MS) 100/100.

Example 78. 3-Methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)

2-Ftorirovannom (141 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) is subjected to interaction according OM and receive 33 mg specified in the header Conn is in (189JO50). MS (ESI) 310 (MH+). Purity for MN+(UV/MS) 100/100.

Example 79. 7-Chloro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50F)

4-Chloro-2-ftorirovannom (175 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) is subjected to interaction according OM and gain of 6.7 mg specified in the connection header (189JO50F). MS (ESI) 344 (MH+). Purity for MN+(UV/MS) 98/96.

Example 80. 8-Chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)

5-Chloro-2-ftorirovannom (175 mg, 1 mmol) and methyl 2-hydroxy-3-methylbenzoate (332 mg, 2 mmol) is subjected to interaction according OM and get 34 mg specified in the connection header (189JO50). MS (ESI) 328 (MH+). Purity for MN+(UV/MS) 100/100.

Example 81. 8-Bromo-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51)

5-Bromo-2-ftorirovannom (220 mg, 1 mmol) and methyl 2-hydroxy-3-methylbenzoate (332 mg, 2 mmol) is subjected to interaction according OM and receive 20 mg specified in the connection header (189JO51). MS (ESI) 372 (MH+). Purity for MN+(UV/MS) 100/100.

Example 82. 4-Methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51)

2-Ftorirovannom (141 mg, 1 mmol) and methyl 2-hydroxy-3-methylbenzoate (332 mg, 2 mmol) is subjected to inter is under the influence of OM and get 1.8 mg specified in the connection header (189JO51). MS (ESI) 294 (MH+). Purity for MN+(UV/MS) 99/98.

Example 83. 2-Bromo-8-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51D)

5-Chloro-2-ftorirovannom (175 mg, 1 mmol) and methyl 5-bromo-2-hydroxybenzoate (462 mg, 2 mmol) is subjected to interaction according OM and get 21 mg specified in the connection header (189JO51D). MS (ESI) 392 (MH+). Purity for MN+(UV/MS) 100/100.

Example 84. 2,8-Dibromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51)

5-Bromo-2-ftorirovannom (220 mg, 1 mmol) and methyl 5-bromo-2-hydroxybenzoate (462 mg, 2 mmol) is subjected to interaction according OM and receive 0.7 mg specified in the connection header (189JO51). MS (ESI) 436 (MH+). Purity for MN+(UV/MS) 94/99.

Example 85. 2-Bromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51F)

2-Ftorirovannom (142 mg, 1 mmol) and methyl 5-bromo-2-hydroxybenzoate (462 mg, 2 mmol) is subjected to interaction according OM and receive 10 mg specified in the connection header (189JO51F). MS (ESI) 358 (MH+). Purity for MN+(UV/MS) 95/99.

Example 86. 2-Bromo-7-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51G)

4-Chloro-2-ftorirovannom (175 mg, 1 mmol) and methyl 5-bromo-2-hydroxybenzoate (462 mg, 2 mmol) is subjected to interaction according ON andget 17 mg specified in the connection header (189JO51G). MS (ESI) 392 (MH+). Purity for MN+(UV/MS) 100/100.

Example 87. 11-(Piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO54)

2-Fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol) and methyl-2-hydroxybenzoate (304 mg, 2 mmol) is subjected to interaction according OM and obtain 19 mg specified in the connection header (189JO54). MS (ESI) 348 (MH+). Purity for MN+(UV/MS) 100/100.

Example 88. 4-Methyl-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO54)

2-Fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol) and methyl 2-hydroxy-3-methylbenzoate (332 mg, 2 mmol) is subjected to interaction according OM and receive 15 mg specified in the connection header (189JO54). MS (ESI) 362 (MH+). Purity for MN+(UV/MS) 100/100.

Example 89. 8-Fluoro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54)

2.5-Diplomarbeit (159 mg, 1 mmol) and methyl-2-hydroxybenzoate (304 mg, 2 mmol) is subjected to interaction according OM and get 14 mg specified in the connection header (189JO54). MS (ESI) 298 (MH+). Purity for MN+(UV/MS) 100/100.

Example 90. 8-Fluoro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54F)

2.5-Diplomarbeit (159 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) were subjected is deystviy according OM and get 9,8 mg specified in the connection header (189JO54F). MS (ESI) 328 (MH+). Purity for MN+(UV/MS) 100/100.

Example 91. 8-Fluoro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54G)

2.5-Diplomarbeit (159 mg, 1 mmol) and 2-hydroxy-3-methylbenzoate (332 mg, 2 mmol) is subjected to interaction according OM and get 9,8 mg specified in the connection header (189JO54G). MS (ESI) 312 (MH+). Purity for MN+(UV/MS) 100/100.

Example 92. 2-Bromo-8-fluoro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54)

2.5-Diplomarbeit (159 mg, 1 mmol) and methyl 5-bromo-2-hydroxybenzoate (462 mg, 2 mmol) is subjected to interaction according OM and get 11 mg specified in the connection header (189JO54). MS (ESI) 376 (MH+). Purity for MN+(UV/MS) 100/100.

Example 93. 8-Methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO58)

4-Fluoro-3-nitrobenzene (155 mg, 1 mmol) and methyl-2-hydroxybenzoate (304 mg, 2 mmol) is subjected to interaction according OM and receive 24 mg specified in the connection header (189JO58). MS (ESI) 294 (MH+). Purity for MN+(UV/MS) 100/98.

Example 94. 3-Methoxy-8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO58)

4-Fluoro-3-nitrobenzene (155 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) is subjected to interaction according OM and p is to obtain 27 mg specified in the connection header (189JO58). MS (ESI) 324 (MH+). Purity for MN+(UV/MS) 100/98.

Example 95. 4,8-Dimethyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO58)

4-Fluoro-3-nitrobenzene (155 mg, 1 mmol) and methyl 2-hydroxy-3-methylbenzoate (332 mg, 2 mmol) is subjected to interaction according OM and receive 24 mg specified in the connection header (189JO58). MS (ESI) 308 (MH+). Purity for MN+(UV/MS) 100/98.

Example 96. 3-Methoxy-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO62)

4-Fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol) and methyl 2-hydroxy-4-methoxybenzoate (364 mg, 2 mmol) is subjected to interaction according OM and receive 12 mg specified in the connection header (189JO62). MS (ESI) 378 (MH+). Purity for MN+(UV/MS) 100/95.

Example 97. 2-Bromo-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO62)

2-Fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol) and methyl 5-bromo-2-hydroxybenzoate (462 mg, 2 mmol) is subjected to interaction according OM and get 11 mg specified in the connection header (189JO62). MS (ESI) 426 (MH+). Purity for MN+(UV/MS) 100/100.

Example 98. 6-Chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO69)

3-Chloro-2-ftorirovannom (352 mg, 2 mmol) and methyl-2-hydroxybenzoate (453 mg, 3 mmol) was subjected to the Ute interaction according OM and obtain 57 mg specified in the connection header (189JO69). MS (ESI) 314 (MH+). Purity for MN+(UV/MS) 100/100.

Example 99. General method 6 (A)

A mixture of methyl ester of aminobenzoic acid (1.0 mmol), 2-peritrabecular (0.5 mmol) and Cs2CO3(0.33 g, 1.0 mmol) in DMF (3 ml) was stirred at 40°C for 2 hours the Mixture is diluted with EtOAc (10 ml) and washed with 2M aqueous NaOH solution (2×5 ml), dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2the system toluene:heptane:EtOAc) and concentrated. The residue is dissolved in THF (4 ml), add 1M aqueous LiOH solution (3 ml), the mixture was stirred at 80°C for 1 hour and then left at room temperature. Add 2M hydrochloric acid up until the pH reaches 2. The aqueous phase is extracted with EtOAc (3×). The combined organic phases are dried (Na2SO4) and concentrate. The residue is dissolved in EtOH, add the mixture To a2CO3(0,359 g, 2.55 mmol) and Na2S2O4(of 0.44 g, 2.5 mmol) in water and the resulting mixture is stirred for 1 hour. The mixture is diluted with water, washed with 1M aqueous NaOH solution (2×5 ml) and then dried (Na2SO4) and concentrate.

