Dibenzo[b,f][1, 4]oxazapine compounds

FIELD: medicine, pharmaceutics.

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

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

39 cl, 25 ex, 8 dwg

 

The prior art of the INVENTION

The technical field to which the invention relates

The present invention relates primarily to compounds dibenzo[b,f][1,4]oxazepine and, more specifically, to compounds 11-(piperazine-1-yl) dibenzo[b,f][1,4]oxazepine.

Technical background

Serotonin or 5-hydroxytryptamine (5-HT) plays an important role in the functioning of the body of a mammal. In the Central nervous system 5-HT is an important neurotransmitter and neuromodulator, which plays a role in such diverse behavior as sleep, nutrition, movement, pain perception, learning and memory, sexual behavior, control of body temperature and blood pressure. In the spine serotonin plays an important role in the control systems of afferent peripheral pain receptors (Mougliner, Rev. Neurol. 150: 3-15, (1994)). Peripheral functions in the cardiovascular, hematopoietic and gastrointestinal systems have also been attributed to 5-HT. It was also found that 5-HT indirectly affects a variety of contractile, secretory, and electrophysiological actions, including reduction of vascular and non-vascular smooth muscles and aggregation of platelets (Fuller, Biology of Serotonergetic Transmission, 1982; Bouillin, Serotonin In Menthal Abnormalities 1:316 91978); Bachas, et al., Serotonin and Bihavior, (1973)). Subtype receptor 5-HT2A(also called sub is a lass) wide, although discrete, is expressed in the human brain, including numerous cortical, limbic and area of the forebrain that is involved believe in a higher consciousness and emotional state.

Serotonin receptors are members of a large family of human genes transmembrane proteins that function as transduction in intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where, when they are activated or their endogenous ligand serotonin or exogenously introduced drugs, they change their conformation and then interact with the following mediators of cell signaling. Many of these receptors, including the subclass of 5-HT2Arepresent the receptor associated G-protein (GPCR), which produce a signal through the activation of binding proteins gurinovka nucleotide (G-proteins), leading to the development or inhibition of molecules of second messengers, such as cyclic ATP, Inositol phosphates and diacylglycerol. Then secondary messengers modulate the function of various intracellular enzymes, including kinases and ion channels that directly affect cellular excitability and function.

Traditionally, I admit that these Rotz the Torah exist in an inactive state, until activated by the binding of the antagonist (drug, which activates the receptor). At the moment accept that many, if not all GPRC monoamine receptors, including serotonin receptors can exist in a partially activated state in the absence of endogenous antagonists. This increases the base activity (constitutive activity), which can be ingibirovany compounds called inverse antagonists. Both agonists and inverse agonists have intrinsic activity at the receptor, consisting in the fact that they can activate and inactivate these molecules, respectively. In contrast, classic or neutral antagonists compete with agonists and inverse agonists for access to the receptor, but do not have the internal ability to inhibit increased primary or constitutively answers.

Were identified and categorised into one of seven families (5-HT1-7at least 15 genetically different subtypes of 5-HT receptors. Each subtype exhibits a unique distribution, preference for different ligands and functional(s) correlation(AI).

Serotonin may represent an important component in various types of pathological conditions, such as mental disorders (depression, aggression, panic attacks, sink the m obsessions, psychosis, schizophrenia, suicidal tendency), neurodegenerative disorders (dementia type Alzheimer's disease, Parkinson's disease, Huntington's chorea), anorexia, bulimia, disorders associated with alcoholism, disorders of the brain and migraine (Meltzer, Neuropsychopharmacology., 21: 106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38: 1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev., 14: 35 (1990)). The latter fact strongly implies involvement of 5-HT2subtype receptors in the etiology of such medical conditions as, among others, hypertension, thrombosis, migraine, vasospasm, ischemia, depression, painful feeling of anxiety, psychosis, schizophrenia, sleep disorders and disturbances of appetite.

Schizophrenia is a particularly devastating neuropsychiatric disturbance, which affects approximately 1% of the human population. It is estimated that the total financial cost of diagnosis, treatment and loss of social productivity of individuals exposed to a specified disease, exceeds 2% of the gross national product (GNP) of the United States. Modern treatment consists primarily of pharmacotherapy class of drugs known as antipsychotics. Antipsychotics are effective for the relief of positive symptoms (e.g. hallucinations and delusions), although this is what they often do not relieve negative symptoms (for example, social and emotional loss, apathy and poverty of speech).

Currently prescribe nine major classes of antipsychotics for the treatment of psychiatric symptoms. However, the use of such compounds is limited due to their profile side effects. Almost all of the "typical" connection or connections of subsequent generations show a significant adverse effect on the motor activity of the person. Is the "extrapyramidal" side effect, called thus because of the effects of drugs on the modulation of the motor system, can be acute (eg, dystonic reaction, a potentially life-threatening, but rare neuroleptic malignant syndrome), and chronic (eg, akathisia, tremor and late dyskinesia). Thus, efforts to develop drugs focused on the latest "atypical" agents, it does not show the specified adverse action.

It was shown that antipsychotic drugs interact with a large number of Central monoaminergic receptors in the nervous mediator, including dopaminergic, serotonergichesky, adrenergic, muscarinic and histamine receptors. Apparently therapeutic and adverse effects of ant is psychotic drugs is associated with an action and an antagonistic effect on different types of receptors. The high degree of genetic and pharmacological homology between subtypes of these receptors has delayed the development of compounds drugs (antipsychotic and other mentioned above and wherever else here), which possess the desired pharmacological profile in the absence or acceptable way reduced side effects.

The INVENTION

One aspect of the invention provides compounds having the structure designated by the formula I:

and their pharmaceutically acceptable salts, where

R1and R2independently represents-Cl, -F, -Br, -I or-H;

R3is an R (not necessarily replaced in a specified only the case when R3)- (C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar -(C0-C6alkyl)-O-(C0-C6alkyl)Ar -(C0-C6alkyl)-OR -(C0-C6alkyl)C(O)Rkor -(C0-C6alkyl) NRaR19;

R4represents-H or-R;

each of R5, R6and R7independently represents-R, -(C0-C6alkyl)-OR -(C0-the 6alkyl)NRaR19, -NO2, -halogen, -CN, -OH, -OOCR, -(C0-C6alkyl)COORe-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)Ar -(C0-C6alkyl)-O-(C0-C6alkyl)Ar -(C0-C6alkyl)Het, -(C0-C6alkyl)-O-(C0-C6alkyl)Het, -(C0-C6alkyl)Hca, -(C0-C6alkyl)-O-(C0-C6alkyl)Hca, -(C0-C6alkyl)Cak, -(C0-C6alkyl)-O-(C0-C6alkyl)Cak, -(C0-C6alkyl)C(O)Hca, -(C0-C6alkyl)C(O)Ar, -(C0-C6alkyl)C(O)Het or -(C0-C6alkyl)C(O)Cak;

w is 1, 2 or 3;

x represents 1, 2 or 3; and

y represents 1, 2 or 3, where

each Reindependently represents-H, -R, -(C1-C6alkyl)C(O)Hca, -(C1-C6alkyl)C(O)Cak, -(C1-C6alkyl)C(O)Het, -(C1-C6alkyl)C(O)Ar, -(C1-C6alkyl)C(O)O-Hca, -(C1-C6alkyl)C(O)O-Cak, -(C1-C6alkyl)C(O)O-Het, -(C1-C6alkyl)C(O)O-Ar, -(C0-C6alkyl)Hca, -(C0-C6alkyl)Het, -(C0-C6alkyl)Ar -(C0-C6alkyl)Cak, -(C1-C6alkyl)C(O)OR, -(C1-C6alkyl)C(O)NR192-(C0-C6alkyl)-or, or -(C0-C6alkyl)-OH;

each Raindependently represents-H, -R, -(C1-C6alkyl)OR -(C 1-C6alkyl)-OH, -(C0-C6alkyl)C(O)OR, -(C1-C6alkyl)C(O)NR192-(C0-C6alkyl)Hca, -(C0-C6alkyl)Ar -(C0-C6alkyl)Het or -(C0-C6alkyl)Cak;

each Rkindependently represents-H, -R, -(C1-C6alkyl)C(O)Hca, -(C1-C6alkyl)C(O)Cak, -(C1-C6alkyl)C(O)Het, -(C1-C6alkyl)C(O)Ar, -(C1-C6alkyl)Hca, -(C0-C6alkyl)Het, -(C0-C6alkyl)Ar -(C0-C6alkyl)Cak, -(C1-C6alkyl)(O)or, or -(C1-C6alkyl)C(O)NR192;

each Cak is an cycloalkyl or cycloalkenyl group optionally substituted by 1, 2 or 3 substituents, independently selected from-R, -(C0-C6alkyl)C(O)OR, =O, -OH, -CN, -(C0-C6alkyl)OR-OCH2CH2-O-, -OCH2-O-, -SO2-R, -SO2-(C1-C6halogenated)- (C0-C6alkyl)C(O)NR192-(C0-C6alkyl)Het, -SO2(C0-C6alkyl)Hca, -(C0-C6alkyl)Ar -(C0-C6alkyl)Het, -(C0-C6alkyl)Hca, -(C0-C6alkyl)C(O)R, -SO2(C0-C6alkyl)Ar, -SO2(C0-C6alkyl)Het and SO2(C0-C6alkyl)cycloalkyl;

each Ar represents an aryl group, not necessarily amestoy 1, 2 or 3 substituents, independently selected from-R, -OR, -(C0-C6alkyl)NR192, -NO2, -Cl, -F, -Br, -I, -CN, -(C0-C6alkyl)OH, -(C0-C6alkyl)C(O)OR, -(C0-C6alkyl)C(O)OH, -(C1-C6halogenated), -O(C1-C6halogenated)- (C0-C6alkyl)heteroseksualci, -SO2R -(C0-C6alkyl)-C(O)-heteroseksualci -(C0-C6alkyl)-C(O)-cycloalkyl -(C0-C6alkyl)-C(O)-heteroaryl -(C0-C6alkyl)-C(O)-aryl, -(C0-C6alkyl)-C(O)O-heteroseksualci -(C0-C6alkyl)-C(O)O-cycloalkyl -(C0-C6alkyl)-C(O)O-heteroaryl -(C0-C6alkyl)-C(O)O-aryl, -(C0-C6alkyl)heteroseksualci -(C0-C6alkyl)heteroaryl -(C0-C6alkyl) aryl and -(C0-C6alkyl)cycloalkyl;

each Het is a heteroaryl group optionally substituted by 1, 2 or 3 groups independently selected from-R, -OR, -(C0-C6alkyl)NR192, -NO2, -Cl, -F, -Br, -I, -CN, -(C0-C6alkyl)OH, -(C0-C6alkyl)CO2R -(C0-C6alkyl)C(O)OH, -(C1-C6halogenated), -O(C1-C6halogenated)- (C0-C6alkyl)heteroseksualci, -SO2R -(C0-C6alkyl)-C(O)-heteroseksualci -(C0-C6alkyl)-C(O)-is cloaker, -(C0-C6alkyl)-C(O)-heteroaryl -(C0-C6alkyl)-C(O)-aryl, -(C0-C6alkyl)-C(O)O-heteroseksualci -(C0-C6alkyl)-C(O)O-cycloalkyl -(C0-C6alkyl)-C(O)O-heteroaryl -(C0-C6alkyl)-C(O)O-aryl, -(C0-C6alkyl)-heteroseksualci -(C0-C6alkyl)-heteroaryl -(C0-C6alkyl)-aryl and -(C0-C6alkyl)-cycloalkyl;

each Hca is geterotsyklicescoe group optionally substituted by 1, 2 or 3 substituents, independently selected from-R, -(C1-C6haloalkyl), -O(C1-C6haloalkyl)- (C0-C6alkyl)C(O)OR, -(C0-C6alkyl)C(O)R, =O, -OH, -CN, -(C0-C6alkyl)OR-OCH2CH2-O-, -OCH2O-, -SO2-R, -SO2-(C1-C6halogenated)- (C0-C6alkyl)C(O)NR192-(C0-C6alkyl)heteroseksualci -(C0-C6alkyl)aryl, -(C0-C6alkyl)heteroseksualci -(C0-C6alkyl)cycloalkyl, -SO2-(C0-C6alkyl)heteroseksualci, -SO2-(C0-C6alkyl)aryl, -SO2-(C0-C6alkyl)heteroaryl, -SO2-(C0-C6alkyl)heteroaryl, -SO2-(C0-C6alkyl)cycloalkyl;

each of R10and R11independently represents-H or-R;

each is th of R 19independently selected from-H, -HE-R, where any -(C1-C8alkyl) or (C1-C8halogenated) group optionally substituted by 1, 2 or 3 substituents, independently selected from =O, -(C0-C6alkoxy), HE or halogen; and (C1-C6halogenated), where (C1-C6halogenated) may be substituted by 1 to 6 halogen, -SO2(C1-C6alkyl) and-C(O)-(C1-C6alkyl);

each of R20is a Hca or Het cycle, where N -(C0-C6alkyl)C(O)NR20represents a heteroatom in Hca or Het cycle, for example, piperidine, piperizine and so on, the cycle is optionally substituted by 1 or 2 substituents, independently selected from =O, -(C1-C6alkoxy), HE or halogen; and (C1-C6halogenoalkane), -SO2(C1-C6alkyl) and-C(O)-(C1-C6alkyl);

each R independently represents -(C1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci)- (C1-C8halogenated) or(C3-C8halogenosilanes), optionally substituted by 1, 2 or 3 substituents, independently selected from -(C1-C6alkoxy), -(C1-C6hydroxyalkyloxy)- (C1-C6hydroxyalkyl), acetoxyethyl, -C(O)O(C1-C6alkyl), -OH, =O, -N(C1-C6alkyl)2 , -NH(C1-C6alkyl), -NH2, -OC(O)(C0-C6alkyl), -SO2(C1-C6alkyl) and- (C0-C6alkyl); and

each (C0-C6alkyl), (C1-C6alkyl) and (C1-C8alkyl) independently represent optionally substituted by 1, 2, 3 or 4 substituents, independently selected from -(C1-C4the alkyl), -(C1-C4alkoxy), -HE, =O, halogen, -C(O)O(C1-C3the alkyl and-C(O)(C1-C3the alkyl); and do not necessarily represent halogenated.

Another aspect of the present invention relates to compounds and salts having the structure of formula I, where

R1and R2independently represents-Cl, -F, -Br, -I or-H, providing that at least one R1and R2represents-Cl, -F, -Br or-I;

R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar or -(C0-C6alkyl)-O-(C0-C6alkyl)Ar;

R4represents-H or-R;

each of R5, R6and R7independently represents-R, -OR, -NRaR19, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-sub> 6alkyl) C(O)ORe-(C0-C6alkyl)C(O)NRaR19or -(C0-C6alkyl)C(O)NRaR19; and

w, x and y independently represent 0, 1 or 2;

where each Reindependently represents-H or-R, each Raindependently represents-H or-R, each R19independently represents-H or-R, each Ar independently represents a phenyl, optionally substituted by 1, 2 or 3 substituents selected from-R, -OR, -NR2, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -C(O)OR, -(C1-C6halogenoalkane) and(C1-C6halogenoalkane), each R independently represents -(C1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci)- (C1-C8foralkyl)- (C3-C8vertikaalsel)- (C1-C8chloroalkyl)- (C3-C8chlorcycloguanil)where -(C1-C6foralkyl)- (C3-C8vertikaalsel)- (C1-C6chloroalkyl) or(C3-C8chlorcycloguanil) can be substituted by 1 to 6 fluorine atoms or chlorine, respectively, each R is optionally substituted by 1, 2 or 3 substituents selected from -(C1-C6alkoxy), -(C1-C8hydroxyalkyl), acetoxyethyl and-C(O)O(C1-C4the alkyl).

In additional desirable embodiments of implementation of the R independently is predstavljaet a -(C 1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci)- (C1-C8foralkyl)- (C3-C8vertikaalsel)- (C1-C8chloroalkyl)- (C3-C8chloralkali)where -(C1-C6foralkyl)- (C3-C8vertikaalsel)- (C1-C6chloroalkyl) or(C3-C8chlorcycloguanil) can be substituted by from 1 to 6 Fermi or harami, respectively, each R is optionally substituted by 1, 2 or 3 substituents selected from -(C1-C6alkoxy), -(C1-C8hydroxyalkyl), acetoxyethyl and-C(O)O(C1-C4the alkyl), ensuring that at least one R represents -(C3-C12heteroseksualci).

Another aspect of the invention relates to compounds and salts having the structure of formula I, where

R1and R2independently represents-Cl, -F, -Br, -I or-H, providing that at least one R1and R2represents-Cl, -F, -Br or-I;

R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192or -(C0-C6alkyl)-C(O)NR20;

R4represents-H or-R;

each of R5, R6and R7 independently represents-R, -OR, -NRaR19, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-C6alkyl) C(O)ORe-(C0-C6alkyl)C(O)NRaR19or -(C0-C6alkyl)C(O)NRaR19; and

w, x and y independently represent 0, 1 or 2; 0 or 1; or 0.

Another aspect of the invention relates to compounds and salts having the structure of formula I, where

R1and R2independently represents-Cl, -F, -Br, -I or-H, providing that at least one R1and R2represents-Cl, -F, -Br or-I;

R3represents -(C0-C6alkyl)C(O)ORe;

R4represents-H or-R;

each of R5, R6and R7independently represents-R, -OR, -NRaR19, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-C6alkyl) C(O)ORe-(C0-C6alkyl)C(O)NRaR19or -(C0-C6alkyl) C(O) NRaR19; and

w, x and y independently represent 0, 1 or 2; 0 or 1; or most preferably 0.

BRIEF DESCRIPTION of DRAWINGS

Figure 1. Schedule Silda antagonism of 5-HT2Areceptor Compound K and compound Q in comparison with clozapine.

Figure 2. The antagonism caused by apomorphine violations when swimming in mice for Connection K and clozapine (in the absence of apomorphine).

Figure 3. The antagonism caused as what morfina violations when swimming in mice for Connection K and clozapine (in the presence of apomorphine).

