Spiroazacyclic compounds, method for inhibition if activity or activation of serotonin 5-НТ2А receptor, method for treatment of morbid state associated with serotonin 5-НТ2А receptor and their using

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

EFFECT: improved method of treatment, valuable medicinal properties of compounds.

35 cl, 3 tbl, 2 dwg, 45 ex

 

The SCOPE of the INVENTION

The present invention relates to new compounds acting on monoamine receptors, including serotonin receptors. Specifically, the invention is provided compounds active as inverse agonists, and therefore also as antagonists against subtype 5-NTA serotonin receptors person. In addition, the invention provides methods, the use of compounds of the present invention for modulation mediated by 5-NTA receptors events, applicable to the treatment or relief of painful conditions in which changes in the activity of these receptors is beneficial.

PRIOR art

Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in the functioning of the body of a mammal. In the Central nervous system 5-HT is an important neurotransmitter and neuromodulator that is involved in such diverse processes and reactions, as sleep, nutrition, movement, feeling pain, learning and memory, sexual behavior, controlling body temperature and blood pressure. In the spine serotonin plays an important role in regulating systems of the afferent peripheral pain receptors (Mouligner,Rev. Neurol. 150:3-15, (1994)). In addition, 5-HT attributed to peripheral functions in the cardiovascular with sudiste, hematological and gastrointestinal systems. It has been found that by means of 5-HT is a lot of contractile, secretory, and electrophysiological effects, including the reduction of vascular and non-vascular smooth muscle and platelet aggregation (Filler,Biology of Serotonin Transmission, 1982; (1973)). 5-NTA subtype receptor (also called a subclass) wide, yet discretely expressed in the human brain, including many cortical, regional and perednebokova areas that, as postulated, participate in modeling higher cognitive and emotional functions. This subtype receptor is also expressed in Mature platelets, where it means is partially platelet aggregation is one of the initial stages in the process of vascular thrombosis. Given the wide distribution of serotonin in the body, there is a huge interest in drugs that affect the serotonergic system (who, et al.,The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et al.,J. Cardiovascular Pharmacol. 15: Supp. 7 (1990)).

Serotonin receptors are members of a large family membranosvyazannaya proteins of human genes that function as transducers intercellular interaction. They exist on the surface of cells of various types, including neurons and platelets, where in achiev is Tate activate them either by their endogenous serotonin ligand, or exogenously introduced medicines they change their conformational structure and subsequently interact with downstream"-mediators of cellular signal transmission. Many of these receptors, including the subclass of 5-NTA represent receptors associated with G-protein (GPCR), the input signal through the activation of the guanine-nucleotide binding proteins (G-proteins), leading to the formation or inhibition of secondary molecules messengers, such as cyclic AMR, Inositol phosphates and diacylglycerol. These secondary messengers then simulate the function of many intracellular enzymes, including kinases and ion channels, which, ultimately, affect cellular excitability and function.

At least 15 genetically distinct 5-HT receptors have been identified and attributed to one of seven families (5-NT-7). Each subtype runs its own distribution, preference to different ligands and functional dependence(addiction).

Serotonin may be an important component in pathological conditions of various types, such as psychiatric disorders (depression, aggressiveness, panic attacks, obsessive-compulsive disorder, psychosis, schizophrenia, susceptibility to suicide), neurodegenerative disorders (dementia type Alzheimer's disease, parkinsonism, chorea, Huntington is a), anorexia, bulimia, disorders associated with alcoholism, stroke, and migraine (Meltzer,Neuropsychopharmacology., 21:106S-115S (1999); Barnes & Sharp,Neuropharmacology, 38:1083-1152 (1999); Glennon,Neurosci. Biobehavioral Rev., 14:35 (1990)). Recent irrefutable evidence point to the involvement of 5-HT2 receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders.

Schizophrenia is a particularly devastating neuropsychiatric disorder that affects about 1% of the human population. It was estimated that the total financial costs of diagnosis, treatment and loss of social productivity of individuals affected by the disease, exceeds 2% of the total national product (GNP) of the United States. Conventional treatment includes, first of all, pharmacotherapy, using the class of drugs known as antipsychotics. Antipsychotics are effective for improvement of positive symptoms (e.g. hallucinations and mania), but they often do not improve negative symptoms (e.g., autism, apathy and poverty of speech).

Currently, for the treatment of psychotic symptoms prescribe antipsychotics nine core classes. However, the use of this is x of connections is limited by the profile of their side effects. Almost all "typical", or compounds of earlier generations, have a material adverse effect on the motor function of the person. Data "extrapyramidal" side effects, so named because of its modulatory effect on the musculoskeletal system of the person, can be acute (eg, dystonic reaction, a potentially life-threatening, but rare neuroleptic malignant syndrome), and chronic (eg, akathisia, tremor and late dyskinesia). Therefore, attempts to develop drugs aimed at newer "atypical" agents that do not have such adverse effects.

It was shown that antipsychotic medications interact with a large number of Central monoaminergic neurotransmitter receptors, including dopaminergic,serotonergic,adrenergic,muscarinicandhistaminergic receptors. Apparently, therapeutic and adverse effects of these drugs is mediated by a variety of receptor subtypes. The high degree of genetic and pharmacological homology between these receptors subtypes have complicated the search for subtype-selective compounds, as well as the definition of normal physiological or pathophysiological role of any particular receptor is adtype. Thus, there is a need to develop drugs that are selective in relation to the receptors of the individual classes and subclasses in a series of monoaminergic neurotransmitter receptors.

One of theories regarding the mechanism of action of antipsychotic drugs include antagonism of dopamine D2 receptors. Unfortunately, it seems that the antagonism of the dopamine D2 receptor also mediates extrapyramidal side effects. Antagonism of 5-NTA represents an alternative molecular mechanism for drug antipsychotic action, possibly through antagonism of the raised or increased signal transmission through the serotonergic system. Therefore, 5-NTA antagonists are good candidates for the treatment of psychosis without extrapyramidal side effects.

Traditionally it was believed that these receptors exist in a passive state until, until they are activated by binding antagonist (any drug that activates the receptor). At present recognize that many, if not most, of the GPCR monoamine receptors, including serotonin receptors can exist in a partially activated state in the absence of their endogenous antagonists. This increased basal activity (constitutive activity is ü) inhibition using compounds called inverse agonists. Both agonists and inverse agonists have their own activity in relation to the receptor, which is expressed in the fact that they can activate or deactivate 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 ability to inhibit elevated base or structural response of the receptors.

Recently, the authors have clarified an important aspect of the functioning of the receptor 5-NTA using technology selection and amplification of receptor (R-SAT) (U.S. patent 5707798, 1998,Chem Abstr. 128:111548 (1998) and in the references) for the study of serotonin receptors subclass 5-HT2. R-SAT is a phenotypic analysis of receptor function, which comprises a heterologous espressione receptors in mammalian fibroblasts. The use of this technology gave the authors the opportunity to show that native receptors 5-NTA have significant constitutive, or agonist-independent receptor activity (Wiener et al.J. Pharmacol. Exp. Ther.2001, 299 (1), 268-276.). In addition, with the direct testing of a large number of centrally active therapeutic compounds with known clinical activity at the neuropsychiatric Soboleva and, the authors found that all compounds with antipsychotic efficacy share a common molecular property. It was found that almost all of these compounds, which are used by psychiatrists to treat psychosis are effective inverse agonists of the 5-NTA. This unique clinico-pharmacological correlation on a single receptor subtype is unequivocal evidence that the reverse agonist receptor 5-NTA represents the molecular mechanism of antipsychotic efficacy in humans.

Through detailed pharmacological characterization of a large number of antipsychotic compounds revealed that they have broad activity against many related receptors subtypes. Most of these compounds exhibit agonistic, competitive, antagonistic or inverse agonistic activity against multiple subtypes of monoaminergic receptors, including serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic receptors. Apparently, this broad activity responsible for sedative, hypotensive and motor side effects of these compounds. Therefore, it would be very advantageous to obtain compounds that are selective inverse agonists in respect of the receptor 5-NTA, but exhibiting low or no activity against other receptors Madaminov subtypes, in particular dopamine D2 receptors. Such compounds may be useful for treatment of human diseases (such as antipsychotic agents) and can avoid the adverse side effects associated with nonselective receptor interactions.

In U.S. patent 4853394 described espiritista piperidine esters and amides, are not included in the scope of compounds of formula I.

Smith et al. (J. Med. Chem,1995, 38, 3772) describes spirobiindane, including oxazolidinone, hydantoins, imidazolidinone, pyrrolidinone, pyrazolidinone and pyrrolidine not included in the scope of compounds of formula I.

Maunkel et al. (J. Med. Chem,1996, 39, 3169) describes antagonists pseudopeptides bradikininovoi B2 receptor containing 1,3,8-triaza[4.5]Decan-4-about cyclic systems are not included in the scope of compounds of formula I.

Strosberg et al. (J. Med. Chem,1981, 24, 1320) describes 1-oxa-3,8-diazaspiro[4.5]Decan-2-ones which are not included in the scope of compounds of formula I.

Strosberg et al. (J. Med. Chem,1983, 27, 855) describes 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecane-3-ons that are not included in the scope of compounds of formula I.

Tsukamoto et al. (Chem. Pharm. Bull,1995, 43(9), 1523) describes 1-oxa-2,8-diazaspiro[4.5]Decan-3-ones as M1m is skarynovich agonists. However, none of the compounds Tsukamoto et al. not included in the scope of compounds of formula I, and compounds Tsukamoto et al. do not apply to methods of the present invention.

In WO 97/11940 described compounds as inhibitors of fibrinogen-dependent platelet aggregation, are not included in the scope of compounds of formula I.

Wiener et al. (J. Pharmacol. Exp. Ther.2001, 299(1), 268-276) describes the inverse agonist at 5-NTA not included in the scope of compounds of formula I.

PCT/US01/07187 described espiritista N-(4-piperidinyl)dibenzylamine and urea, are not included in the scope of compounds of formula I.

In U.S. patent 6150393, 6140509, 6107324 and EP 1071701 described espiritista connections that are not included in the scope of compounds of formula I.

In WO 99/52927 described espiritista derivatives phenylpyrazole not included in the scope of compounds of formula I.

BRIEF description of the INVENTION

The invention provides compounds of formula I, salts thereof and stereoisomers

in which X is chosen from the group comprising SN2CH2CH2CH2Oh, och2, O, CH2S, SCH2, S, CH2N(RN), N(RN)CH2and N(RN); where RNselected from hydrogen and C1-6-alkyl;

Y is chosen from the group comprising O and S;

Z is absent or is selected from the group comprising SN and N;

R1selected from the group comprising water is od optionally substituted C1-6-alkyl, C2-8alkenyl,2-8-quinil, optionally substituted C3-6-cycloalkyl, aryl and heteroaryl;

m is chosen from the group comprising 0 and 1;

R4, R5and R6independently selected from the group including hydrogen, C1-6is alkyl, aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl), heterocyclyl(C1-6-alkyl), hydroxy(C1-6-alkyl), amino(C1-6-alkyl), halogen(C1-6-alkyl), optionally substituted C3-6-cycloalkyl, aryl and heteroaryl, where at least two of R4, R5and R6independently selected from the group including aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl) and heterocyclyl(C1-6-alkyl);

R2and R3independently selected from the group comprising hydrogen, halogen, hydroxy, and optionally substituted C1-6-alkyl, or are chosen so that R2and R3together form a cyclic system such that

selected from the group including

in which R7and R8independently selected from the group comprising hydrogen, halogen, hydroxy and C1-6-alkyl.

The invention also provides pharmaceutical compositions containing compounds of the invention. In one embodiments the composition contains sedimentary I, its pharmaceutically acceptable salt or stereoisomer together with a pharmaceutically acceptable carrier or excipient.

In addition, the invention provides methods of inhibiting the activity or activation of a monoamine receptor. In one embodiments the method includes contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of formula I for inhibiting the activity of this monoamine receptor. In the following embodiment, the method comprises contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of formula I for the inhibition of the activation of this monoamine receptor.

In addition, in the invention provided methods of treating painful conditions associated with monoamine receptor. In one embodiments the method includes administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of formula I. In various aspects of the disease state is chosen from the group including schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.

In addition, it is proposed the use of the compounds of formula I is La obtain drugs for the treatment of painful conditions. In one of the embodiments of the use of the compounds of formula I to obtain a medicinal product intended for the treatment of painful conditions associated with monoamine receptor. In various aspects of the disease state is chosen from the group including schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.

In addition, the invention provides methods of identifying a genetic polymorphism predisposing a subject for susceptibility to one or more compounds of formula I. In one of the embodiments the method includes:

introduction to the subject therapeutically effective amounts of compounds;

determination of the reaction of the specified entity on the specified connection to identify, thus, susceptible of a subject with superior painful condition associated with monoamine receptor; and

identification of genetic polymorphism in susceptible subject, where this genetic polymorphism predisposes a subject for susceptibility to this connection.

In an additional aspect, the invention provides methods of identifying a subject suitable for treatment with one or more compounds of formula I. In one of the embodiments the method includes determining whether a polymorphism is the subject where this polymorphism predisposes the subject to susceptibility to the compound, and where the presence of the polymorphism indicates that the subject is suitable for treatment with one or more compounds of formula I.

The invention provides kits comprising one or more compounds of this invention and instructions for practical application of the method of the invention. In one of the embodiments of the instructions are for methods of inhibiting the activity or activation of a monoamine receptor. In another embodiment the instructions are intended for the treatment of painful conditions associated with monoamine receptor. In yet another embodiment, the instructions are intended for administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of formula I. In various aspects of the subject suffers from or is at risk of disease, schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disturbance or disorder of appetite.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the effect 69NLS75 on hyperactivity in mice treated with an agonist of the NMDA receptor, MK-801, ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-Imin, gidromaleat salt).

Figure 2 shows the effect of dose 69NLS75 spontaneous engine in the optimum activity.

Description of the INVENTION

For the purposes of this disclosure to describe technical terms will be used the following definitions in their entirety. The term "constitutive activity" determine the increased basal activity of the receptor, which does not depend on the presence of agonist. Constitutive activity of the receptor can be determined using a number of different ways, including cellular (e.g., membrane) drugs (see, e.g., Barr & Manning,J. Biol. Chem. 272:32979-87 (1997)), peeled restored receptors, whether or not containing associated G-protein in phospholipid vesicles (Cerione et al.,Biochemistry23:4519-25 (1984)), and functional cellular assays (patent application U.S. serial No. 09/413626).

The term "agonist" is defined compound that increases the activity of the receptor when it is contact with the receptor.

The term "antagonist" is defined molecule that competes with an agonist or inverse agonist for binding to the receptor, thus blocking the action of an agonist or inverse agonist to the receptor.

The term "inverse agonist" is defined connection, reducing the basal activity of the receptor (i.e. mediated by the receptor signal transmission). Such compounds are also known as negative antagonists. Inverse agonist is a ligand for a receptor, revolade to that the receptor adopts an inactive state with respect to the basal condition in the absence of any ligand. Thus, although the antagonist can inhibit the activity of the agonist, inverse agonist is a ligand that can change the conformation of the receptor in the absence of agonist. The concept of inverse agonist was studied by Bond et al. inNature374:272 (1995). More specifically, Bond et al. suggested that is not associated with ligand β2-adrenergic receptors exist in equilibrium between an inactive conformation and spontaneously active conformation. Suggest that agonists stabilize the receptor in an active conformation. On the contrary, it is believed that inverse agonists stabilize the inactive conformation of the receptor. Thus, although the antagonist exerts its activity by inhibiting agonist, inverse agonist is able, moreover, to show its activity in the absence of agonist, inhibiting spontaneous transition is not associated with the ligand of the receptor in the active conformation.

The term "5-NTA receptor determine the receptor with activity, the activity subtype of serotonin receptor human, characterized by using molecular cloning and pharmacology, which are described in detail in Saltzman et al.,Biochem. Biophys. Res. Comm. 181:1469-78; and Julius et al.,Proc. Natl. Acad. Sci. 87:928-932.

The term "subject" refers to an animal such as a mammal, such as man, which is the object of treatment, observation or experiment.

The term "selective" define the connection property, whereby the quantity of this compound, sufficient to cause the desired response from the receptor of a specific type, subtype, class, or subclass, causes significantly less or no impact on the activity of the receptors of other types.

