New substituted diasaspiropyridine derivatives applied in treating mch-1-mediated diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl- and heteroarylsubstituted diasaspiropyridine derivatives of formula (I) to its pharmaceutically acceptable acid- or base-additive salt wherein A represents a radical of formula (II) wherein each k, l, m, n independently represents an integer equal to 0, 1, 2, 3 or 4, provided (k+1) and (m+n) are equal to 2, 3, 4 or 5; wherein one of -CH2-fragments can be substituted by atom O; and wherein one of -CH2-fragments can be substituted by an oxo group; X represents CH or N; R3 is specified in a group consisting of hydrogen, C1-5alkyl and C3-6cycloalkyl; each R4, R5 is independently specified in a group including hydrogen, halogen, oxo, C1-3alkyl and C1-3alkyloxy; p represents an integer equal to zero, 1, 2 or 3; q represents an integer equal to zero, 1, 2 or 3; each Y1, Y3, is independently specified in a group including a single bond and O; Y2 represents saturated or unsaturated C1-6hydrocarbon radical with a straight chain; B is specified in a group including phenyl optionally substituted by the number of the substitutes R6 each of which is independently specified in halogen; and wherein r represents an integer equal to zero, 1 or 2; alkyl represents a saturated hydrocarbon radical with a straight and branched chain containing said number of carbon atoms; wherein said radical can be optionally substituted by one or more carbon atoms or more radicals specified in a group including halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl; and halogen represents fluorine, chlorine, bromine or iodine. Also, the invention refers to a pharmaceutical composition based on the compounds of formula I as an active ingredient for preparing a drug for preventing and/or treating mental disorders, including but not limited to anxiety, eating behavior disorder, affective disorders, such as bipolar disorders and depression, psychosis, such as schizophrenia, and sleeping disorders; obesity, diabetes; sexual disorders and neurological disorders; to a method for preparing a pharmaceutical composition, and to using the compounds of formula I for preparing the drug.

EFFECT: there are prepared and described new compounds possessing melanin-concentrating hormone (MCH), particularly MCH-1 antagonist activity.

19 cl, 4 ex, 7 tbl

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to aryl - and heteroarylboronic desesperadamente derivatives having antagonistic activity against melaninconcentrating hormone (MCH), including activity against MCH-1. The invention also relates to receive them, including their compositions and their use as pharmaceuticals.

BACKGROUND of the INVENTION

Melaninconcentrating hormone (MCH) is a cyclic polypeptide consisting of 19 amino acids, which mainly is produced by neurons of the hypothalamus, widespread in the Central nervous system (CNS) (J. Comp. Neurol. (1992) 319, 218-245). MCH performs its effects indirectly through two G blackwashing receptor (GPCR), referred to as the MCH-1 and MCH-2 (described in Doggrell, 2003). While in rodents is expressed only MCH-1 receptor in humans and primates is the expression of both receptor, MCH-1 and MCH-2 (Genomics (2002), 79, 785-792). Originally MCH-1 receptor was considered to be a valuable target for the treatment of obesity, since MCH activates feeding behavior in rodents (Nature (1996), 380, 243-247). However, it was recently shown that antagonism of the MCH-1 produces anxiolytic and antidepressant profile in rodents (Nat. Med. (2002) 8, 825-830; Neuropharmacology (2004), 46, 457-467; Neuropsychopharmacology. (2006), 31(1), 112-120; Neuropsychopharmacology. (206), 31(6), 1135-1145). Thus, at present, it is generally acknowledged that MCH receptors, in particular the MCH-1 receptor is an important target in the treatment of affective spectrum disorders (Eur. J. Neuroscience (2000) 12, 1194-1216).

MCH mRNA-1-receptor and protein distributed in various nuclei of the hypothalamus, including paraventrikulyarnoe the core, and some limbic structures, all of which are involved in the regulation of emotions and stress (Eur. J. Neuroscience (2000) 12, 1194-1216). In addition, dense labeling was detected in areas adjacent to the core shell (J. Comp. Neurol. (2001) 435, 26-40). It was found that injection of MCH directly in paraventrikulyarnoe the core increases in the plasma levels of adrenocorticotropic hormone (ACTH) and alters sleep architecture (Verret et al. 2003, BMC Neurosci 4:19). MCH also induces the secretion corticotropinreleasing hormone (CRF) from hypothalamic explants, an effect that is sensitive to blockade by the antagonist MCH-1 receptor (J. Neuroendrocrinol. (2003) 15, 268-2729). Thus, it seems likely that stimulation of the MCH-1 receptor causes activation of the axis hypothalamus - pituitary - adrenal (HPA) through an improved allocation of CRF. Injection of MCH in areas adjacent to the core of the shell, where large quantities are present MCH-1 receptor, increased immobility in the test the forced swimming in rats, indicating increased depressive behavior (Soc. Neurosci. Abstr.(2004) 763,9). Moreover, Borowsky et al. (Nat. Med. (2002) 8, 825-830) reported antagonist MCH-1, SNAP-7941, which showed an antidepressant - and anxiolytikum steps in test rodents, confirming the role in relation to the MCH-1 receptor in depression and anxiety.