Figure 4. The antagonism caused by apomorphine violations when swimming in mice to Connect Q (in the presence and in the absence of apomorphine).

Figure 5. Evaluation of catalepsy in murine models catalepsy for Compound K and Compound Q.

6. Evaluation of catalepsy in murine models catalepsy clozapine.

7. Compound K and Compound Q restore failure of NMDA-induced antagonist, when preimposed inhibition.

Fig. Connection K does not reduce spontaneous locomotor activity in rats (open field).

DEFINITION

As used here, the term "alkyl" includes alkyl, alkeline and alkyline group, as with all carbon chains, or cycles, and includes one or more heteroatoms, such as N, O or S. the Term "Cm-Cnalkyl" denotes alkyl, alkenylphenol and alkylamino group having m to n carbon atoms, providing that alkeneamine or alkyline group must have at least two carbon atoms. For example, "C0-C6alkyl" represents an alkyl group having from zero to six carbon atoms, and alkenylphenol group having from two to six atomos carbon, or alkylamino group having from two to six carbon atoms. The preferred alkyl group is an alkyl.

As used here, the term is alkyl" includes alkyl groups with the specified number of carbon atoms, preferably in the range of from 1 to 12 carbon atoms. The term "Cm-Cnalkyl" denotes an alkyl group having in the range from m to n carbon atoms. For example, "C0-C6alkyl" represents an alkyl group having from zero to six carbon atoms. In that case, if the alkyl group contains zero carbon atoms (i.e.0), the group is a simple covalent bond. Alkyl groups can be an unbranched or branched, and depending on the environment, may represent a monovalent radicals or divalent radicals (i.e. alkylenes group). For example, the fragment "-(C0-C6alkyl)-Ar shows the accession of the aryl group through a single bond or alkalinous bridge having from 1 to 6 carbon atoms. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, ISO-, sec - and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl etc. If the number of carbon atoms is not specified, consider "alkyl" fragment has from 1 to 12 carbon atoms.

As used here, the term "alkenyl includes alkeneamine group having at least 2 carbon atoms, preferably in the range of from 2 to about 12. As alkyl groups, alkeline group can be an unbranched or branched and, depending on the environment, may represent a monovalent radicals or divalent radicals. Can be one or more double bonds and which can be contained inside alkenyl (for example, -CH2SN=SNSN2-), positioned on the coupling end of alkenyl (for example, -CH=SNSN(CH3)2or on a terminal end of alkenyl (for example, -CH2CH2CH2C=CH). As used here, the term "alkenyl" also refers to hydrocarbon chains that contain one or more heteroatoms in place of one or more carbon atoms, for example, the heteroatoms are O, N or S.

As used here, the term "quinil includes alkyline group having at least 2 carbon atoms, preferably in the range of from 2 to about 12. As alkyl groups, alkyline group can be an unbranched or branched and, depending on the environment, may represent a monovalent radicals or divalent radicals. Can be one or more double bonds and which can be contained inside of quinil (for example, -CH2SN=SNSN2-), positioned on the coupling end of the quinil (for example, -CH=SNSN(CH3)2or on a terminal end of quinil (for example, -CH2CH2CH2WITH≡CH). As used here, the term "quinil" which also refers to hydrocarbon chains, which include one or more heteroatoms in place of one or more carbon atoms, for example, the heteroatoms are O, N or S.

The term "alkoxy" represents an alkyl group with a given number of atoms of a hydrocarbon, United with the source fragment oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy.

The terms "halogenated and halogenoalkane" refer to alkyl and alkoxy groups substituted by at least one halogen atom and optionally additionally substituted by at least one additional halogen atom, where each halogen is independently represents F, Cl, B, or I. Preferred Halogens are F or Cl, while F is particularly preferred. Preferred halogenated, halogenoalkane groups contain, for example, 1 to 6 carbon atoms, 1-4 carbon atoms or 1-2 carbon atoms. Halogenated, halogenoalkane groups can be perhalogenated, as in the case of-OCF3and-OCF2CF3. As used here, the term "halogenated" also refers to hydrocarbon chains that contain one or more heteroatoms instead of one or more carbon atoms, for example, the heteroatoms are O, N or S.

The term "aryl" represents an aromatic Carbo is clichesque group, having one cycle (e.g., phenyl)which is optionally condensed or connected in other ways with other aromatic hydrocarbon cycles or non-aromatic hydrocarbon cycles. "Aryl" includes multiple condensed cycles, in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), where each cycle does not necessarily represent mono-, di - or tizamidine groups defined below, as well as multiple cycles, which are not condensed, such as, for example, biphenyl or binaphthyl. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphtho, fluorenyl, tetralinyl, 2,3-dihydrobenzofuranyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferably the aryl group is a phenyl or naphthyl. Even more preferably the aryl group is a phenyl.

The term "heteroaryl" refers to the system of the aromatic cycles containing at least one heteroatom selected from nitrogen, oxygen and sulfur. Heteroaryl cycle can be condensed or otherwise associated with one or more heteroaryl, aryl, cycloalkyl or heteroseksualnymi cycles. Examples of heteroaryl groups is clucalc, for example, pyridyl, pyrimidinyl, chinoline, benzothiazyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, ethanolic, hintline, honokalani, phthalazine, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazoles, benzothiazoles, benzimidazoles, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolin, naphthyridine, isopropanol, bromanil, tetrahydroisoquinoline, isoindolines, isobenzofuranyl, isobenzofurandione, isobenzofuranyl, benzoxazolyl, pyridopyrimidines, bettererererer, betterregulation, pyrenyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridines, imidazothiazoles, dihydroergotoxine, benzisoxazole, benzoxazine, dihydromethysticin, benzopyranyl, benzothiophene, chromones, chromanones, pyridinyl-N-oxide, tetrahydroquinoline, dihydroquinoline, dihydroquinoline, dihydroisoquinoline, dihydrocoumarin, dihydroisocoumarin, isoindolines, benzodioxane, benzoxazolinone, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, chinoline N-oxide, indolyl N-oxide, indolyl N-oxide, ethanolic N-oxide, hintline N-oxide, honokalani N-oxide, N phthalazine oxide, imidazolyl N-oxide, isoxazolyl N-oxide, OK is azolyl N-oxide, triazolyl N-oxide, indolizinyl N-oxide, indazole N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiophene S-oxide, benzothiophene S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, chinoline, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazoles, thiazolyl and benzothiazolyl.

The term "cycloalkyl" refers to non-aromatic carbocyclic cycles or loops, which can be saturated (i.e. "cycloalkyl") or unsaturated (i.e. "cycloalkenyl"). Cycloalkenyl cycle optional condensed or otherwise attached to other cycloalkyl cycles, heteroseksualnymi cycles, aryl cycles or heteroaryl cycles. Preferred cycloalkyl groups have from 3 to 7 members. More preferred cycloalkyl groups have 5 or 6 members. Examples cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl and tetrahydronaphthyl.

The term "heteroseksualci" refers to non-aromatic cycles or cycles containing at least one heteroatom, preferably selected from nitrogen, oxygen and sulfur, where the heteroatom is in a non-aromatic cycle. Goethe is cycloalkyl may be saturated (i.e. "heteroseksualci") or unsaturated (i.e. "geteroseksualen"). Heteroseksualci cycle optional condensed or otherwise attached to other heteroseksualci cycles and/or non-aromatic hydrocarbon cycles and/or phenyl cycles. Preferred heteroseksualci groups have from 3 to 12 members. More preferably a single heteroseksualci groups have 5 or 6 members; whereas the preferred heteroseksualci system cycles have from 10 to 12 members. Examples geterotsiklicheskikh groups include, for example, azabicyclo[2.2.2]octyl, (in each case also hinokitiol" or giocodigitale derived) azabicyclo[3.2.1]octyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, 2-oxazolidinyl, piperazinil, homopiperazine, piperazinonyl, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothieno, isoindolines, homopiperazine, homomorpholine, homotaurine, homotaurine S,S-dioxide, oxazolidinones, dihydropyrazolo, dihydropyrrole, dihydropyrazine, dihydropyridines, dihydropyrimidines, dihydrofuran, dihydropyran, imidazolidinyl, tetrahydrofuranyl S-oxide, tetrahydrothieno S,S-dioxide and homotaurine S-oxide. Particularly desirable heteroseksualci group include morpholinyl, tet is hydroporini, piperidinyl, azabicyclo[2.2.2]octyl, γ-butylester (i.e. oxo-substituted tetrahydrofuranyl), pyrrolidinyl, piperazinil, thiomorpholine, thiomorpholine S,S-dioxide, 2-oxazolidinyl, imidazolidinyl, isoindolines, piperazinonyl and mono - and di-sahariana sugars, such as glucose, fructose, sucrose, mannose, arabinose and galactose.

The term "pharmaceutically acceptable salts or their pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Because the connection of the present invention is a base, the salt can be derived from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention include acetate, benzosulfimide (besylate), benzoic, campolongo, lemon, atenololbuy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, muzinovy, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate etc. Preferred additive acid salts are the chloride and sulfate salts and the Li di - and tricarboxylic acids, for example, tartrate, citrate, maleate, succinate, etc.

DETAILED DESCRIPTION of embodiments of the INVENTION

One aspect of the present invention refers to a compound having a structure according to Formula (I)

and its pharmaceutically acceptable salt.

The structure of the formula (I) based on dibenzo[b,f][1,4]oxazepine kernel with the numbering system shown in the Formula (II) below.

R1attached one of 6-9 provisions dibenzo[b,f][1,4]oxazepine, whereas R2attached on one of the 1-4 positions. R1and R2independently represents-Cl, -F, -Br, or-H. Preferably, R1attached to 7 or 8 position of the dibenzo[b,f][1,4]oxazepine. Similarly, R2preferably attached in the 2 or 3 position of the dibenzo[b,f][1,4]oxazepine. According to a preferred variant of the invention, at least one of R1and R2independently represents-F, -Cl, -Br, or I. More preferably, only one of R1and R2independently represents-F, -Cl, -Br or-I, and the other represents-H.

Piperazine substituted R3when the carbon atom located perifericheskie towards dibenzo[b,f][1,4]oxazepine, as shown in the Formula (I). R3can depict ablate a-R (but not necessarily replaced in this case with R 3)- (C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar -(C0-C6alkyl)-O-(C0-C6alkyl)Ar -(C0-C6alkyl)-OR -(C0-C6alkyl)C(O)Rkor -(C0-C6alkyl)NRaR19where R, Re, Ra, R19, Ar, Het, Hca, Cak are as described below. Each alkyl group may be, for example, alkyl group. In preferred embodiments, the implementation of R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar or -(C0-C6alkyl)-O-(C0-C6alkyl)Ar. In another preferred embodiment of the invention R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)N RaR19-(C0-C6alkyl)C(O)NR192or -(C0-C6alkyl)C(O)NR20. In an additional preferred embodiment, the image is etenia R 3represents -(C0-C6alkyl)C(O)ORe. In yet another additional embodiment of the invention R3represents -(C0-C6alkyl)C(O)ORewhere -(C0-C6alkyl) is -(C1-C6alkyl), -(C1-C4alkyl), or -(C1-C2alkyl).

Other preferred substituents R3have hem-, mono - or dialkyl substitution at the alpha-position of the functional group, for example, the carbon atom. Thus, in certain preferred embodiments, the implementation of the present invention each (C0-C6alkyl) directly associated with piperazinonyl cycle, as part of R3represents -(C0-C5alkyl)C(C1-C3alkyl)2where (C0-C5alkyl) independently optionally substituted by 1 or 2 substituents, independently selected from -(C1-C4alkyl), -(C1-C4alkoxy), -HE, =O, -halogen, -C(O)O(C1-C3alkyl),- C(O)(C1-C3alkyl), and optionally galogenidov.

In certain particularly preferred embodiments of the invention R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)N RaR19-(C0-C alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20. In yet another preferred embodiment of the invention R3represents -(C0-C6alkyl)C(O)ORe. In these embodiments, the implementation of each0-C6alkyl is directly linked to piperazinonyl cycle, as part of R3can represent, for example, With2-C6alkyl or, alternatively, With1-C2alkyl. In certain embodiments of the invention R3represents -(C0-C5alkyl)C(C1-C3alkyl)2C(O)ORe-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NRa2-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NRaR19-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NR192-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NR20-(C0-C5alkyl)C(C1-C3alkyl)2Ar -(C0-C6alkyl)-O-(C0-C5alkyl)C(C1-C3alkyl)2Ar -(C0-C5alkyl)C(C1-C3alkyl)2CR -(C0-C5alkyl)C(C1-C3alkyl)2C(O)Rkor -(C0-C5alkyl)C(C1-C3alkyl)2NRaR19. Finally, the decree of the different variants of the invention, each of R 5, R6and R7preferably independently represents-R, -OR, -NR192, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-C2alkyl)C(O)or, or -(C0-C2alkyl)C(O)NR192.

The group R3will form a chiral center in piperazinovom cycle. The group R3can be attached to pieperazinove cycle inSconfiguration orRconfiguration. The compound or salt can exist as a racemic mixture or in the form of a mixture enriched enantiomers or diastereoisomers having at least 80% enantiomeric or diastereoisomeric excess of the hydrocarbon, joining R3group to the piperazine.

Piperazine substituted R4when nitrogen peripheral in relation to the dibenzo[b,f][1,4]oxazepine, as shown in the Formula (I). R4can represent, for example, -N or-R In certain particularly preferred embodiments of the invention R4represents-N.

Benzene fragments dibenzo[b,f][1,4]oxazepine nuclei can be substituted by substituents different from R1or R2. For example, as shown in the Formula (I), 6-9 provisions dibenzo[b,f][1,4]oxazepine can be substituted by 0, 1, 2, or 3 R5substituents (i.e. x represents 0, 1, 2 or 3). Similarly, 1-4 provisions can be is substituted by 0, 1, 2, or 3 R6substituents (i.e. y is 0, 1, 2 or 3). The substituents R5and R6independently represent-R, -(C0-C6alkyl)-OR -(C0-C6alkyl)NRaR19, -NO2, -halogen, -CN, -OH, -OOCR, -(C0-C6alkyl)COORe-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)Ar -(C0-C6alkyl)-O-(C0-C6alkyl)Ar -(C0-C6alkyl)Het, -(C0-C6alkyl)-O-(C0-C6alkyl)Het, -(C0-C6alkyl)Hca, -(C0-C6alkyl)-O-(C0-C6alkyl)Hca, -(C0-C6alkyl)Cak, -(C0-C6alkyl)-O-(C0-C6alkyl)Cak, -(C0-C6alkyl)C(O)Hca, -(C0-C6alkyl)C(O)Ar, -(C0-C6alkyl)C(O)Het or -(C0-C6alkyl)C(O)Cak, where R, Ra, R19, Ar, Het, Hca, Cak are as described below. Each of the alkyl groups may represent, for example, alkyl group. Particularly preferred R5and R6the substituents include-R, -OR, -NR192, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-C2alkyl)C(O)OR, and -(C0-C2alkyl)C(O)NR192. Preferably dibenzo[b,f][1,4]oxazepine substituted by 0 or 1 R5substituents (i.e. x represents 0 or 1). Similarly, dibenzo[b,f][1,4]oxazepine preferably is substituted by 0 or 1 R 6substituents (i.e. y is 0 or 1). In certain preferred embodiments, the implementation of dibenzo[b,f][1,4]oxazepine not substituted R5or R6groups (i.e. both x and y are 0).

Similarly, pieperazinove cycle structure of formula (I) may be substituted by substituents other than R3and R4. For example, as shown in the Formula (I), pieperazinove cycle may be substituted by 0, 1, 2, or 3 R7substituents (i.e. w represents 0, 1, 2 or 3). The substituents R7independently represent-R, -(C0-C6alkyl)-OR -(C0-C6alkyl)NRaR19, -NO2, -halogen, -CN, -OH, -OOCR, -(C0-C6alkyl)COORe-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)Ar -(C0-C6alkyl)-O-(C0-C6alkyl)Ar -(C0-C6alkyl)Het, -(C0-C6alkyl)-O-(C0-C6alkyl)Het, -(C0-C6alkyl)Hca, -(C0-C6alkyl)-O-(C0-C6alkyl)Hca, -(C0-C6alkyl)Cak, -(C0-C6alkyl)-O-(C0-C6alkyl)Cak, -(C0-C6alkyl)C(O)Hca, -(C0-C6alkyl)C(O)Ar, -(C0-C6alkyl)C(O)Het or -(C0-C6alkyl)C(O)Cak, where R, Ra, R19, Ar, Het, Hca, Cak are as described below. Each of the alkyl groups may constitute, in the example, alkyl group. Particularly preferred R7the substituents include-R, -OR, -NR192, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-C2alkyl)C(O)OR, and -(C0-C2alkyl)C(O)NR192. Preferably piperazine is substituted by 0 or 1 R7substituents (i.e. w represents 0 or 1). In certain preferred embodiments, the implementation of the piperazine is not substituted R7groups.

In certain preferred embodiments, the implementation of the 11-piperazine-1-yl dibenzo[b,f][1,4]oxazepine not substituted R5, R6or R7groups (i.e. w, x and y each represents 0). In other preferred embodiments of the invention w, x and y each represents 0 and R4represents-N.

In the compounds according to the present aspect of the invention each Recan independently represent-H, -R, -(C1-C6alkyl)C(O)Hca, -(C1-C6alkyl)C(O)Cak, -(C1-C6alkyl)C(O)Het, -(C1-C6alkyl)C(O)Ar, -(C1-C6alkyl)C(O)O-Hca, -(C1-C6alkyl)C(O)O-Cak, -(C1-C6alkyl)C(O)O-Het, -(C1-C6alkyl)C(O)O-Ar, -(C0-C6alkyl)Hca, -(C0-C6alkyl)Het, -(C0-C6alkyl)Ar -(C0-C6alkyl)Cak, -(C1-C6alkyl)C(O)OR, -(C1-C6alkyl)C(O)NR192-(C0-C6and the keel)-or, or -(C 0-C6alkyl)-OH, where R, R19, Ar, Het, Hca, Cak are as described below. Each of the alkyl groups may represent, for example, alkyl group. Particularly preferred Reindependently represent-H or-R.