The term "selectivity"or "selective" in relation to the inverse agonist imply a connection property, whereby the number of connections, which effectively renders the inverse agonistic effect on 5-NTA the receptor and, thus, reduces its activity, causes little or no inverse agonistic or antagonistic activity at other, related or unrelated receptors. In particular, it has been unexpectedly found that the compounds of the present invention do not interact strongly with other serotonin receptors (5-ht1a, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6 and 7) at the concentrations at which signal transmission 5-NTA receptor strongly or completely ingibirovany. Compounds of the present invention can also exhibit selectivity towards other monolingualism receptor is, such as dopaminergic, histaminergic, adrenergic and muscarinic receptors. Compounds having a high selectivity to 5-NTA receptors, may be beneficial in the treatment of psychosis, schizophrenia or similar neuropsychiatric disorders, without, at the same time, the adverse effects associated with other medications.

It is implied that the EU50for agonist means the concentration of compound required to achieve 50% of maximal response observed in R-SAT. For inverse agonists implies that EU50means the concentration of compound required to achieve 50% inhibition of the response in R-SAT compared to basal levels in the absence of a connection.

As used here, the term "co-administration" refers to the delivery of two or more separate chemical substances either in vitro or in vivo. Co-administration refers to the simultaneous delivery of a single agent, for simultaneous delivery of a mixture of agents, as well as to the delivery of a single agent with subsequent delivery of the second agent or additional agents. In all cases it is assumed that jointly administered agents act in conjunction with each other.

In this context, the term "C1-6-alkyl" means linear or branched hydrocarbon chain, where the may long chain contains from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.

In this context, the term "C2-8alkenyl" means linear or branched hydrocarbon group containing from two to eight carbon atoms and containing one or more double bonds. Illustrative examples2-8-alkenyl groups include allyl, Gamaliel, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Illustrative examples2-8-alkenyl groups with more than one double bond include butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadienyl and octatriene, as well as their branched form. The position of unsaturation (double bond) can be in any position of the carbon chain.

In this context, the term "C2-8-quinil" means linear or branched hydrocarbon group containing from two to eight carbon atoms and containing one or more triple bonds. Illustrative examples2-8-etkinlik groups include ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl and octenyl, as well as their branched form. The position of unsaturation (triple bond) can be in any position of the carbon chain. Unsaturated may be more than one link, so2-8-quinil" is the Wallpaper diin or endian, as is well-known specialist in this field.

Is understood that the terms "halogenated", "hydroxyalkyl and aminoalkyl include defined above With1-6is an alkyl group containing at least one halogen atom, a hydroxy-group or amino group, respectively.

In this context, the term "lower alkylene" means a divalent hydrocarbon link containing from one to six carbon atoms. In addition, the "lower alkylene the links can optionally contain one or more substituents selected from C1-6-alkyl, halogen, hydroxyl and amino. Non-limiting examples of "lower alkilinity" groups are methylene, ethylene, propylene, tetramethylene, hexamethylene.

In this context, the term "C3-8-cycloalkyl includes three-, four-, five-, six-, seven - and eight-membered cycles containing only carbon atoms, while the term "heterocyclyl" means three-, four-, five-, six-, seven - and eight-membered cycles, where the cycle consists of carbon atoms in addition to 1-3 heteroatoms. Heteroatoms such heterocyclyl groups independently chosen from oxygen, sulfur and nitrogen.

The term "heterocyclyl" group may also include one or more carbonyl or thiocarbonyl functional group so that this definition is included occasi themes and tosystem, such as lactams, lactones, cyclic imides, cyclic thioamide, cyclic carbamates, and so on.

With3-8-cycloalkyl and heterocyclyl rings can optionally contain one or more unsaturated bonds located, however, so that there are no aromatic π-electronic systems.

Heterocyclyl rings optionally may be condensed with aryl rings, so this definition includes bicyclic structure. Such condensed heterocyclyl group can have one common bond with the benzene ring. Examples benzododecinium heterocyclyl groups include, but are not limited to benzimidazolidinone, tetrahydroquinoline and methylenedioxybenzene cyclic structures.

Illustrative examples "C3-8-cycloalkyl" are carbocycle cyclopropane, CYCLOBUTANE, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, Cycloheptane, cycloheptene, 1,2-cycloheptadiene, 1,3-cycloheptadiene, 1,4-cycloheptadiene and 1,3,5-cycloheptatrien.

Illustrative examples of "heterocyclyl represent heterocycles tetrahydrothiopyran, 4H-Piran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-axation, 1,4-oxathiin, 1,4-about satian, tetrahydro-1,4-thiazin, 2H-1,2-oxazin, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperidin, as dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolin, pyrrolidine, pyrrolidone, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiol, 1,3-ditiolan, isoxazolin, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, 1,3-oxathiolan. Linking with this heterocycle may occur at the position of the heteroatom or carbon atom of the heterocycle, or, in the case benzododecinium derivatives on carbon atom bentinho cycle.

In this context, the term "aryl" means a carbocyclic aromatic ring or ring system. In addition, the term "aryl" includes condensed ring system in which at least two aryl rings or at least one aryl ring and at least one aryl and at least one3-8-cycloalkyl have at least one common chemical bond. Illustrative examples of "aryl" rings include optionally substituted phenyl, naphthalenyl, phenanthrene, anthracene, tetralinyl, fluorenyl, indenyl and indanyl. Another example of the aryl group is phenyl. The term "aryl" refers to aromatic, in the example benzoinum, groups associated with one of the forming ring carbon atoms and optionally containing one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl,1-6-aminoalkyl,1-6-alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. Established that the aryl group can be phenyl, which includes substituted phenyl group containing one or two identical or different substituent listed above. A specific example of a type of substitution ispairand/ormeta. Representative examples of aryl groups include, but are not limited to phenyl 3-halogenfree, 4-halogenfree, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-AMINOPHENYL, 4-AMINOPHENYL, 3-were, 4-were, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimetilfenil, naphthyl, hydroxynaphthyl, hidroximetilpropan, cryptomaterial, alkoxyphenyl.

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

In addition, in the present context the term "heteroaryl" includes condensed ring system in which at least one aryl ring, or at least one heteroaryl ring, at least two heteroaryl ring, at least one heteroaryl ring and at least one heterocyclyl ring, or at least one heteroaryl ring and at least one3-8-cycloalkyl ring have at least one common chemical bond.

It is implied that the term "heteroaryl" refers to aromatic C2-6-cyclelimit groups containing, besides one O or S atom, or up to four N atoms, or a combination of one O or S atom and two N atoms, and their substituted and benzo - and pyridinediamine derived, usually attached through one of the forming ring carbon atoms. Heteroaryl group can contain one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl,1-6-aminoalkyl,1-6-alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl, or trifloromethyl. Particular heteroaryl groups are five - and six-membered aromatic heterocyclic system, soderjashie, 1 or 2 substituent selected from the above list, which may be the same or different from each other. Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono - or disubstituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazol, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole and tetrazole and furazane, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, pteridine, pyrrole, phenoxazone, oxazole, isoxazol, oxadiazole, benzopinacol, indazole, hemolysin, cinnoline, phthalazine, hinzelin and finokalia. Most likely the substituents are halogen, hydroxy, cyano, O-C1-6-alkyl, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl.

The term "aryl(C1-6-alkyl)" means aryl groups connected, as substituents, via a lower alkylene, each of which is defined above. Aryl group, the aryl(C1-6-alkyl)may be substituted or unsubstituted. Examples include substituted benzyl, 2-phenylethyl, 3-phenylpropyl and nafcillin.

The term "heteroaryl(C1-6-alkyl)" mean göta the ilen group, connected, as substituents, via a lower alkylene, each of which is defined above. Heteroaryl group heteroalkyl groups can be substituted or unsubstituted. Examples include 2-thienylmethyl, 3-thienylmethyl, furylmethyl, titilate, pyrrolidinyl, pyridylethyl, isoxazolyl, imidazolylalkyl and their substituted and benzododecinium counterparts.

The term "heterocyclyl(C1-6-alkyl)" mean heterocyclyl groups connected, as substituents, via a lower alkylene, each of which is defined above.

The term "cycloalkyl(C1-6-alkyl)" mean cycloalkyl groups connected, as substituents, via a lower alkylene, each of which is defined above.

When used herein, the term "O-C1-6-alkyl" means1-6-alkoxy or alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy. In addition, it is understood that the definition of "O-C1-6-alkyl" includes cyclic alkoxygroup containing a maximum of six carbon atoms. Illustrative non-limiting examples of cyclic alkoxygroup include CYCLOBUTANE, cyclopropylmethoxy, cyclohexyloxy and so on.

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

In this context, that is, in connection with the terms "C1-6-alkyl", "aryl", "heteroaryl", "heterocyclyl", "heteroaryl(C1-6-alkyl), aryl(C1-6-alkyl)", "cycloalkyl(C1-6-alkyl)", "C3-8-cycloalkyl", "heterocyclyl(C1-6-alkyl)", "O1-6-alkyl", "C2-8alkenyl" and "C2-8-quinil", the term "optionally substituted" means that the group may be substituted one or more times, for example, from 1 to 5 times 1 to 3 times, or 1 to 2 times, by one or more groups selected from C1-6-alkyl, C1-6-alkoxy, oxo (which may be represented by the tautomeric enol form), carboxyl, amino, hydroxy (which when present in the enol system may be represented in the tautomeric ketoform), nitro, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl,1-6-alkoxycarbonyl,1-6-alkylsulphonyl, formyl, amino, mono - and di(C1-6-alkyl)amino, carbamoyl, mono - and di(C1-6-alkyl)aminocarbonyl, amino-C1-6-alkylaminocarbonyl, mono - and di(C1-6-alkyl)amino-C1-6-alkylaminocarbonyl,1-6-alkylcarboxylic, cyano, guanidino, carbamide,1-6-alkanoyloxy,1-6-alkylsulfonate, dihalogen-C1-6-alkyl, trihalogen-C1-6of alkyl and halogen. In General, it is possible to prevent a further optional substitution of the above substituents.

the Ermin "homochiral" should be interpreted in accordance with the definition in "Principles of Asymmetric Synthesis" (Gawley and Aubé , Pergamon, 1996, ISBN 0 08 0418759).

The term "salt" means pharmaceutically acceptable salt accession acid that can be obtained when processing the main form functional groups such as amine, with appropriate acids such as inorganic acids, such as halogen acids, typically hydrochloric, Hydrobromic, hydrofluoric, or itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic, propionic, hydroxylases, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandiol, propandiol, butandiol, (Z)-2-butandiol, (E)-butandiol, 2-hydroxybutanoic, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, econsultancy, benzosulfimide, 4-methylbenzenesulfonic acid, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and other acids known to the person skilled in the field.

The invention is provided compounds of subgroups which show relatively high selectivity towards serotonin receptors, in particular 5-NTA receptors, which can have a beneficial effect in the treatment of neuropsychiatric disorders.

In a preferred variant of the embodiment the Oia compounds of the present invention are defined by formula I, including their salts and stereoisomers, as well as pharmaceutical compositions.

in which X is chosen from the group comprising SN2CH2CH2CH2Oh, och2, O, CH2S, SCH2, S, CH2N(RN), N(RN)CH2and N(RN); where RNselected from hydrogen and C1-6-alkyl;

Y is chosen from the group comprising O and S;

Z is absent or selected from the group comprising SN and N;

R1selected from the group comprising hydrogen, optionally substituted C1-6-alkyl, C2-8alkenyl,2-8-quinil, optionally substituted C3-6-cycloalkyl, aryl and heteroaryl;

m is chosen from the group comprising 0 and 1;

R4, R5and R6independently selected from the group including hydrogen, C1-6is alkyl, aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl), heterocyclyl(C1-6-alkyl), hydroxy(C1-6-alkyl), amino(C1-6-alkyl), halogen(C1-6-alkyl), optionally substituted C3-6-cycloalkyl, aryl and heteroaryl,

where at least two of R4, R5and R6independently selected from the group including aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl) and heterocyclyl(C1-6-alkyl);

R2and R3independently selected from the group comprising hydrogen, halogen, hydroxy, and optionally substituted C1-6-alkyl, or vybirayutsa, to R2and R3together form a cyclic system such that

selected from the group including

in which R7and R8independently selected from the group comprising hydrogen, halogen, hydroxy and C1-6-alkyl.

The compounds of formula I exhibit activity against monoamine receptors, in particular serotonin receptors. Some compounds share a common property act as inverse agonists at the 5-NTA receptor. Thus, the experiments conducted on cells, temporarily expressionwhich specified receptor of the human phenotype, showed that the compounds of General formula I weaken the signal transmission of such receptors in the absence of additional ligands acting on the receptor. Thus, it was found that these compounds possess own activity in relation to this receptor and is able to reduce basal, stimulated not agonists, the constitutive response of the transmission signal, the solidity of the receptor 5-NTA. The observation that compounds of General formula (I) are inverse agonists, also indicates that these compounds have a JV is the ability to anlagenservice activation of 5-NTA receptors mediated by endogenous or exogenous agonists synthetic agonistic ligands.

Thus, the present invention provides compounds of formula I, their salts and stereoisomers, including compounds exhibiting a relatively high degree of selectivity towards 5-NTA subtype of serotonin receptors compared with other subtypes of the family of serotonin (5-HT) receptors, and other receptors, most specifically, the aminergic G protein binding receptors, such as dopamine receptors. In one embodiments of the compounds of the invention act as inverse agonists in relation to 5-NTA subtype of serotonin receptors.

Therefore, compounds of General formula (I) can be useful for the treatment or relief of symptoms of painful conditions associated with impaired function, in particular elevated levels of activity, in particular, 5-NTA receptors, where it weakened the function associated with improper levels of stimulation of receptors, or phenotypic aberrations.

Previously others had made the assumption that some neurophysiological disease, possibly caused by altered levels of constitutive activity monoamine receptors. Such constitutive activity could be modified is th bringing the appropriate receptor in contact with the synthetic inverse agonist. With the direct testing of a large number of centrally acting used in medicine compounds with known clinical activity in neuropsychiatric diseases, all connections antipsychotic actions have the General molecular property. It was found that almost all of these connections used by psychiatrists to treat psychosis are effective inverse agonists of the 5-NTA. This conformity is irrefutable proof that the inverse agonism in relation to 5-NTA receptor is a molecular mechanism of antipsychotic efficacy in humans.

When detailed pharmacological characterization of a large number of antipsychotic compounds in the laboratory of the authors revealed that they have broad activity against receptors of many related subtypes. Most of these compounds are either agonistic, competitive, antagonistic or inverse agonistic activity towards monoaminergic receptors of many subtypes, including serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic receptors. Apparently, this broad activity one is responsible for sedative, hypotensive and motor side effects of these compounds. Therefore, disclosed here, the connection will have efficiency, for example, as new antipsychotic agents, but will have fewer or less severe side effects than existing connections.

The present invention is also directed to pharmaceutical compositions containing a compound of General formula I.

In this variant embodiment, at least two of R4, R5and R6can be independently selected from the group comprising 4-monosubstituted aryl(C1-6-alkyl), and 4-monosubstituted heteroaryl(C1-6-alkyl).

Usually, at least two of R4, R5and R6independently selected from the group comprising aryl(C1-6-alkyl) and heteroaryl(C1-6-alkyl), chosen from the group comprising fluoro-substituted aryl(C1-6-alkyl), and fluoro-substituted heteroaryl(C1-6-alkyl). Further, the other of the at least two of R4, R5and R6independently selected from the group comprising aryl(C1-6-alkyl) and heteroaryl(C1-6-alkyl), usually chosen from the group comprising (O-C1-6-alkyl)substituted aryl(C1-6-alkyl) and (O-C1-6-alkyl)substituted heteroaryl(C1-6-alkyl).

In some embodiments, embodiment, at least one of R4/sup> , R5and R6independently selected from the group comprising fluoro-substituted aryl(C1-6-alkyl), and fluoro-substituted heteroaryl(C1-6-alkyl).

Usually, at least, each of the two R4, R5and R6independently selected from the group comprising aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl) and heterocyclyl(C1-6-alkyl), substituted by 1, 2 or 3 times a Deputy selected from the group comprising halogen, and optionally substituted O-C1-6-alkyl. In one aspect, the halogen is a fluorine. In one variation of the embodiment of the cyclic system is one of at least two of R4, R5and R6independently selected from the group comprising aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl), heterocyclyl(C1-6-alkyl), substituted 1-3 times optionally substituted O-C1-6-alkyl, such as fluorinated O-C1-6-alkyl.