The residue is dissolved in CH3CN and add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (143 mg, 0.75 mmol), hydroxybenzotriazole hydrate (160 mg, 0.75 mmol), triethylamine (311 μl, 2.25 mmol) and N,N-dimethylamino ridin (catalytic amount). The resulting mixture was heated in a sealed tube using a microwave oven (140°C, 10 min). The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrate. The residue is dissolved in dioxane and 50°C is added to a mixture of TiCl4(with 0.55 ml, 0.55 mmol, 1M solution in toluene) and piperazine (0,22 g, 2.5 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases are concentrated and the residue purified HPLC.

Example 100. 8-Bromo-8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO63)

4-Fluoro-3-nitrotoluene (78 mg, 0.5 mmol) and methyl 5-bromo-2-hydroxybenzoate (231 mg, 1 mmol) is subjected to interaction according A and 13 mg specified in the connection header (189JO63). MS (ESI) 372 (MH+). Purity for MN+(UV/MS) 100/100.

Example 101. 7-Chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO63)

4-Chloro-2-ftorirovannom (88 mg, 0.5 mmol) and methyl 2-hydroxy-3-methylbenzoate (166 mg, 1 mmol) is subjected to interaction according OM and the floor is up 24 mg specified in the connection header (189JO63). MS (ESI) 328 (MH+). Purity for MN+(UV/MS) 100/100.

Example 102. 8-Phenyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO64)

To a mixture of 8-bromo-10H-dibenzo[b,f][1,4]oxazepine-11-she (189JO56) (30 mg, 0.12 mmol), benthivorous acid (18 mg, 0.15 mmol) and K2CO3(34 mg, 0.24 mmol) in obeskislorozhennaja a mixture of toluene/EtOH/H2O (1.5 ml) is added tetrakis(triphenylphosphine)palladium(0) (catalytic amount) and the resulting mixture heated in a sealed tube using a microwave oven (140°C, 15 min). The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrate, and get the crude 8-vanillacream. A mixture of intermediate 8-phenylacetate and dioxane (1 ml) at 50°C is added to a mixture of TiCl4(of 0.27 ml, 0.27 mmol, 1M solution in toluene) and piperazine (0,103 g, 1.2 mmol) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (3 ml, 2M) and then the aqueous phase is extracted with EtOAc (2×4 ml). To the aqueous phase add an aqueous solution of NaOH (6 ml, 2M) and the resulting suspension extracted with EtOAc (3×3 ml). The combined organic phases contribute in a column of ion exchange resin SCX-2. The column was washed with Meon, then the reaction product elute NH3(7h. the solution in the Meon), the solution to the end of tryout, the residue is purified HPLC and receive 16 mg specified in the connection header (189JO64). MS (ESI) 356 (MH+). Purity for MN+(UV/MS) 100/99.

Example 103. 8-Chloro-11-(piperidine-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE67)

To a solution of 8.5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (106 mg, 0.4 mmol) and PdCl2(PPh3)2(18 mg, 0.04 mmol) in dry THF (2 ml) at 50°C add 4-CBZ-piperidineacetic (obtained from 4-CBZ-piperidylidene (345 mg, 1.0 mmol) using metallic zinc and dibromethane) (0.8 mmol). The reaction mixture was shaken for 16 h and then the reaction quenched by adding aqueous saturated solution of NH4Cl. The resulting mixture was twice extracted with ether, the combined ether phases are washed with brine and dried (Na2SO4). Filtration followed by concentration of the organic phase under reduced pressure to give the crude reaction product. To the crude product dissolved in CH2Cl2(1 ml), at -30°C add BBr3(100 ál). Then the temperature of the reaction mixture is gradually raised to 0°C. TLC shows complete conversion of the original substance, and to the reaction mixture successively added Et3N, H2O and EtOAc. The organic phase is washed with brine and dried (Na2SO4). Filtration followed by concentration under reduced pressure the AI give the crude reaction product, which cleanse HPLC and get to 2.3 mg specified in the connection header (160FE67). MS (ESI) 312 (MH+). Purity for MN+(UV/MS) 99/96.

Example 104. 5-Benzyl-8-chloro-11-(piperidine-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE67)

Named the title compound (4.4 mg) was isolated as a side product of the synthesis in example 102. MS (ESI) 402 (MH+). Purity for MN+(UV/MS) 85/87.

Example 105. General method 7 (A)

A mixture of 2-aminobenzoic acid (1 EQ.), 2-peritrabecular (2 EQ. or 3 equiv.) and K2CO3(3 equiv.) in DMF is heated at 100°C for 2 hours and then left at room temperature. The organic phase is extracted with 0.1m aqueous NaOH solution (3×). The combined aqueous phases are acidified with 4M hydrochloric acid and extracted with EtOAc (3×). The combined organic phases are dried (Na2SO4) and concentrate. The residue is dissolved in EtOH, add a solution To a2CO3(5 EQ.) and Na2S2O4(5 EQ.) in water and the resulting mixture is stirred for 1 hour. The mixture is concentrated and the residue dissolved in EtOAc. The mixture is acidified with hydrochloric acid (2M), then the aqueous phase is extracted with EtOAc (3×) and the combined organic phases are concentrated.

The residue is dissolved in xylene and the mixture was stirred at 130°C during the night. The mixture is diluted with EtOAc, the industry is with saturated aqueous NaHCO 3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2the system heptane:EtOAc).

Example 106. 8-Bromo-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (166JO31)

5-Bromo-2-ftorirovannom (1.6 g, 7.4 mmol) and 2-aminobenzoic acid (0.50 g, 3.6 mmol) is subjected to interaction according OM and get 331 mg specified in the connection header (166JO31). MS (ESI) 289 (MH+). Purity for MN+(UV) 93%.

Example 107. 5,10-Dihydrobenzo[b,e][1,4]diazepin-11-he (160FE15)

2-Ftorirovannom (847 mg, 6 mmol) and 2-aminobenzoic acid (274 mg, 2.0 mmol) is subjected to interaction according OM and get 130 mg specified in the connection header (160FE15).

Example 108. 8-Fluoro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-he (160FE15)

2,4-Diplomarbeit (0.96 g, 6 mmol) and 2-aminobenzoic acid (274 mg, 2.0 mmol) is subjected to interaction according OM and receive 100 mg specified in the connection header (160FE15).

Example 109. 8,5-Dichloro-5H-dibenzo[b,e][1,4]diazepin (160FE64)

To a mixture of 8-chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-she (of 2.45 g, 10 mmol) and dry toluene (20 ml) is added N,N-dimethylaniline (5,1 ml, 40 mmol) and phosphorus oxychloride (2.8 ml, 30 mmol). The mixture is shaken at 95°C for 2 hours and Then the temperature is ur lower and excess N,N-dimethylaniline and phosphorus oxychloride is removed under reduced pressure using an oil pump. The remaining oil is dissolved in dioxane (20 ml) and added aqueous solution of Na2CO3(10 ml, 2M). A two-phase mixture was shaken at 80°C for 30 minutes Then reduce the temperature to the reaction mixture and add the ether. The ether phase is washed with saturated aqueous NaCl, dried (Na2SO4and finally concentrated under reduced pressure. The resulting oil crystallizes upon standing at room temperature. Recrystallization (heptane-ether) gives 1.8 g (69%) specified in the connection header (160FE64).