In the compounds according to this aspect of the invention each Racan independently represent-H, -R, -(C1-C6alkyl)OR -(C1-C6alkyl)-OH, -(C1-C6alkyl)C(O)OR, -(C1-C6alkyl)C(O)NR192-(C0-C6alkyl)Hca, -(C0-C6alkyl)Ar -(C0-C6alkyl)Het or -(C0-C6alkyl)Cak, where R, R19, Hca, Ar, Het and Cak are as described below. Each of the alkyl groups may represent, for example, alkyl group. Preferably Raindependently represent-H or-R.

In the compounds according to this aspect of the invention each Rkindependently represents-H, -R, -(C1-C6alkyl)C(O)Hca, -(C1-C6alkyl)C(O)Cak, -(C1-C6alkyl)C(O)Het, -(C1-C6alkyl)C(O)Ar, -(C1-C6alkyl)Hca, -(C0-C6alkyl)Het, -(C0-C6alkyl)Ar -(C0-C6alkyl)Cak, -(C1-C6alkyl)(O)or, or -(C1-C6alkyl)C(O)NR192where R, Hca, Cak, Het, Ar and R19represent such as op is Sano below. Each of the alkyl groups may represent, for example, alkyl group.

In the compounds according to the present aspect of the invention, each Cak is an cycloalkyl group optionally substituted by 1, 2 or 3 substituents, independently selected from-R, -(C0-C6alkyl)(O)OR, =O, -OH, -CN, -(C0-C6alkyl)OR-OCH2CH2-O-, -OCH2-O-, -SO2-R, -SO2-(C1-C6halogenated)- (C0-C6alkyl)C(O)NR192-(C0-C6alkyl)Het, -SO2(C0-C6alkyl)Hca, -(C0-C6alkyl)Ar -(C0-C6alkyl)Het, -(C0-C6alkyl)Hca, -(C0-C6alkyl)C(O)R, -SO2(C0-C6alkyl)Ar, -SO2(C0-C6alkyl)Het and SO2(C0-C6alkyl)cycloalkyl, where R, R19, Het, Hca and Ar are as described below. Each of the alkyl groups may represent, for example, alkyl group. Each of cycloalkyl groups may represent, for example, cycloalkyl group. Preferably Cak is cycloalkyl group. In certain preferred embodiments of the invention each Cak is an optionally substituted cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl.

In the compounds according to the present aspect of the invention, each Ar p is ecstasy an aryl group, optionally substituted by 1, 2 or 3 substituents, independently selected from-R, -OR, -(C0-C6alkyl)NR192, -NO2, -Cl, -F, -Br, -I, -CN, -(C0-C6alkyl)OH, -(C0-C6alkyl)C(O)OR, -(C0-C6alkyl)C(O)OH, -(C1-C6halogenated), -O(C1-C6halogenated)- (C0-C6alkyl)heteroseksualci, -SO2R -(C0-C6alkyl)-C(O)-heteroseksualci -(C0-C6alkyl)-C(O)-cycloalkyl -(C0-C6alkyl)-C(O)-heteroaryl -(C0-C6alkyl)-C(O)-aryl, -(C0-C6alkyl)-C(O)O-heteroseksualci -(C0-C6alkyl)-C(O)O-cycloalkyl -(C0-C6alkyl)-C(O)O-heteroaryl -(C0-C6alkyl)-C(O)O-aryl, -(C0-C6alkyl)heteroseksualci -(C0-C6alkyl)heteroaryl -(C0-C6alkyl)aryl, -(C0-C6alkyl)cycloalkyl, where R and R19are as described below. Each of the alkyl groups may represent, for example, alkyl group. Each of geterotsiklicheskikh groups may represent, for example, geterotsyklicescoe group. In certain preferred embodiments of the invention, each Ar is an optionally substituted 1, 2 or 3 substituents selected from-R, -OR, -NR2, -NO2, -Cl, -F, -Br, -I, -CN, -OH and-C(O)OR.

In connected is provided according to the present aspect of the invention, each Het is a heteroaryl group, optionally substituted by 1, 2 or 3 groups independently selected from-R, -OR, -(C0-C6alkyl)NR192, -NO2, -Cl, -F, -Br, -I, -CN, -(C0-C6alkyl)OH, -(C0-C6alkyl)CO2R -(C0-C6alkyl)C(O)OH, -(C1-C6halogenated), -O(C1-C6halogenated)- (C0-C6alkyl)heteroseksualci, -SO2R -(C0-C6alkyl)-heteroseksualci -(C0-C6alkyl)-C(O)-cycloalkyl -(C0-C6alkyl)-C(O)-heteroaryl -(C0-C6alkyl)-C(O)-aryl, -(C0-C6alkyl)-C(O)O-heteroseksualci -(C0-C6alkyl)-C(O)O-cycloalkyl -(C0-C6alkyl)-C(O)O-heteroaryl -(C0-C6alkyl)-C(O)O-aryl, -(C0-C6alkyl)-heteroseksualci -(C0-C6alkyl)-heteroaryl -(C0-C6alkyl)-aryl and -(C0-C6alkyl)-cycloalkyl, where R and R19are as described below. Each of the alkyl groups may represent, for example, alkyl group. Each of cycloalkyl groups may represent, for example, cycloalkyl group. Each of geterotsiklicheskikh groups may represent, for example, geterotsyklicescoe group. In certain preferred embodiments of the invention, each Het is an optionally substituted n is Ridel, pyrimidyl, chinoline, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, indazoles, thiazolyl or benzothiazolyl.

In the compounds according to the present aspect of the invention, each Hca is geterotsyklicescoe group optionally substituted by 1, 2 or 3 substituents, independently selected from-R, -(C1-C6halogenated), -O(C1-C6halogenated)- (C0-C6alkyl)C(O)OR, -(C0-C6alkyl)C(O)R, =O, -OH, -CN, -(C0-C6alkyl)OR-OCH2CH2-O-, -OCH2O-, -SO2-R, -SO2-(C1-C6halogenated)- (C0-C6alkyl)C(O)NR192-(C0-C6alkyl)geterotsiklicheskie -(C0-C6alkyl)aryl, -(C0-C6alkyl)geterotsiklicheskie -(C0-C6alkyl)cycloalkyl, -SO2(C0-C6alkyl)geterotsiklicheskie, -SO2(C0-C6alkyl)aryl, -SO2-(C0-C6alkyl)heteroaryl, -SO2-(C0-C6alkyl)heteroaryl, -SO2-(C0-C6alkyl)cycloalkyl, where R and R19are as described below. Each of the alkyl groups may represent, for example, alkyl group. Each of cycloalkyl groups may represent, for example, cycloalkyl group. Each of geterotsiklicheskikh groups can represent, e.g. the, geterotsyklicescoe group. In certain preferred embodiments of the invention, each Hca is an optionally substituted morpholinyl, tetrahydropyranyl, piperidinyl, Aza-bicyclo [2.2.2]octyl, γ-butylacetyl, pyrrolidinyl, piperazinil, thiomorpholine, thiomorpholine, S,S-dioxide, 2-oxazolidinyl, imidazolidinyl, isoindolines, piperazinonyl.

In the compounds according to the present aspect of the invention, each of R10and R11independently represents-H or-R, where-R is the same as described below.

In the compounds according to the present aspect of the invention, each of R19independently selected from-H, -HE-R, where-R is the same as described below. Each of the alkyl groups may represent, for example, alkyl group.

In the compounds according to the present aspect of the invention, each of R20is a Hca or Het cycle, where N -(C0-C6alkyl)C(O)NR20represents a heteroatom in Hca or Het cycle, the cycle is optionally substituted by 1 or 2 substituents, independently selected from =O, -(C1-C6alkoxy), HE or halogen; and (C1-C6halogenoalkane), -SO2(C1-C6alkyl) and-C(O)-(C1-C6alkyl).

In the compounds according to the present aspect of the invention, each R is independently presented yet a -(C 1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci)- (C1-C8halogenated) or(C3-C8halogenosilanes), optionally substituted by 1, 2 or 3 substituents, independently selected from -(C1-C6alkoxy), -(C1-C6hydroxyalkoxy)- (C1-C6hydroxyalkyl), acetoxyethyl, -C(O)O(C1-C6the alkyl), -OH, =O, -N(C1-C6alkyl)2, -N(C1-C6alkyl), -NH2, -OC(O)(C0-C6alkyl), -SO2(C1-C6alkyl) and- (C0-C6alkyl). Each (C1-C8halogenated) or (C3-C8halogenosilanes) may be optionally substituted from 1 to 6 additional halogen. Each of the alkyl groups may represent, for example, alkyl group.

In the compounds according to the present aspect of the invention, each (C0-C6alkyl), (C1-C6alkyl) and (C1-C8alkyl) independently represents an optionally substituted 1, 2, 3 or 4 substituents, independently selected from -(C1-C4the alkyl), -(C1-C4alkoxy), -HE, =O, halogen, -C(O)O(C1-C3the alkyl and-C(O)(C1-C3the alkyl); and do not necessarily represent halogenated. Each of the alkyl groups may represent, for example, al is safe group.

According to this aspect of the invention, one or more alkyl groups can be alkeneamine group or alkyline group. In certain embodiments of the invention at least one alkyl group is alkenylphenol group or alkylamino group. Alternatively, in certain preferred embodiments, the implementation of the present invention, all the alkyl groups are alkyl groups.

Another aspect of the present invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, in which R1and R2independently represents-Cl, -F, -Br, -I or-H, providing that at least one R1and R2represents-Cl, -F, -Br or-I; R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar or -(C0-C6alkyl)-O-(C0-C6alkyl)Ar; R4represents-H or-R; each R5, R6and R7independently represents-R, -OR, -NRaR19, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -OOCR, -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa, R 19or -(C0-C6alkyl)C(O)NRaR19; and w, x and y independently represent 0, 1 or 2; where each of Reindependently represents-H or-R, each Raindependently represents-H or-R, each R19independently represents-H or-R, each Ar is a phenyl, independently optionally substituted by 1, 2 or 3 substituents selected from-R, -OR, -NR2, -NO2, -Cl, -F, -Br, -I, -CN, -OH, -C(O)OR, -(C1-C6halogenoalkane) and(C1-C6halogenoalkane), and each R independently represents -(C1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci)- (C1-C8foralkyl)- (C3-C8vertikaalsel)- (C1-C8chloroalkyl)- (C3-C8chlorcycloguanil)where -(C1-C6foralkyl)- (C3-C8vertikaalsel)- (C1-C6chloroalkyl) or(C3-C8chlorcycloguanil) can be substituted by from 1 to 6 Fermi or harami, respectively, each R is optionally substituted by 1, 2 or 3 substituents selected from -(C1-C6alkoxy), -(C1-C8hydroxyalkyl), acetoxyethyl and-C(O)O(C1-C4the alkyl).

In preferred compounds according to the present invention, only one of R1and R2represents-Cl, -F, -Br or-I, whom all the rest are-H. For example, one of R1or R2can be Cl, and the other may be-N. R1preferably attached to 7 or 8 position of the dibenzo[b,f][1,4]oxazepine and R2preferably joined by his 2 or 3 position.

In preferred compounds according to the present invention R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6)C(O)NR192or -(C0-C6alkyl)C(O)NR20. More preferably R3represents -(CH2)pCO2Re, -(CH2)pCONRa2, -(CH2)pC(O)ONRaR19, -(CH2)pC(O)NR20or -(CH2)pCONR192where p is a 0, 1, 2, 3, 4, 5 or 6. For example, p may represent 1 or 2. In yet another embodiment of the invention R3represents -(CH2)pCO2Re, -(CH2)pCONRa2, -(CH2)pC(O)ONRaR19. In certain preferred embodiments the invention, the R3 group can have hem-mono or dialkyl substitution at the alpha-position of its functional groups. So, each (C0-C6alkyl) directly related to piperazinonyl cycle, PQS is LCU part R 3preferably represents -(C0-C5alkyl)-C-(C1-C3alkyl)2- group. For example, R3can be a -(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)ORe-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NRa2-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NRaR19-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NR192-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NR20, -(CH2)qCRd2CO2Re, -(CH2)qCRd2CONRa2, -(CH2)qCRd2CONR192, -(CH2)qCRd2CONRaR19or -(CH2)qCRd2CONR20where q represents 0, 1, 2, 3, 4 or 5 and each Rdis an independently-Me, -Et or-Pr. Preferably q represents 0, 1 or 2. In certain preferred embodiments of the invention R3represents -(C0-C6alkyl)C(O)ORe. Recan represent, for example, -H, -Me, -Et, Pr or Bu. In a more particularly preferred embodiment of the invention R3represents -(C0-C3alkyl)C(O)ORe where Recan represent, for example, -H, -Me, -Et, Pr or Bu. In a further particularly preferred embodiment of the invention R3represents -(C1-C2alkyl)C(O)ORewhere Recan represent, for example, -H, -Me, -Et, Pr or Bu. In other preferred embodiments of the invention R3represents -(C0-C6alkyl)C(O)othera-(C0-C3alkyl)C(O)otheraor -(C1-C2)C(O)otherawhere Racan represent, for example, -H, -Me, -Et, Pr or Bu.

This aspect of the invention R3the group may be attached to pieperazinove cycle inSconfiguration orRconfiguration. The compound or salt can exist as a racemic mixture, selamicesme mixture, or enriched enantiomers or diastereoisomers mixture having at least 80% of the excess enantiomer or diastereoisomer when the carbon joining R3group to the piperazine.

In certain embodiments of the implementation according to this aspect of the invention R4is a-H. In other preferred embodiments, the implementation of w, x and e are zero.

In other preferred embodiments, the implementation of the alkyl group is an alkyl.

Another aspect of the present invention relative to the HSIA connection, having the structure of Formula (III)

and its pharmaceutically acceptable salts.

The structure of the formula (III) is also based on dibenzo[b,f][1,4]oxazepine kernel with the numbering system shown above in Formula (II).

In embodiments, the implementation of this aspect of the invention R1attached to 8th position dibenzo[b,f][1,4]oxazepine, whereas R2attached at the 2 position. R1and R2independently represents-Cl, -F, -Br, -I or-H. According to a preferred variant of the invention, at least one of R1and R2independently represents-F, -Cl, -Br, or I. More preferably only one of R1and R2independently represents-F, -Cl, -Br or-I, and the other represents-H.

Piperazine substituted R3when the carbon atom located perifericheskie against dibenzo[b,f][1,4]oxazepine, as shown in the Formula (III), or 3' position. R3can be a-R (but not necessarily replaced in this case with R3)- (C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar -(C0-C6lcil)-O-(C 0-C6alkyl)Ar -(C0-C6alkyl)-OR -(C0-C6alkyl)C(O)Rkor -(C0-C6alkyl)NRaR19where R, Re, Ra, R19, Ar, Het, Hca, Cak are as described below. Each alkyl group may be, for example, alkyl group. In preferred embodiments, the implementation of R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192-(C0-C6alkyl)C(O)NR20-(C0-C6alkyl)Ar or -(C0-C6alkyl)-O-(C0-C6alkyl)Ar. In another preferred embodiment of the invention R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192or -(C0-C6alkyl)C(O)NR20. In an additional preferred embodiment of the invention R3represents -(C0-C6alkyl)C(O)ORe. In yet another additional embodiment of the invention R3represents -(C0-C6alkyl)C(O)ORewhere -(C0-C6alkyl) is -(C1-C6alkyl), -C 1-C4alkyl), or -(C1-C2alkyl).

Other preferred substituents R3have gem-dialkyl or monoalkyl substitution in the alpha-position of the functional group, for example a carbon atom. Thus, in certain preferred embodiments, the implementation of the present invention each (C0-C6alkyl)directly associated with piperazinonyl cycle, as part of R3represents -(C0-C5alkyl)C(C1-C3alkyl)2where (C0-C5alkyl) independently optionally substituted by 1 or 2 substituents, independently selected from -(C1-C4alkyl), -(C1-C4alkoxy), -HE, =O, -halogen, -C(O)O(C1-C3alkyl) and-C(O)(C1-C3alkyl); and optional galogenidov.

In certain particularly preferred embodiments of the invention R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192or -(C0-C6alkyl)C(O)NR20. In these embodiments, the implementation of each0-C6alkyl is directly linked to piperazinonyl cycle, as part of R3can represent, for example, With2-C6alkhalili, alternatively, With1-C2alkyl. In certain embodiments of the invention R3represents -(C0-C5alkyl)C(C1-C3alkyl)2C(O)ORe-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NRa2-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NRaR19-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NR192-(C0-C5alkyl)C(C1-C3alkyl)2C(O)NR20-(C0-C5alkyl)C(C1-C3alkyl)2Ar -(C0-C6alkyl)-O-(C0-C5alkyl)C(C1-C3alkyl)2Ar -(C0-C5alkyl)C(C1-C3alkyl)2CR -(C0-C5alkyl)C(C1-C3alkyl)2C(O)ORkor -(C0-C5alkyl)C(C1-C3alkyl)2NRaR19.

The group R3will form a chiral center in piperazinovom cycle. The group R3can be attached to pieperazinove cycle inSconfiguration orRconfiguration. The compound or salt can exist as a racemic mixture, selamicesme mixture, or enriched enantiomers or diastereoisomers mixture having at least 80% of the excess enantiomer or diastereoisomer when the carbon joining R3gr is PPI to piperazine.

Piperazine substituted R4when the nitrogen atom, located perifericheskie towards dibenzo[b,f][1,4]oxazepine, as shown in the Formula (I). R4can represent, for example, -N or-R In certain particularly preferred embodiments of the invention R4represents-N.

In the compounds according to the present aspect of the invention each Re, Ra, Cat, Ar, Het, Hca is as defined under formula (I) and (II).

In the compounds according to the present aspect of the invention, each of R10and R11independently represents-H or-R, where R is such as described below.

In the compounds according to the present aspect of the invention, each of R19independently selected from-H, -HE-R-R such as described below. Each of the alkyl groups may represent, for example, alkyl group.