In yet another variant embodiment, at least two of R4, R5and R6represent optionally substituted aryl(C1-6-alkyl). In a preferred variant embodiment, at least two of R4, R5and R6represent optionally substituted benzyl.

It is established that at least two of R4, R5and R6independently selected from the group including aryl(C1-6-alkyl), heteroaryl(C 1-6-alkyl), heterocyclyl(C1-6-alkyl). Usually With1-6the alkyl in the above aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl), heterocyclyl(C1-6-alkyl) represents a C1-4-alkyl, such as methylene(C1-alkyl), ethylene(C2-alkyl) or propylene(C3-alkyl) or butylene(C4-alkyl), more often With1-alkyl or C2-alkyl, most often With1-alkyl. In a suitable embodiment, the embodiment With1-6the alkyl in the above aryl(C1-6-alkyl), heteroaryl(C1-6-alkyl), heterocyclyl(C1-6the alkyl may be substituted so as to form a branched hydrocarbon.

In combination variants embodiment, at least two of R4, R5and R6represent optionally substituted benzyl. One of R4, R5and R6may be a 4-halogenmethyl group and the other may be a 4-alkoxybenzyl group. Usually 4-halogenosilanes group is a 4-terbisil. 4-alkoxybenzyl group is usually a2-5-alkoxybenzyl or optionally fluorinated 4-methoxybenzyloxy group, such as farmacocinetica, deformationally, triphtalocyaninine group and 2,2,2-triftoruranmetilidina.

Found that compounds of the invention can be selected from the group including (i) 1-the KSA-4,9-diazaspiro[5.5]undecane-3-one, (ii) 1-oxa-3,8-diazaspiro[4.5]decane-2-it, (iii) 1,3,8-diazaspiro[4.5]decane-2-it, (iv) 1,2,9-diazaspiro[5.5]undecane-3-one, (v) 1,2,8-diazaspiro[4.5]decane-3-one, (vi) 1,2,8-diazaspiro[4.5]decane-3-one, (vii) 1,2,4,8-tetrazepam[4.5]decane-3-one, (viii) 2,4,9-diazaspiro[5.5]undecane-3-one, (ix) 2,8-diazaspiro[4.5]decane-3-one, (x) 2-oxa-4,9-diazaspiro[5.5]undecane-3-one, (xi) 1-thia-3,8-diazaspiro[4.5]decane-2-he (xii) 1-oxa-3,9-diazaspiro[5.5]undecane-2-on.

Suitable variants of the embodiment of the compounds of the invention can be selected from the group comprising 4-(4-terbisil)-3-(4-methoxybenzyl)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-ethoxybenzyl)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-8-methyl-3-(4-propoxymethyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-isopropoxyphenyl)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-butoxybenzoyl)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-deformational)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-8-methyl-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-8-methyl-3-(4-phenoxybenzyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-ethyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)3-(4-salutogenesis)-8-isopropyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopropylmethyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclohexylmethyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopentyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-(3-morpholine-4-ylpropyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-[3-(2-oxo-2,3-dehydrobenzperidol-1-yl)propyl]-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-(2-methylthiazole-4-ylmethyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-Chlorobenzyl)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-ethyl-4-(4-Chlorobenzyl)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-Chlorobenzyl)-3-(4-salutogenesis)-8-isopropyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopropylmethyl-4-(4-Chlorobenzyl)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclohexylmethyl-4-(4-chlorbenzyl)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-(2-[1,3]dioxolane-2-retil)-4-(4-Chlorobenzyl)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-Chlorobenzyl)-3-(4-salutogenesis)-8-[2-(2-Oxymetazoline-1-yl)ethyl]1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-deformational)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-deformational)-8-ethyl-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-deformational)-4-(4-terbisil)-8-isopropyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopropylmethyl-3-(4-deformational)-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclohexylmethyl-3-(4-deformational)-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-deformational)-8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-deformational)-4-(4-terbisil)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-ethyl-4-(4-terbisil)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-8-isopropyl-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopropylmethyl-4-(4-terbisil)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclohexylmethyl-4-(4-terbisil)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopentyl-4-(4-terbisil)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-he, 4-(4-terbisil)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-ethyl-4-(4-terbisil)-3-(4-propoxyphenyl)-1-oxa-3,8-diesase what about the[4.5]decane-2-it, 4-(4-terbisil)-8-isopropyl-3-(4-propoxyphenyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopropylmethyl-4-(4-terbisil)-3-(4-propoxyphenyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclohexylmethyl-4-(4-terbisil)-3-(4-propoxyphenyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-cyclopentyl-4-(4-terbisil)-3-(4-propoxyphenyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-3-(4-propoxyphenyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-3-(4-propoxyphenyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-8-ethyl-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-isopropyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-8-cyclopropylmethyl-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decane-2-it, 8-(2-[1,3]dioxane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-3-one, 4-(4-terbisil)-3-(4-salutogenesis)-8-{3-[(S)-4-isopropyl-2-oxoacridine-3-yl]propyl}-1-oxa-3,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-2-(4-methoxybenzyl)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-ethoxybenzyl)-1-(4-terbisil)-8-methyl-1,2,8-t is azaspiro[4.5]decane-3-one, 1-(4-terbisil)-8-methyl-2-(4-propoxyphenyl)-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-2-(4-isopropoxyphenyl)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-butoxybenzoyl)-1-(4-terbisil)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-cyclopropylmethoxy)-1-(4-terbisil)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-2-(4-salutogenesis)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-deformational)-1-(4-terbisil)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-8-methyl-2-(4-cryptomaterial)-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-8-methyl-2-(4-phenoxybenzyl)-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-Chlorobenzyl)-2-(4-ethoxybenzyl)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-Chlorobenzyl)-8-methyl-2-(4-propoxyphenyl)-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-Chlorobenzyl)-2-(4-salutogenesis)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-Chlorobenzyl)-2-(4-cyclopropylmethoxy)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-Chlorobenzyl)-2-(4-deformational)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-active compounds)-2-(4-ethoxybenzyl)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-active compounds)-2-(4-isopropoxyphenyl)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-active compounds)-2-(4-salutogenesis)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-active compounds)-2-(4-cyclopropylmethoxy)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-active compounds)-8-methyl-2-(4-cryptomaterial)-1,2,8-diazaspiro[4.5]decane-3-about the, 2-(4-deformational)-1-(4-terbisil)-8-ethyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-deformational)-1-(4-terbisil)-8-isopropyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-deformational)-1-(4-terbisil)-8-cyclopropylmethyl-1,2,8-diazaspiro[4.5]decane-3-one, 2-(4-deformational)-1-(4-terbisil)-8-(2-[1,3]dioxolane-2-retil)-1,2,8-diazaspiro[4.5]decane-3-one, 8-ethyl-1-(4-terbisil)-2-(4-salutogenesis)-1,2,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-2-(4-salutogenesis)-8-isopropyl-1,2,8-diazaspiro[4.5]decane-3-one, 8-cyclopropylmethyl-1-(4-terbisil)-2-(4-salutogenesis)-1,2,8-diazaspiro[4.5]decane-3-one, 8-(2-[1,3]dioxolane-2-retil)-1-(4-terbisil)-2-(4-salutogenesis)-1,2,8-diazaspiro[4.5]decane-3-one, 4-(4-ethoxybenzyl)-5-(4-terbisil)-9-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-terbisil)-9-methyl-4-(4-propoxyphenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-terbisil)-4-(4-salutogenesis)-9-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-terbisil)-9-methyl-4-(4-cryptomaterial)-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-Chlorobenzyl)-4-(4-salutogenesis)-9-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-Chlorobenzyl)-4-(4-cyclopropylmethoxy)-9-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 9-ethyl-5-(4-terbisil)-4-(4-propoxyphenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-ethoxybenzyl)-9-methyl-1,2,9, diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-cyclopropylmethoxy)9-methyl-1,2,9, diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-salutogenesis)-9-methyl-1,2,9, diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-propoxyphenyl)-9-methyl-1,2,9, diazaspiro[5.5]undecane-3-one, 1-(4-active compounds)-2-(4-salutogenesis)-9-methyl-1,2,9, diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-cyclopropylmethoxy)-9-ethyl-1,2,9-diazaspiro[5.5]undecane-3-one, 2-(4-ethoxybenzyl)-1-(4-terbisil)-8-methyl-1,2,4,8-tetraterpene[4.5]decane-3-one, 1-(4-terbisil)-1-(4-salutogenesis)-8-methyl-1,2,4,8-tetraterpene[4.5]decane-3-one, 2-(4-deformational)-1-(4-terbisil)-8-methyl-2,8-diazaspiro[4.5]decane-3-one, 1-(4-terbisil)-2-(4-salutogenesis)-8-methyl-2,8-diazaspiro[4.5]decane-3-one, 2-(4-cyclopropylmethoxy)-1-(4-terbisil)-8-methyl-2,8-diazaspiro[4.5]decane-3-one, 8-ethyl-1-(4-terbisil)-2-(4-salutogenesis)-2,8-diazaspiro[4.5]decane-3-one, 8-(2-[1,3]dioxolane-2-retil)-1-(4-terbisil)-2-(4-salutogenesis)-2,8-diazaspiro[4.5]decane-3-one, 3-(4-deformational)-4-(4-terbisil)-8-methyl-1,3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1,3,8-diazaspiro[4.5]decane-2-it, 3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-methyl-1,3,8-diazaspiro[4.5]decane-2-it, 8-ethyl-4-(4-terbisil)-3-(4-salutogenesis)-1,3,8-diazaspiro[4.5]decane-2-it, 8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1,3,8-diazaspiro[4.5]decane-2-it, 1-(4-terbisil)-2-(4-ethoxybenzyl)-9-methyl-2,4,9-diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-cyclopropylmethoxy is benzyl)-9-methyl-2,4,9-diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-salutogenesis)-9-methyl-2,4,9-diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-cryptomaterial)-9-methyl-2,4,9-diazaspiro[5.5]undecane-3-one, 1-(4-terbisil)-2-(4-salutogenesis)-9-ethyl-2,4,9-diazaspiro[5.5]undecane-3-one, 4-(4-ethoxybenzyl)-5-(4-terbisil)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 3-(4-ethoxybenzyl)-5-(4-terbisil)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 3-(4-ethoxybenzyl)-4-(4-terbisil)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-he, 5-(4-terbisil)-4-(4-propoxyphenyl)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 5-(4-terbisil)-3-(4-propoxyphenyl)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 4-(4-terbisil)-3-(4-propoxyphenyl)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 5-(4-terbisil)-4-(4-salutogenesis)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-9-methyl-1-oxa-3,9-diazaspiro[5.5]undecane-2-it, 4-(4-ethoxybenzyl)-5-(4-terbisil)-9-methyl-2-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-terbisil)-4-(4-methoxybenzyl)-9-methyl-2-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-terbisil)-4-(4-propoxyphenyl)-9-methyl-2-oxa-4,9-diazaspiro[5.5]undecane-3-one, 5-(4-terbisil)-4-(4-salutogenesis)-9-methyl-2-oxa-4,9-diazaspiro[5.5]undecane-3-one, 4-(4-ethoxybenzyl)-5-(4-terbisil)-9-methyl-2-oxa-4,9-diazaspiro[5.5]undecane-3-one, 3-(4-ethoxybenzyl)-4-(4-terbisil)-8-methyl-1-thia-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-methoxybenzyl)-8-methyl-1-t is a-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-propoxyphenyl)-8-methyl-1-thia-3,8-diazaspiro[4.5]decane-2-it, 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-thia-3,8-diazaspiro[4.5]decane-2-it.

Some embodiments of compounds of this invention possess chirality or have a chiral center. The invention provides compounds of the invention in racemic form, enantiomerically enriched form or enantiomerically pure form. These researchers were selected individual enantiomers of some chiral embodiments of the compounds of the invention with high enantiomeric excess and found unequal activity of these two forms in relation to monoamine receptors.

The preferred embodiment of the compounds of the invention includes the compounds of formula I, which are homochirality in relation to the compound of formula II.

In examples illustrate suitable methods of obtaining many of the compounds of the invention, the said means adapted to obtain all of the compounds of the invention by methods known to the person skilled in the art. In the scope of this invention also includes pharmaceutically acceptable salts of compounds of formula I.

In General, the compounds of the invention can be obtained by the methods described below. In many of the following synthetic approaches require the use of protective groups, including g PPI, described in T. W. Green and P. G. M. Wuts,Protective Groups in Organic Chemistry, 3 Ed. John Wiley & Sons, 1999, and should be chosen in such a way that they are stable in the reaction conditions and can be easily removed at an appropriate stage, using known in the field of methodology. Typical protective groups are N-Boc, N-Cbz, N-Bn.

In General, the cyclization of the corresponding intermediate compounds can be achieved using phosgene or its analogues, such as CDI, with chloroacetylation or its equivalents, or in the processing of carbon disulfide and subsequent oxidation.

The introduction of desirable piperidino substituent (R1) usually can be accomplished by alkylation or by reductive amination after removing the N-protecting, if necessary.

Compounds of the invention in which m=1, Z=CH and X=Oh or och2can be obtained from suitably protected 4-piperidone as described Bassus et al. (Eur. J. Med. Chem.-Chim. Ther.9:416-423 (1974)). Alkylation of the nitrogen atom of the carbamate and the introduction of desirable piperidino N-substituent leads to 3,5-disubstituted spirocycles. 3,4 - or 4,5-disubstituted derivatives can be obtained as described in Fisera et al. (Monatsh. Chem. 125:909-919 (1994)), through appropriately protected isoxazolin with subsequent reductive cleavage. Cyclization received γ-aminoalcohols p is igodit to the required spirocycles. Alternatively, 4,5-disubstituted or 3,4,5-triple-substituted spirocyclic can be obtained from the corresponding complex β-keeeper reaction with the halide for the introduction of the 5-substituent, by reductive amination (with the primary amine for 3-substituent), the processing allylanisole, cyclization, as described above, oxidative cleavage of double bonds (e.g., ozonolysis) and education piperidino rings by reductive amination.

Compounds of the invention in which m=1, Z=N and X=Oh or och2you can obtain the synthesis of Striker using the corresponding aldehyde, for example, tert-BUTYLCARBAMATE. This nitrile can be converted into an ester, which is injected into reaction with allylanisole with subsequent oxidative cleavage of the two olefins, the formation of piperidine using reductive amination. Alkylation, unprotect hydrazide and cyclization yield the desired spirocycles. Depending on the desired substituents and their position data stage can be swapped, and may require an additional stage of protection of functional groups. Alternatively, these compounds can be obtained from the corresponding β-keeeper reaction with a derivative of bis(2-chloroethyl)amine with education piperidino cycle. Restore the tion of Mineralnie, saponification and rearrangement of kurzius lead to cyclic derivative of urea.

Compounds of the invention in which m=1, Z=N and X=N(R), can be obtained by adapting the methods described by Bhatia et al. (J. Med. Chem.39:3938-3950 (1996)), on the basis of appropriately protected product Strecker 4-amino-4-cyanopiperidine.

Compounds of the invention in which m=0, Z=CH and X=CH2CH2you can get by joining Michael nitrile derivative to a suitably protected 4-methoxycarbonylmethylene, the restoration of the nitrile groups to amine with subsequent closure lactam cycle, obtained by alkylation of the amide and the introduction of desirable piperidino Deputy.

Compounds of the invention in which m=0, Z=CH and X=CH2Oh, can be obtained from the corresponding complex β-keeeper reaction with a suitably protected bis(2-chloroethyl)amine. Reductive amination and subsequent reduction of the nitrile to the alcohol followed by cyclization and introduction piperidino Deputy alkylation or by reductive amination leads to the desired spirocyclic.

Compounds of the invention in which m=0, Z=CH and X=CH2N, can be obtained from the corresponding β-ketonitriles reaction with a suitably protected bis(2-chloroethyl)amine. In Starowislna amination and subsequent reduction of the nitrile to the amine followed by cyclization and introduction piperidino Deputy alkylation or by reductive amination leads to the desired spirocycles.

Compounds of the invention in which m=0, Z=CH and X=co2can be obtained as described in example 1.