1H NMR (CDCl3) δ to 7.61 (DD, 1H, J=1,4, and 7.8 Hz), 7,31 (dt, 1H, J=1.5 and 8.0 Hz), to 7.15 (d, 1H, J=2.5 Hz), 7,02 (m, 2H), 6,66 (DD, 1H, J=1,0, and 7.8 Hz), to 6.58 (d, 1H, J=8,4 Hz), 4,94 (USS, 1H).13C NMR (CDCl3) δ 157,2, 152,4, 140,3, 138,9, 134,0, 131,9, 129,7, 128,5, 128,0, 127,0, 123,5, 121,0, 119,8.

Example 110. 8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50)

A mixture of 8-chloro-5,10-dihydrobenzo[b,e][1,4]diazepin-11-she (500 mg, 2.05 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (480 mg, 1,19 mmol) in toluene (4 ml) is heated in a sealed tube in a microwave oven (120°C, 30 minutes). The mixture chromatographic (SiO2, heptane:EtOAc, 2:1) and receive 599 mg of intermediate thiolactam. To a mixture of intermediate thiolactam and THF (10 ml) was added MeI (633 μl, of 10.3 mmol) and the resulting mixture is refluxed for 4 hours the Mixture is concentrated and receive the Ute 610 mg of the crude specified in the connection header (166JO50) (purity of 59%.

Example 111. N,N-Diethyl(2-bromobenzyl)amide (189JO10)

To a mixture of 2-bromobenzonitrile (3.5 g, 16 mmol) and CH2Cl2(50 ml) at 0°C is added dropwise diethylamine (3.2 ml, 32 mmol) and the resulting mixture left at room temperature. After 30 minutes, water is added, the mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3and saturated aqueous NH4Cl, dried (Na2SO4), concentrate, and get a 3.9 g (95%) specified in the connection header (189JO10).

1H NMR (CDCl3) δ rate of 7.54 (m, 1H), 7,32 (m, 1H), 7,22 (m, 2H), 3,79 (m, 1H), 3.33 and (m, 1H), 3,13 (m, 2H), 1.26 in (t, 3H, J=7.2 Hz), of 1.05 (t, 3H, J=7,0 Hz).13C NMR (CDC13) δ 168,5, 139,0, 132,8, 130,0, 127,61, 127,59, 119,3, 42,8, 39,0, 14,0, 12,6.

Example 112. 2-[(4-Chloro-2-were)(4-methoxybenzyl)amino]-N,N-diethylbenzamide (189JO26)

To a mixture of N,N-diethyl(2-bromobenzyl)amide (189JO10) (1,41 g of 5.50 mmol) and 4-chloro-2-methylaniline (1.01 g, 7,15 mmol) in obeskislorozhennuju toluene (14 ml) is added NaO-t-Bu (0.74 g, 7.7 mmol), RAC-BINAP (110 mg, 0,17 mmol) and Pd(OAc)2(18 mg, 0.08 mmol) and the resulting mixture was stirred in an atmosphere of Ar for 14 h at 80°C. the Mixture is filtered through celite, concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc, 10:1-4:1), which gives an intermediate ketone without protective group (1.50 g), containing approximately 15% of impurities.

The mixture, with the holding of the intermediate connection dissolved in DMF (20 ml). Add p-methoxybenzylamine (0,90 ml, 6.6 mmol) and then in parts add NaH (0,23 g, 5.6 mmol, 60% in mineral oil). The resulting mixture was stirred at room temperature for 1 hour and then the reaction quenched by adding saturated aqueous solution of NaHCO3. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, toluene:EtOAc, 10:1) and obtain 1.66 g (68%) specified in the connection header (189JO26).

1H NMR (CDCl3) δ 7,35 (m, 2H), 7,20 (m, 1H), 7,09-6,99 (m, 4H), 6,91 (m, 2H), to 6.80(m, 2H), 4,84-of 4.54 (Abq, 2H, J=16.2 Hz), 3,74 (s, 3H), 3,18 (t, 2H), 3,03 (m, 1H), 2,48 (m, 1H), 2,17 (s, 3H), of 1.01 (t, 3H, J=7.2 Hz), to 0.97 (t, 3H, J=7,0 Hz).13C NMR (CDCl3) δ 169,6, 158,7, 146,53, 146,51, 137,0, 131,3, 130,9, 130,4, 129,6, 129,3, 128,7, 127,8, 127,4, 126,3, 122,8, 121,4, 114,0, 57,1, 55,3, 43,3, 39,0, 19,1, 13,9, 12,9. MC (ESI) 437 (MH+).

Example 113. 2-Chloro-5-(4-methoxybenzyl)-5,11-dihydrobenzo[b,f]azepin-11-he (189JO27)

To a mixture of Diisopropylamine (1,09 ml, 7.8 mmol) and N,N,N,N-tetramethylaniline (1,17 ml, 7.8 mmol) in dry THF (19 ml) at -20°C. add n-BuLi (5,54 ml, 1.4m solution in hexane) and the resulting mixture was stirred at -20°C for 5 minutes. Then add a mixture of 2-[(4-chloro-2-were)(4-methoxybenzyl)amino]-N,N-diethylbenzamide (189JO26) (1,36 g, 3.1 mmol) and dry THF (38 ml) and the resulting mixture was stirred at -20°C in t is the increase in the 4 o'clock The reaction is quenched by adding saturated aqueous solution of NH4Cl. The mixture is diluted with EtOAc, washed with water, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, toluene:heptane, 7:1-1:0) and receive 665 mg (59%) specified in the connection header (189JO27).

1H NMR (CDCl3) δ 8,15 (DD, 1H, J=1,8, 8.0 Hz), the 7.43 (m, 1H), 7,24 (m, 4H), 7,17 (d, 1H, J=8.6 Hz), 7,12 (DD, 1H, J=2,4, 8.6 Hz), 7,00 (dt, 1H, J=0,8, 7,0 Hz), for 6.81 (m, 2H), 5,09 (s, 2H), 4.00 points (s, 2H, in), 3.75 (s, 3H).13C NMR (CDC13) δ 190,3, 159,1, 149,5, 146,2, 134,1, 132,4, 131,3, 131,1, 129,1, 129,0, 128,6, 127,3, 126,4, 123,4, 121,0, 118,5, 114,2, 55,5, 19,3. MC (ESI) 364 (MH+).

Example 114. Methyl ester of 2-(4-chloro-2-nitrophenyloctyl)benzoic acid (189JO09)

To a mixture of 5-chloro-2-nitrofluoranthene (176 mg, 1 mmol) and methylthioadenosine (275 μl, 2 mmol) in DMF (5 ml) add Cs2CO3(652 mg, 2 mmol) and the resulting mixture was stirred at room temperature for 2 hours the Mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, heptane:toluene, 1:10-1:4) and receive 300 mg (92%) specified in the connection header (189JO09).

1H NMR (CDCl3) δ of 8.15 (d, 1H, J=2.4 Hz), 7,94 (m, 1H), 7,53-7,46 (m, 3H), 7,34 (DD, 1H, 2,4, 8.6 Hz), to 6.95 (d, 1H, J=8,8 Hz), 3,82 (s, 3H).

Example 115. Methyl ester 2-(2-amino-4-chlorophenylsulfonyl)benzoic acid (189JO11)

To a mixture of methyl ester of 2-(4-chloro-2-nitrophenyloctyl)benzoic acid (189JO09) (232 mg, to 0.72 mmol) and EtOH (5 ml) is added SnCl2·2H2O (812 mg, 3.6 mmol), the mixture was stirred at 80°C for 2 h and then concentrated. The residue is treated with ice and then add Na2CO3up until the pH reaches 10. Add EtOAc, and the suspension filtered through celite. The EtOAc phase was washed with water and brine, dried (Na2SO4), concentrate, and get 149 mg (70%) specified in the connection header (189JO11).