In the compounds according to the present aspect of the invention, each of R20is a Hca or Het cycle, where N -(C0-C6alkyl)C(O)NR20represents a heteroatom in Hca or Het cycle, the cycle is optionally substituted by 1 or 2 substituents, independently selected from =O, -(C1-C6alkoxy), HE or halogen; and (C1-C6halogenoalkane), -SO2(C1-C6alkyl) and-C(O)-(C1-C6alkyl).

In the compounds according to the present is the SPECTA of the invention, each R independently represents -(C 1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci)- (C1-C8halogenated) or(C3-C8halogenosilanes), optionally substituted by 1, 2 or 3 substituents, independently selected from -(C1-C6alkoxy), -(C1-C6hydroxyalkyloxy)- (C1-C6hydroxyalkyl), acetoxyethyl, -C(O)O(C1-C6the alkyl), -OH, =O, -N(C1-C6alkyl)2, -N(C1-C6alkyl), -NH2, -OC(O)(C0-C6alkyl), -SO2(C1-C6alkyl) and- (C0-C6alkyl). Each (C1-C8halogenated) or (C3-C8halogenosilanes) may be optionally substituted from 1 to 6 additional halogen. Each of the alkyl groups may represent, for example, alkyl group.

In the compounds according to the present aspect of the invention, each (C0-C6alkyl), (C1-C6alkyl) and (C1-C8alkyl) independently represents an optionally substituted 1, 2, 3 or 4 substituents, independently selected from -(C1-C4the alkyl), -(C1-C4alkoxy), -HE, =O, halogen, -C(O)O(C1-C3the alkyl and-C(O)(C1-C3the alkyl); and may not be halogenated. Each of the alkyl groups may represent, for example, alkyl GRU is PU.

According to this aspect of the invention, one or more alkyl groups can be alkeneamine group or alkyline group. In certain embodiments of the invention, at least one alkyl group is alkenylphenol group or alkylamino group. Alternatively, in certain preferred embodiments, the implementation of the present invention, all the alkyl groups are alkyl groups.

In preferred compounds according to this aspect of the invention R3represents -(C0-C6alkyl)C(O)ORe-(C0-C6alkyl)C(O)NRa2-(C0-C6alkyl)C(O)NRaR19-(C0-C6alkyl)C(O)NR192or -(C0-C6alkyl)C(O)NR20. More preferably R3represents -(CH2)pCO2Re, -(CH2)pCONRa2, -(CH2)pC(O)ONRaR19, -(CH2)pC(O)NR20or -(CH2)pCONR192where p is a 0, 1, 2, 3, 4, 5 or 6. For example, p may represent 1 or 2. In certain preferred embodiments the invention, the R3 group is gem-dialkyl substitution at the alpha-position of its functional groups. So, each (C0-C6alkyl) include the directly with piperazinonyl cycle, as part of R3preferably represents -(C0-C5alkyl)-C-(C1-C3alkyl)2- group. For example, R3can be a -(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)ORe-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NRa2-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NRaR19-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NR192-(C0-C5alkyl)-C-(C1-C3alkyl)2C(O)NR20, -(CH2)qCRd2CO2Re, -(CH2)qCRd2CONRa2, -(CH2)qCRd2CONR192, -(CH2)qCRd2CONRaR19or -(CH2)qCRd2CONR20where q represents 0, 1, 2, 3, 4 or 5 and each Rdis an independently-Me, -Et or-Pr. Preferably q represents 0, 1 or 2. Particularly preferred variants of the invention, R3represents -(C0-C6alkyl)C(O)ORe. Recan represent, for example, -H, -Me, -Et, Pr or Bu. In a more particularly preferred embodiment of the invention R3represents -(C0-C alkyl)C(O)ORewhere Recan represent, for example, -H, -Me, -Et, Pr or Bu. In a further particularly preferred embodiment of the invention R3represents -(C1-C2alkyl)C(O)ORewhere Recan represent, for example, -H, -Me, -Et, Pr or Bu. In other preferred embodiments of the invention R3represents -(C0-C6alkyl)C(O)othera-(C0-C3alkyl)C(O)otheraor -(C1-C2alkyl)C(O)otherawhere Racan represent, for example, -H, -Me, -Et, Pr or Bu.

This aspect of the invention R3the group may be attached to pieperazinove cycle inSconfiguration orRconfiguration. The compound or salt can exist as a racemic mixture, selamicesme mixture, or enriched enantiomers or diastereoisomers mixture having at least 80% of the excess enantiomer or diastereoisomer when the carbon joining R3group to the piperazine.

In certain embodiments of the implementation according to this aspect of the invention R4is a-H.

Another aspect of the present invention refers to the compound having the structure of Formula (IV)

or its pharmaceutically acceptable salts, where R1and R2illegal is isimo are-Cl, -F, -Br, -I or-H, providing that at least one of R1and R2independently represents-F, -Cl, -Br or-I; R4represents-H or-R, R8represents-H, -Me, -Et or-Pr; R9represents-H, -Me, -Et or-Pr; B is O or NH and R12represents-H, -Me, -Et or-Pr. In certain preferred embodiments of the invention B is O. In certain preferred embodiments of the invention R8and R9both represent-Me. In certain other preferred embodiments of the invention R8and R9both represent-Et. In certain other preferred embodiments of the invention one of R8and R9represents-H and the other represents-Me, -Et or-Pr. On the seventh position of the dibenzo[b,f][1,4]oxazepine or 8 position of the dibenzo[b,f][1,4]oxazepine can be attached-Cl. In other preferred embodiments of the invention R4is a-H.

Another aspect of the present invention refers to compounds having one of the following structures or their pharmaceutically acceptable salts:

(E)ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate
ConnectionConnection.
And
(E)ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-isobutylacetateB
(E)ethyl 2-(4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate
* (S)or (R) stereocenter
C
(R,E)methyl 4-((4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)methoxy)benzoateD
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acidE
(E)-ethyl 4-(2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)ethyl)benzoateF
(E)-methyl 4-((4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)methoxy)benzoateG
(E)-ethyl 2-(4-(7-chlorodibenzo[b,f][1,4]OK what azepin-11-yl)piperazine-2-yl)acetate H

(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateI
(E)-ethyl 2-(4-(7-Ferdinando[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateJ
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateK
(E)-isopropyl 2-(4-(8-chlorodibenzo[b,f] [1,4]oxazepine-11-yl)piperazine-2-yl)acetateL
(E)-isopropyl 2-(4-(7-Ferdinando[b,f] [1,4]oxazepine-11-yl)piperazine-2-yl)acetateM
(S,E)methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateN
(R,E)ethyl 2-(4-(8-chloro what benzo[ b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateO
(R,E)methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateP
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acidQ
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoic acidR
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoic acidS

(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acidT
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acidU
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoate acid X
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanol acidY
(R,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acidAB
(R)-2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoic acidAC
(S)-2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoic acidAD
(R)-2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acidAE
(S)-2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acidAF
(R,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoate Isleta AI

(R,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanol acidAJ
(2R)-2-(4-((E)-2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoic acid
* (S) or (R) stereocenter
AM
(2S)-2-(4-((E)-2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-propanoic acid
* (S) or (R) stereocenter
AN
(2R)-2-(4-((E)-2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acid
* (S) or (R) stereocenter
AO
(2S)-2-(4-((E)-2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acid
* (S) or (R) stereocenter
AP
(E)-2-(4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-m is typomania acid
* (S) or (R) stereocenter
AS

(E)-2-(4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanol acid
* (S) or (R) stereocenter
AT
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateAW
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateAX
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)pentanoateAY
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateAZ
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanal BA
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylbutanoateBB

(2R)ethyl-2-(4-((E)-2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoate
* (S) or (R) stereocenter
BC
(2S)ethyl-2-(4-((E)-2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoate
* (S) or (R) stereocenter
BD
(2R)-ethyl-2-(4-((E)-2-chlorodibenzo[b,f] [1,4]oxazepine-11-yl)piperazine-2-yl)butanoate
* (S) or (R) stereocenter
BE
(2S)-ethyl-2-(4-((E)-2-chlorodibenzo [b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoate
* (S) or (R) stereocenter
BF
(E)-ethyl 2-(4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoate
* (S) or (R) stereocenter
BI
(E)-ethyl 2-(4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanal
* (S) or (R) stereocenter
BJ
(R)-ethyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateBM
(S)-ethyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateBN
(R)-ethyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-butanoateBO

(S)-ethyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateBP
(R,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateBS
(R,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanalBT
(S)-ethyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)about anout BW
(R)-ethyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateBX
(S)-ethyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateBY
(R)-ethyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateBZ
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateCC
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanalCD
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateCG
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateCH
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-and the)piperazine-2-yl)pentanoate CI
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateCJ

(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanalCK
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylbutanoateCL
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoic acidCM
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butane acidCN
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)pentane acidCO
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoate acidCP
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanol acidCQ
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxaz the pin-11-yl)piperazine-2-yl)-2-methylbutanoate acid CR
(R)-methyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateCS
(S)-methyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateCT
(R)-methyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateCU
(S)-methyl 2-((R)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateCV
(R,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateCY
(R,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanalCZ

(S)-methyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateDC
(R)-methyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)propanoateDD
(R)-methyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateDE
(S)-methyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)butanoateDF
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateDI
(S,E)-methyl 2-((4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanalDJ
(E)-methyl 2-((4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)methoxy)acetateDM
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl) acetateDN
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetic acidDO

(E)-methyl 2-(4-(8-(trifluoromethyl) d is benzo[ b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetateDQ
(S,E)-cyclopentyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetateDR
(S)-Hinkley-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetateDS
(R)-Hinkley-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetateDT
(S)-Hinkley-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetateDU
(S,E)-tetrahydro-2H-Piran-4-yl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetateDV
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetateDW
(S,E)-cyclopentyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetateDX

Second-butyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1 methylpiperazin-2-yl)acetateDY
(S,E)-tetrahydro-2H-Piran-4-yl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetateDZ
(S,E)-neopentyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateEA
(S,E)-3-methoxy-3-methylbutyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateEB
(S,E)-3-hydroxy-3-methylbutyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateEC
(R)-4-hydroxy-4-methylpentan-2-yl 2-((S)-4-((E)8 chlorodibenzo[ b,f][1,4]oxazepine-11-yl)-piperazine-2-yl) acetateED
(S)-((R)-4-hydroxy-4-methylpentan-2-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl) propanoateEE
(R)-((R)-4-hydroxy-4-methylpentan-2-yl) 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl) piperazine-2-yl) propanoateEF
(S)-((R)-4-hydroxy-4-methylpentan-2-yl) 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl) piperazine-2-yl) butanoateEG

(R)-((R)-4-hydroxy-4-methylpentan-2-yl) 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl) piperazine-2-yl) butanoateEH
(R)-4-hydroxy-4-methylpentan-2-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-methylpropanoateEK
(R)-4-hydroxy-2-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethylbutanalEL
(2S, 4S)-4-hydroxypentanal-4-methylpentan-2-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-the l)acetate EO
Second-butyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateEP
(S)-tetrahydrofuran-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetateEQ
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)1-isobutylpyrazine-2-yl)-acetateER
(R)-1-methylpyrrolidine-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetateES

(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-cyclopropylmethyl)piperazine-2-yl)-acetateET
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide EU
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)-N-(1,3-ditropan-2-yl)ndimethylacetamideEV
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)-N,N-(2,2,2-triptorelin)ndimethylacetamideEW
(S,E)-3-forprofit 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl) acetateEX
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)ndimethylacetamideEY
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)-N-(2-hydroxyethyl)-N-propylacetamideEZ
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-hydroxyethyl)ndimethylacetamideFA
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-((R)-2-hydroxypropyl)ndimethylacetamide FB

(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)ndimethylacetamideFC
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)propanamideFD
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)propanamideFE
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)butanamideFF
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)butanamideFG
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)-2-methylpropanamideFJ
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethyl-N-(2-methoxyethyl)butanamideFK
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-(2-hydroxyethoxy)ethyl)ndimethylacetamide FN
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-hydroxyethyl)-N-methylacetamideFO
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(6-methoxypyridine-3-yl)ndimethylacetamideFP
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2,2-dottorati)ndimethylacetamideFQ
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(((S)-tetrahydrofuran-2-yl)ndimethylacetamideFR
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)ndimethylacetamideFS
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)propanamideFT

(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)propanamideFU
(R)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)butanamideFV
(S)-2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)butanamideFW
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)-2-methylpropanamideFZ
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-2-ethyl-N-(3-hydroxypropyl)butanamideGA
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-methoxypropyl) ndimethylacetamideGD
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-1((R)-3-hydroxypyrrolidine-1-yl)alanonGE
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3,3,3-Cryptor-2-hydroxypropyl)ndimethylacetamideGF
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)Pipera the Jn-2-yl)-1-morpholinoethyl GG
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-1-((S)-2(trifluoromethyl)pyrrolidin-1-yl)alanonGH
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)1-(2-hydroxyethyl)piperazine-2-yl)-N-(2-methoxyethyl)ndimethylacetamideGI

All names and patterns were obtained using ChemDraw Ultra v.9,01, available from Cambridgesoft (www.cambridgesoft.com).

Another aspect of the present invention relates to compounds listed here that gidroksilirovanii one or more times in positions 1-4 or 6-9 according to the numbering shown by the Formula (V).

,

where a hydroxyl group replaces H.

Another aspect of the present invention relates to a method for obtaining compounds of Formula F

,

including the conversion of the compounds of formula (A)

,

or its salts in the compound of formula (In)

,

or its salt, respectively, where Z1and Z2represent a protective nitrogen group (which can be used widely known group, for example, N-gasoline; N; N-nitrobenzyl; N-BoC, N-oxide; N-parametersjpanel; N-benzylmethyl, N-carbobenzoxy (N-CDZ)); the conversion of the compounds of formula (B)

,

in the acid chloride, followed by conversion into the corresponding DIACID formula (C)

,

where Z1and Z2represent a protective nitrogen group; treating the compounds of formula (C)

,

silver catalyst and alcohol to obtain the compounds of formula (D)

,

where Z1and Z2represent a protective nitrogen group, Rerepresents the same as presented here is the formula I, in the form of ester. In additional embodiments of the invention Recan be a -(C1-C6alkyl), -(C1-C6alkyl)-OR, (C1-C6alkyl)-OH, -(C1-C6alkyl)C(O)OR, -(C1-C6alkyl)NR192-(C0-C6alkyl)Hca, -(C0-C6alkyl)Ar -(C0-C6alkyl)Het or -(C0-C6alkyl)Cak. In additional embodiments of the invention Recan be a -(C1-C6alkyl), -(C1-C4alkyl), (C1-C2alkyl) or (C2alkyl); unprotect the compounds of formula (D)

,/p>

or its salt to obtain the compounds of formula (E)

,

or a salt thereof, respectively; alkylation of compounds of formula (E);

,

or its salt with the compound of the formula (G)

,

or its salt to the compounds of formula (F)

,

or its salt, respectively, where R2and R1independently represent-H, -I, -Br, Cl or I and where in each case the relationship between the piperazine and carbonyl fragment is a racemic,RorS. Rerepresents the same as defined here, in the formula I. In additional embodiments of the invention Recan be a -(C1-C6alkyl), -(C1-C6alkyl)-OR -(C1-C6alkyl)-OH, -(C1-C6alkyl)C(O)OR, -(C1-C6alkyl)C(O)NR192-(C1-C6alkyl)Hca, -C0-C6alkyl)Ar -(C0-C6alkyl)Het or -(C0-C6alkyl)Cak. In an additional embodiment of the invention Recan be a -(C1-C6alkyl), -(C1-C4alkyl), -(C1-C2alkyl), or -(C2alkyl). See example 1 for sample synthesis.

Another aspect of the present invention relates to methods for treating various disorders associated with linking the affector with receptors. Given as examples of the symptoms listed here, for each of the compounds include one or more of the following: emergency treatment and supportive therapy in the case of schizophrenia is not curable schizophrenia, childhood schizophrenia, cognitive symptoms or disorders (e.g., the problem of processing speed, attention/alertness, short-term memory, verbal learning, visual learning, reasoning and social cognitively), negative symptoms (such as blunted or ostentatious affects, aphasia, apathy, anhedonia, and impaired attention), bipolar disorder, childhood bipolar disorder, depression, psychotic depression, untreatable depression, the treatment of obsessive-compulsive disorder (OCD), autism, dementia, psychotic dementia, L-DOPA-induced psychosis, psychogenic polydipsia, other delusional States (for example, erotomania, secondary alcohol, etc.), psychotic symptoms associated with neurological disorders (e.g., horii of Herington, Wilson's disease), sleep disturbances, depressive States associated with schizophrenia (e.g., suicidal patients, suicidality, anxiety, deficit disorder (ADD) and hyperactivity deficit disorder attention to detail is I (ADHD), atypical psychosis, mania, schizophreniform disorders, psychotic disorders associated with medications or chemicals, schizoaffective disorder, personality disorders cluster a, delusional disorder, and brief psychiatric disorders. The compounds, salts and compositions according to the invention can be used by themselves or in combination therapies, that is, one with another, or in combination with other agents, such as antidepressants, antipsychotics, etc. the Invention also relates to combination therapy using the compounds, salts and compositions according to the invention with nicotine.