Compounds of the invention in which m=0, Z=N and X=CH2CH2you can get protected 8-Aza-1-oxaspiro[4.5]decane-2-it (Mullen et al.J. med. Chem. 43:4045 (2000)) by reaction with hydrazine, then S-ethyltryptamine with subsequent reaction of Mitsunobu according to Meng et al. (Tetrahedron47:6251 (1991)). The respective substituents in the 1, 2 - and 9-provisions introduced by alkylation and/or by reductive amination.

Compounds of the invention in which m=0, Z=N and X=CH2Oh, you can get on the synthesis of Striker from an appropriately protected 4-piperidone and carbazate (or the corresponding hydrazine). The transformation of the obtained nitrile alcohol, cyclization using the methods described above, the alkylation of (after basic hydrolysis ekzoticheskoy carbazate functions, if any) and the introduction of piperidino N-substituent leads to the desired connection.

Compounds of the invention in which m=0, Z=N and X=CH2N, can be obtained using the same strategy as when receiving 1,2,9-triaza-4-oxaspiro[5.5]undecane-3-one, except that the nitrile reduced to the corresponding amine.

Compounds of the invention in which m=0, Z=CH and X=CH2you can get a connection at the Michael NITR is derived by suitably protected 4-methoxycarbonylmethylene, the restoration of the nitro group to the amine, followed by the closing of the lactam cycle, obtained by alkylation of the amide and the introduction of desirable piperidino Deputy.

Compounds of the invention in which m=0, Z=CH and X=O, can be obtained as described in example 1. An alternative way to obtain the desired intermediate 1,2-amerosport you can use nitroaldol reaction after the restoration of the nitro group followed by cyclization. Alternatively, these compounds can be obtained by epoxydecane corresponding olefin obtained by the Wittig reaction or Horner-Wordsworth-Emmons from an appropriately protected 4-piperidone. The disclosure of the epoxide with ammonia or a primary amine followed by cyclization using the equivalent of phosgene, the alkylation of carbamates, if necessary, and the introduction of desirable piperidino Deputy alkylation or by reductive amination leads to the target connection. In addition to obtaining enantiomerically pure compounds, as described in example 1, enantioselective modification can include how asymmetric epoxidation of olefin described in the literature, for example, Jacobsen or other. Alternatively, you can use the method of asymmetric dihydroxypropane he sang sharpless followed the education epoxy cycle. Alternatively, a suitably protected 4-methoxycarbonylmethylene can be restored to allyl alcohol, which is subjected to the asymmetric epoxydecane on he sang sharpless according to literature methods. Disclosure epoxide ORGANOMETALLIC reagent and oxidation of the resulting primary alcohol leads to γ-hydroxycarbonic acid, which translate into desirable spiritlessly enantiomer, as described in example 1. Alternatively, a suitably protected 4-methoxycarbonylmethylene can be transformed into enantiomerically pure epoxide by epoxydecane by Jacobsen and subsequent erection cycle with ammonia or the appropriate amine, by reaction with an ORGANOMETALLIC reagent with an ester group, recovery, cyclization, alkylation, if necessary, and the introduction of piperidino Deputy. Alternatively, stereocenter you can enter by using the appropriate ester γγ-amino acids as chiral matrix. Interaction with allylanisole, cyclization, oxidative cleavage of the allyl groups, education piperidino cycle with regenerative aminating and final alkylation of the carbamate yield the desired enantiomerically pure derivative.

Compounds of the invention, in the which m=0, Z=CH and X=N or NCH2can be obtained by means of synthesis of Striker using appropriately protected 4-piperidone and the corresponding primary amine. The interaction of the resulting nitrile with a Grignard reagent leads to the ketone, which is then subjected to reductive aminating. Cyclization of the resulting diamine (after the stage of removing the protection, if necessary) with phosgene or its equivalent leads to a cyclic urea. For the introduction of N-piperidino Deputy can be used under alkylation or reductive amination. Similarly, you can get a 6-membered analogue (X=NCH2) when used for cyclization of chloroacetanilide or similar reagent (may require additional use of protective groups).

Compounds of the invention in which m=0, Z=N and X=CH2can be obtained as described in example 1.

Compounds of the invention in which m=0, Z=N and X=N(R), can be obtained by literary methods (Glash et al.Synthesis803-808 (1990)) in the processing of appropriately protected 4-piperidone reaction with a derivative of hydrazine and the interaction of the intermediate hydrazone with potassium cyanate. To introduce the desired substituents after removing the protection, you can use the alkylation and/or rehabilitation of Mineralnie.

Alternatively, the connection is subramania, in which X=S or SCH2or CH2Scan be obtained by the methods described for the equivalent compounds containing X=Oh, och2or CH2Oh, when turning before cyclization of corresponding hydroxyl group in Tilney using known literature methods (for example, by treatment with acetylchloride and substitution benzylthio and transformation into a free mercaptan). Similarly, the hydroxyl group can be converted into the corresponding amines, which represents an alternative way to get some compounds of the invention in which X=N(R)N(R)CH2CH2(R).

Compounds of the invention in which Y=S, can be obtained from corresponding compounds in which Y=O when processing, for example, a Lawson reagent, or bis(tricyclohexyltin)sulfide and BCl3or other tielrooij reagents.

In addition, in the invention provided pharmaceutical compositions containing the compounds of the invention. In one variant embodiment, the composition includes a compound of formula I, its pharmaceutically acceptable salt or a stereoisomer, along with a pharmaceutically acceptable carrier or excipient.

In some embodiments the embodiment of the compounds of the invention show efficacy in the inhibition of the activity of a monoamine receptor. Thus, in the image the attachment provides methods of inhibiting the activity of monoamine receptor. In one variant embodiment, the method comprises contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of the invention for inhibiting the activity of this monoamine receptor. The invention also provides methods of inhibiting activation of a monoamine receptor. In one variant embodiment, the method comprises contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of the invention for the inhibition of the activation of this monoamine receptor.

Usually monoamine receptor is a serotonin receptor. Typically, the serotonin receptor is a 5-NTA subclass. Serotonin receptor can be selected from the Central nervous system or peripheral nervous system. In various aspects of the serotonin receptor is located in the Central nervous system, or blood cells, or platelets. In other aspects of serotonin receptor is mutated or modified.

Usually the activity, inhibiting by the method of the invention, represents the activity signal. In addition, the activity or activation usually is constitutive. The activity is typically associated with activation of the her serotonin receptor.

In addition, there are methods of inhibiting activation of a monoamine receptor. In one variant embodiment, the method comprises contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more compounds of the invention for inhibiting activation of a monoamine receptor. In one aspect of the inhibiting activation is an activation related to agonistic agent. This agonistic agent may be exogenous or endogenous.

In addition, there are ways to treat painful conditions associated at least with one monoamine receptor. In one variation of the embodiment the method includes administration to a subject in need of such treatment, an effective amount of one or more compounds of the invention for the treatment of painful conditions associated at least with one monoamine receptor.

As described here, this painful condition can be associated with dysfunction of at least one monoamine receptor. Alternatively, or additionally, this painful condition can be associated with the activation of a monoamine receptor. In addition, a painful condition may be associated with increased activity of monoamine receptor. Painful the status can be selected from the group including schizophrenia, psychosis, caused by drugs, psychosis, treatment-induced psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.

The invention also presents the use of the compounds of formula I to obtain drugs for the treatment of painful conditions associated with monoamine receptor. In specific embodiments, the embodiment of application of the compounds of formula I to obtain drugs for the treatment of diseases selected from the group including schizophrenia, psychosis (including that caused by medications or treatment of psychosis, such as hallucinosis, caused by drugs used to treat Parkinson's disease), migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety (including General anxiety disorder), sleep disorders and appetite disorders.

A special aspect of the invention is a method of treatment and use of the compounds of formula I to obtain drugs for the treatment of schizophrenia. In one variation of the embodiment the method includes administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of the invention for the treatment of schizophrenia. In another variant embodiment of the use of the compounds of formula I consists in the application for which Holocene medicines for the treatment of schizophrenia.

A special aspect of the invention is a method of treatment and use of the compounds of formula I to obtain drugs for the treatment of migraine. In one variation of the embodiment the method includes administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of the invention for treatment of migraine. In another variant embodiment of the use of the compounds of formula I is used to produce drugs for the treatment of migraine.

The following particular aspect of the invention is a method of treatment and use of the compounds of formula I to obtain drugs for treatment caused by medications or treatment-induced hallucinosis or psychosis. In one variation of the embodiment the method includes administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of the invention for the treatment caused by medications or treatment hallucinosis or psychosis. In another variant embodiment of the use of the compounds of formula I consists in obtaining drugs for treatment caused by medications or treatment hallucinosis or psychosis.

Given the nature of the activity of a serotonin receptor, its modulation may have one or more "downstream"-EF is known to be beneficial to treat more than one disease condition. Some compounds of the invention can best be suitable for the treatment of schizophrenia, whereas the other compounds of the invention can be most useful for treatment of, for example, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disturbances and disorders of appetite. Thus, in further aspects the invention provides methods of treatment of psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disturbances and disorders of appetite. In different embodiments the method includes administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds of the invention for the treatment of psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders. It is also proposed the use of the compounds of formula I to obtain drugs for the treatment of psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disturbances and disorders of appetite.

In addition, there are ways of identifying genetic polymorphism predisposing a subject for susceptibility to one or more compounds of formula I. In one variation of the embodiment of the method includes:

introduction to a subject a therapeutically effective amount is soedineniya;

determination of the reaction of the specified entity on the specified connection to identify, thus, susceptible of a subject with advanced disease associated with monoamine receptor; and

identification of genetic polymorphism in a susceptible subject, where the genetic polymorphism predisposes the subject to susceptibility to this compound. Generally improved condition associated with 5-HT class or 5-NTA subclass of monoaminergic receptors.

In addition, the invention provides methods of identifying a subject suitable for treatment with one or more compounds of formula I. In one variation of the embodiment of the method includes detecting the presence of the polymorphism in the subject, where the polymorphism predisposes the subject to susceptibility to this connection, and where the presence of the polymorphism indicates that the subject is suitable for treatment with one or more compounds of formula I.

In examples illustrate suitable methods of obtaining non-limiting variants of the embodiment of the present invention and shows the selectivity and activity of the compounds of the invention in relation to monoamine receptors.

EXAMPLES

Example 1: synthetic chemistry

General methods. Spectra1H NMR were recorded at 400 M is C, while the spectra of the13With NMR was measured at 100 MHz with proton splitting at ambient temperature. Chemical shifts are given in units δ [ppm] relative to the residual solvent peak of chloroform (CDCl3) at 7, 26 and 77,0 and methanol (CD3OD) at 3,31 and 49.2 ppm Constants of spin-spin interaction,Jgiven in Hertz.

Reagents and solvents were of the highest quality available from industrial sources and were used without additional purification. Cartridges for anion-exchange solid-phase extraction was a MEGA BE-SCX from Varian.

A General method LC-MS: HPLC/MS analysis was performed using one of two methods (method a or method B).

Method a: Agilent HP1100 HPLC/MCD. Binary pump G1312, automatic sampler G1313, tier column G1316, the detector G1315A diode array (190-450 nm), A MSD, electrospray ionization.

Chromatography: mobile phase: 8 mm ammonium acetate in a mixture of water/acetonitrile. Gradient start with 70% of org. 100% org. for 12 min, reduction to 70% of org. for 0.5 min, keeping within 3.5 minutes Total time passage 16 min flow Rate 1 ml/min

Column: Phenomenex Luna18(2) 3 μm, 75×4,6 mm

MC-options: gas dryer, 10 l/min Pressure sprayer 40 psi (wt.), the pace. gas 350°S, Vol. production. 4000.

Method: Waters/Micromass VE the H/MC. 600 LC-pump, control samples 2700, 996 detector diode matrix (190-450 nm), ZMD mass spectrometer (Micromass, electrospray ionization.

Chromatography: mobile phase: 10 mm ammonium acetate in a mixture of water/acetonitrile. The gradient started with 30% of org. for 0.5 min to 100% org. during the 9.5 min, holding for 2 min, up to 30% reduction org. for 0.5 min, holding for 5.5 minutes Total time passage 18 min flow Rate 1 ml/min

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

MC-options: desalvatore gas, 404 l/h Capillarity, to 5.3 kV. Taper, 36 Century Extractor, 3rd Century Pace. power supply 130°s Pace. desolvatation, 250°C.

Example 2: Obtain 4-[1-carboxy-2-(4-forfinal)ethyl]-4-hydroxy-1-methylpiperidine (69NLS42)

To a cooled solution of N,N-Diisopropylamine of 4.2 ml, 30 mmol) in THF (25 ml) at -40°with stirring, was added dropwise n-utility (1.6 M in hexane, 18.8 ml, 30 mmol) for 5 minutes, the Solution was heated to 0°and there was added a solution of 3-(4-forfinal)propionic acid (2,53 g, 15 mmol) in THF (20 ml). The mixture was stirred for 30 min at K.T. (room temperature), was cooled to -78°and for 15 min was added dropwise N-methylpiperidin (2.2 ml, 18 mmol). The solution was allowed to warm to K.T. and poured with stirring into a mixture of diethyl ether (100 ml) and water (60 ml). The organic layer is discarded, odny layer was extracted following portion of diethyl ether. The aqueous layer was acidified with 4 M aq. HCl and once was extracted with methylene chloride and n-butanol (3×100 ml). The combined n-butanole extracts were concentrated in vacuum, obtaining 69NLS42 in the form of a light yellow oil which is used without further purification.

Rf=0,13 (MeOH/CH2Cl21:9).

Example 3: Obtain 4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it (69NLS44)

The crude piperidine derivative 69NLS42 (approx. 15 mmol) was dissolved in toluene (200 ml), was added triethylamine (4,18 ml, 30 mmol) and diphenylphosphoryl (3,88 ml, 18 mmol) and boil the mixture under reflux overnight. The solvent was removed in vacuo, the residue was dissolved in methylene chloride (200 ml) and was extracted with 1 M HCl (3×100 ml). The combined aqueous extracts were podslushivaet 20%aq. the KOH solution and was extracted with methylene chloride (3×150 ml). The combined organic layers were dried over Na2SO4, was filtered and was evaporated, getting 69NLS44 from 2.06 g, 49% after two steps) as a yellow solid, which was used without further purification.

Rf=0,25 (MeOH/CH2Cl21:9). IHMS m/z 278 [M+H]+. HPLC tR=1,9 min (method B).

Example 4: Obtaining 4-isobutoxyethene (69NLS69)

Alkylating reagent was obtained according to literature methods from p-cresol synthesis of simple broadcast on Williamson followed the book on the Will-Ziegler.

Example 5: the Hydrochloride of 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it (69NLS75)

Oxazolidinone 69NLS44 (raw, approx. 7 mmol) was dissolved in a mixture of DMF/THF (1:9, 50 ml), was added sodium hydride (50% in oil, of 0.67 g, 14 mmol) and stirred suspension when K.T. for 30 min before dropwise addition of bromide 69NLS69 (1.5 g, 7 mmol). The mixture was stirred at K.T. within 4 h, and then was distributed between ethyl acetate and water. The organic layer was separated, and the aqueous layer was twice extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel with elution with a gradual gradient of 0-6% methanol in methylene chloride. The re-purification of the combined fractions by anion-exchange SPE cartridge has been specified in the header connection 69NLS75 in the form of free amine (1.10 g, 34%) as a colourless oil. This compound was dissolved in methylene chloride, treated with excess 2 M HCl in diethyl ether, besieged from n-heptane, getting hydrochloride salt as a colourless oil in quantitative yield.