1H NMR (CDCl3) δ 8,02 (DD, 1H, J=1,6, 7,8 Hz), 7,39 (d, 1H, J=8,2 Hz), 7,29 (m, 1H), 7,15 (dt, 1H, J=1,2, 7,8 Hz), 6.87 in (d, 1H, J=2.2 Hz), to 6.80 (DD, 1H, J=2,2, 8,2 Hz), 6,76 (DD, 1H, J=1,2, 8.0 Hz), of 3.96 (s, 3H).

Example 116. 8-Chloro-10H-dibenzo[b,f][1,4]diazepin-11-he (189JO13)

A mixture of methyl ester of 2-(2-amino-4-chlorophenylsulfonyl)benzoic acid (189JO11) (149 mg, 0.51 mmol) and AlMe3(355 μl, 0.71 mmol, 2M solution in toluene) in CH2Cl2(3 ml) was stirred at ambient temperature for six days and then carefully add water. The mixture was diluted with CH2Cl2and acidified with 2M hydrochloric acid. The organic phase is separated, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (heptane:EtOAc, 5:1-3:1) and obtain 38 mg (29%) specified in the connection header (189JO13). MS (ESI) 262 (MH)+.

Example 117. Methyl ester of 2-(chloro-2-nitrophenoxy)benzoic acid (189JO29)

To a mixture of 5-chloro-2-nitrofluoranthene (352 mg, 2 mmol) and methyl 2-hydroxybenzoate (0,52 ml, 4 mmol) in DMF (6 ml) add Cs2CO3(of 1.30 g, 4 mmol) and the resulting mixture was stirred at room temperature for 2 hours the Mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, heptane:EtOAc, 10:1-4:1) and receive 505 mg (82%) specified in the connection header (189JO29).

1H NMR (CDCl3) δ 8,02 (DD, 1H, J=1,8, 7,8 Hz), of 7.96 (d, 1H, J=1.9 Hz), to 7.59 (dt, 1H, J=2.0 a, 7,6 Hz), 7,39 (DD, 1H, J=2.5 and 9.0 Hz), 7,24 (dt, 1H, J=1,2, 7,6 Hz), 7,13 (DD, 1H, J=1,2, 8.0 Hz), 6,74 (d, 1H, J=9.0 Hz), of 3.77 (s, 3H).

Example 118. 8-Chloro-10H-dibenzo[b,f][1,4]oxazepine-11-he (189JO29)

To a solution of methyl ester of 2-(chloro-2-nitrophenoxy)benzoic acid (189JO29) (505 mg, of 1.64 mmol) in EtOAc (20 ml) is added Pd (catalytic amount, 5% coal), the resulting mixture hydronaut (H2, 1 ATM) for 48 h, then filtered through celite and concentrated. The residue is dissolved in toluene (6 ml) and add NaH (160 mg, 4.0 mmol, 60% in mineral oil). The resulting mixture was stirred at 80°C overnight and then the reaction quenched by adding saturated aqueous solution of NH4Cl. The resulting mixture was diluted with EtOAc, prom is live water, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2, toluene:EtOAc, 4:1) and obtain 171 mg (42%) specified in the connection header (189JO29).

1H NMR (CDCl3) δ 8,12 (USS, 1H), 7,95 (DD, 1H, J=1,8, 8.0 Hz), 7,54 (dt, 1H, J=1,8, 8.0 Hz), 7,29-7,19 (m, 3H), was 7.08 (DD, 1H, J=2,3, 8.6 Hz),? 7.04 baby mortality (d, 1H, J=2.3 Hz). MC (ESI) 246 (MH+).

Example 119. 3-Chloro-5,11-dihydrobenzo[b,e]azepin-6-he (189JO59)

To a mixture of 5-chloro-2-methylphenylhydrazine (100 μl, 0.73 mmol) and CCl4(2 ml) add sulfurylchloride (118 μl, 0.88 mmol) and 2,2'-azobis(isobutyronitrile) (catalytic amount) and the resulting mixture is refluxed for 20 hours, the Mixture is left at room temperature, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrate. The mixture is dissolved in benzene (2 ml) and add a mixture of AlCl3(160 mg, 1.2 mmol) and benzene (1 ml). The resulting mixture was stirred at 80°C for 4 h and then left at room temperature. The mixture is filtered through a short column (SiO2, heptane:EtOAc, 1:1) and receive 25 mg (14%) specified in the connection header (189JO59).

1H NMR (CDCl3) δ 8,18 (USS, 1H), 7,92 (DD, 1H, J=1,2, 7,8 Hz), 7,46 (dt, 1H, J=1,4, 7,4 Hz), 7,34 (dt, 1H, J=1,2, 7,4 Hz), 7.23 percent (m, 2H), 7,07 (m, 2H), 3,92 (s, 2H). MC (ESI) 244 (MH+).

Example 120. 8-Bromo-10H-dibenzo[b,f][1,4]oxaz the pin-11-he (189JO56)

A mixture of methyl 2-hydroxybenzoate (1.0 ml, 10.0 mmol), 5-bromo-2-peritrabecular (of 0.62 ml, 5.0 mmol) and Cs2CO3(3.3 g, 10.0 mmol) in DMF (12 ml) was stirred at 40°C for 2 hours the Mixture is diluted with EtOAc and washed with 1M aqueous NaOH solution. The EtOAc phase add EtOH, H2O, K2CO3(2.8 g, 20 mmol) and Na2S2O4(3.5 g, 20 mmol) and the resulting mixture was vigorously stirred for 1 hour. The aqueous phase is removed, the organic phase is washed with 1M aqueous NaOH solution and then concentrated. The residue is dissolved in DMF (1 ml), then add toluene (4 ml) and NaH (60 mg, 1.5 mmol, 60% in mineral oil), the mixture was stirred at 80°C overnight and then the reaction quenched by adding saturated aqueous solution of NH4Cl. The resulting mixture was diluted with EtOAc, washed with 2M aqueous NaOH solution, dried (Na2SO4), concentrated, filtered through a short column with SiO2, concentrated and the residue crystallized from a mixture of heptane:EtOAc and get 130 mg specified in the connection header (189JO56). MS (ESI) 290 (MH)+. Purity for MN+(UV/MS) 100/100.

Example 121. A General method 8 (A)

8-chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (purity 50%, 1 EQ.) in the add pyridine diamine with a protective TREATMENT group (1.8 EQ.). The resulting mixture was heated in a sealed tube at 110°C for 66 h the Mixture was concentrated and then diluted with a mixture of CH 2Cl2:triperoxonane acid (2:1 ratio). The resulting mixture was stirred at ambient temperature overnight and then concentrated. The residue is dissolved in CH2Cl2and washed with saturated aqueous NaHCO3. The organic phase contribute in a column of ion exchange resin SCX-2. The column was washed with Meon, then the reaction product elute NH3(7h. the solution in the Meon), concentrate and purify HPLC.

Example 122. (8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(S)-1-pyrrolidin-2-ylmethylamino (166JO51)

8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (50 mg, 0.11 mmol) and (S)-(2-aminomethyl)-1-N-(tert-butoxycarbonylamino)pyrrolidine (39 mg, 0.2 mmol) is subjected to interaction according OM and receive 3.0 mg specified in the connection header (166JO51). MS (ESI) 327 (MH)+. Purity for MN+(UV/MS) 100/92.

Example 123. 1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperidine-4-ylamine (166JO55)

8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (50 mg, 0.11 mmol) and 4-(tert-butoxycarbonylamino)aminopiperidin (39 mg, 0.2 mmol) is subjected to interaction according ON and get to 6.5 mg specified in the connection header (166JO55). MS (ESI) 327 (MH)+. Purity for MN+(UV/MS) 100/99.