"Combination therapy" (or "co-therapy") includes the introduction of the compound, salt or composition according to the invention and at least a second agent as part of the system special treatment designed to ensure the positive impact from the co-action of these therapeutic agents. The positive effect from the combination includes, but is not limited to, pharmacokinetic and pharmacodynamic joint action derived from a combination of therapeutic agents. Combinations of the compounds of the present invention and other active agents can be administered simultaneously in one combination or separately. When using separate is doing, the introduction of one element may be prior to, simultaneously with or after administration of other agents. The introduction of these therapeutic agents in combination is usually carried out within a certain period of time (usually minutes, hours, days, or weeks, depending on the selected combination). In one embodiment, implementation of combinational therapy combines the introduction of two or more of these therapeutic agents as part of separate systems monotherapy, which are randomly and arbitrarily result in the combinations of the present invention. In another embodiment, "combination therapy" is intended to cover the introduction of these therapeutic agents in a consistent way, which is that each therapeutic agent is administered at different times. As well as the introduction of these therapeutic agents, or at least two therapeutic agents substantially simultaneously. Substantially simultaneous administration can be accomplished, for example, the introduction to the patient a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each therapeutic agent. Sequential or substantially simultaneous introduction of each therapeutic agent may be made by any who agodnym way including but not limited to, oral routes of administration, the intravenous route of administration, intramuscular route of administration, and direct absorption through mucous membrane tissues.

Therapeutic agents can be entered in the same way or in different ways. For example, the first therapeutic agent from the selected combination can be entered when using intravenous, while the other therapeutic agent of the combination can be administered orally. Alternatively, for example, all of therapeutic agents can be administered orally or all therapeutic agents can be entered via intravenous injection. The sequence in which the administered therapeutic agents, is not narrowly critical. "Combination therapy" also includes the introduction of therapeutic agents, as described above in further combination with other biological ingredients and non-drug therapy (e.g. surgery, radiation treatment or medical equipment). In the case where combination therapy further includes a non-drug treatment, non-drug treatment can be performed at any suitable time, yet achieves a beneficial effect from the co-action of the combination of therapeutic agents and non-drug therapy. For example, for the affected cases, the favorable effect continues to be achieved when non-drug therapy temporarily removed from the appointment of therapeutic agents, it is possible for a few days and even weeks.

"Processing" includes any action, such as reducing, lowering, modulation or exclusion, which leads to improved conditions, diseases, disorders, etc. "Treatment" or "therapy" painful condition includes: (1) preventing the disease condition, that is, the conversion to nerazviti symptoms painful condition in the subject, which can be located or is prone to a painful condition, but not yet experiencing or does not show symptoms of the disease condition; (2) inhibiting the disease condition, i.e. delay development of the disease condition or its clinical symptoms; or (3) the relief of painful conditions i.e. induction of temporary or permanent retreat painful condition or its clinical symptoms. "A painful condition" means any disease, condition, symptom or manifestation.

As used here, the term "sleep disorders" includes state recognized expert in this field of technology as sleep disorders, for example, the condition known in the art, or States, which are supposed to constitute violations is on or identified as sleep disorders. Sleep disorders also occur in the subject, which has other medical disorders, diseases or damage to, or the subject, which is subjected to treatment with other medications or medical therapy, where the subject is, as a result, has difficulty falling asleep and/or maintaining the waking state, or experience powerusage or non sleep, for example, a subject suffering from insomnia. Treatment of sleep disorders one or more components, salts or compositions described herein, by itself or in combination also includes treatment of sleep disorders with other disorders, such as CNS disorders (eg, mental or neurological disorders, such as anxiety).

Standards dosage and route of administration described compounds are similar to the standards dosage, already known in the art and known to the expert in this technique (see, e.g., Physicians' Desk Reference, 54thEd, Medical Economics Company, Montvale, NJ, 2000).

Compounds of General formula I, III, IV and V according to the invention can be administered orally, place, parenteral, inhalation or spray or rectally in the form of dosage formulations containing conventional non-toxic pharmaceutically acceptable excipients, adjuvants and carriers. The term parenteral as used here, including the AET cutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal technique of injection or infusion, etc. Additionally, there is provided a pharmaceutical composition containing compounds of General formula I, III, IV and V and a pharmaceutically acceptable carrier. One or more compounds of General formula I, III, IV and V may be present in combination with one or more non-toxic pharmaceutically acceptable excipients and/or diluents and/or adjuvants, and if desired, other active ingredients, for example other antidepressant or antipsychotic drug. Pharmaceutical compositions containing compounds of General formula I, III, IV and V may be in a form suitable for oral use, for example, in the form of tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs and of themselves can be combined with at least one pharmaceutically acceptable control flowability, solvent, adjuvant, diluent, lubricant agent, excipients or their combination.

Compositions intended for oral use can be obtained according to any method known in the art for the production of f the pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and with attractive taste compounds. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the production of tablets. These excipients may constitute, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja agents such as corn starch or alginic acid; binding agents, for example starch, gelatin or gum, and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated using known technological methods. In some cases, these coatings can be obtained by using the known technological methods to delay disintegration and absorption in the gastrointestinal tract, thus providing a prolonged effect over a longer period. For example, there may be used a material providing a time delay, such as glycerine earth or glycerylmonostearate. Additionally, there can be obtained the compounds of the delayed release of one or more coatings.

Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Formulations for oral use may also be presented in the form of lozenges.

Aqueous suspensions contain the active substance in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspendresume agents, for example, carboxymethylcellulose sodium, methylcellulose, gidropropilmetilzelluloza, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum Arabic; dispersing or wetting agents may be a natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecafluorooctane, or condensation products of ethylene oxide with Nepal the mi esters, derived from fatty acids and hexitol, such as polyethyleneglycol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides hexitol, such as polietilensorbit monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Oil suspensions can be formulated by suspendirovanie active ingredients in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Can be added sweeteners and flavoring agents to provide with a pleasant taste compounds. These compositions can be saved by adding an antioxidant such as ascorbic acid.

Dispersively powders and granules suitable for obtaining aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. the examples of suitable dispersing or wetting agents presents dispersing or wetting agents, already mentioned above. There may be additional excipients, for example sweetening, flavoring agents and dyes.

The pharmaceutical compositions according to the invention can also be in the form of an emulsion of oil in water. The oil phase may be a vegetable oil or mineral oil, or a mixture. Suitable emulsifying agents may be a natural gums, for example gum Arabic or tragacanth gum, natural phosphatides, for example soy bean, lecithin, and esters and partial esters derived from fatty acids and hexitol, anhydrides, for example, monooleate sorbitol, and condensation products partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

Syrups and elixirs may be formulated with sweeteners, such as glycerin, propylene glycol, sorbitol, glucose and sucrose. Such compositions may also contain softening agent, preservative, flavoring and dyes. The pharmaceutical composition may be in the form of aqueous or oily input sterile injection. This suspension may be formulated agree prior art when using those dispersing or wetting agents such as those mentioned above. Sterile compositions for and what jacci can also be a sterile solution or sterile suspension in a nontoxic source suitable diluent or solvent, for example, as a solution of 1,3-butanediol. Additional suitable carriers or solvents that can be used are water, ringer solution and isotonic sodium chloride solution. Additionally, sterile fatty oil is traditionally used as a solvent or medium for suspension. For these purposes, can be used any aseptic fatty oils, including synthetic mono - or diglycerides. Additionally, the compositions for injection are used in fatty acids such as oleic acid.

Compounds of General formula I, III, IV and V can also be entered in the form of suppositories, e.g., for rectal administration of medical preparations. Such compositions can be obtained by mixing the drug with a suitable non causing irritation excipient, which is a solid at ordinary temperatures, but is a liquid at the rectal temperature and will therefore melt in the rectum to release the drug product. Such materials include cocoa butter and polyethylene glycols.

Compounds of General formula I, III, IV and V may be administered parenterally in a sterile environment. The drug, depending on the carrier and concentration, can be dissolved or suspended in the carrier. Mainly adjuvants, such as the local anesthetics, preservatives and buffering agents can be dissolved in the carrier.

The compositions can also be used as a topically applied gel, spray or cream, or as a suppository, containing the active ingredients in a total amount from about 0,075% to 30% wt./wt., preferably from 0.2 to 20% wt./wt. And most preferably from 0.4 to 15% wt./wt. In the preparation of the ointment, the active ingredients can be applied or paraffin, or a water-soluble materials.

Alternatively, the active ingredients can be formulated in a cream with ground-based cream the butter in the water. If desired, the aqueous phase of the basis for the cream may include, for example, at least 30% wt./wt. a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol and mixtures thereof. Local composition can include, if desired, a substance that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such enhancers of skin permeability include dimethyl sulfoxide and related analogues. Compounds of the present invention can also be entered when using the device for transcutaneous administration. Preferably local introduction will be carried out when using the patch or the type of reservoir and porous membrane, or a variant of the solid is wow matrix. In each case, the active ingredient is delivered continuously from a reservoir or microcapsules through a membrane permeable to the active component viscous material which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules encapsulating agent may also function as a membrane. Transdermal patch may include a connection in a suitable system of solvents with an adhesive system, such as an acrylic emulsion, and the plaster of polyester. The oil phase of the emulsions according to the present invention may be constituted from known ingredients in a known manner. While the phase may include just the emulsifier, it may include a mixture of at least one emulsifier with a fat or oil or simultaneously with fat and oil. Preferably hydrophilic emulsifier include together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferable to include both oil and grease. Together the composition of the emulsifier(s) with or without stabilizer(s) forms a so-called emulsifying wax, and the wax together with the oil and fat forms a so-called emulsified ointment base which forms the oily var is Giovanna phase compositions cream. Emulsifiers and emulsion stabilizers suitable for use in the compositions of the present invention, among others, include Tween 60, Span 80, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate. The choice of a suitable oil or fat composition is based on achieving the desired cosmetic properties, since the solubility of active ingredients in most of the oils that can be used in the chemical compositions of the emulsions is very low. Thus, the cream should preferably be non-greasy, necrosadism and washable product with acceptable consistency to avoid leakage from tubes or other containers. Can be used direct or razvetvlenno chain mono - or dienone alkalemia esters, di-Saadiyat, isolatedstore propylene glycol fluids coconut fatty acids, isopropyl myristate, decillia, isopropylpalmitate, butilstearat, 2-ethylhexyl palmitate or a mixture of esters with branched chain. They can be used by themselves or in combination, depending on the desired properties. In the alternative, can be used lipids with high melting point, such as white soft paraffin and/or liquid paraffin or other mineral oils.

Used dosage of about 0.1 mg to use the but 140 mg per kilogram of body weight per day in the treatment of conditions defined above (approximately from 0.5 to 7 g of the patient per day). The amount of active ingredient which can be combined with the filler material to obtain a dosage form for a single injection, will largely depend on the organism under treatment, and the specific input forms. Dosage forms for a single injection will usually contain from about 1 mg to about 500 mg of the active ingredient. The daily dose can be introduced in the form of one to four doses per day.

It will be understood that the specific dose for each particular patient will depend upon a variety of factors including the activity of the specific components used, age, body weight, General health, sex, diet, time of administration, route of administration, and rate of excretion, combination drug and the severity of the particular disease, therapy is.

For administration to animals other than human, the composition can be added to the animal food or water for drinking. It may be convenient to make the composition of food and drinking water of the animal so that the animal receives a therapeutically acceptable amount of a composition together with diet. Also it may be convenient to provide the composition as a pre-mixture to be added to food or water for PI the article.

Example 1

The connection K and partial esters:

A 2-liter 3-necked flask dissolve 20 g of 98.5 mmol) dichloride R-piperazinecarboxamide acid (1) in 500 ml water and 500 ml of stabilized dioxane. Cooled in an ice bath and add the indicator phenolphthalein. When using an additional funnel, add conc. NaOH to pH 10 (solution immediately turns pink). When using the second additional funnel type of 30.6 ml (216,7 mmol) benzylbromide in proportions, while keeping the pink color (pH 10) conc. NaOH. Add more phenolphtalein in the middle of add, which takes 0.5 hours. Stirred over night at room temperature (RT). Extracted with 1 l of a simple ester. Acidified chilled on ice water layer 6N HCl and extracted with ethyl acetate. Washed with brine and dried over magnesium sulfate. Concentrate to about 40 g butter. Chiral HPLC was proved no loss of chiral purity.

Dissolve 19.5 g (49,0 mmol) 2 in 200 ml of anhydrous toluene (if necessary, SM can azeotrope dried with toluene). Cooled in ice under nitrogen atmosphere. Add 1 ml of DMF (DMF) and 8,55 ml (98,0 mmol) oxalicacid for 1 min. Stirred in the cold for about 1 hour, then at room temperature (it is) for about 1.5 hours. Gently bubbled with nitrogen to remove HCl. Check the remaining SM repayment of the sample pyrrolidino, shaken with dilute HCl solution and ethyl acetate (EA). Conducting thin-layer chromatography (TLC) EA layer using 50:10:1 mixture of DMF/MeOH/NH4OH. If necessary add additional oxalyl chloride to absorb the entire SM. Decanted or filtered, if necessary (washing toluene), throwing insoluble substance. Concentrate at about 30°C to an orange syrup. Dissolve in 200 ml of anhydrous acetonitrile and cooled in ice under nitrogen atmosphere. Quickly add a 2M solution of TMS-diazomethane/ether. After a short induction period is excreted nitrogen. Stirred in the cold for about 1 hour and concentrated at 40°C to oil. Dissolved in EA and washed with sodium bicarbonate solution, brine and dried over sodium sulfate. The sample is concentrated to about 21 g of syrup amber color. Use directly.

Dissolve 21 g (~49 mmol)4in 200 ml of ethanol. Add a solution of 2.2 g (9.8 mmol) of silver benzoate in 27 ml (196 mmol) of TEA, while the reaction mixture is subjected to the action of ultrasound in standard ultrasonic water bath. Adding complete within about 5 minutes, stopping several times to impart a rotational motion of the mixture is Excreted nitrogen and forms a brown precipitate (ppt). Subjected to the action of ultrasound for 15 minutes, then concentrated in oil. Dissolve EA and filtered through a pad of silica. Describes the sample was chromatographically on 250 g of silica, elwira 1:1 mixture of EA/hexane to obtain an 18.4 g of light brown oil.

Was dissolved 18 g (39 mmol)of6in 400 ml of EtOH was added 1.8 g of 10% Pd/C in suspension in EtOH. Gidrogenizirovanii in the device Pair followed by filtration through cellit and concentration resulted in approximately 5.2 g of an oil which formed a waxy crystalline solid on standing. Used directly.

Combined 5 g (29 mmol) ethylpiperazin-2-acetate, 4.7 g (29 mmol) of chlorimide and 12 ml, 3 EQ. TEA in 100 ml of EA/20 ml ETOH and heated at about 80°C for approximately 36 hours. The reaction mixture was then concentrated in a rotary evaporator, was divided between EA and diluted with sodium carbonate solution and washed with brine. Was dried over sodium sulfate. Chromatography on silicagel, elwira 1% (10% mixture of TEA/EtOH)/EA to remove residues of the original substance and increasing to 3% (10% mixture of TEA/EtOH)/EA, then 5% (10% mixture of TEA/EtOH)/EA led to 4.2 product as a yellow foam.

Example 2

Obtaining incomplete 3'-(S) substituted esters:

The solution is ut 1.2 g (3 mmol) of compound K in 30 ml of THF. Added 720 mg (3.3 mmol) of BOC-anhydride and heated at room temperature (RT) for about 5 hours, then at 80°C for about 12 hours. Cool on ice and add 30 ml of MeOH and 10 ml of 4 N solution of KOH and stirred at RT over night. Set pH 3 1M citric acid solution and extracted with MTBE. Washed with brine and dried over sodium sulfate. Concentrate to about 1.4 g of a yellowish brown solid and used in this form for the synthesis of various esters according to the invention. Use of the standard conditions of removal of the protective group BOC removal of the BOC, for example, TFU/DCM or 1 M HCl/EtOH, or, for example, 1M HCl/dioxane-EA for the higher ethers.

Example 3

The connection is ED

(S)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl) acetic acid (288 mg, 0.61 mmol) can be dissolved in DMF (5 ml). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222 mg, of 1.16 mmol) and 4-dimethylaminopyridine (48 mg, 0,39 mmol) can be added in this order at room temperature in a nitrogen atmosphere. After about fifteen minutes you can add R-(-)-2-methyl-2,4-pentanediol (92 mg, 0.78 mmol) and the mixture should be heated to about 50°C. in a nitrogen atmosphere. The product can be purified flash chromatography using a 10% mixture of acetone/di is Loretan as eluent to obtain (S)-tert-butyl 4-((E)8 chlorodibenzo[ b,f][1,4]oxazepine-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate. (S)-tert-butyl 4-((E)8 chlorodibenzo[b,f][1,4]oxazepine-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate can be dissolved in dichloromethane (1.1 ml) and cooled in an ice bath. Triperoxonane acid (0.5 ml) should be added by precapitalism in nitrogen atmosphere and allow to slowly reach room temperature over night. The mixture should be concentrated under vacuum and clean flash chromatography using a 10% mixture of acetone/dichloromethane as eluent to obtain Compound ED.

Example 4

Getting connection EK

(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chloro dibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid (300 mg, of 0.60 mmol) can be dissolved in DMF (0.25 M). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol) and 4-dimethylaminopyridine (0.3 mmol) can be added in this order at room temperature in a nitrogen atmosphere. After about fifteen minutes you can add R-(-)-2-methyl-2,4-pentanediol (0,60 mmol) and the mixture is heated to about 50°C. in a nitrogen atmosphere. The product can be selected as usual and purified flash chromatography using a 10% mixture of acetone/dichloromethane as eluent to obtain (S)-Tr is t-butyl 4-((E)8 chlorodibenzo[ b,f][1,4]oxazepine-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate as a white foam. (S)-tert-butyl 4-((E)8 chlorodibenzo[b,f][1,4]oxazepine-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate can be dissolved in anhydrous THF and cooled in an ice acetone bath under nitrogen atmosphere. 2.0 M solution of butyl lithium in cyclohexane (about 1 mol equivalent), you can add precapitalism in nitrogen atmosphere. After about 15 minutes can be added dropwise itmean (about 1 mol equivalent) in nitrogen atmosphere. After about one hour 2.0 M solution of butyl lithium in cyclohexane (about 1 mol equivalent), you can add precapitalism in nitrogen atmosphere. After about 15 minutes can be added dropwise itmean (about 1 mol equivalent) in nitrogen atmosphere. After about one hour the solution can be concentrated under vacuum to obtain (S)-tert-butyl 4-((E)8 chlorodibenzo[b,f][1,4]oxazepine-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxypropane-2-yl)piperazine-1-carboxylate as a white foam. (S)-tert-butyl 4-((E)8 chlorodibenzo[b,f][1,4]oxazepine-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxypropane-2-yl)piperazine-1-carboxylate can be dissolved in dichloromethane (1.1 ml) and cooled in an ice bath. Triperoxonane acid (about 0.5 ml) EXT is manage by precapitalism in nitrogen atmosphere and allow to slowly reach room temperature over night. The mixture can be concentrated under vacuum and clean flash chromatography using a 10% mixture of acetone/dichloromethane as eluent to obtain Compound EK.