Rf=0,39 (MeOH/CH2Cl21:9). IHMS m/z 441 [M+H]+.1H NMR (CDCl3free Amin) δ to 0.96 (d, 6N, J=6,8, CH3), 1,24-1,32 (m, 1H, PIP-H), 1,50 (m, 1H, PIP-H), 1,62 is 1.70 (m, 1H PIP-H), to 1.83 (m, 1H, PIP-H), 1,96-to 2.06 (m, 1H, CH(CH3)2), 2,17 (s, 3H, NCH3), and 2.26-of 2.34 (m, 2H, PIP-H), 2,46 (m, 1H, PIP-H), 2,60 (m, 1H, PIP-H), 2,70 (DD, 1H, J=7,3, 14,2, CH2ArF), 2,85 (DD, 1H, J=6,6, 14,2, CH2ArF), to 3.34 (t, 1H, J=7,0, H-4), of 3.57 (d, 1H, J=15,2, CH2ArOiBu), 3,63 (d, 2H, J=6,6, OCH2CH), 4,69 (d, 1H, J=15,2, CH2ArOiBu). 6.73 x-6,97 (m, 8H, Ar-H).13With NMR (CDCl3) δ 19,5, 28,5, 31,3, 34,2, 36,8, 46,1, 46,3, 51,2, 51,3, 63,5, 74,7, 79,6, 114,9, 116,0 (d, JC-F=21,0), 127,7, 129,6, 130,6 (d, JC-F=7,7), 132,9 (l, JC-F=34), 157,3, 159,2, 162,0 (d, JC-F=244,0). HPLC tR=10,4 min (method B).

Example 6: Hydrochloride 3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it (69NLS52)

Specified in the title compound was obtained by the method similar to that described for 69NLS75, 69NLS44 and the corresponding derived benzylbromide.

Alternatively, 69NLS44 you can alkilirovanii 4-acetoxybenzoic with subsequent processing of the substrate and obtained by alkylation of the free hydroxyl functions cyclopropanemethylamine.

Rf=0,45 (MeOH/CH2Cl21:9). IHMS m/z 439 [M+H]+.1H NMR (CD3OD, free amine) δ 0,60 0,33 and (2 m, 4H, CH(CH2)2), 1,20-of 1.26 (m, 1H, CH(CH2)2), 1,37-of 1.45 (m, 1H, PIP-H), was 1.58 (m, 1H, PIP-H), 1,79 is 1.86 (m, 1H, PIP-H), to 1.98 (m, 1H, PIP-H), and 2.26 (s, 3H, NCH3), 2,34-to 2.42 (m, 2H, PIP-H), 2.63 in (m, 1H, PIP-H), 2,77 (m, 1H, PIP-H), 2,87 (DD, 1H, J=7,0, 14,2, CH2Ar F), 2,98 (DD, 1H, J=7,0, 14,2, CH2ArF), to 3.58 (t, 1H, J=7,0, H-4), and 3.72 (d, 1H, J=15,2, CH2ArOMecPr), 3,80 (d, 2H, J=6,8, OCH2), br4.61 (d, 1H, J=15,2, CH2ArOMecPr), 6,84-7,21 (m, 8H, Ar-H). HPLC tR=6,5 min (method A).

Example 7:

Obtain tert-butyl ether complex 4-[1-carboxy-2-(4-forfinal)ethyl]4-hydroxypiperidine-1-carboxylic acid (69NLS56).

To a cooled solution of N,N-Diisopropylamine (2.0 ml, 14.0 mmol) in THF (10 ml) at -40°C was added dropwise n-utility (1.6 M in hexane, to 8.8 ml, 14.0 mmol) under stirring for 5 minutes the Solution was heated to 0°and there was added a solution of 3-(4-forfinal)propionic acid (1.18 g, 7.0 mmol) in THF (8 ml). The mixture was stirred for 30 min at K. T., was cooled to -78°and for 15 min was added dropwise N-Boc-4-piperidone (1.68 g, 8.4 mmol) in THF (7 ml). The solution was allowed to warm to K.T. and poured with stirring into a mixture of diethyl ether (100 ml) and water (50 ml). The organic layer is discarded, the aqueous layer was extracted following portion of diethyl ether. The aqueous layer was acidified with 2 M aq. HCl to pH 3.5 and extracted with methylene chloride (3×100 ml). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum, obtaining 69NLS56 in the form of a yellow solid which is used without further purification.

Rf=0,42 (MeOH/CH2Cl21:19). IHMS m/z 268 [M-BOC+2H]+. HPLC tR=3.7 min (method B).

Example 8: Obtain tert-butyl ether complex of 4-(4-terbisil)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid (69NLS58)

The crude piperidine derivative 69NLS56 (approx. 7 mmol) was dissolved in toluene (100 ml)was added triethylamine (2.0 ml, 14.0 mmol) and diphenylphosphoryl (1.8 ml, 14.0 mmol) and boil the mixture under reflux overnight. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (200 ml) and washed with water and saturated salt solution. The organic layer was dried over Na2SO4, was filtered and was evaporated, getting 69NLS58. As a result of clearing of remnant column chromatography on silica gel with gradual elution 0-2% methanol in methylene chloride was received 69NLS58 in the form of a yellow solid (1.47 g, total yield 58%).

Rf=0,63 (MeOH/CH2Cl21:19). Rf=0,33 (ethyl acetate/n-heptane 1:1). IHMS m/z 265 [M-BOC+2H]+. HPLC tR=10,3 min (method B).

Example 9: Obtain tert-butyl ether complex of 4-(4-terbisil)-3-(4-salutogenesis)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid (69NLS77)

Specified in the title compound was obtained by alkylation of tert-butyl complex ester of 4-(4-terbisil)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid 69NLS58 (7,40 g, 20.3 mmol) 4-isobutoxyethanol (4,88 g, 20.3 mmol) according to the method than the primary one, described for the 69NLS75. After purification of the crude product column chromatography on silica gel with gradual elution 0-60% ethyl acetate in n-heptane compound was dissolved in minimum amount of ethyl acetate and precipitated with n-heptane, after receiving filter 69NLS77 (5,86 g, 55%) as a colourless solid.

Rf=0,64 (ethyl acetate/n-heptane 1:1). IHMS m/z 544 [M+NH4]+.1H NMR (CDCl3) δ of 1.02 (d, 6N, J=6,6, CH3), 1,36 is 1.60 (m, N, (CH3)3, PIP-H), a 1.88 (m, 1H, PIP-H), 2,05-2,11 (m, 1H, CH(CH3)2), is 2.74 (DD, 1H, J=7,6, 14,2, CH2ArF), 2,95 (DD, 1H, J=6,6, 14,2, CH2ArF), is 3.08 (m, 2H, PIP-H), 3,39 (t, 1H, J=7,2, H-4), 3,66 (d, 1H, J=15,0, CH2ArOiBu). 3,71 (d, 2H, J=6, 6, OCH2CH), 3,82 (m, 1H, PIP-H), 3,92 (m, 1H, PIP-H), of 4.77 (d, 1H, J=15,0, CH2ArOiBu), 6,82-7,03 (m, 8H, Ar-H). HPLC tR=14,8 min (method B).

Example 10: Hydrochloride of 8-(2-[1,3]dioxolane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS79-II)

With 69NLS77 (300 mg, or 0.57 mmol) was filmed by N-BOC protection of the processing solution TFU (2 ml) in methylene chloride (2 ml) at K.T. within 1.5 hours the Solvent was removed in vacuo, the residue was twice evaporated with acetonitrile and re-dissolved in the same solvent (10 ml). Was added potassium carbonate (110 mg, 0.80 mmol) and 2-(2-bromacil)-1,3-dioxolane (80 μl, of 0.68 mmol), then sodium iodide (102 mg, of 0.68 mmol) and stirred cm is camping for 3 days at 50° C. In the distribution of the mixture between water and methylene chloride, a double extraction of the aqueous layer methylene chloride, drying of the combined organic layers over Na2SO4, filtration and evaporation of solvent received raw 69NLS79-II. The residue was purified column chromatography on silica gel with elution with a gradual gradient of 0-4% methanol in methylene chloride, getting 69NLS79-II (127 mg, 0.24 mmol) as a colourless oil. The connection is translated in HCl form processing 2 M HCl in diethyl ether, as described above for 69NLS75, getting salt in the form of colorless powder.

Rf=0,61 (MeOH/CH2Cl21:9). IHMS m/z 527 [M+H]+.1H NMR (CD3OD, free amine) δ 1,00 (d, 6N, J=6,6, CH3), 1,34-of 1.42 (m, 1H, PIP-H), and 1.56 (m, 1H, PIP-H), 1,72-of 1.81 (m, 3H), PIP-H, O2CHCH2), with 1.92 (m, 1H, PIP-H), 1,97-to 2.06 (m, 1H, CH(CH3)2), and 2.27 to 2.35 (m, 1H, PIP-H), 2,44 (m, 2H, NCH2), 2,63 (m, 1H, PIP-H), was 2.76 (m, 1H, PIP-H), 2,85 (DD, 1H, J=7,0, 14,2, CH2ArF), 2,95 (DD, 1H, J=7,0, 14,2, CH2ArF), of 3.60 (m, 1H, H-4), of 3.69 (d, 2H, J=6,5, OCH2CH), 3,70 (d, 1H, J=15,2, CH2ArOiBu), 3,76-is 3.82 and 3.85-3,91 (2 m, 4H, och2), 4,60 (d, 1H, J=15,2, CH2ArOiBu), 4,82 (t, 1H, J=4,7, O2CH), 6,83-7,19 (m, 8H, Ar-H). HPLC tR=11,3 min (method B).

Example 11: the Dihydrochloride of 4-(4-terbisil)-3-(4-salutogenesis)-8-(3-morpholine-4-ylpropyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS83)

With 69NLS77 (300 mg, 0,57 IMO is b) was removed N-BOC protection as described in obtaining 69NLS79-II, and was dissolved in acetonitrile (3 ml) and DMF (1 ml). To a solution of the research (65 μl, of 0.74 mmol) in acetonitrile (3 ml) and DMF (1 ml) was added dropwise 1-chloro-3-jumprope (73 μl, of 0.68 mmol) and potassium carbonate (300 mg, 2,17 mmol). The mixture was heated at 50°C for 3 h before addition of a solution containing spiroperidol without protection, and then sodium iodide (102 mg, of 0.68 mmol). The mixture was stirred over night at 50°and processed as described above for 69NLS79-II. As a result of clearing of remnant column chromatography on silica gel with elution with a gradual gradient of 0-6% methanol in methylene chloride was obtained the desired compound (127 mg, 40%) as a colourless oil. Treatment of the product in methylene chloride 2 M HCl in diethyl ether, as described above for 69NLS75, led to the corresponding dihydrochloride salt as a colorless powder.

Rf=0,48 (Meon/CH2Cl21:9). IHMS m/z 544 [M+H]+.1H NMR (CD3OD, free amine) δ a 1.01 (d, 6N, J=6,9, CH3), 1,36 was 1.43 (m, 1H, PIP-H), 1.56 to to 1.83 (m, 4H, PIP-H, NCH2CH2), 1,94-to 2.06 (m, 2H, och2SN, PIP-H), 2,30-2,49 (m, 10H, PIP-H, NCH2CH2O NCH2CH2CH2N), 2,68 (m, 1H, PIP-H), 2,79-is 2.88 (m, 2H, PIP-H, CH2ArF), of 2.97 (DD, 1H, J=6,8, 14,3, CH2ArF), 3,56-3,74 (m, 8H, H-4, OCH2CH, CH2ArOiBu, NCH2CH2O)4,60 (d, 1H, J=1,0, CH2ArOiBu), 6,84-7,20 (m, 8H, Ar-H). HPLC tR=10,2 min (method B).

Example 12: the Hydrochloride of 4-(4-terbisil)-3-(4-isobutoxy-ZIL)-8-isopropyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS85)

With 69NLS77 (320 mg, of 0.60 mmol) was filmed by N-BOC protection, as described in obtaining 69NLS79-II, and was dissolved in DMF (3 ml). Were added potassium carbonate (250 mg, of 1.80 mmol), then Isopropylamine (68 μl, 0.73 mmol) and sodium iodide (110 mg, 0.73 mmol) and the mixture was stirred over night at 50°C. Processing of data was performed, as in the case of 69NLS79-II. The residue was purified column chromatography on silica gel with elution with a gradual gradient of 0-6% methanol in methylene chloride followed by re-purification of compounds by anion-exchange column, receiving 69NLS85 (150 mg, 53%) as a colourless oil. The connection is translated in the form of the hydrochloride by treatment with 2 M HCl in diethyl ether, as described above, receiving salt as a colorless powder.

Rf=0,75 (MeOH/CH2Cl21:9). IHMS m/z 469 [M+H]+.1H NMR (CD3OD, free amine) δ 1,00 (d, 6N, J=6,7, CH3), a 1.01 (d, 6N, J=6,4, CH3), 1,35-of 1.42 (m, 1H, PIP-H), 1.56 to to 1.60 (m, 1H, PIP-H), 1,72-to 1.79 (m, 1H, PIP-H), 1.93 and e 2.06 (m, 2H, och2CH, PIP-H), 2,44 is 2.51 (m, 2H, PIP-H), 2,59 is 2.75 (m, 3H), PIP-H, NCH(CH3)2), 2,82-of 2.97 (m, 2H, CH2ArF), of 3.56 (t, 1H, J=6,8, H-4), 3,69-to 3.73 (m, 3H, OCH2CH, CH2ArOiBu), br4.61 (d, 1H, J=15,2, CH2ArOiBu), 6,83-7,19 (m, 8H, Ar-H). WAS the t R=11,0 min (method B).

Example 13: the Hydrochloride of 4-(4-terbisil)-3-(4-salutogenesis)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-1-oxa-3,8-diazaspiro[4,5]decane-2-it (M-HCl)

Specified in the title compound was obtained as a colourless solid with a yield of 29% from 69NLS77 (180 mg, 0.34 mmol) by the same method described for the 69NLS85. As alkylating reagent used 2-(2-Oxymetazoline-1-yl)ethyl ester toluene-4-sulfonic acids.

Rf=0,63 (MeOH/CH2Cl21:9). IHMS m/z 539 [M+H]+.1H NMR (CD3OD, free amine) δ a 1.01 (d, 6N, J=6,8, CH3), 1,34-of 1.42 (m, 1H, PIP-H), and 1.56 (m, 1H, PIP-H), 1,77-of 1.85 (m, 1H, PIP-H), was 1.94 (m, 1H, PIP-H), 1,99-2,07 (m, 1H, CH(CH3)2), 2,33-to 2.42 (m, 2H, PIP-H), to 2.55 (t, 2H, J=6,6, NCH2CH2), a 2.71 (m, 1H, PIP-H), 2,83-2,89 (m, 2H, PIP-H, CH2ArF), of 2.97 (DD, 1H, J=7,0, 14,2, CH2ArF)at 3.25 (t, 2H, J=6,6, NCH2CH2), 2,89-3,36, 3,42-3,46 (2 m, 4H, CONCH2), of 3.56 (t, 1H, J=7,0, H-4), 3,71 (d, 2H, J=6,4, OCH2CH), 3,70 (d, 1H, J=15,0, CH2ArOiBu), 4,60 (d, 1H, J=15,0, CH2ArOiBu), 6,84-7,20 (m, 8H, Ar-H). HPLC tR=10,0 min (method B).

Example 14: Hydrochloride of 4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS81)

With 69NLS77 (300 mg, or 0.57 mmol) was filmed by N-BOC protection, as described in obtaining 69NLS79-II. The residue was purified column chromatography on silica gel with elution with a gradual gradient of 0-6% methanol is methylene chloride and purification by anion-exchange SPE cartridge, getting 69NLS81 (127 mg, 52%) as a colourless oil. Obtaining cleaners containing hydrochloride salt was performed as described previously for 69NLS75, getting mentioned in the title compound as a colourless solid.

Rf=0,29 (MeOH/CH2Cl21:9). IHMS m/z 427 [M+H]+.1H NMR (CD3OD, free amine) δ 1,00 (d, 6N, J=6,8, CH3), a 1.25 and 1.33 (m, 1H, PIP-H), of 1.52 (m, 1H, PIP-H), 1,65-of 1.73 (m, 1H, PIP-H), at 1.91 (m, 1H, PIP-H), 1,98-to 2.06 (m, 1H, CH(CH3)2), 2,73-of 2.97 (m, 6N, PIP-H, CH2ArF), 3,53 (t, 1H, J=7,0, H-4), 3,68-3,71 (m, 3H, och2CH, CH2ArOiBu), 4,59 (d, 1H, J=15,2, CH2ArOiBu), 6,83-7,19 (m, 8H, Ar-H). HPLC tR=9,7 min (method B).

Example 15: Hydrochloride 8-cyclopropylmethyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-C,8-diazaspiro[4,5]decane-2-it (M-HCl)

Specified in the title compound was obtained as a colourless solid with a yield of 10% of 69NLS77 (180 mg, 0.34 mmol) by the same method described for the 69NLS85.