Example 124. 1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)pyrrolidin-3-ylamine(166JO64)

8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (100 mg, 0.22 mmol) and 3-(tert-butoxycarbonylamino)pyrrolidine (73 mg, 0.4 mmol) is subjected to interaction according OM and get 8,1 mg specified in the connection header (166JO64). MS (ESI) 313 (MH)+. Purity for MN+(UV/MS) 100/94.

Example 125. (8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(R)-1-pyrrolidin-2-ylmethylamino (166JO70)

8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (100 mg, 0.22 mmol) and (R)-(2-aminomethyl)-1-N-(tert-butoxycarbonylamino)pyrrolidine (78 mg, 0.4 mmol) is subjected to interaction according ON and get to 7.6 mg specified in the connection header (166JO70). MS (ESI) 327 (MH)+. Purity for MN+(UV/MS) 100/90.

Example 126. (8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)pyrrolidin-3-ylamine (166JO74)

8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (100 mg, 0.22 mmol) and 3-amino-1-N-(tert-butoxycarbonylamino)pyrrolidine (73 mg, 0.4 mmol) is subjected to interaction according OM and receive 7.7 mg specified in the connection header (166JO74). MS (ESI) 313 (MH)+. Purity for MN+(UV/MS) 100/90.

Example 127. 8-Chloro-11-(2,5-diazabicyclo[2,2,1]hept-2-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO39-2)

8-Chloro-11-methylsulfonyl-5H-dibenzo[b,e][1,4]diazepin (166JO50) (50 m is, 0.11 mmol) and N-(tert-butoxycarbonylamino)-2,5-diazabicyclo[2,2,1]heptane (34 mg, 0.2 mmol) is subjected to interaction according OM and receive 15 mg specified in the connection header (166JO39-2). MS (ESI) 324 (MH)+. Purity for MN+(UV/MS) 93/100.

Example 128. Azetidin-3-yl-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)amine (166JO65)

To 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (30 mg, 0.11 mmol) in dioxane add tert-butyl ester 3-aminoamides-1-carboxylic acid (59 mg, 0.34 mmol) and Cs2CO3(74 mg, 0.23 mmol) and the resulting mixture heated in a sealed tube using a microwave oven (170°C, 40 minutes). The mixture is diluted with EtOAc, washed with water, dried (Na2SO4) and concentrate. The residue is dissolved in CH2Cl2(2 ml) and add triperoxonane acid (1 ml). The resulting mixture was stirred at ambient temperature overnight and then concentrated. The residue is dissolved in CH2Cl2and washed with saturated aqueous NaHCO3. The organic phase contribute in a column of ion exchange resin SCX-2. The column was washed with Meon, then the reaction product elute NH3(7h. the solution in the Meon), concentrated and purified HPLC and receive 16 mg specified in the connection header (166JO65). MS (ESI) 299 (MH)+. Purity for MN+(UV/MS) 97/90.

Example 129. A General method 9 (OHMS)

A mixture of 3-aminomethylated ether (1 equiv.) 5-bromo-2-peritrabecular (1 EQ.) and K2CO3(4 equiv.) in DMF is heated at 60°C for 1 hour and then left at room temperature. The mixture was diluted with CH2Cl2and washed with saturated aqueous NH4Cl, dried (Na2SO4) and concentrate. The residue is dissolved in EtOH, add the mixture To a2CO3(5 EQ.) and Na2S2O4(5 EQ.) in water and the resulting mixture was vigorously stirred for 1 hour. The aqueous phase is extracted with EtOAc (3×), the combined organic phases are dried (Na2SO4) and concentrate.

The residue is dissolved in CH3CN add H2SO4(10 vol.%, 98%) and the resulting mixture was stirred at 80°C for 1 hour. The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried (Na2SO4), concentrated and the residue is subjected to flash chromatography (SiO2the system heptane:EtOAc), concentrated and receive the intermediate lactam.

The residue is dissolved in dioxane and 50°C is added to a mixture of TiCl4(1.1 EQ., 1M solution in toluene) and piperazine (5 EQ.) in dioxane. The resulting mixture was stirred at 100°C. over night and then leave at room temperature. To the mixture of hydrochloric acid (2M) up until the solution is acidic, and then the aqueous phase EC is tracerout EtOAc (2×). To the aqueous phase add an aqueous solution of NaOH (2M) up until the solution is alkaline, and the resulting suspension extracted with EtOAc (3×). The combined organic phases are concentrated and the residue is subjected to flash chromatography system (SiO2CH2Cl2:MeOH, NH3(7h. the solution in the Meon)).

Example 130. 7-Bromo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin (166JO47)

5-Bromo-2-ftorirovannom (440 mg, 2.0 mmol) and hydrochloride methyl-3-aminopropionic (920 mg, 3.0 mmol) is subjected to interaction according OM and get 4.0 mg specified in the connection header (166JO47). MS (ESI) 309 (MH)+. Purity for MN+(UV/MS) 100/100.

Example 131. 7-Bromo-2-methyl - (piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin (166JO95)

5-Bromo-2-ftorirovannom (440 mg, 2.0 mmol) and methyl-3-aminobutyrate (787 mg, 3.0 mmol) is subjected to interaction according OM and receive 12 mg specified in the connection header (166JO95). MS (ESI) 323 (MH)+. Purity for MN+(UV/MS) 100/100.

Example 132. 7-Bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin (189JO20)

5-Bromo-2-ftorirovannom (440 mg, 2.0 mmol) and hydrochloride ethyl-3-amino-3-phenylpropionate (394 mg, 1.5 mmol) is subjected to interaction according OM and get 9,8 mg specified in the connection header (189JO20). M is (ESI) 385 (MH) +. Purity for MN+(UV/MS) 97/88.

Example 133. 7-Bromo-10-(piperazine-1-yl)-1,2,3,3A,4,10A-hexahydrobenzo[b]cyclopent[e][1,4]diazepin (166JO46)

5-Bromo-2-ftorirovannom (110 mg, 0.5 mmol) and hydrochloride CIS-2-amino-1-cyclopentanecarboxylic acid (138 mg, 0.75 mmol) is subjected to interaction according OM and receive 3.0 mg specified in the connection header (166JO46). MS (ESI) 349 (MH)+. Purity for MN+(UV/MS) 99/88.

Example 134. A General method 10 (A)

To a solution of 8.5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (53 mg, 0.2 mmol) and PdCl2(PPh3)2(9 mg, 0.02 mmol) in dry THF (1 ml) at room temperature add zinc reagent (0.4 mmol). The reaction mixture was shaken until complete conversion (1-16 h, TLC) and then the reaction quenched by adding aqueous saturated solution of NH4Cl. The resulting mixture was twice extracted with ether, the combined ether phases are washed with brine and dried over Na2SO4. Filtration followed by concentration of the organic phase under reduced pressure to give the crude reaction product, which was purified using column chromatography (system heptane:EtOAc).

Example 135. 8-Chloro-11-(4-terbisil)-5H-dibenzo[b,e][1,4]diazepin (160FE59)

4-Propensityscore (0.8 ml, 0.5m solution in THF, 0.4 mmol) and 8,5-dichloro-5H-diben what about[b,e][1,4]diazepin (160FE64) (53 mg, 0.2 mmol) is subjected to interaction according AM and get up to 52 mg specified in the connection header (160FE59). MS (ESI) 337 (MH)+. Purity for MN+(UV/MS) 90/90.

Example 136. 8-Chloro-11-(4-terbisil)-5H-dibenzo[b,e][1,4]diazepin (160FE70)

4-Tormentillae (0.5 ml, 0.5m solution in THF, 0.4 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepin (160FE64) (26 mg, 0.1 mmol) is subjected to interaction according OM and get 23 mg specified in the connection header (160FE70). MS (ESI) 323 (MH)+. Purity for MN+(UV/MS) 98/100.