Example 5

Getting hemimelaena 3' esters

(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid can be dissolved in DMF (0.25 M). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol) and 4-dimethylaminopyridine (approximately 0.5 mol equivalent) can be added in this order at room temperature in a nitrogen atmosphere. After about fifteen minutes, add the alcohol to obtain the corresponding ether complex, for example, propanol for complex propyl ether (about 1 equivalent)and the mixture should be heated to about 50°C. in a nitrogen atmosphere. The product can be selected as usual and purified flash chromatography using a standard mixture of acetone/dichloromethane as eluent to obtain the BOC-protected complex ester. The BOC protected ester can be dissolved in anhydrous THF and cooled in a bath of dry ice and acetone in nitrogen atmosphere. 2.0 M solution of butyl lithium in cyclohexane (about 1 mol equivalent), you can add precapitalism in nitrogen atmosphere. After about 15 minutes can be added dropwise itmean (approximately 1 mo the R equivalent) in nitrogen atmosphere. After about one hour 2.0 M solution of butyl lithium in cyclohexane (about 1 mol equivalent), you can add precapitalism in nitrogen atmosphere. After 15 minutes may be added dropwise itmean (about 1 mol equivalent) in nitrogen atmosphere. After about one hour the solution can be concentrated under vacuum to obtain hemimetabola product. Protected VOS geminately product can be dissolved in dichloromethane (1.1 ml) and cooled in an ice bath. Triperoxonane acid (about 0.5 ml) can be added precapitalism in nitrogen atmosphere and allow to slowly reach room temperature over night. The mixture should be concentrated under vacuum and clean flash chromatography using a standard mixture of acetone/dichloromethane as eluent to obtain the free primary hemimetabola product.

Example 6

Getting connection BW, BX of racemate:

Mono(S,E)-tert-butyl 4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-2-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate are dissolved in anhydrous THF and cooled to -78°C. in a nitrogen atmosphere. Utility should add precipiation in hexane. After about 30 minutes, add methyliodide of (0.95 EQ.) and leave to slowly reach room temperature. The mixture should be concentrated under vacuum and clean flash chromate what graphy using a standard mixture of acetone/dichloromethane as eluent to obtain the free primary nanometrology the BOC protected product. The BOC protected onomatology product was dissolved in dichloromethane and cooled in an ice bath. Triperoxonane acid should be added by precapitalism in nitrogen atmosphere and left to slowly reach room temperature over night. The mixture should be concentrated under vacuum and clean flash chromatography using a standard mixture of acetone/dichloromethane as eluent to obtain the free primary nanometrology product. See diagram for example 7 below.

Example 7

The connection of the SS

Mono(S,E)-tert-butyl 4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-2-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate are dissolved in anhydrous THF and cooled to -78°C. in a nitrogen atmosphere. Utility should add precipiation in hexane. After about 30 minutes, add methyliodide (2.2 EQ.) and leave to slowly reach room temperature. The mixture should be concentrated under vacuum and clean flash chromatography using a standard mixture of acetone/dichloromethane as eluent to obtain the free primary hemimetabola the BOC protected product. The BOC protected geminately product was dissolved in dichloromethane and cooled in an ice bath. Triperoxonane acid should be added by precapitalism in which atmosphere nitrogen and leave to slowly reach room temperature over night. The mixture should be concentrated under vacuum and clean flash chromatography using a standard mixture of acetone/dichloromethane as eluent to obtain the free primary hemimetabola product.

Example 8

Getting the racemate of compound N and connections P

Obtaining (E)-8,11-dichlorodibenzo[b,f][1,4]oxazepine:

The phosphorus oxychloride (40 ml) and dimethylalanine (7,6 ml, 60 mmol) was added to a solution of amide (4.35 g, 30 mmol) in toluene (120 mmol) under nitrogen atmosphere. Attach a condenser and was heated under reflux under nitrogen atmosphere overnight. The reaction was heated to 100°C for 48 hours the Reaction was then cooled and diluted with toluene (100 ml), then was rapidly distilled at 150°C to about half the initial volume. The reaction was again diluted with toluene (120 ml) and again distilled to remove excess phosphorus oxychloride. The reaction was cooled and was added toluene (150 ml), then the mixture was poured into ethyl acetate (200 ml). The reaction was washed in 1 M HCl solution and dried over MgSO4then immediately used in the form of a solution in a mixture of toluene/ethyl acetate.

Getting substituted piperizine:

1. Getting ethyl 1,4-dibenzylpiperazine-2-carboxylate:

To a hot (about 80°C) solution of N,N'-dibenziletilendiaminom (216 g, 0.9 mol) and triethylamin is a (300 μl, of 2.16 mol) in toluene (650 ml) was quickly added by precapitalism ethyl 2,3-dibromopropionate (240 g of 0.93 mmol) in toluene (650 ml). After the addition the reaction mixture was stirred at 80°C for approximately three hours. Maintained the temperature below 95°C. a Heavy precipitate was filtered and then the solvent and excess TEA was removed. Added t-butyl methylether (approximately 300 ml). The reaction was well mixed and any formed precipitate was filtered. The reaction was concentrated to a light yellow oil (approximately 287 g, approximately 94%)

2. Obtaining 1,4-dibenzyl-2-(hydroxymethyl)piperazine

To a stirred ice-cold (0°C.) solution of LAH (2.0 M in TFU, 2 ml, 4.0 mmol) in TFU (20 ml) was added a solution of ester (1.8 g, 5.3 mmol) precapitalism within 15 minutes. The mixture was stirred for about 20 hours at room temperature, then cooled and carefully treated with wet ether and aqueous NaOH (0.5 M, 200 ml), while longer reaction after adding. The aqueous layer was extracted with ether and the extracts were dried over NaSO4. The reaction was concentrated to a clear oil (1.55 g, 99%).

3. Obtaining 1,4-dibenzyl-2-(chloromethyl)piperazine

Alcohol (1.6 g, 5.3 mmol) was dissolved in chloroform (50 ml) and cooled to 0°C (ice bath). A solution of thionyl chloride (3.0 ml, of 40.3 mmol) in chloroform (primer the 20 ml) was added dropwise over about 5 minutes. The reaction was left to warm to room temperature and was monitored by TLC (TLC). To the reaction vessel was attached a condenser and was heated under reflux in nitrogen atmosphere for 15 hours. The reaction mixture was cooled and was diluted with dichloromethane, then washed with saturated sodium bicarbonate solution and dried over NaSO4. The product was filtered and concentrated to a yellow oil.

4. Obtaining 1,4-dibenzyl-2-(lanmeter)piperazine

To heated under reflux a solution of KCN (4.0 g, is 61.5 mmol) in water (75 ml) and ethanol (80 ml) was added precapitalism the solution from the previous stage of the halide (12.7 g, of 40.3 mmol) in ethanol (20 ml). The mixture was stirred and heated under reflux for 7 hours, then concentrated to remove ethanol. The crude residue was absorbed dichloromethane, washed with water and dried over MgSO4. The product was filtered and was concentrated to 12 g of an orange oil, which was then purified on silica using flash chromatography with a mixture of 4:1 hexane/EtOH.

5. Obtaining methyl 1,4-dibenzylpiperazine-2-ilaclama

The nitrile from the previous stage (0.3 g, 0.98 mmol) was dissolved in methanol (30 ml), to the specified solution was added sulfuric acid (5 ml). The reaction was attached a condenser is heated under reflux overnight and was monitored by TLC. Added additional sulfuric acid (8 ml) and the mixture was heated under reflux for about 20 hours. The reaction was cooled and poured into dichloromethane and water. Carefully neutralized pH by the addition of saturated sodium bicarbonate solution to pH 9. The product was extracted into dichloromethane and dried over MgSO4, then filtered and concentrated to obtain a clear oil (0.3 g, 91%).

6. Getting methylpiperazin-2-ilaclama

Ether dibenzylpiperazine (0.87 g, 2.5 mmol) was dissolved in ethanol (10 ml) and was added into the flask Pair for shaking. Added palladium hydroxide (20% wt.) Pd on carbon, of 0.54 g). The vessel was pumped H2(3×) and was shaken in an atmosphere of H2(50 psi) for 15 hours. The product was filtered through a disc filter (Whatman 0,7 µm) to remove the palladium on carbon and then concentrated to a yellow oil.

7. The binding of nuclei with substituted piperidinol

The triethylamine (14 ml, 100 mmol) was added to a solution of ester piperidine (6.3 g, 40,1 mmol) in methanol (25 ml) under nitrogen atmosphere. The reaction mixture was heated to 50°C. and added with stirring for about 30 seconds, the solution of chlorimide in a mixture of toluene/ethyl acetate (650 ml, 0.46 M). The reaction was attached a condenser and was heated at about 90°C (with britishtelecom) with stirring overnight. The reaction mixture was cooled, then added methanol (30 ml) and triethylamine (15 ml). The reaction was subjected to the action of ultrasound for about 2 minutes and was heated under reflux for an additional 7 hours. The reaction mixture was cooled and was diluted with ethyl acetate (250 ml), washed with saturated sodium bicarbonate solution and dried over NaSO4. The reaction was filtered and concentrated to about 100 ml of the crude product in toluene, which was filtered to remove the white solid residue was purified by chromatography on silicagel (230-400 mesh mesh) using a gradient elution with a mixture of 1:1 hexane/ethyl acetate 100:10:1 dichloromethane/MeOH/NH4OH. The main fraction was isolated and concentrated from the receipt of 3.84 g (10 mmol, 33% yield) of light yellow foam of high purity (99% according to HPLC).

Example 9

Getting connection FS

Ethyl ester (400 mg, 1.0 mmol) was dissolved in Amina (1.5 ml, 20 mmol) in 20 ml vial and heated at 90°C under stirring for about 48 hours. The reaction mixture was cooled and directly purified HPLC using a mixture of acetonitrile/water. The collected fractions were frozen and subjected to freeze drying to yield compounds of FS in the form of a white solid (95 mg, 22%).

Example 10

Ways

Culture of neurons. Cut is whether the cerebral cortex of newborn rats and was treated with 0.25% trypsin for dissociation of cells, again suspended in modified according to the method of Dulbecco environment Needle (DMEM)containing 10% plasma derived from horse serum (PDHS), and was applied to the coated poly-L-lysine 35 mm plastic cups for kultivirovanii tissues (3,0×106cells/Cup. 2 ml of medium). The cultures were maintained in an atmosphere of 5% CO2/95% air.

Acute effect of the compounds according to the invention the function of the NMDA receptor

Electrophysiological registration: registration of fixing the potential of membrane ion fluxes was performed using Axopatch 200B and Axoclamp 1D amplifier (Axon Instruments, Foster City, CA). Neurons were used for electrophysiological registrations in the range from 12 to 24 daysin vitro. If the neuron showed a significant change in the maintenance thread, or a noticeable change in the amplitude or shape of the capacitive change in the course of the experiment, data for this neuron was excluded. Contact microelectrodes were pulled from 1.5 mm borosilicate glass capillaries using a two-stage vertical devices for pulling pipettes (Narishige, East Meadow, NY). When the content recorded by the solution of the contact microelectrode will have a resistance of 3-5 Mω. For quick application to neuron solutions containing agonist, used the SF-77B system (Warner Instruments Corp., Hamden, CT). In other cases, spent more than slow the initial exchange of extracellular solution at the baths of their own making.

The activity of the NMDA receptor has changed as the standard deviation (SD) of membrane flow. To study the strong influence of drugs was measured SD of membrane flow in the control solution media and in the presence of various concentrations of drugs (1-100 μm). For screening purposes, for most substances used concentrations of 1 and 10 μm. For lead compounds and classic Comparators (e.g., clozapine) were obtained full curves of the concentration - response. Drugs used for at least 10 minutes drive Control of the media was monitored during the same time period. To measure functional changes in the function of the NMDA receptor during chronic exposure to drugs, recorded currents induced by the intense concentration of NMDA (1 mm) in treated drug and control culture. After culturing neurons within 5-7 days half of the cultivated cups were treated with a fixed concentration of the drug and the other half only carrier. Registration was performed in 7 to 14 days after drug use. The amplitude of the induced NMDA flows in the control medium and treated cultures were compared. SD membrane flows and NMDA-induced flows recorded in the containing TTX (0,-1 μm) extracellular solution. In case associated with NMDA receptor mEPSC registrations, Mg2+excluded from the reaction solution. To isolate the NMDA component associated with glutamate receptor flows, added antagonist of non-NMDA (AMPA/Kainat) receptor NBQX (10-20 μm) in the extracellular solution, Vh=-60mV. Induced NMDA currents recorded at -30 mV in the presence of physiological concentrations of Mg2+(1 mm). Strychnine (1 mm) and picrotoxin (100 μm) was added in all cases to the extracellular solution to block glycine receptors and GABA, respectively. The main extracellular solution contained (in mm): NaCl (140), KCl (4), CaCl2(2), MgCl2(1), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (10) and glucose (11). the pH of the extracellular solution was established to 7.4 using NaOH. The main solution for filling the contact electrodes contained (in mm): Cs gluconate (135), NaCl (5), KCl (10), MgCl2(1), CaCl2(1), EGTA (11), HEPES (10), Na2ATP (2), Na2GTP (0,2) mm. intracellular pH of the solution was set at 7,4 when using CsOH. Different concentrations of clozapine and ATI-compounds were added to the extracellular solution according to the described protocols.

Digital data were analyzed by non-real-time when using Mini Analysis Program (Synaptosoft, Leonia, NJ) or pCLAMP9 (Axon Instruments, Union City, CA).

Example 11

Acute effect of ATI-9000 connections on the functioning of the GABAA Rotz the Torah

Electrophysiological registration

To study the effects of ATI-9000 compounds induced GABA receptor mIPSC, bicucullin (20 mm) in the extracellular solution and CS gluconate (135 mm) in the intracellular solution, which was used for experiments with NMDA receptor was replaced with 1,2,3,4-tetrahydro-6-nitro-dioxobenzo[f]cinoxacin-7-sulfonamide (NBQX; 5-10 µm) and KCl (135 mm), respectively. All IPSX were recorded at the holding potential of -60 mV. Digital data were analyzed by non-real-time when using Mini Analysis Program (Synaptosoft, Leonia, NJ) with thresholding mIPSC amplitude, set at ≥8 PA.

Example 12

Connection K, but not the connection Q, binds D2Sand D2Ldopamine receptors

D2receptors known as the receptor subtype involved in the activity of clozapine. The connection has a low micromolar IC50binding affinity to the D2Sand D2Lthe receptors. The affinity of Compounds To the D2Sand D2Lthe receptor was comparable to the affinity of clozapine to these receptors.

Connection To and its metabolite Compound Q also binds to the H1, 5-HT1Aand 5-HT2Cbut with extremely low affinity for M3and M1the receptors. The affinity of compounds To H1and 5-HT2Cthe receptors were in 69 and 1.2 times less than what the Oia with clozapine and 4 times higher for the 5-HT 1Areceptors.

The method of analysis linking radio

In accordance with the standard analysis of competitive binding of radio-method was based on the displacement of the radio from the tissue (or cell lines), bearing the analyzed receptors (Cheng, Y. and Prusoff, W.H. (1973) Biochem. Pharmacol. 22, 3099-3108). Measurement was based on the binding of a single concentration of ligands with radioactive label in the presence of various concentrations of unlabeled ligand.

Tissue (or fragments of the plasma membrane of cells) were incubated in the presence of radioligand in equilibrium and in the presence of a range of concentrations of the compounds under study (which did not contain radioactive labels), and replaced the radio was separated from the membrane filtration. Nonspecific binding was assessed by measuring the substitution radioligand in the presence of compounds known as impeding the binding of radioligand with the receptor. Finally, the ratio of the concentration-response to displacement of radioligand (corrected for nonspecific binding) was used to assess binding of the compounds to the receptor.

The Protocol conditions are presented in table 1 (Fig.9).

Example 13

Connection K is a partial agonist of human D2Sreceptor

Assessmentin vitroconducted on the basis trims the ablation adenylyl the cyclase in cells designed for stable expression of human D2Sthe receptor. Compound K was a partial agonist D2receptor and an antagonist of D2receptor and clozapine. Estimated IC50to connect K is 13 μm.

How adenylylcyclase

HitHunterTMcATP XS (DiscoveRx, CA) is chemoluminescent analysis, ideally suited for tracking Gi-coupled GPCR from the error correcting signal to the preceding relations for both agonistic and antagonistic responses. He is a competitive immunoasays based onin vitro.Available CATF from lysates of cells compete for binding of the antibody relative to the marked ED-catp the conjugates, small peptide fragments of β-galactosidase (β-gal). In the absence of free CATF ED-Catt conjugates bind antibodies and become unable to complementaly, leading to low signal. In the presence of free CATF, antibodies are employed, leaving ED-Catt conjugates free to complimentary with EA to form active β-gal EFC enzyme for hydrolysis of the substrate with getting chemiluminescence signal. A positive signal is generated in direct proportion to the number of free CATF associated antibodies.

The HEK 293 cells expressing functional human D2Sreceptors Scottish Biomedical), collected and re-suspended in PBS buffer (medium not containing serum). Cells were cultivated in 96-well plate at 20,000 cells/well. A series of dilutions of Forskolin and dopamine tested (positive control for agonistic analysis). Serial dilution of patented compounds were tested in a volume of 10 μl in the presence of 27 μl of Forskolin (agonist assay) or in the presence simultaneously of 28 microns Forskolin and 30 μm dopamine (antagonistic analysis). The plates were incubated at 37°C for 30 minutes. After induction cells reagents were added and incubated for 60 minutes at room temperature. The luminescence was detected using TopCount NXT detector (PerkinElmer).