Rf=0,64 (MeOH/CH2Cl21:9). IHMS m/z 481 [M+H]+.1H NMR (CD3OD, free amine) δ 0,25, 0,62 (2 m, 4H, CH(CH2)2), 0,92 is 0.99 (m, 1H, CH(CH2)2), of 1.03 (d, 6N, J=6,6, CH3), 1,52-to 1.59 (m, 1H, PIP-H), 1,71 (m, 1H, PIP-H), 1,89-of 2.15 (m, 3H), PIP-H, CH(CH3)2), 2,60 (d, 2H, J=6,8, NCH2), 2,73-2 80 (m, 2H, PIP-H), 2,90 (DD, 1H, J=7,2, 14.4V, CH2ArF), 3,03 (DD, 1H, J=7,0, 14.4V, CH2ArF), 3,25-3,13 (m, 2H, PIP-H), 3,66 (t, 1H, J=7,2, NCH), to 3.73 (d, 1H, J=64, OCH2CH), 3,76 (d, 1H, J=15,0, CH2ArOiBu), 4,63 (d, 1H, J=15,0, CH2ArOiBu), 6,85-of 7.23 (m, 8H, Ar-H). HPLC tR=11,4 min (method B).

Example 16: the Hydrochloride of 4-(4-terbisil)-3-(4-salutogenesis)-8-ethyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (38-M)

With 69NLS77 (190 mg, 0.45 mmol) was filmed by N-BOC protection, as described in obtaining 69NLS79-II, and was dissolved in DMF (3 ml). Was added potassium carbonate (250 mg, of 1.80 mmol), then ethylbromide (50 μl, 0.45 mmol) and stirred the mixture overnight at K.T. Processing of the product was carried out as in the case of 69NLS79-II. The residue was purified column chromatography on silica gel with elution with a gradual gradient of 0-6% methanol in methylene chloride, followed by purification on anion-exchange SPE cartridge, getting 38-RN (77 mg, 38%) as a colourless oil. The connection is transferred to the cleaners containing hydrochloride form by treatment with 2 M HCl in diethyl ether, as described above, receipt of this salt as a colorless powder.

Rf=0,52 (MeOH/CH2Cl21:9). IHMS m/z 455 [M+H]+.1H NMR (CDCl3, salt) δ to 0.96 (d, 6N, J=6,6, CH3), 1,39-of 1.55 (m, 6N, NCH2CH3, PIP-H), 1,98-2,04 (m, 2H, PIP-H, CH(CH3)2), a 2.75-of 2.86 (m, 2H, CH2ArF), 2,98 (m, 4H, NCH2CH3, PIP-H), 3,19 (d, 1H, J=14,6, CH2ArOiBu), 3,25-3,50 (m, 3H), PIP-H, H-4), 3,62 (d, 2H, J=6.3, IN OCH2CH), 4,60 (d, 1H, J=14,6, CH2ArOiBu), 6,70-7,19 (m, 8H, Ar-H). HPLC tR=4,7 min (method A).

P the emer 17: Hydrochloride 3-(4-deformational)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (84AF8-30)

Specified in the title compound was obtained as a colourless solid with a yield of 25% of 69NLS44 (85 mg, 0.30 mmol) by the same method described for the 69NLS75.

Rf=0,44 (MeOH/CH2Cl26:94). IHMS m/z 434 [M+H]+.1H NMR (CDCl3free Amin) δ 1,42 of 1.50 (m, 1H, PIP-H), 1,58-to 1.63 (m, 1H, PIP-H), 1,76 of-1.83 (m, 1H, PIP-H), 1,90-1,95 (m, 1H, PIP-H), 2,28 (m, 3H, NCH3), 2,37 at 2.45 (m, 2H, PIP-H), 2,60 (m, 1H, PIP-H), of 2.72 (m, 1H, PIP-H), 2,80 (DD, 1H, J=6,8, 14.4V, CH2ArF), 2,87 (DD, 1H, J=7,6, 14.4V, CH2ArF), of 3.45 (t, 1H, J=6,8, NCH), to 3.73 (d, 1H, J=15,2, CH2ArOiBu), 4,71 (d, 1H, J=15,2, CH2ArOiBu), of 6.50 (t, 1H, JC-F=73,6, CF2H)of 6.96-7,06 (m, 8H, Ar-H). HPLC tR=2,7 min (method A).

Example 18: Obtain 4-[1-carboxy-2-(4-were)ethyl]-4-hydroxy-1-methylpiperidine (69NLS13)

Specified in the title compound was obtained in analogy to the procedure described for 69NLS42, based on 3-(4-were)propionic acid (0,70 g, 4.26 deaths mmol).

Rf=0,14 (MeOH/CH2Cl21:9).

Example 19: Obtaining 4-(4-methylbenzyl)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS15)

Specified in the title compound was obtained from 69NLS13 by analogy with the method described for 69NLS44.

Rf=0,5 (MeOH/CH2Cl21:9). IHMS m/z 275 [M+H]+. HPLC tR=3,8 min (method B).

Example 20: Obtaining hydrochloride 8-methyl-4-(4-methylbenzyl)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4,5]decane-2-o is a (69NLS21)

Specified in the title compound was obtained with a total yield of 24% by alkylation 69NLS15 p-cryptomethodoverrides, as described in the method for 69NLS75. Conversion of the free amine in cleaners containing hydrochloride salt was performed as described above, receiving specified in the title compound as a colourless solid.

Rf=0,26 (MeOH/CH2Cl21:9). IHMS m/z 449 [M+H]+.1H NMR (CD3OD, free amine) δ 1,46-of 1.53 (m, 1H, PIP-H), of 1.64 (m, 1H, PIP-H), 1,81-1,89 (m, 1H, PIP-H)of 1.97 (m, 1H, PIP-H), 2,24, 2,30 (2, 6N, Ar-CH3, NCH3), 2,30-of 2.38 (m, 2H, PIP-H), 2.63 in (m, 1H, PIP-H), to 2.74 (m, 1H, PIP-H), 2,85 (DD, 1H, J=6,7, 14,2, CH2ArMe), of 2.92 (DD, 1H, J=7,4, 14,2, CH2ArMe), to 3.67 (t, 1H, J=7,0, H-4), 3,90 (d, 1H, J=15,2, CH2ArOCF3), 4,59 (d, 1H, J=15,2, CH2ArOCF3), 7,03-7,21 (m, 8H, Ar-H). HPLC tR=10,9 min (method B).

Example 21: Hydrochloride 3-(4-methoxybenzyl)-8-methyl-4-(4-methylbenzyl)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS35)

Specified in the title compound was obtained with a yield of 20%, by analogy with the method described for 69NLS75, alkylation 69NLS15 p-methoxybenzylamine. However, in this case the reaction was carried out by boiling under reflux for 3 hours, the Conversion of the free amine in cleaners containing hydrochloride salt was performed as described above, receiving specified in the title compound as a colourless solid.

Rf=0,45 (MeOH/CH2Cl 1:9). IHMS m/z 395 [M+H]+.1H NMR (CD3OD, free amine) δ 1,33-of 1.41 (m, 1H, PIP-H), 1,51-of 1.56 (m, 1H, PIP-H), 1,77-of 1.85 (m, 1H, PIP-H), 1,92-of 1.97 (m, 1H, PIP-H), 2.22 and 2,30 (2, 6N, Ar-CH3, NCH3), 2,27-of 2.36 (m, 2H, PIP-H), of 2.56 (m, 1H, PIP-H), 2,70(m, 1H, PIP-H), of 2.81 (DD, 1H, J=7,2, 14,2, CH2ArMe), to 2.94 (DD, 1H, J=7,0, 14,2, CH2ArMe), of 3.56 (t, 1H, J=7,0, H-4), and 3.72 (d, 1H, J=15,2, CH2ArOMe), 3,76 (s, 3H, och3), 4,59 (d, 1H, J=15,2, CH2ArOMe), 6,84-7,13 (m, 8H, Ar-H). HPLC tR=6.2 min (method A).

Examples 22 and 23: Hydrochloride (4R)- and (4S)-4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (78NLS59 and 78NLS62)

The separation of the racemate 64NLS44 held in the temporary introduction Campanile chiral auxiliary group. Two diastereoisomer obtained were separated by fractional crystallization, Deputy campanulas acid was removed, and the resulting spirobiindane alkilirovanie derivative of the corresponding benzylbromide.

Examples 24 and 25: Obtain 3-[(-)-campanil]-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-she and the separation of the two diastereomers (78NLS52-Krist. and 78NLS52-filter.)

To the cooled solution 69NLS44 (360 mg, 1,29 mmol) in THF (10 ml) at -78°C was added dropwise n-utility (2.7 M in heptane, of 0.53 ml of 1.42 mmol) and stirred the mixture for 30 minutes was Added dropwise at -78°With saline (-)campanulas acid (307 mg, of 1.42 mmol) in THF (2 ml), p is the target was stirred for 15 min at -78° With, and then 3 h at K.T. was Added a saturated solution of ammonium chloride (5 ml) and was extracted three times a mixture of ethyl acetate. The combined organic extracts were washed a feast upon. a solution of NaHCO3and saturated salt solution, dried over Na2SO4, was filtered and was evaporated. The residue was led from a mixture of ethyl acetate/n-heptane while K.T. was Filtered light yellow crystals 78NLS52-Krist. (155 mg, 26%, de>98%, determined by1H NMR), the mother liquor was concentrated and was purified column chromatography with elution with a gradual gradient of 0-2% methanol in methylene chloride. The second diastereoisomer gathered in the initial fractions was evaporated and the residue was led, as before. During the process of evaporation of the mother liquor was received 78NLS52-filter. (28 mg, 5%, de 98%, determined by1H NMR) as a colourless oil.

78NLS52-Krist. (de>98%): Rf=0,40 (Meon/CH2Cl21:9). IHMS m/z 459 [M+H]+.1H NMR (CDCl3) δ 0,87, of 1.09 and 1.15 (3C, 3×3H, CH3), 1,45-of 1.53 (m, 1H, PIP-H), 1,70-1,80 (m, 3H, PIP-H, Kamp-H), 1,83-of 1.92 (m, 1H, camp-H), 1,97-2,02 (m, 1H, PIP-H), 2,13-of 2.20 (m, 1H, camp-H), 2,24 (s, 3H, NCH3), 2,29-of 2.38 (m, 2H, PIP-H), 2,55-2,61 (m, 2H, PIP-H, Kamp-H)to 2.66 (m, 1H, PIP-H), 2,80 (DD, 1H, J=9,0, 14,2, CH2Ar), a 3.06 (DD, 1H, J=4,9, 14,2, CH2Ar), 4,59 (DD, 1H, J=4,9, 9,0, H-4), 6,98-7,25 (m, 4H, Ar-H). HPLC tR=8,1 min (method B).

78NLS52-filter. (de 98%): Rf=0,40 (Meon/CH2Cl21:9). IHMS m/z 459 [M+H] .1H NMR (CDCl3) δ and 0.98, 1,09, and 1,13 (3C, 3×3H, CH3), 1,59 is 1.70 (m, 2H, PIP-H), 1,73 and 1.80 (m, 1H, camp-N), 1,84 is 1.91 (m, 1H, camp-N)of 1.97 (m, 2H, PIP-H), 2,08-of 2.15 (m, 1H, camp-N in), 2.25 (s, 3H, NCH3), 2,24-is 2.37 (m, 2H, PIP-H), 2,50-2,60 (m, 2H, PIP-H), 2,94-a 3.01 (m, 2H, CH2Ar, PIP-H), of 3.12 (DD, 1H, J=4,1, 14,2, CH2Ar), 4,32 (DD, 1H, J=4,1, 9,0, H-4), 6,95-7,24 (m, 4H, Ar-H). HPLC tR=8,7 min (method B).

Examples 25 and 26: Obtain (4R)- and (4S)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (78NLS57 and 78NLS61)

To a solution of 78NLS52-Krist. (100 mg, 0.22 mmol) in a mixture of THF/water (4 ml, 3:1) at 0°With monohydrate was added lithium hydroxide (20 mg, 0.47 mmol). After stirring for 1 h at 0°With added feast upon. aq. NaHCO3(3 ml), the solution was extracted three times with diethyl ether, and the combined organic extracts were dried over Na2SO4, was filtered and was evaporated. The crude compound 78NLS57 (60 mg) was used without further purification. Similarly when processing 78NL352-filter. (28 mg, 61 μmol) and lithium hydroxide received 78NLS61.

Examples 27 and 28: Obtaining hydrochloride (4R)- and (4S)-4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (78NLS59 and 78NLS62)

In the alkylation 78NLS57 (approx. 0.22 mmol) by the method described for 69NLS75, got enantiomer 78NLS59 (45 mg, 48% after two steps). Similarly, when the alkylation of the second enantiomer 78NLS61 (approx. 61 μmol) was received 78NLS6 (7 mg, 25% after two steps). Spectrochemical data for both compounds were identical to the data obtained for 69NLS75. Certain enantiomeric excess (EE) was 98% for 78NLS59 and 93% for 78NLS62 using analysis of chiral HPLC (column Chiracel OD-H, 4,6×250 mm, hexane/ISO-D/deja 95:5:0,2; 0,5 ml/min, tR20,8 and 23.6 min for 78NLS59 and 78NLS62 respectively).

Subsequent x-ray diffraction analysis of the intermediate 78NLS52-Krist. let set (S)-configuration for aliremove at the beginning of the enantiomer (78NLS59, formula (II). When biological evaluation of in vivo it was shown that the (S)-enantiomer is eutomer in relation to 5-NTA receptor (example 2, table 1).

Formula II

78NLS59

Example 29: Bromide [2-(4-forfinal)ethyl]triphenylphosphine (78NLS66)

4-perforative (700 mg, 3,44 mmol) was dissolved in toluene (4 ml), was added triphenylphosphine (904 mg, 3,44 mmol) and the solution was heated for 10 min in a sealed flask at 200°under microwave irradiation. After cooling to ctestmodell decantation and got mentioned in the title compound in quantitative yield in the form of residual glassy solid, which was used without further purification.

Rf=0,70 (MeOH/CH2Cl21:9).1H NMR (CDCl3) δ 2,99-of 3.06 (m, 2H, RSN2CH2),4,16-to 4.23 (m, 2H, RSN2), 6,86-7,35 (m, 4H, ArF-N), to 7.67-of 7.90 (m, 15 NM, PPh3).

Example 30: Benzyl ester 4-[2-(4-forfinal)ethylidene]piperidine-1-carboxylic acid (103NLS05)

To a suspension of the bromide of phosphonium 78NLS66 (4,69 g, 10.1 mmol) in THF (100 ml) at 0°C was added n-utility (1.6 M in hexane, 6.3 ml, 10.1 mmol)to give a dark red solution. After stirring for 1 h at kt, was added dropwise a solution of benzyl-4-oxo-1-piperidinecarboxylate (2.24 g, 9.6 mmol) in THF (10 ml) for 30 min. the Mixture was stirred at K.T. for 20 h, then was added water and was extracted three times a mixture of diethyl ether. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. As a result of clearing of remnant column chromatography on silica gel with elution with a gradual gradient of 0-10% ethyl acetate in n-heptane has been specified in the title compound (0.56 g, 17%) as a colourless oil.

Rf=0,63 (ethyl acetate/n-heptane 2:3). IHMS m/z 362 [M+Na]+.1H NMR (CDCl3) δ of 2.24 (m, 2H, PIP-H), to 2.35 (m, 2H, PIP-H), 3,37 (d, 2H, J=7,2, CH2ArF), 3,55 (m, 4H, PIP-H), 5,16 (s, 2H, OCH2), 5,43 (t, 1H, J=1,2, CH=), of 6.96-7,40 (m, N, Ar-H). HPLC tR=10,7 min (method B).

Example 31: Benzyl ester 2-(4-terbisil)-1-oxa-6-azaspiro[2,5]Octan-6-carboxylic acid (103NLS09)

To a solution of olefin 103NLS05 (79 mg, 0.23 mmol) in chloride IU is Ilene (3 ml) at 0° C was added dropwise a solution of m-chloroperbenzoic acid (70% in N2O, 69 mg, 0.28 mmol). The mixture was stirred at K. T. for 24 h, diluted with methylene chloride and washed with 10%aq. a solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Specified in the title compound was obtained with quantitative yield and used without further purification.