Example 137. A General method 11 (A)

To a solution of 8.5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (53 mg, 0.2 mmol), Pd(PPh3)4(10 mg) and the appropriate reagent Bronevoy acid (0.12 mmol) in dioxane (3 ml) at room temperature, add aqueous solution of Na2CO3(1 ml, 1M). The mixture is then shaken at 80°C. until complete conversion imidocloprid (TLC). The temperature is reduced and the reaction mixture is added ether and N2O. the Ether phase is washed with brine and dried over Na2SO4. Filtration followed by concentration of the organic phase under reduced pressure to give the crude reaction product, which was purified using column chromatography (system heptane:EtOAc).

Example 138. 8-Chloro-11-(4-nonylphenyl)-5H-dibenzo[b,e][1,4]diazepin (160FE63)

4-Nonylphenylether acid (30 mg, 0.12 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepin (160FE64) (26 mg, 0.1 mmol) is subjected to interaction according OM and receive 25 mg specified in the connection header (160FE63). MS (ESI) 431 (MH)+. Purity for MN+(UV/MS) 85/85.

Example 139. 8-Chloro-11-(pyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE69)

4-Pyridyl-4-Bronevoy acid (14 mg, 0.12 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepin (160FE64) (26 mg, 0.1 mmol) is subjected to interaction according ON and get to 9.3 mg specified in the connection header (160FE69). MS (ESI) 306 (MH)+. Purity for MN+(UV/MS) 98/95.

Example 140. 8-Chloro-11-(1H-pyrazole-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE59)

4-(4,4,5,5,-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (22 mg, 0.1 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepin (160FE64) (26 mg, 0.1 mmol) is subjected to interaction according ON and get to 8.7 mg specified in the connection header (160FE59). MS (ESI) 295 (MH)+. Purity for MN+(UV/MS) 95/100.

Example 141. Functional screening

Some compounds disclosed herein, to assess activity against muscarinic receptors using technology selection and amplification of receptor (R-SAT), described in U.S. patent No. 5707798 included in this description by SS the CTL. Efficiency (eff) and the activity (expressed as RES50such compounds receptor M1, M2 and M3 shown in table 1.

tr>
Table 1
NameM1M2M3
EffRES50EffRES50EffRES50
2,7-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F1)-2-14-
2-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F6)-58-
2,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F2)1 24-
2-Bromo-2-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO85F3)10295,5-
2-Chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (166JO85F7)1019-
6-Chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (189JO77)---
7-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE35B)486,653of 5.4-
8-Bromo-1-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F36)66 6,91055,64
8-Bromo-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F40)844of 5.4-
4,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F41)787,21186,0446,8
8-Chloro-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F41)14285,9-
8-Chloro-2-fluoro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F42-F3)326,81215,5-
3,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F42-F4)34 6,9585,8-
2-Bromo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F43-F6)619-
3,7-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F58D1)1519-
8-Bromo-3-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F58D3)316,6346,5-
3-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F58D6)1627the 5.7-
3-Chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (160F58D7)11 --
7-Chloro-2-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F581)-35-
2-Methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F586)19-
2-Methyl-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (160F587)1514-
8-Chloro-4-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160F74)927,21626,016
1,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (203F03)- 84the 5.7-
8-Bromo-5-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO32)926,4755,6-
7,8-Dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO28)327,18-
11-(Piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin (166JO23)536,51315,5-
11-(Piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19)386,1705,6-
8-Fluoro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19)326,795 the 5.7-
11-(Piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin-8-carbonitrile (160FE19D)496,61066,0-
8-Bromo-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19)637,21216,313
8-Methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE19F)496,8986,0-
3-Fluoro-6-piperazine-1-yl-11N-dibenzo[b,e]azepin (160FE02)23556,1-
2-(Tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE13)-89 -
2-(Tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]oxazin (160FE13)-114-
8-Chloro-2-(tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE13)-216-
8-(Tripterocalyx)-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE13D)19625,6-
11-(Piperazine-1-yl)dibenzo[b,f][1,4]diazepin (160FE17)4416,5-
11-(Piperazine-1-yl)-2,3-dihydro-1,4-benzodioxin[6,7-b][1,4]benzodiazepin (160FE17)628 -
8-Chloro-11-[1,4]diazepam-1-yl-5H-dibenzo[b,e][1,4]diazepin (160FE16)377,0826,2-
N'-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine (160FE16D)411-
N'-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-diethylether-1,2-diamine (160FE16)69-
8-Chloro-11-(4-methyl[1,4]diazepam-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE16F)18505,9-
8-Chloro-2-methoxy-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE20)77 -
N'-(5H-Dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine (160FE20)1020-
11-[1,4]Diazepam-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE20)1825-
N'-(8-Fluoro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N,N-dimethylated-1,2-diamine (160FE20D)721-
8-Fluoro-11-[1,4]diazepam-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE16)256,7676,6-
N'-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-mutilate-1,2-diamine (160FE22)58 -
8-Chloro-11-(TRANS-2,5-dimethylpiperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE33)824-
8-Chloro-11-(3,5-dimethylpiperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE33)18975,6-
8-Chloro-11-(3-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE38)287,01595,819
8-Chloro-11-(3-phenylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE45)523
8-Chloro-5-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (189JO25)657,11385,9 14
8-Chloro-5-benzyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE46-PIPBN)416,316-
8-Iodine-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO38)757,21876,0-
2-Iodine-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO54)310-
8-Phenyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (189JO53)-104the 5.7-
8-Chloro-11-(piperidine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO69)475,89-
8-Chloro-11-(morpholine-4-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO69)116-
5-Allyl-8-chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO68)12465,8-
6-Chloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin (189JO68)-71of 5.4-
8-Chloro-5-piperazine-1-yl-11N-benzo[b]pyrido[2,3-e][1,4]diazepin (166JO63)515,57-
2-Chloro-10-piperazine-1-yl-5H-dibenzo[b,f]azepin (189JO39)23-
8-chlorine is-11-(piperazine-1-yl)dibenzo[b,f][1,4]diazepin (189JO16) 11525,9-
8-Chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO31)527,0586,0-
8-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (189JO47)13465,8-
3-Chloro-6-piperazine-1-yl-11N-dibenzo[b,e]azepin (189JO60)-1135,9-
8-Bromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO48)-705,9-
11-(Piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO48)-58the 5.7-
7-Chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)-535,9-
8-Chloro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)-19-
8-Bromo-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50D)-21-
3-Methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)-455,6-
7-Chloro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50F)- 446,0-
8-Chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO50)-716,2-
8-Bromo-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51)-485,8-
4-Methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51)-22-
2-Bromo-8-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51D)-13-
2,8-Dibromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51)-6 -
2-Bromo-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51F)-9-
2-Bromo-7-chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO51G)-15-
11-(Piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO54)-585,9-
4-Methyl-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO54)-756,1-
8-Fluoro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54)-485,6 -
8-Fluoro-3-methoxy-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54F)-495,6-
8-Fluoro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54G)-505,8-
2-Bromo-8-fluoro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO54)-21-
8-Methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO58)-765,5-
3-Methoxy-8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO58)-455,5-
4,8-Dimethyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO58)-466,1-
3-Methoxy-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO62)-17-
2-Bromo-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine (189JO62)-11-
6-Chloro-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO69)---
2-Bromo-8-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO63)-17-
7-Chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO63)-286,4-
8-Phenyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine (189JO64)-335,9-
8-Chloro-11-(piperidine-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE67)576,231the 5.7-
5-Benzyl-8-chloro-11-(piperidine-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE67)125-
(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(S)-1-pyrrolidin-2-ylmethylamino (166JO51)776,323-
1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperidine-4-ylamine (166JO55)6955,6-
1-(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)pyrrolidin-3-ylamine (166JO64)8365,5-
(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-(R)-1-pyrrolidin-2-ylmethylamino (166JO70)45-
(8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)pyrrolidin-3-ylamine (166JO74)1018-
8-Chloro-11-(2,5-diazabicyclo[2,2,1]hept-2-yl)-5H-dibenzo[b,e][1,4]diazepin (166JO39-2)346,6495,6-
Azetidin-3-yl-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)amine (189JO65)-17-
7-Bromo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin (166JO47)565,63-
7-Bromo-2-methyl - (piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin (166JO95)1623-
7-Bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo[b][1,4]diazepin (189JO20)319-
7-Bromo-10-(piperazine-1-yl)-1,2,3,3A,4,10A-hexahydrobenzo[b]cyclopent[e][1,4]diazepin (166JO46)505,812-
8-Chloro-11-(4-terbisil)-5H-dibenzo[b,e][1,4]diazepin (160FE59)37-
8-Chloro-11-(4-forfinal)-5H-dibenzo[b,e][1,4]diazepin (160FE70)134-
8-Chloro-11-(4-nonylphenyl)-5H-dibenzo[b,e][1,4]diazepin (160FE63)18-
8-Chloro-11-(pyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE69)66-
8-Chloro-11-(1R-pyrazole-4-yl)-5H-dibenzo[b,e][1,4]diazepin (160FE59)93-