Example 14

Connection K is a potential antagonist of 5-HT2Areceptor

The ability of antipsychotic drugs to affect the function of 5-HT2Athe receptor is widely anticipated as contributing to their therapeutic properties. Connection K is a potential antagonist of 5-HT2Areceptors (RA2=8,5), comparable with Kazarina (RA2=8,4). The affinity of the compound Q to 5-HT2Athe receptor was 8 times lower in comparison with the connection K. See Figure 1.

Methodology incubator bodies

The aorta of the rat (approximately 7 cm) of insulation is ovale and removed from the animal (male rats Sprague Dawley, Charles River Laboratories, Hollister, CA). The endothelium was mechanically removed. Eight bands of tissue (0.5 cm long) were cut and mounted in 10 ml of the camera to work with authorities, supported at 37°C With Krebs solution (composition in mm: NaCl (118,2), KCl (4,6), CaCl2(2,5), MgCl2(1,2), KH2PO4(1,2), Na2HCO3(24,8) and dextrose (10,0)), which was constantly aeronavali Carbogen gas (95% O2/5% CO2) to obtain pH 7.4. Tissue was subjected to tension rest 2 g (3 times in 15 minutes, balanced in Krebs solution). Then after 15 minutes, the fabric was washed. Ten minutes later, the tissue was subjected to 0.1 µm phenylephrine. For the maximum effect was added to 1 μm acetylcholine to confirm the absence of endothelium and then washed twice in 2 minutes. Fifteen minutes later, the carrier (DMSO), compound comparison (clozapine) and test compound (the Compound K, Compound Q, 10 nm to 0.3 μm, or 0.1-1 μm) was added to the chamber and the tissues were washed every 10 minutes for 60 minutes by the media, clozapine, compound K or Connection of Q. Then was built non-cumulative curve of the effect of concentration of 5-HT (serotonin, of 0.01 μm to 0.1 μm, or up to the maximum of the obtained response).

The concentration was recorded as the change in tension from baseline and expressed as percentage of maximum response curve, the concentration of agonist (5-HT)effect. Curves is oncentrate agonist - the effects were compared using non-linear interactive mapping program (GraphPad Prism) using the proportion of Parker and Vawda (Parker, R.B. and WAud, D.R. (1971). Pharmacological evaluation of the constants of the drug-receptor dissociation. I. Agonists. J. Pharmacol. Exp. Ther., 1977, 1-12). Efficacy agonists were expressed as EC50(molar concentration of agonist causing 50% of maximum response). The ratio of concentrations (CRs) was determined from EC50values in the presence and absence of antagonist and was determined by evaluation of the antagonistic affinity (PKInand pA2values). All data are presented as mean ± standard error of the mean.

Example 15

Compound K as a potential antagonist caused by apomorphine violations swimming

The antagonism caused apomorphic violations swimming in mice (Warawa, E.J. et al. (2001) Behavioral approach to nondyskinetic dopamine antagonist: identifications of seroquel. J. Med. Chem., 44, 372-389) was used for estimation of the studied compounds. Mice that were injected apomorphine, are not able to swim and remain in place, scribes on the chamber wall for swimming or making futile attempts at swimming. Certain atypical antipsychotic compounds "normalize" the behavior of navigation in these mice.

Compound K was more effective in comparison with clozapine as the antagonist caused by apomorphine drug is deprivation of swimming in mice (see Figure 2, 3). Compound Q was also changed caused by apomorphine violation of swimming in mice (3 and 10 mg/kg; Figure 4).

Methodology floating test

Animals (Swiss Webster females, about 20 g; Charles River) were injected compounds according to the invention (0.1 ág/kg 30 ág/kg intraperitoneally) for thirty minutes before they were injected dose of apomorphine HCl 1.25 mg/kg subcutaneously. Thirty seven minutes after administration of the test compounds and fifteen minutes after the injection of apomorphine each mouse was placed in a round tank for swimming for 2 minutes and record the number of "races". Tank height is 15 cm and the diameter is 28 see Round the obstacle of 1.05 cm in diameter and a height of 17 cm was placed in the center of the tank, forming a rounded channel swim a width of 8.75 see the water Level is 5.5 cm and water maintained at room temperature (about 20°C). On the bottom and sides of the vessel inflicted marks at a distance of 180 degrees. Swim was recorded every time the mouse floated from one level to another and the average number of heats for all mice used as the result for the specified injection.

Example 16

Connection K and catalepsy

Model catalepsy in mice was used to study the potential side effects of antipsychotic agents. Connection K did not cause catalepsy in the concentration of the emission up to 30 mg/kg, intraperitoneally, whereas the highest doses of clozapine (30 mg/kg) caused catalepsy. See Figure 5 and 6, respectively.

The way catalepsy

The way catalepsy used here was adapted from Tada, M. et al. ((2004) Physichopharmacol., 176, 94-100), and Wang et al. ((2000). J. Neurosci., 20, 8305-8314).

Animals (Swiss Webster females, about 20 g; Charles River) were injected compounds according to the invention (1 μg/kg 30 μg/kg, intraperitoneally). Twenty-seven minutes after the introduction of the subjugated connection front paws of mice were placed on a horizontal steel bar (diameter 0.2 cm), raised by 3-5 cm above the table surface, and record up to 2 minutes time, which required the animal to remove both legs.

Example 17

Compound K and Compound Q restore caused by the antagonist MNDA deficits in the inhibition of rapid pulse

The purpose of this study was to assess the validity of patented compounds in violation of inhibition of auditory rapid pulse (PPI) in rats. When the PPI procedure reflex of the whole body caused by heavy sound, reduced or inhibited pre-playback weaker sound (rapid pulse). PPI is a measure of sensory-motor synchronization, which is impaired in schizophrenics (Braff, D.L. et al. (1995) Gating and habituation deficits in the schizophrenia diorders. Clin. Neurosci., 3, 131-139). As postulated contribution of reduced glutamate function in the symptomatology of schizophrenia (Carlsson, M. and Carlsson, A. (1990). Interactions between glutamatergic and monoaminergic systems within the basal ganglia: Implications for schizophrenia and PA's disease. Trends Neurosci., 13, 272-276). MK-801, PCP, and also violated by apomorphine PPI serves as an animal model for a specific neurochemical imbalances. Animals were injected with antipsychotic drugs such as clozapine or the compounds for anthonii induced disturbances to assess their potential positive action in the present model. Cm. Fig.7.

The way PPI

The way PPI used here was adapted from Bast, T. Et al. ((2000)Effects of MK-801 and neuroleptics on prepulse inhibition: a re-examination in two strains of rats. Pharmacol. Biochem. Behav., 67, 647-658)and Bubenikova et al. ((2005) The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating. Pharmacol. Biochem. Behav., 80, 591-596).

Rats (Sprague Dawley, 300-450 g, Charles River) were injected by the injection of the carrier (DMSO) or compounds intraperitoneally (0.5 ml/kg) for 45 min to PPI experiment. PCP (1.5 mg/kg, 0.5 ml/kg) was subcutaneously injected 15 min prior to PPI experiment. Then the animals were placed in the start chamber (SR-LAB, San Diego Instruments, USA), which included a transparent cylinder made of Plexiglas (8.2 cm in diameter, 10×20 cm), which was located on the piezoelectric vibration sensor inside ventilated and illuminated camera. Piezoelect the ical vibration sensor defined and measured movement inside the cylinder. Speaker system high frequency inside the chamber (24 cm above the animal) produced at the same time the background noise 77 dB and acoustic stimuli. Only background noise (77 dB) was presented for 5 min (acclimatization period) and then continued throughout the session. After a period of acclimatization started the test with 5 initial stimuli with different types of trials, presented in random order: a single pulse of 120 dB, duration 20 MS; rapid pulse (83, 86, or 89 dB) duration 20 MS, 100 MS before joining one pulse, rapid pulse (83, 86 or 89db) duration 20 MS, without stimulation. Spend just 5 views of each type of test in the interval between stimuli in about 30 seconds. PPI was measured as the difference between the mean values of a single pulse and testing ahead of the impulse-momentum and expressed in percentage of PPI [100-(average response to the test ahead of the impulse-pulse/original response for testing one-pulse) ×100].

Example 18

Connection K not reduce spontaneous locomotor activity (open field) in rats

One of the common side effects of many antipsychotic drug is a sedative effect. It was shown that agents that have a calming effect on people, have the same action is e on animals. The purpose of these studies was to assess the validity of the test compounds on locomotor activity in rats, which were used to determine the sedative properties of antipsychotic compounds.

The connection K (0.03-10 mg/kg) or compound Q (10 mg/kg) reduced locomotor activity in rats (see chart below), whereas clozapine showed a tendency to the sedative effect. Cm. Fig.

The open fields

Rats (Sprague Dawley, approximately 300-450 g, Charles River) were determined on the ability to move within 30 minutes after the introduction of the medium or the test compounds. Animals were placed into the chamber of the open field (san diego Instruments, USA), which consisted of a transparent cylinder of plexiglass (16×16), equipped with spaced cross beams with solar cells. Locomotor activity was quantitatively assessed by the number of beams with solar cells crossed by the animal for several intervals of 3×10 minutes

Example 19

Metabolism studies using microsomal preparations obtained from human liver

Compounds were incubated in pooled human liver microsomes (HLM) in the presence or absence of the NADPH-generating system. NADP required for activity of cytochrome P450 (CYP) and other oxidative enzymes present in HLM, but not for esterase activity. More the positive incubation was performed in the absence of HLM, to determine the stability of the connection. The disappearance of the original and the appearance of the corresponding acid metabolite was monitored during the incubation time when using liquid / mass spectrometry (LC-MS/MS).

The main solution (20 mm) of each suitable compounds in DMSO were obtained and stored at -20°C until use. Work source solution (0.2 mm) was obtained for each suitable connection by adding aliquots of the basic solution (10 μl) to acetonitrile (990 μl).

An aliquot of the solution HLM were removed from the -80° C freezer and placed on ice. Tris buffer (50 IMB pH 7.4)containing MgCl2(uranyl, 5 mm), pre-incubated in a water bath at 37°C. a Set of Eppendorf microcentrifuge tubes (1.5 ml) was marked in a suitable way. To each tube was added Tris buffer with and without NADPH generating system. An aliquot of pooled HLM) was added to all inquireys substances, except those which represented the buffer control.

Tube pre-incubated for 5 minutes on shaker incubation bath (37°C, 900 rpm./min) and the reaction was initiated by adding a suitable aliquots of the working solution (5 μm). Adding carefully synchronized in time for the regulation of the sampling below. Small aliquots (50 ál) were taken at 0, 5, 15, 30, 60 and 90 min and transferred in soo is relevant tube containing dextrophan (100 μl of a solution of 0.5 μg/ml), dissolved in methanol or acetonitrile. Samples were centrifuged at 14000 g for 15 minutes at 4°C. the Supernatant was transferred into a clean residue " injection HPLC vials and stored at -80°C until analysis. An aliquot of the supernatant (25 μl) was added to water (75 μl)were mixed and injected into LC-MS/MS system for analysis. The results for some compounds according to the invention can be seen in the table of example 20.

Example 20

Metabolic studies using esterase pig liver

Asteroseismic metabolism of these compounds were investigated using commercially available esterase pig liver in the presence and absence of proteins of human plasma. The disappearance of the original metabolite monitored during the incubation time when using LC-MS/MS system definition.

The main solution and work the basic solution was obtained for each suitable connection, as described for incubations microsomal preparations of human liver. Working solutions esterase pig liver in potassium phosphate buffer (10 mm, pH 7.4) and esterase pig liver in protein human plasma was obtained by dissolving esterase pig liver (of 2.51 mg) in solutions of phosphate buffer or protein of human plasma, respectively.

Set of three microcentrifuge samples of the rock Eppendorf (1.5 ml) was marked in a suitable way. To each tube was added 1.5 ml of phosphate buffer, esterase pig liver in the buffer or esterase pig liver in solution protein of human plasma. These solutions are pre-incubated (37°C, 900 rpm./min) and the reaction was initiated by adding to each tube aliquots (37,5 ml) working solution suitable connection. An aliquot (100 μl) from each tube were taken at 0, 5, 30, 60 and 120 min and transferred to the appropriate tube containing acetonitrile (200 μl) to stop the reaction.

Samples were centrifuged at 14000 g for 15 minutes at 4°C. the Supernatant was transferred into a clean residue " injection HPLC vials and stored at -80°C until analysis. An aliquot of the supernatant (25 μl) was injected into the LC-MS/MS system for analysis. The results for some compounds according to the invention can be seen in the table below.

ConnectionHLMThe esterase pig liver (t½ min)
t½ (min)Enzyme(+) plasma(-) plasma
A(E)ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)piperazine-2-yl)acetate 30the esterase15<5
J(E)ethyl 2-(4-(7-Ferdinando[b,f][1,4]-oxazepine-11-yl)piperazine-2-yl)acetate10the esterase15<5
L(E)-isopropyl 2-(4-(8-chlorodibenzo[b,f] [1,4]oxazepine-11-yl)piperazine-2-yl)acetate30P45030<5
M(E)-isopropyl 2-(4-(7-Ferdinando[b,f] [1,4]oxazepine-11-yl)piperazine-2-yl)acetate30P45015<5
DR(S,E)-cyclopentyl 2-(4-(8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)-piperazine-2-yl)acetate30the esterase15<5
DV(S,E)-tetrahydro-2H-Piran-4-yl 2-(4-(8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)-piperazine-2-yl)acetate60 the esterase15<5
DYSecond-butyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)-piperazine-2-yl)acetate<5the esterase30<5
EQ(S)-tetrahydrofuran-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)piperazine-2-yl)acetate15the esterase305
ER(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)1-isobutylpyrazine-2-yl)-acetate5the esterase60<5
EU(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]-oxazepine-11-yl)-1-methylpiperazin-2-yl)-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide60P450Stable-
on
Stable

Example 21

The following tables presents pKi and pKb values (negative logKi and negative logKb, meet the but) patentable compounds for various receptors in the scale of 1 to 5, where pKi and pKb are defined for each receptor as follows:

Receptor12345
5HT2A≤7,007,01-7,507,51-8,008,01-8,50≥8,51
D2S≤5,005,01-the ceiling of 5.605,61-6,206,21-6,80≥for 6.81
D2L≤5,005,01-the ceiling of 5.605,61-6,206,21-6,80≥for 6.81
5HTIA≤5,005,01-6,006,01-7,007,01-8,00≥8,01
5HT2C≤5,005,01-6,006,01-7,007,01-8,00≥8,01
M3≤5,005,01-5,105,11-5,20to 5.21-and 5.30≥5,31
H1≤5,005,01-6,006,01-7,007,01-8,00≥8,01
5HT7≤5,005,01-of 5.405,41-5,805,81-6,20≥6,21
M1≤5,005,01-and 5.305,31-the ceiling of 5.605,61-5,90≥5,91

3 4
Connection5HT2A(pKb)D2S(pKi)D2L(pKi)5HT1A(pKi)5HT2C(pKi)M3(pKi)H1(pKi)5HT7(pKi)M1(pKi)
A3234132
B241
C221
D2331
E21123131
F1324
G3222
H2334131
I32234132
J22233 131
K433341341
L32334131
M31233121
N433341342
022 23413
P2222313
Q31133131
AB2111313
DM31
DN2223133
DO1234
DQ122331221
DR333441234
DS112 211
DT111331212
DU122431322
DV432441231
DW212231325
DX 322231312
DY32231411
DZ223311
EA32441314
EB335414 32
EC33441441
ED433451442
EO33541441
EP34432
EQ43 442
ER22231
ES1241
ET13233
EU12231
EV22242
EW112232
EX22342
EY433441441
EZ22254141
FA 9313433441441
FB533441441
FC433441441
FN433441441
FO32 2341443
FP333541432
FQ333441442
FR444441441
FS433441551
GD333441441
GE3233
GF332341441
GG422442544
GH22333 2435
GI2121

Example 22

The review of conditions of the analysis hD2Sreceptor and h5-HT7receptor

hD2Sreceptorh5-HT7receptor
SourceMembranes from cells of the ovary of the Chinese hamster, transfection human D2Sdopamine receptorsMembranes from cells of the ovary of the Chinese hamster, transfection human h5-HT7receptors
The ligand0.1 nm/0.2 nm [3H]spiperone0.3 nm [3H]5-CT
KD0.1 nm0.2 nm
BMAX2.5 pmol (mg protein1.6 pmol mg protein
Nonspecific ligand5 μm (+)-butaclamol25 mm Clozapine
Specific binding78%66%
Media0,1% DMSO0,1% DMSO
The incubation period180 min120 min
The incubation temperature26°C27°C
The incubation buffer20 mm Hepes, pH 7.4, 1 mm EGTA, 6 mm MgCl2·6H2O, 1 mm EDTU50 mm Tris-HCl, pH 7.4, 10 mm MgSO4·7H2O, 0,5mm EDTU

Example 23

The review of conditions of the analysis hD2Lreceptor and hH1receptor

The review of conditions of the analysis hD2Lreceptor and hH1receptorhD2LreceptorhH1receptor
SourceMembranes from insect cells sf9 expressing human D2Lthe dopamine receptorsThe ligand0.4 nm [3H]spiperone2.0 nm [3H]pyrilamine
KD0.4 nm1,1 nm
BMAX1,36 pmol (mg protein1.55 pmol (mg protein
Nonspecific ligand1 μm (+)-butaclamol1 mm pyrilamine
Specific binding81%88%
Media0,1 DMSO0,1 DMSO
The incubation period60 min60 min
The incubation temperature27°C27°C
The incubation buffer50 mm Tris-HCl, pH 7.4, 120 mm NaCl, 1 mm EDTU,
10mm MgCl2·6 H2O
50mm Tris-HCl, 10 mg/ml Saponin, pH 7.4

Example 24

About the PR conditions analysis hM 1receptor and hM3receptor

135/75 min
hM1receptorhM3receptor
SourceMembranes from cells of the ovary of the Chinese hamster, transfection human M1receptorsMembranes from cells of the ovary of the Chinese hamster, transfection human M3receptors
The ligand1 nm of [3H]HMS0.1 nm [3H] HMS
KD0.49 nm0.1 nm
BMAX1,42 pmol/mg protein3,57 pmol/mg protein
Nonspecific ligand2 μm HMS5 μm atropine
Specific binding90%96%
Media0,1% DMSO0,1% DMSO
The incubation period60 min
The incubation temperature25°C26°C
The incubation buffer50 mm Tris-HCl, 10 μg/ml Saponin, pH 7.4Phosphate-saline buffer Dulbecco w/o calcium or magnesium, pH 7.4

Example 25

An overview of the conditions of the analysis of the h5-HT1Areceptor and h5-HT2creceptor

h5-HT1Areceptorh5-HT2creceptor
SourceMembranes from cells of the ovary of the Chinese hamster, transfection human 5HT1Adopamine receptorsMembranes from cells of a human embryo expressing T2Ctransfection human 5hT2Creceptors
The ligand2.5 nm [3H]8OH-DPAT1.2 nm [3H]mesulergine
KD9 nm1.2 nm
BMAXto 4.98 µm /mg protein1,7 gr /mg protein
Nonspecific ligand4 µm /mg of 5-HT creatinine sulfate1 µm /mg mianserin
Specific binding84%68%
Media0,1% DMSO0,1% DMSO
The incubation period120 min60 min
The incubation temperature37°C27°C
The incubation buffer50 mm Tris-HCl, pH 7.4, 5 mm MgSO4·7H2O50 mm Tris-HCl, pH 7.4, with 0.1% BSA, 1mm EDTU,
10mm MgCl2·6H2O

The invention, as well as the execution and the method thereof are now described in such full, clear, specific and exact terms as to enable any person skilled in the art to which it pertains to make and use it. It should be understood that the above described preferred embodiments of the invention and that can be implemented modifications without departure from the essence and scope of the invention as set forth in the following claims. In order to emphasize and what to move claims on the subject, consider the invention, the following claims completes this specification.