Rf=0,53 (ethyl acetate/n-heptane 2:3). IHMS m/z 356 [M+H]+.1H NMR (CDCl3) δ of 1.39 (m, 1H, PIP-H)of 1.66 (m, 1H, PIP-H), 1,83-1,90 (m, 2H, PIP-H), 2,79 of 2.92 (m, 2H, CH2Ar2), 3,03 (m, 1H, och), 3,39 is-3.45 (m, 2H, PIP-H), 3,83-to 3.89 (m, 2H, PIP-H), 5,16 (s, 2H, och2), 6,98 and 7.36 (m, N, Ar-H). HPLC tR=9,3 min (method B).

Example 32: Benzyl ester 4-[1-amino-2-(4-forfinal)ethyl]-4-hydroxypiperidine-1-carboxylic acid (103NLS28)

To a solution of ammonia in methanol (7 N., 5 ml) was added crude epoxide 103NLS09 (520 mg, of 1.40 mmol) and the solution was heated for 20 h in a sealed flask at 100°C. After cooling to ctestmodell was removed, and the residue was purified C18solid-phase extraction with reversed phase when elution with a gradual gradient of 0-80% methanol in methylene chloride, getting amerosport 103NLS28 (459 mg, 88%).

Rf=0,62 (MeOH/CH2Cl21:9). IHMS m/z 373 [M+H]+.1H NMR (CDCl3) δ 1,52-to 1.67 (m, 4H, PIP-H), is 2.37 (DD, 1H, J=11,3, 13,8, CH2Arsub> F), 2,70 (m, 3H, NH2HE), of 2.81 (DD, 1H, J=2,9, 11,3, CH2ArF), of 2.97 (DD, 1H, J=2,9, 13,8, CHNH2), 3,20-3,26 (m, 2H, PIP-H), a 4.03-4,08 (m, 2H, PIP-H), further 5.15 (s, 2H, och2), 6,98-7,38 (m, N, Ar-H). HPLC tR=5,5 min (method B).

Example 33: Benzyl ester 5-(4-terbisil)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid (103NLS30C)

Specified in the title compound was obtained from amerosport 103NLS28 (303 mg, 0.81 mmol) according to the literature method (Clark et al., J. Med. Chem. 26:855-861 (1983)) by acylation of aminophenol chloroacetylation followed by halogen exchange under the action of NaI and closing cycle of iodine is derived in the presence of tert-butoxide. In the refining of crude product column chromatography on silica gel with gradual elution 0-100% ethyl acetate in n-heptane has been specified in the title compound (64 mg, total yield 19%) as a colourless solid.

Rf=0,19 (ethyl acetate/n-heptane 3:2). IHMS m/z 458 [M+H]+.lH NMR (CDCl3) δ 1,52-of 1.74 (m, 2H, PIP-H), 1,87-to 1.98 (m, 2H, PIP-H), 2,47 (DD, 1H, J=11,7, 13,3, CH2ArF), of 2.81 (DD, 1H, J=2,7, 13,3, CH2ArF), 3.04 from-3,22 (m, 2H, PIP-H), 3,40 is-3.45 (m, 1H, H-5), 4,05-4,20 (m, 4H, H-2, PIP-H), further 5.15 (s, 2H, och2Ph)of 5.55 (s, 1H, NH), 6,99-7,37 (m, N, Ar-H). HPLC tR=12,4 min (method B).

Example 34: Benzyl ester 5-(4-terbisil)-4-(4-salutogenesis)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid (103NLS33)

Alkylation of spirocyclic 103NLS30C (61 mg, 0,148 mmol) was carried out as described for obtaining 69NLS75, using 4-isobutoxyethene 69NLS69 as alkylating reagent. After purification of the residue column chromatography on silica gel with gradual elution 0-70% ethyl acetate in n-heptane specified in the header connection 103NLS33 (62 mg, 73%) was obtained as a colourless oil.

Rf=0,37 (ethyl acetate/n-heptane 1:1). IHMS m/z 575 [M+H]+.1H NMR (CDCl3) δ 0,79-0,88 (m, 1H, PIP-H), of 1.02 (d, 6N, J=64, CH3), of 1.32 to 1.37 (m, 1H, PIP-H), 1,69-of 1.81 (m, 2H, PIP-H), 2,03-of 2.09 (m, 1H, CH(CH3)2), of 2.72 (d, 1H, J=14,3, CH2ArOiBu), 2,86-2,95 and of 3.07-3.15 in (2 m, 5H, H-5, CH2ArF, PIP-H), 3,70 (d, 2H, J=6,4, OCH2CH), 3,80-of 3.85 (m, 2H, PIP-H), 4,16 (AB, 2H, J=17,6, H-2), is 5.06 (s, 2H, OCH2Ph), to 5.35 (d, 1H, J=14,3, CH2ArOiBu), 6,78 and 7.36 (m, 13H, Ar-H). HPLC tR=10,9 min (method B).

Example 35: 5-(4-terbisil)-4-(4-salutogenesis)-9-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-3-one (103NLS35)

From spirozine 103NLS33 (62 mg, 0,107 mmol) in ethanol (5 ml) was filmed protection N-CBz by hydrogenation in the presence of Pd/C (10%, 40 mg) under pressure of H2from the container. The catalyst was filtered, and the filtrate was evaporated under reduced pressure to give crude 5-(4-terbisil)-4-(4-salutogenesis)-1-oxa-4,9-diazaspiro[5.5]undecane-3-one. The residue was dissolved in methanol (3 ml), was added formaldehyde (37% in water, of 0.017 ml), after agoprobably acetic acid (0,03 ml) and cyanoborohydride sodium (60 mg, 0.95 mmol). The solution was stirred at K.T. for 5 h, then added water and podslushivaet a mixture of 2 n aq. NaOH solution. The mixture was extracted three times methylene chloride, the combined organic layers were washed a feast upon. solution of ammonium chloride and a saturated salt solution, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified column chromatography on silica gel with elution with a gradual gradient 0-7% methanol in methylene chloride, getting 103NLS35B (43 mg, 88% after both steps) as a colourless oil. The connection is translated in HCl form processing 2 M HCl in diethyl ether, as described above for 69NLS75, getting salt in the form of colorless powder.

Rf=0,50 (MeOH/CH2Cl21:9). IHMS m/z 455 [M+H]+.1H NMR (CDCl3) δ 0,94 was 1.06 (m, 7H, PIP-H, CH3), 1,50-of 1.57 (m, 1H, PIP-H), 1,69 to 1.76 (m, 2H, PIP-H), 2,00-2,09 (m, 2H, PIP-H, CH(CH3)2), 2,22-to 2.29 (m, 4H, NCH3, PIP-H), 2,37-to 2.40 (m, 1H, PIP-H), to 2.55 (m, 1H, PIP-H), 2,62 (d, 1H, J=14,3, CH2ArOiBu), 2,87 (DD, 1H, J=7,8, 13,5, CH2ArF), a 3.06-3,14 (m, 2H, H-5, CH2ArF, PIP-H), 3,66 (d, 2H, J=6,4, OCH2CH), 4,12 (AB, 2H, J=17,6, H-2), from 5.29 (d, 1H, J=14,3, CH2ArOiBu), 6,75-to 7.18 (m, 8H, Ar-H). HPLC tR=7,5 min (method B).

Example 36: Tert-butyl ester 3-oxo-1,2,8-diazaspiro[4,5]decane-8-carboxylic acid (84AF15)

A solution of hydrazine monohydrate (5,28 ml, 108.8 mmol) in n-BU is anole (20 ml) was added dropwise to a solution of N-BOC-4-ethoxycarbonylpyrimidine (1.39 g, 5,44 mmol) in n-butanol (120 ml) at K.T. Mixture was stirred for 15 h at 120°and gave the mixture to cool to K.T. the Solvent was removed by evaporation under reduced pressure, the residue was distributed between ethyl acetate and water and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness. As a result of clearing of remnant column chromatography on silica gel with elution with a gradual gradient 3-6% methanol in methylene chloride was obtained the desired compound (0.88 g, 63%) as a white solid.

Rf=0,34 (MeOH/CH2Cl26:94). IHMS m/z 200 [M+H-(tert-Bu)]+, 156 [M+H+VOS]+.1H NMR (CDCl3) δ 1,45 (s, N, CH3), 1,61-of 1.74 (m, 4H, PIP-H), 2,34 (s, 2H, H-4), 3,38-to 3.52 (m, 4H, PIP-H), 4,01 (s, 1H, NH), to 7.15 (s, 1H, NH).

Example 37: Tert-butyl ester 1-(4-terbisil)-3-oxo-1,2,8-diazaspiro[4,5]decane-8-carboxylic acid (84AF84-19)

To a solution of 84AF15 (289 mg, 1.13 mmol) in dry DMF (50 ml) was added dropwise at K.T. 4-florantyrone (0,37 ml of 2.97 mmol). The mixture was stirred at K.T. for 6 days in an argon atmosphere. The solvent was removed by evaporation under reduced pressure, the residue was distributed between chloroform and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. As a result of clearing of remnant column chromatography on silica gel with elution holdem is restim with methylene received the desired compound (160 mg, 39%).

Rf=0,53 (Meon/CH2Cl26:94). IHMS m/z 308 [M+H-BOC]+, 364 [M+H]+.1H NMR (CDCl3) δ 1,47 (s, N, CH3), 1,71 to 1.76 (m, 2H, PIP-H), 1,87-of 1.93 (m, 2H, PIP-H), a 2.45 (s, 2H, H-4), 3,31-to 3.38 (m, 2H, PIP-H), 3,64-3,70 (m, 2H, PIP-H), 3,80 (s, 2H, CH2ArF), 6,62 (s, 1H, NH), 7,01-7,30 (m, 4H, Ar-H).

Example 38: Tert-butyl ester 1-(4-terbisil)-2-(4-salutogenesis)-3-oxo-1,2,8-diazaspiro[4,5]decane-8-carboxylic acid (118AF94-23)

To a solution of 84AF84-19 (0,149 g, 0.41 mmol) in dry DMF (5 ml) was slowly added NaH (24 mg, 0.50 mmol) and stirred the mixture at K.T. within 30 minutes To the mixture was added dropwise a solution of 4-isobutoxyethene 69NLS69 (117 mg, 0.48 mmol) in dry DMF (1 ml). After 1 h stirring, the mixture was distributed between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. As a result of clearing of remnant column chromatography on silica gel with elution with a gradual gradient 3-6% methanol in methylene chloride with subsequent preparative HPLC with reversed phase (C18) was obtained the desired compound (109 mg, 50%).

Rfor =0.51 (MeOH/CH2Cl21:99). IHMS m/z 526 [M+H]+, 470 [M+H-(tert-Bu)]+.1H NMR (CDCl3) δ 1,00 (d, 6N, J=6,8, CH(CH3)2), is 1.35 (m, 4H, PIP-H), 1,40 (s, N, (CH3)3), to 2.06 (m, 1H, CH(CH3)2), is 2.41 (s, 2H, H-4), is 3.08-3.15 in (m, 2H, PIP-H), 3,22-3,29 (who, 2H, PIP-H), to 3.67 (d, 2H, J=6,4, OCH2), 3,92 (m, 4H, CH2ArFCH2ArOiBu), 6,77-7,37 (m, 8H, Ar-H).

Example 39: 1-(4-terbisil)-2-(4-salutogenesis)-1,2,8-diazaspiro[4,5]decane-3-one (84AF99-24)

With 118AF94-23 (100 mg, 0.21 mmol) was shot N-BOC-protection, as described in obtaining 69NLS79-II, receiving specified in the title compound, which was used without further purification.

Rf=0,40 (MeOH/CH2Cl21:9). IHMS m/z 426 [M+H]+.1H NMR (CDCl3) δ 0,99 (d, 6N, J=64, CH(CH3)2), is 1.35 (m, 4H, PIP-H), 1,49 (s, 1H, NH), 2,00-2,05 (m, 1H, CH(CH3)2), 2,42 (s, 2H, H-4), of 2.50 (m, 2H, PIP-H), was 2.76 (m, 2H, PIP-H), 3,66 (d, 2H, J=6,4, OCH2), to 3.92 (s, 2H, CH2Ar), of 3.95 (s, 2H, CH2Ar), 6.75 in-7,34 (m, 8H, Ar-H).

Example 40: Hydrochloride 1-(4-terbisil)-2-(4-salutogenesis)-8-methyl-1,2,8-diazaspiro[4,5]decane-3-one (84AF100-25)

Required spirits received from 84AF99-24 (60 mg, 0.14 mmol) by the same method described for obtaining 103NLS35. Synthesis of cleaners containing hydrochloride salt was carried out as for 69NLS75, getting mentioned in the title compound (39 mg, 63%) as a colourless solid.

Rf=0,57 (MeOH/CH2Cl21:9). IHMS m/z 440 [M+H]+.1H NMR (CDCl3) δ 0,94 (d, 6N, J=6,4, CH(CH3)2), 1,38 by 1.68 (m, 4H, PIP-H), 1,96-2,02 (m, 1H, CH(CH3)2), 2,23 is 2.46 (m, N, PIP-H, NCH3, H-4), 3,61 (d, 2H, J=6,4, co2), 3,85 (m, 4H, CH2ArOiBuCH2ArF), 6,70-7,28 (m, N, Ar-H).

Example 41: Oxalate 8-(2-[1,3]-dioxane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4,5]decane-2-it (118AF02-74)

With 69NLS77 shot N-BOC-protection, as described in obtaining 69NLS79-II, and the resulting compound (172 mg, 0.40 mmol) alkilirovanie 2-(2-bromacil)-1,3-dioxane according to the method similar to getting 69NLS85. When translating this compound (139 mg, 64%) in the form of oxalate has been specified in the title compound as a colourless solid.

Rf=0,33 (MeOH/CH2Cl21:24). IHMS m/z 541 [M+H]+.1H NMR (CDCl3) δ 1/00 (d, 6N, J=6,8, CH(CH3)2), 1,23-of 1.36 (m, 2H, PIP-H, dioxane-H), 1,54-of 1.66 (m, 1H, PIP-H), 1,67-of 1.74 (m, 3H, CH2CH2N, PIP-H), 1,86-1,90 (m, 1H, PIP-H), 1,97-of 2.15 (m, 2H, dioxane-H, CH(CH3)2), 2,31 is 2.43 (m, 4H, CH2CH2N, PIP-H), to 2.55 (m, 1H, PIP-H), 2,69 (m, 1H, PIP-H), 2.71 to 2,89 (m, 2H, CH2ArF), to 3.36 (t, 1H, J=6,8, H-4), of 3.56 (d, 1H, J=15,2, CH2ArOiBu), 3,67-3,74 (m, 4H, och2CH(CH3)2, dioxane-H), a 4.03-4,07 (m, 2H, dioxane-H), 4,51 (t, 1H, J=5,2 BASED), 4,72 (d, 1H, J=15,2, CH2ArOiBu), 6,79? 7.04 baby mortality (m, 8H, Ar-H).

Example 42: Oxalate of 4-(4-terbisil)-3-(4-salutogenesis)-8-{3-[(S)-4-isopropyl-2-oxoacridine-3-yl]propyl}-1-oxa-3,8-diazaspiro[4,5]decane-2-it (118AF04-75)

With 69NLS77 shot N-BOC-protection, as described in obtaining 69NLS79-II, and the resulting compound (172 mg, 0.40 mmol) alkilirovanie (4S)-3-(3-chloropropyl)-4-isopropyl-2-oxazolidin-2-it is m in DMF (3 ml) in the presence of sodium iodide (72 mg, 0.48 mmol), following the same technique as when receiving 69NLS85. When translating this compound (130 mg, 55%) in the form of oxalate has been specified in the title compound as a colourless solid.