1. The compound has a structure represented by formula I

or its pharmaceutically acceptable salt, ester or amide,
where a has the structure

where each link in And represented by a dashed and solid line represents a carbon-carbon simple communication;
each of a, b, C and d represents a carbon atom;
each of e, f, g, and h represents a carbon atom;
X represents nitrogen;
X' represents S;
L is absent;
each n is 1;
Y represents nitrogen;
W represents nitrogen;
R1represents hydrogen;
each of R2, R3and R4represents a hydrogen atom;
each of R6, R8and R9represents a hydrogen atom;
R5selected from the group consisting of halogen, C1-6the alkyl, optionally substituted by a hydroxy-group, and C1-6alkoxy;
R7selected from the group consisting of halogen, C1-6the alkyl and perhalogenated;
Z is chosen from the group consisting of NR11oxygen and CH2;
R11represents hydrogen; and
each link in the formula I, represented by a dashed and solid line represents a carbon-carbon double bond.

2. The compound according to claim 1, where R5selected from the group consisting of halogen and C1-6the alkyl, optionally substituted hydroxy-group.

3. The connection is .2, where the specified alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

4. The compound according to claim 2, where the specified halogen selected from the group consisting of fluorine, chlorine and bromine.

5. The compound according to claim 1, where R5represents chlorine.

6. The compound according to claim 1, where the specified alkyl, R7selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

7. The compound according to claim 1, where the specified halogen, R7selected from the group consisting of fluorine, chlorine and bromine.

8. The compound according to claim 1, where the specified perhalogenated R7represents a perfluoroalkyl.

9. The connection of claim 8, where the specified perfluoroalkyl represents trifluoromethyl.

10. The compound according to claim 1, where R7selected from the group consisting of methyl, chlorine and trifloromethyl.

11. The compound according to claim 1, selected from the group which includes
4,8-dichloro-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,
8-chloro-4-methyl-11-(piperazine-1-yl)-5H-dibenzo[b,e][1,4]diazepin,
8-chloro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,
8-bromo-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,
4-methyl-11-(piperazine-1-yl)-8-tripteroides[b,f][1,4]oxazepine,
8-fluoro-4-methyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine,
4,8-dimethyl-11-(piperazine-1-yl)dibenzo[b,f][1,4]oxazepine.

12. The way of sin is ESA the compounds of formula V

including the interaction of the compounds of formula VII

with the compound of the formula VIII

with the formation of the condensed-cyclic compound of formula IX

and the interaction of the compounds of formula IX with the compound of the formula X

with the formation of the compounds of formula V;
where X represents a halogen;
W represents nitrogen;
R1represents hydrogen;
each of R2, R3and R4represents a hydrogen atom;
each of R6, R8and R9represents a hydrogen atom;
R5selected from the group consisting of halogen, C1-6the alkyl, optionally substituted by a hydroxy-group, and C1-6alkoxy; and
R7selected from the group consisting of halogen, C1-6the alkyl and perhalogenated.

13. Pharmaceutical composition for modulating the activity of a muscarinic receptor, containing a physiologically acceptable carrier, diluent or excipient or their combination and connection according to claim 1.

14. A method of treating neurological disorders in a patient, including the introduction of the indicated patient a therapeutically effective amount of a compound according to claim 1.

15. A method of treating neuropsychiatric RA is disorder in a patient, comprising contacting a therapeutically effective amount of a compound according to claim 1 with the specified patient.

16. A pharmaceutical composition comprising a compound according to claim 1 and neuropsychiatric tool.

17. The composition according to item 16, where the specified neuropsychiatric tool is chosen from the group consisting of a selective inhibitor of the reuptake of serotonin, an inhibitor of reuptake of norepinephrine, dopamine agonist, antagonist muscarinic receptor, antipsychotics, antagonist of serotonin 2A and inverse agonist of the serotonin 2A.

18. The composition according to 17, where the specified antipsychotic agent selected from the group consisting of fenotiazina, privatelyoperated, dibenzepin, benzisoxazole and lithium salts.

19. The composition according to p where specified phenothiazines are selected from the group consisting of chlorpromazine (Thorazine®), mezoridazina (Serentil®), prochlorperazine (Compazine®) and thioridazine (Mellaril®).

20. The composition according to p where specified privatelyoperated selected from the group consisting of haloperidol (Haldol®) and pimozida (v®).

21. The composition according to p where specified dibenzepin selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®).

22. The composition according to p, where the specified benzisoxazol selected from the group consisting of risperidone (Reperidal®) and ziprasidone (Geodon®).

23. The composition according to p where the specified lithium salt is a lithium carbonate.

24. The composition according to 17, where the specified antipsychotic agent selected from the group consisting of Clozaril, Compazine, Etrafon (Triavil), Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Orap, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Trilafon and Zyprexa.

25. The composition according to 17, where specified, a selective inhibitor of the reuptake of serotonin selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, ESCITALOPRAM, sibutramine, DULOXETINE, and venlafaxine, and pharmaceutically acceptable salts or prodrugs.

26. The composition according to 17, where the specified inhibitor of the reuptake of norepinephrine selected from the group consisting of cialisonline and reboxetine.

27. The composition according to 17, where the specified dopamine agonist selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zolmitriptan, cabergoline, amantadine, e.g., pergolid, ropinirole, pramipexole and bromocriptine.

28. The composition according to 17, where the specified antagonist of the serotonin 2A is a compound of formula XIV or its related similar

29. A method of treating neurological disorders in a patient, comprising the introduction of a specified patient tera is efticiency effective amount of the composition according to item 16.

30. A method of treating neurological disorders in a patient, including the introduction of the indicated patient a therapeutically effective amount of a compound according to claim 1 and a therapeutically effective amount of neuropsychiatric tools.

31. The method according to item 30, where specified stage of introducing includes introducing the compounds according to claim 1 and the specified neuropsychiatric means almost simultaneously.

32. The method according to item 30, where specified stage of introducing includes introducing first, one of the compounds according to claim 1 and the specified neuropsychiatric means and then the introduction of another active of the compounds according to claim 1 and the specified neuropsychiatric tools.

33. The method according to item 30, where the specified neuropsychiatric disorder selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, disorders of appetite, affective disorders such as major depression, bipolar disorder and depression with psychotic features, and Tourette's syndrome, psychosis, caused by drugs, illness, secondary to neurological disorders such as Alzheimer's or Huntington's disease.