1. The compound having the structure

or its pharmaceutically acceptable salt,
where
R1and R2independently represents-CL, -F, -Br, -I or-H;
R3represents -(C0-C6alkyl)C(O)ORe, -(C0-C6alkyl) C(O)NRa2, -(C0-C6alkyl)C(O)NR20, -(C0-C6alkyl)AG, (C0-C6alkyl)-O-(C0-C6alkyl)AG or -(C0-C6alkyl)-OR;
R4represents-H or-R;
R5is a-R;
w is 0;
x is 0 or 1 and
y means 0,
where
each Reindependently represents-H, -R, -(C0-C6alkyl)Cak, -(C0-C6alkyl)-or, or -(C0-C6alkyl) -;
each Raindependently represents-H, -R, -(C1-C6alkyl)OR -(C1-C6alkyl)-OH, -(C0-C6alkyl)NSA or -(C0-C6alkyl)Het;
each Cak is an cycloalkyl group,
each AG is a phenyl, optionally substituted -(C0-C6alkyl)C(O)OR;
each Het is a pyridyl, optionally substituted-OR;
each NSA is hinokitiol, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, ka is each optionally substituted by R;
each of R20represents the ECA cycle, where N -(C0-C6alkyl)C(O)NR20represents a heteroatom in the ECA cycle, the cycle is optionally substituted by 1 or 2 substituents, independently selected from IT, or (C1-C6halogenoalkane);
each R independently represents -(C1-C6alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci) or(C1-C8halogenated), optionally substituted by 1, 2 or 3 substituents, independently selected from -(C1-C6alkoxy), C(O)O(C1-C6alkyl), or-IT; and
each (C1-C8alkyl) independently optionally substituted by 1, 2 or 3 substituents, independently selected from -(C1-C4alkyl), -(C1-C4alkoxy), -HE, or halogen, and optionally is halogenated.

2. The compound according to claim 1, where R3represents -(C0-C6alkyl) C(O)ORe-(C0-C6alkyl) C(O)NRa2or -(C0-C6alkyl) C(O)NR20.

3. The compound according to claim 2, where R3represents -(C0-C6)alkyl C(O)or SIGe.

4. The compound or salt according to claim 3, where each altergroup represents an alkyl group.

5. The compound or salt according to claim 3, where at least one of R1and R2represents-F, -Cl, -Br or-I.

6. The compound or salt according to claim 3,where both x and y equal to 0.

7. The compound or salt according to claim 3, where all of x, y and z is equal to 0.

8. The compound or salt according to claim 3, having the S-configuration of the carbon atom joining R3group.

9. The compound or salt according to claim 3, having the R-configuration of the carbon atom joining R3group.

10. The compound or salt according to claim 3, having a mixed configuration of the carbon atom joining R3group.

11. The compound or salt according to claim 3, where all of x, y and z equal to 0 and R4represents-N.

12. The compound or salt according to claim 1, where R1and R2independently represents-Cl, -F, -Br, -I or-N, provided that at least one of R1and R2represents-Cl, -F, -Br or-I;
R3represents -(C0-C6alkyl)C(O)OReor -(C0-C6alkyl)CONRa2;
where
each Reindependently represents-H or-R
each Raindependently represents-H or-R
each AG independently represents a phenyl, optionally substituted
-C(O)OR,
each R independently represents -(C1-C8alkyl), -(C3-C8cycloalkyl)- (C3-C12heteroseksualci), -(C1-C8foralkyl),
or -(C1-C8chloroalkyl), where(C1-C6foralkyl) or(C1-C6chloroalkyl) can be substituted by 1 to 6 fluorine atoms or chlorine, respectively, which each R is optionally substituted 1, 2 or 3 substituents selected from -(C1-C6alkoxy, and-C(O)O(C1-C4alkyl).

13. The compound or salt according to item 12, where each altergroup represents an alkyl group.

14. The compound or salt according to item 12, where R3represents -(C0-C6alkyl)C(O)ORe.

15. The compound or salt 14, where R3represents-H, -Me, -Et, Pr or Bu.

16. The compound or salt according to item 12, having the S-configuration of the carbon atom joining R3group.

17. The compound or salt according to item 12, having the R-configuration of the carbon atom joining R3group.

18. The compound or salt according to item 12, having a mixed configuration of the carbon atom joining R3group.

19. The compound or salt according to item 12, where R4represents-N.

20. The compound or salt according to item 12, where each of w, x and y equal to 0.

21. The compound or salt according to claim 1, having the structure

where R1and R2independently represents-CL, -F, -Br, -I or-N, provided that at least one of R1and R2represents-F, -CL, -Br or-I;
R4represents-H or-R;
R8represents-H, -Me, -Et or-RG;
R9represents-H, -Me, -Et or-RG;
In represents O or NH and
R12represents-H, -Me, -Et or-WG.

22. The compound or salt according to claim 2, where In represents O.

23. The compound or salt according to claim 1, where the connection is a
(E)- ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-isobutylacetate;
(E)-ethyl 2-(4-(2-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate
*(S) or (R) stereocenter;
(R,E)-methyl 4-((4-(2-chlorodibenzo[b,f}[1,4]oxazepine-11-yl)piperazine-2-yl)methoxy)benzoate;
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid;
(E)-ethyl 4-(2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)ethyl)benzoate;
(E)-methyl 4-((4-(8-chlorodibenzo[b,f}[1,4]oxazepine-11-yl)piperazine-2-yl)methoxy)benzoate;
(E)-ethyl 2-(4-(7-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(E)-ethyl 2-(4-(7-Ferdinando[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(E)-isopropyl 2-(4-(8-chlorodibenzo[b,f)[1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(E)-isopropyl 2-(4-(7-Ferdinando[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(R,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(R,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-2-(4-(8-chlorodibenzo[b,f][I,4]on azepin-11-yl)piperazine-2-yl)acetic acid;
(R,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid;
(E)-methyl 2-((4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)methoxy)acetate;
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetic acid;
(E)-methyl 2-(4-(8-(trifluoromethyl)-dibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl) acetate;
(S,E)-cyclopentyl 2-(4-(8-chlorodibenzo[b,f}[1,4]oxazepine-11-yl)-piperazine-2-yl)acetate;
(S)-Hinkley-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][f,4]oxazepine-11-yl)-1-methylpiperazin-2-yl) acetate;
(R)-Hinkley-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetate;
(S)-Hinkley-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetate;
(S,E)-tetrahydro-2H-Piran-4-IL2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetate;
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(S,E)-cyclopentyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
second-butyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)acetate;
(S,E)-tetrahydro-2H-Piran-4-yl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(S,E)-neopentyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-3-methoxy-3-methylbutyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-the l)acetate;
(S,E)-3-hydroxy-3-methylbutyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(R)-4-hydroxy-4-methylpentan-2-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(2S,4S)-4-hydroxypentanal-2-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
second-butyl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S)-tetrahydrofuran-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)1-isobutylpyrazine-2-yl)-acetate;
(R)-1-methylpyrrolidine-3-yl 2-((S)-4-((E)-8-chlorodibenzo[b,f}[1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-(cyclopropylmethyl)piperazine-2-yl)-acetate;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)-N-(1,3-ditropan-2-yl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)-N,N-(2,2,2-triptorelin)ndimethylacetamide;
(S,E)-3-forprofit 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-piperazine-2-yl)-N-(2-hydroxyethyl)-N-propylacetamide;
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]OK what azepin-11-yl)piperazine-2-yl)-N-((R)-2-hydroxypropyl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-(2-hydroxyethoxy)ethyl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-hydroxyethyl)-N-methylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(6-methoxypyridine-3-yl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2,2-dottorati)ndimethylacetamide;
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(((S)-tetrahydrofuran-2-yl)methylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl) piperazine-2-yl)-N-(3-methoxypropyl)ndimethylacetamide;
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-1((R)-3-hydroxypyrrolidine-1-yl)Etalon;
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3,3,3-Cryptor-2-hydroxypropyl)ndimethylacetamide;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-1-morpholinoethyl;
2-((S)-4-((E)-8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-1-((S)-2(trifluoromethyl)pyrrolidin-1-yl)-Etalon; or
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)-1-(2-hydroxyethyl)piperazine-2-yl)-N-(2-methoxyethyl)ndimethylacetamide.

24. The compound or salt according to claim 1, where the connection is a
(E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)and the Etat;
(E) -2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid;
(E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(R,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(R,E)-methyl 2-(4-(8-chlorodibenzo[b,f][I,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid;
(R)-4-hydroxy-4-methylpentan-2-yl 2-((S)-4-((E)-8-chlorodibenzo [b,f][1,4]oxazepine-11-yl)-1-methylpiperazin-2-yl)acetate;
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(2-methoxyethyl)ndimethylacetamide; or
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)-N-(3-hydroxypropyl)ndimethylacetamide.

25. The compound or salt according to item 21, where the connection is a
(S,E)-ethyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate;
(S,E)-methyl 2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetate.

26. The compound or salt according to item 21, where the connection is a
(S,E)-2-(4-(8-chlorodibenzo[b,f][1,4]oxazepine-11-yl)piperazine-2-yl)acetic acid.

27. Pharmaceutical composition having antagonistic activity against 5-HT2areceptors containing the compound or salt according to claim 1 and at least one farmaci is almost acceptable control flowability, the solvent adjuvant, diluent, lubricating agent, excipient or a combination of both.

28. Pharmaceutical composition having antagonistic activity against 5-HT2areceptors containing the compound or salt according to claim 3 and at least one pharmaceutically acceptable control flowability, solvent, adjuvant, diluent, lubricating agent, excipient or a combination of both.

29. Pharmaceutical composition having antagonistic activity against 5-HT2areceptors containing the compound or salt according to item 12, and at least one pharmaceutically acceptable control flowability, solvent, adjuvant, diluent, lubricating agent, excipient or a combination of both.

30. Pharmaceutical composition having antagonistic activity against 5-HT2areceptors containing the compound or salt according to item 21 and at least one pharmaceutically acceptable control flowability, solvent, adjuvant, diluent, lubricating agent, excipient or a combination of both.

31. Pharmaceutical composition having antagonistic activity against 5-HT2areceptors containing the compound or salt according to item 23 and at least one pharmaceutically acceptable control flowability, solvent, adjuvant, diluent, lubricating agent, excipient is whether a combination of both.

32. Pharmaceutical composition having antagonistic activity against 5-HT2areceptors containing the compound or salt according to paragraph 24, and at least one pharmaceutically acceptable control flowability, solvent, adjuvant, diluent, lubricating agent, excipient or a combination of both.

33. A method of treating schizophrenia is not curable schizophrenia, bipolar disorder, psychotic depression, untreatable depression, treatment of obsessive-compulsive disorder (OCD), autism, dementia, psychotic dementia, L-DOPA-induced psychosis, psychogenic polydipsia, psychotic symptoms associated with a neurological disorder, sleep disorders, depression associated with schizophrenia, comprising introducing the compound or salt according to claim 1 to a patient in need of such treatment.

34. A method of treating schizophrenia is not curable schizophrenia, bipolar disorder, psychotic depression, untreatable depression, the treatment of obsessive-compulsive disorder (OCD), autism, dementia, psychotic dementia, L-DOPA-induced psychosis, psychogenic polydipsia, psychotic symptoms associated with a neurological disorder, sleep disorders, depression associated with schizophrenia include the rd introducing the compound or salt according to item 23 of the patient, in need of such treatment.

35. A method of treating schizophrenia is not curable schizophrenia, bipolar disorder, psychotic depression, untreatable depression, treatment of obsessive-compulsive disorder (OCD), autism, dementia, psychotic dementia, L-DOPA-induced psychosis, psychogenic polydipsia, psychotic symptoms associated with a neurological disorder, sleep disorders, depression associated with schizophrenia, comprising introducing the compound or salt according to point 24 to a patient in need of such treatment.

36. The method according to p, where the compound or salt according to claim 1 is administered to a patient in need of such treatment, in combination with one or more antipsychotic agents, antidepressants, sedative agents or nicotine.

37. The method according to clause 34, where the compound or salt according to item 23 is administered to a patient in need of such treatment, in combination with one or more antipsychotic agents, antidepressants, sedative agents or nicotine.

38. The method according to p, where the compound or salt according to point 24 is administered to a patient in need of such treatment, in combination with one or more antipsychotic agents, antidepressants, sedative agents or nicotine.

39. The method of obtaining the compounds of formula F

kiuchumi
(1) the conversion of compounds of formula (A)

or its salts in the compound of formula (In)

or its salt, respectively, where Z1and Z2are azatadine group;
(2) the conversion of compounds of formula (In)

in the acid chloride with subsequent transformation into diazed formula (C)

where Z1and Z2are azatadine group;
(3) treatment of compounds of formula (C)

silver catalyst and alcohol to obtain formula (D)

where Z1and Z2are azatadine group, Rerepresents a C1-C6alkyl;
4) removing the protection from the compounds of formula (D)

or its salt to obtain the compounds of formula (E)

or its salt, respectively, where Rerepresents a C1-C6alkyl;
5) alkylation of compounds of formula (E)

or its salt with the compound of the formula (G)

or its salts, where R1and R2independently represent H, I, Br, Cl or I, in the compound of formula (F)

or its salt, respectively, where Re represents a C1-C6alkyl, R1and R2independently represent H, I, Br, Cl or I and where in each case the relationship between the piperazine and carbonyl fragment is a racemic, R or S.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) wherein R4 represents a group of formula (II) and R1, R2, R3, R5 and X are those as specified in the patent claim.

EFFECT: preparing the pharmaceutical composition applicable in treating chronic obstructive pulmonary disease and containing the compound of formula (I).

8 cl, 3 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: medicine.

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

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

FIELD: chemistry.

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

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

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

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

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I), its optical isomer or pharmaceutically acceptable salt, R is specified in cl.1 of the patent claim. The compounds may be presented both as an optical isomer, and as a racemic substance, and may be used for mental disorders, such as schizophrenia.

EFFECT: higher efficacy of using the compounds.

8 cl, 4 tbl, 3 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (VI): or its pharmaceutically acceptable salts; wherein n is equal to 0, 1, 2 or 3; R1 means -OH, H; R2a means OH, -CH3, provided at least one of R1 and R2a means -OH;R3 means Cl, Br, cyclopropyl, branched C3-5alkyl R4a means H; R8 means H; wherein the fragment: may be one of the groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B54, B56, B58, B59, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B84, B86, B87, B88, B89, B90, B91, B93, B94, B95, B96, B97, B98, B99, B100 and B101 wherein the values are disclosed in the patent claim 1.

EFFECT: compounds show Hsp90 inhibitory activity that enables using them for treating the diseases caused by abnormal cell growth in mammals.

26 cl, 8 dwg, 2 tbl, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine.

SUBSTANCE: invention refers to new heterocyclic compounds of formula I wherein: n and m may have values 0, 1, 2 and 3; the sign (#) in what follows means the potential presence of a chiral centre; R represents optionally substituted C5-C10aryl or 5-6-member hetaryl containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur optionally condensed with a benzene ring with the substitutes specified in C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, NO2, CF3O, COOH, an unsubstituted amino group or mono-C1-6alkyl- or di(C1-6alkyl)substituted amino-group, C1-8alkylsulphanyl, C1-8alkoxycarbonyl; A1 and A2 independently represent optionally substituted 5-6 member saturated, or aromatic azaheterocycle containing 1 to 2 nitrogen atoms in the cycle and optionally condensed with the benzene ring; or to their pharmaceutically acceptable salts or alkyl esters in the form of isolated optical isomers, or their mixtures. Also, the invention refers to a pharmaceutical composition on the basis of the compound of formula I, to a drug on the basis of the compound of formula I, as well as to a method for preparing the compound of formula I.

EFFECT: there are prepared new non-peptide heterocyclic low-molecular peptidomimetics of a secretory amyloid peptide precursor sAAP showing an ability to have an effective effect on the processes of formation, storage and restoration of the memory lost in health and none.

10 cl, 4 dwg, 22 ex

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