Rf=0,29 (MeOH/CH2Cl21:19). IHMS m/z 596 [M+H]+.1H NMR (CDCl3) δ 0,84-0,88 (m, 6N, CH3iBu), 1/01 (d, 6N, J=6,8, CH3iBu), of 1.24 to 1.34 (m, 1H, PIP-H), 1,55-of 1.74 (m, 4H, PIP-H, CHZepi), 1,87-of 1.93 (m, 1H, PIP-H), 1,97 and 2.13 (m, 2H, CHOiBuCHiPr), and 2.27-2.40 a (m, 4H, PIP-H, NCHZepi), of 2.56 (m, 1H, PIP-H), 2,69 (m, 1H, PIP-H), of 2,75 2,80 (m, 1H, C2ArF), 2,87 are 2.98 (m, 2H, CH2ArF, NCHZepi), 3,37 (t, 1H, J=6,8, H-4), 3,48-3,55 (m, 1H, NCHZepi), to 3.58-to 3.64 (m, 1H, CH2ArOiBu), the 3.65-3,71 (m, 3H, och2CH(CH3)2CHisox), 4,00-Android 4.04 (m, 1H, ochisox), 4,11-4,16 (m, 1H, ochisox), and 4.75 (d, 1H, J=15,2, CH2ArOiBu), to 6.80-7.03 is (m, 8H, Ar-H).

Example 43: pharmacological data

The choice of receptor and amplication (R-SAT) tests

For screening compounds for efficacy in relation to 5-NTA receptor used functional receptor analysis, technology selection and receptor amplification (R-SAT) (with minor changes compared to the previously described in U.S. patent 5707798). Briefly, 96-well cell culture tablets grew NIH3T3 cells to 70-80% confluence. The cells were transfusional 12-16 hours NAM is-plasmids using superfect (Qiagen Inc.) no protocols of the manufacturer. R-SAT is usually carried out with 50 ng/well of receptor and 20 ng/well of beta-galactosidase plasmid DNA. All used the design of receptors and G-proteins were in the pSI expressing vector mammals (Promega Inc)as described in U.S. patent 5707798. Gene receptor 5-NTA amplified nested PCR from cDNA of the brain using oligodeoxynucleotide based on the published sequence (see Saltzman et al. Biochem. Biophys. Res. Comm. 181:1469-78 (1991)). Large-scale transfection cells were transfusional for 12-16 hours, then was trypsinization and frozen in DMSO. Subsequently, the frozen cells were thawed, placed in the number of capabilities from 10,000 to 40,000 cells per well of 96-hole tablet containing a drug. In both methods the cells were then grown in a humid atmosphere with 5% CO2in the environment for 5 days. After that, plates were removed environment and determined the activity of the marker gene by adding beta-galactosidase substrate ONPG (in PBS with 5% NP-40). The obtained colorimetric reaction was determined in spectrophotometric tablet reader (Titertek Inc.) at 420 nm. All data were analyzed using the computer program XLFit (IDBSm). Efficiency represents the percentage of maximum repression compared to the repression under the action of the control connection (ritanserin in the case of 5-NTA). pIC 50is a negative value from log(IC50), where IC50represents the estimated concentration in moles, which leads to 50% of maximum repression. The results obtained for several compounds of this invention listed in table 1 below.

Table 1
Efficiency and pIC50compounds in relation to the receptor 5-NTA compared with ritanserin
Connection ID, Example No.NTA pIC50NIC50STD DEVNTA, % inhibitionN, % inhibitionSTD DEV, % inhibition
209,140,583411
219,670,2103720
59,5150,3941622
69,670.387714
108,140,2101412
148,3 40,185410
11840,185410
129,140,39589
158,140,295418
138,850,384812
169,350,3100109
279,6170,3982219
288,250,38947

Profile selectivity for 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS75) (the compound of Example 5)

To study the selectivity of 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it used R-SAT assay (described above in the example). The results of the extensive analysis of the profile of this compound in relation to a number of receptors are shown in table 2 below. HP means there is no reaction, that is, issled the bath connection has no effect on the target receptor.

Table 2

The selectivity of 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it 69NLS75 (Primer)

ReceptorAnalysispEC50or pIC50
NTAagonistHP
reverse9,5 (94%)
NTVagonistHP
reverse<5,6
antagonistHP
NTSagonistHP
reverse7,5 (77%)
NTAagonistHP
antagonist6,4
NTVagonistHP
antagonist<5,5
5HT1DagonistHP
antagonist<6,25
5HT1EagonistHP
antagonist<6,2
5HT1FagonistHP
Anta is onist HP
5HT6AreverseHP
5HT7AagonistHP
reverseHP
D1agonistHP
antagonistHP
D2agonistHP
antagonistHP
D3agonistHP
antagonistHP
m1agonistHP
m2agonistHP
m3agonistHP
reverseHP
antagonist6,4
m4agonist<5,5
m5agonistHP
H1agonistHP
antagonist6,7
alpha 2AagonistHP
antagonist6,3
alpha 2Bagonist HP
antagonistHP
alpha 2CagonistHP
antagonist<5,5
alpha 1BagonistHP
antagonistHP
oprk 1agonistHP
antagonistHP

Example 44: Pharmacology in vivo 4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-it (69NLS75)

Ways

Animals and machines

Males nessacary mice albino (Harlan Sprague-Dawley) were settled, (4 mice/cage) in a room with controlled temperature and humidity with free access to water and food (Harlan Teklad). Mice kept at a 12-hour cycle of light : dark. For the experiments on motor activity plastic cages (20×20×30 cm) for registration activity were provided with a matrix of photocells (AccuScan Instruments).

The method

Motor activity

For experiments on hyperactivity of mice were treated with 0.3 mg/kg dizocilpine I.P. Pavlova. 15 min before the session. Mice were treated 69NLS75 s.c. for 10 min before the session or r.o. 30 minutes before the session and placed in cells for registration activity. For spontaneous Akti the values entered one 69NLS75. Data on physical activity was collected during the 15-minute session without addiction in a lit room. The combination of each dose was tested in a separate group of animals (n=8). Distance traveled (cm) was calculated and averaged by ANOVA and post-hoc comparisons by t-criterion of Dunnet.

Results

69NLS75 caused a dose-dependent decrease in the hyperactivity caused by the agonist of the NMDA receptor, MK-801, ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a, d)cyclohepten-5,10-Imin gidromaleat salt) in mice, consistent with antipsychotic efficacy. A statistically significant decrease compared with control media occurred at 3 mg/kg after s.c., and r.o. introduction, which implies excellent oral bioavailability. In addition, the weakening of MK-801 hyperactivity occurred at doses that did not affect spontaneous locomotor activity, indicating no adverse musculoskeletal effects at effective doses.

Example 45: Pharmacology in vivo additional connections

The effect of various compounds on locomotor activity in mice treated MC, watched as described above.

Animals received 0.1 to 30 mg/kg of the compounds by subcutaneous injection or oral administration. EDR is the minimum effective dose at which there is a statistically significant decrease in Whateley activity (described above). MED = minimum effective dose in vivo.

Table 4
Comparison of analogues for their ability to weaken MC-induced hyperactivity in mice
ConnectionDose rate (mg/kg) s..Dose rate (mg/kg) r.o.
Example 6n10
Example 533
Example 10n3

1. Spermatoceles the compounds of formula I, their salts and stereoisomers

in which X is chosen from the group comprising SN2CH2Oh, och2and;

Y represents O;

Z is chosen from the group comprising SN and N;

R1selected from the group including C1-6-alkyl, optionally substituted C5-C6heterocyclyl or3-8cycloalkyl,2-8-alkilany ester and benzyl ester;

where C5-C6heterocyclyl selected from the group including morpholinyl, 1,3-dioxane, 1,3-DIOXOLANYL, 1,4-dioxane, 2-Oxymetazoline, imidazolidinyl, 2-oxoacridine and oxazolidinyl;

m is chosen from the group comprising 0 and 1;

R4missing or choose the group, comprising hydrogen and benzyl, optionally substituted with halogen or1-4-alkyl;

R5selected from the group comprising hydrogen and benzyl, optionally substituted with halogen, C1-4-alkyl or C1-4-alkoxy;

R6selected from the group comprising hydrogen and benzyl, optionally substituted C1-4-alkoxy, cycloalkyl(C1-4-alkoxy or halogen(C1-4-alkoxy);

where at least two of R4, R5and R6represent optionally substituted benzyl; and

R2and R3represent hydrogen.

2. The compound according to claim 1, where X represents O.

3. The compound according to claim 1, where Z represents CH.

4. The compound according to claim 1, where m is equal to zero.

5. The compound according to claim 1, where the connection homochiral relative to the (4S)-4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it, HCl.

6. The compound according to claim 1, where two of R4, R5and R6are not hydrogen, and the remaining one of R4, R5and R6, if present, is hydrogen.

7. The compound according to claim 1, where R1selected from the group including C1-6-alkyl, optionally substituted C5-C6heterocyclyl.

8. The compound according to claim 1, where the specified represents benzyl (4-substituted)benzyl.

9. The connection according to claim 6, where at least one of the R 4, R5and R6represents a halogen-substituted benzyl.

10. The connection according to claim 9, where the halogen-substituted benzyl represents (4-halogen-substituted)benzyl.

11. The connection of claim 10, where halogen represents fluorine.

12. The compound according to claim 1, where (i) X=OCH2Z=CH and m=0, (ii) X=0, Z=CH and m=O, or (iii) X=CH2, Z=N and m=0.

13. The connection section 12, selected from the group including

3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

3-(4-deformational)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4,5]decane-2-he;

8-ethyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4,5]decane-2-he;

4-(4-terbisil)-3-(4-salutogenesis)-8-isopropyl-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

4-(4-terbisil)-3-(4-salutogenesis)-8-(3-morpholine-4-ylpropyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

8-(2-[1.3]dioxolane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

4-(4-terbisil)-3-(4-salutogenesis)-8-[2-(2-Oxymetazoline-1-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

8-(2-[1.3]dioxane-2-retil)-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

4-(4-terbisil)-3-(4-salutogenesis)-8-{3-[(S)-4-isopropyl-2-oxoacetate the n-3-yl]propyl}-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

1-(4-terbisil)-2-(4-salutogenesis)-8-methyl-1,2,8-diazaspiro[4.5]decane-3-one;

5-(4-terbisil)-4-(4-salutogenesis)-9-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-3-one;

8-methyl-4-(4-methylbenzyl)-3-(4-cryptomaterial)-1-oxa-3,8-diazaspiro[4.5]decane-2-he; and

3-(4-methoxybenzyl)-8-methyl-4-(4-methylbenzyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-it.

14. The connection section 12, selected from the group including

8-cyclopropylmethyl-4-(4-terbisil)-3-(4-salutogenesis)-1-oxa-3,8-diazaspiro[4.5]decane-2-he;

benzyl ester 5-(4-terbisil)-4-(4-salutogenesis)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid;

tert-butyl ester 4-(4-terbisil)-3-(4-salutogenesis)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid; and

tert-butyl ester 1-(4-terbisil)-2-(4-salutogenesis)-3-oxo-1,2,8-diazaspiro[4.5]decane-8-carboxylic acid.

15. The connection 13, which represents an

3-(4-cyclopropylmethoxy)-4-(4-terbisil)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it.

16. The connection 13, which represents a racemic (4S)/(4R)-4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it.

17. The connection 13, which is enantio-enriched (4S)-4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-he is and (4R)-4-(4-terbisil)-3-(4-salutogenesis)-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-it.

18. A connection represents 1-(4-terbisil)-2-(4-salutogenesis)-1,2,8-diazaspiro[4.5]decane-3-one.

19. A method of inhibiting the activity or activation of serotonin 5-NTA receptor, comprising contacting a specified receptor or a system containing the specified receptor with an effective amount of one or more of the compounds defined in claim 1.

20. The method according to claim 19, where the serotonin 5-NTA receptor is located in the Central nervous system.

21. The method according to claim 19, where the serotonin 5-NTA receptor is located in the peripheral nervous system.

22. The method according to claim 19, where the serotonin 5-NTA receptor is in the blood cells or platelets.

23. The method according to claim 19, where the serotonin 5-NTA receptor is mutated or modified.

24. The method according to claim 19, where the activity is an activity signal.

25. The method according to claim 19, where the activity is constitutive activity.

26. A method for the treatment of painful conditions associated with serotonin 5-NTA receptor comprising the administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds according to claim 1.

27. The method according to p, where the disease state is selected from the group including schizophrenia, psychosis, caused by drugs, psychosis, treatment-induced psychosis, migraine, hypertension, shall rombos, vasospasm, depression, anxiety, sleep disorders and appetite disorders.

28. The method according to p, where a painful condition associated with a dysfunction of the serotonin 5-NTA receptor.

29. The method according to p, where a painful condition associated with increased activity of serotonin 5-NTA receptor.

30. The method according to p, where serotonin receptor is located in the Central nervous system.

31. The method according to p, where serotonin 5-NTA receptor is located in the peripheral nervous system.

32. The method according to p, where serotonin 5-NTA receptor is in the blood cells or platelets.

33. The method according to p, where serotonin 5-NTA receptor is mutated or modified.

34. The use of the compounds of formula I defined in claim 1, to obtain drugs for the treatment of painful conditions associated with serotonin 5-NTA receptor.

35. The use of the compounds of formula I according to § 34, where the disease is selected from the group including schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

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

SUBSTANCE: invention describes novel spiropyrazole compounds of the general formula (I): wherein W means hydrogen atom, (C1-C10)-alkyl, (C3-C7)-cycloalkyl, cyano-(C1-C10)-alkyl, -(C1-C4)-alkyl-COOV1 wherein V1 means hydrogen atom (H) or (C1-C6)-alkyl, -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-group, or -(C1-C5)-alkyl-NHS(=O)2-W1 wherein W1 means -(C1-C10)-alkyl; Q means phenyl; n mean a whole number 0 or 1; A, B and C mean hydrogen atom; Z means a simple bond, methylene or ethylene group; R1 means (C3-C12)-cycloalkyl substituted optionally with (C1-C10)-alkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl, norbornyl, dibenzocycloheptyl, 9-acenaphthyl, phenyl substituted optionally with benzyloxy-group, biphenyl or (C1-C10)-alkyl substituted optionally with 1-3 substitutes chosen from phenyl, cyano-group, -COOV1 wherein V1 means (C1-C6)-alkyl and -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-, (C1-C4)-alkylamino- or di-(C1-C4)-alkylamino-group; R2 means (C1-C10)-alkyl, (C3-C7)-cycloalkyl or halogen atom. Also, invention to their pharmaceutically acceptable salts, solvates, pharmaceutical composition containing thereof, a method for treatment of pain and a method for modulation of pharmacological response of described ORL-1- or μ-receptors. Invention can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 3 tbl, 5 ex

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

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1)

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

FIELD: pharmaceutical industry and technology, pharmacy, medicine, phytotherapy.

SUBSTANCE: method involves three-times extraction of milled coriander herb with 40% ethyl alcohol taken in the ratio raw : extractant = 1:5 for 1 h in each extraction step. Extracts are combined, filtered, ethyl alcohol is removed and prepared aqueous residue is kept at temperature +10°C, not above, for 5 h, not less. Deposit is separated, aqueous extract is dried and the end product is prepared. Invention provides realizing the indicated designation.

EFFECT: improved preparing method.

5 tbl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: biotransplant has nucleus-containing bone marrow cells with ones predifferentiated in endothelial and cardiomyocytic direction. Method involves introducing biotransplants into native and/or stenotic coronary artery and/or coronary bypass as suspension in physiologic saline and/or intravenously by dripping, and/or intramyocardially in performing surgical interventions on open heart.

EFFECT: enhanced effectiveness of treatment.

10 cl

FIELD: medicine.

SUBSTANCE: method involves introducing 48 mg/l disodium salt of uridine triphosphate and 3.5-4.7 g/l of sodium chloride concurrently with radiopaque substance.

EFFECT: improved coronographic examination safety without worsening physical and chemical properties of radiopaque substance.

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to diosmin solid medicinal formulation possessing the vein-tonic and angioprotective activity. Invention proposes the diosmin solid medicinal formulation comprising an active substance, red grape leaves extract as a special additive and accessory substances. Tablet consists of a core and envelope. Therapeutic effect in using tablet exceeds that of the known diosmin formulations as 95-97% of active substance is released from tablet for 45 minutes.

EFFECT: improved and valuable pharmaceutical properties of formulation.

2 cl, 1 ex

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents of prolonged effect used in treatment of arterial hypertension. Medicinal agent of prolonged effect used in treatment of arterial hypertension comprises indapamide, accessory substance represented by interpolymeric complex of polymethacrylic acid with polyethylene glycol or polypropylene glycol. The claimed invention provides preparing a stable and easily dosed medicinal formulation of prolonged effect.

EFFECT: improved and valuable medicinal properties of agent.

1 tbl, 3 ex

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