34. The compound according to claim 1 for use in the treatment of neuropsychiatric disorders.

35. The composition according to claim 1 for use in the treatment of neuropsychiatric disorders.

36. A composition comprising a compound according to claim 1 and neuropsychiatric tool for use in the treatment of neuropsychiatric disorders.

37. The composition according to p, where the specified neuropsychiatric disorder selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, disorders of appetite, affective disorders such as major depression, bipolar disorder and depression with psychotic features, and Tourette's syndrome, psychosis, caused by drugs, illness, secondary to neurological disorders such as Alzheimer's or Huntington's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: medicine.

SUBSTANCE: invention covers compound 6-amino-4-chloropyrazolo[3,4-d]pyrimidine. Offered compound is made of 2-amino-4,6-dichloropyrimidine by the two-staged method based on a common reaction of selective replacement of hydroxyl group with chlorine atom (chlorodehydroxylation) and replacement of hydrogen atom with carbonyl group followed with ring closure of the product with hydrazine. The declared compound provides a specific inhibiting action on human 8-oxoguanine-DNA-glycosylase enzyme (hOggl).

EFFECT: low-price and available compound, extended range of specific inhibitors of said enzyme and possibility for effective application in medicine.

2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to derivatives of substituted pyridazinylamine of formula or to their pharmaceutically acceptable salts or hydrates, where X is C or N; Y is O or S; W is C or N; R1, R2, R3 each independently represents hydrogen or halogen; R4, R5, R6 each independently represents hydrogen, halogen, C1-C8-straight or branched alkyl, C1-C8-straight or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7; R7 independently represents hydrogen or C1-C8-straight or branched alkyl. The invention also relates to a method of producing said compounds, to pharmaceutical compositions containing said compounds and to use of the said compounds as picornavirus inhibitors for preventing and/or treating diseases caused by pircornaviruses.

EFFECT: novel compounds have useful biological properties.

10 cl, 1 tbl, 33 ex

Novel insecticides // 2379301

FIELD: chemistry.

SUBSTANCE: compounds with formula I are described, where each of E and Z is oxygen; A is C1-C6alkylene or a 3-member monocyclic ring system, which can be monosubstituted; Y is C1-C6alkylene; p equals 0; q equals 0 or 1; B represents a 3- or 4-member ring system which is completely or partially saturated and can contain a heteroatom selected from oxygen, possibly substituted; each R1 independently represents halogen, nitro group, C1-C6alkyl; or each R1 independently represents an amino group; n equals 1, 2; each of R2 and R3 represents hydrogen; D represents a group and agronomically acceptable salts of said compounds. Also described is a method of producing formula I compounds, intermediate compounds, a pesticide composition containing a formula I compound, as well as an insect control method and a method of protecting plant propagation material.

EFFECT: novel anthranylamide derivatives have good insecticidal activity.

16 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention covers new compounds of formula I: or its pharmaceutically acceptable salt with antagonist activity to corticotrophin release factor (CRF). In formula (I) X means heteroaryl chosen of pyrazolyl and imidazolyl optionally substituted with (C1-C6)alkyl, haloid or phenyl; Y means -NRaRb where Ra means hydrogen, and Rb means phenyl optionally substituted with (C1-C6)alkyl or haloid; Z means (C1-C6)alkyl; and R1 means hydrogen, (C1-C6)alkyl or haloid.

EFFECT: compounds can find application in treatment, eg of neurodegenerative diseases, neuropsychiatric disorders and stresses.

19 cl, 1 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to psychoneurology, particularly to an agent for treating multiple sclerosis. A composition (solid or liquid dosage form) contains triiodide 1,3-diethylbenzimidazolium as an agent, low-molecular surgical polyvinylpyrrolidone, presented as a solubiliser, and an agent stabiliser, and in addition in the liquid dosage form - ethanol as a solvent.

EFFECT: composition under the invention exhibits high therapeutic effectiveness in treating multiple sclerosis, and is characterised by relieving undesirable by-effects.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).

EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.

24 cl, 9 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at treating the conditions associated with amnesia and impaired cognition. A medically indigent patient is prescribed with the effective amount of a composition containing a mixed extract prepared of Scutellaria plants with high concentration of free V-ring flavonoids, including Baicalin, and an extract of Acacia plants with high concentration of flavanes, including catechine and epicatechin.

EFFECT: methods ensure restoration and preservation of cognition and memory.

44 cl, 15 ex, 2 tbl, 17 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds of the general formula (I) , where R1, R2 are independently H or C1-C6-alkyl; R3, R4 are independently H or C1-C6-alkyl; R5 is halogen, CN; n, m or o are 0, 1 or 2; and to pharmaceutically acceptable salts thereof.

EFFECT: compounds with monoaminooxidase B inhibition properties applicable in obtainment of pharmaceutical drugs with relevant effect.

14 cl, 3 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to serotonin 5-HT6 receptor antagonists - new substituted 3-sulphonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-e]pyrimidines of formula and substituted 3-sulphonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-c1]pyrimidines of general formula 2, a medicinal base and pharmaceutical compositions containing the medicinal base in form of the said compounds, as well as to a method of treating and preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals. In formulae and Ar is phenyl which is optionally substituted with halogen atoms, or a 6-member heteroaryl which contains a nitrogen atom in the ring; R1 is a hydrogen atom, C1-C3alkyl, hydroxy C1-C3alkyloxy group, C1-C3alkylsulphanyl group; R2 is a hydrogen atom or C1-C3alkyl, R3 is a hydrogen atom optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.

EFFECT: obtaining compounds for preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals.

16 cl, 3 tbl, 1 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmaceutical industry and represents pharmaceutical combination for treatment of cerebral circulatory insufficiency and psychodependent form of erectile dysfunction, including choline alfoscetate in amount 50-600 mg per one intake and hopantenic acid or its pharmaceutically acceptable salt in amount 20-800 mg per one intake.

EFFECT: invention ensures reduction of frequency, duration and intensity of headache, dizziness, fatigability, irritability, improvement of memory for current events and sleep, as well as increase of erectile dysfunction (ED), reduction and fixation of stable positive motivation for quality erection and full orgasm in case of psychodependent form of ED; simultaneously, due to manifestation of synergic effect, which results from the use of claimed combination, it became possible to reduce day dose of hopantenic acid or its salt from 1,5 mg to 0,5 mg.

12 cl, 4 ex, 24 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: methods according to the invention consist in introducing an Aβ 16-23 fragment having an amino acid sequence KLVFFAED of 16-23 residues SEQ ID NO:1. Besides the invention concerns the Aβ 16-23 fragment and a pharmaceutical composition containing it.

EFFECT: feasible prevention and treatment of Alzheimer's disease ensured by inhibition of amyloid deposition in cerebrum.

72 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology, and can be used in treating the patients with multiple sclerosis. That is ensured by infusion of rituximab in a dose 1 g followed by introduction of mitoxantrone in a dose 20 mg and another infusion of rituximab in a dose 1 g 13-15 days later. A common preanaesthetic medication precedes infusion of rituximab.

EFFECT: method ensures fast therapeutic effect and prolonged remission in all forms of multiple sclerosis without a concomitant therapy, including chemotherapy.

1 ex, 11 dwg

Antitumour agent // 2391982

FIELD: medicine.

SUBSTANCE: invention belongs to medicine and pharmacology, notably to antitumour agent for gastrointestinal tract cancer treatment. Agent includes component (A) and component (B). Component (A) is R-(-)-3-[3-(1-tret-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-bensodiazepine-3-yl)ureido]bensoic acid or its pharmaceutically acceptable salt. Component (B) is antitumour agent.

EFFECT: higher efficiency.

21 cl, 13 ex, 1 tbl

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