Prior art

Currently, many companies are making active attempts to develop antagonists of the MCH-1, and there were reports in some patent publications about various types of structures, mostly in connection with the regulation of food intake and energy consumption (Expert Opin. Ther. Patents (2005) 15(10)). Most MCH antagonists, reported include the main centre and two (hetero)aromatic part, connected by linkers. WO 2005/085200 (Banyu Pharmaceutical Co., Ltd) discloses pyridinone, pyrimidinone and pyridazinone derivatives for use as antagonists of the MCH-1. WO 2003/033480, WO 2003/033476 and WO 2005/05042541 (Glaxo Group Limited), WO 2004/024702 (Boehringer Ingelheim Pharma GMBH & Co. KG) and WO 2005/103039 (Neurocrine Biosciences Inc.) reveal various bicyclic heterocycles, such as thienopyridine-4-one-, benzopyrene-4-one - and telemicroscopy, for use as antagonists of the MCH-1. WO 2003/097047 and WO 2005/040157 (Eli Lilly and Company) and WO 2005/070925 (Aventis Pharma Deutschland GmbH) reported various aromatic 5-membered ring heterocycles, such as oxazoline and oxadiazoline derivatives, for use as the antagonists of the MCH-1. WO 2004/011438 and WO 2005/070898 (Aventis Pharma Deutschland GMBH) reveal diarylethylene cyclic urea derivatives as antagonists of the MCH-1.

Description of the INVENTION

The task, which was sent to the present invention is to provide compounds with affinity binding receptor melaninconcentrating hormone (MCH), in particular in respect of the MCH-1 receptor, in particular as an antagonist.

Moreover, it was found that the compounds in accordance with the present invention show very low interaction with hERG channels or no interaction, however, such interactions are undesirable, but largely related compounds of the prior art. Therefore, the compounds of the present invention are preferred in comparison with the compounds of the prior art due essentially to the absence of their interactions with hERG channels and the absence of QT prolongation.

This object is achieved by using the new substituted diazospiropentane derivative according to General formula (I)

its pharmaceutically acceptable acid or basic additive salts, its N-oxide form, or its Quaternary ammonium salt, where

And p is ecstasy a radical of the formula (II)

where k, l, m, n, each independently from each other represent an integer of 0, 1, 2, 3, or 4, provided that (k+l) and (m+n) is 2, 3, 4 or 5; where one of the-CH2fragments can be replaced by an atom About; and where each of the-CH2fragments can be replaced by oxopropoxy;

X represents CH or N;

R3selected from the group comprising hydrogen, C1-5alkyl, C3-6cycloalkyl and C1-5allyloxycarbonyl;

R4, R5each independently from each other selected from the group comprising hydrogen, halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy;

p is an integer of zero, 1, 2 or 3;

q is an integer of zero, 1, 2 or 3;

Y1, Y3each independently from each other selected from the group including a simple bond, O, NR7, S, SO and SO2; where R7selected from the group comprising hydrogen and C1-3alkyl;

Y2represents a saturated or unsaturated C1-6a hydrocarbon radical straight or branched chain, where one or more hydrogen atoms can be optionally replaced by a radical selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl;

Represents a 6-membered ring which ring containing zero, 1, 2 or 3 nitrogen atom, optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from the group comprising hydrogen, halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy; and where r is an integer of zero, 1 or 2; or two substituent R6can be combined in the radical-CH2CH2CH2- or-OCH2O-;

alkyl represents a saturated hydrocarbon radical with a straight or branched chain, containing the indicated number of carbon atoms; where this radical optionally may be substituted on one or more carbon atoms by one or more radicals selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl;

aryl represents naphthyl or phenyl, each of which is optionally substituted by 1, 2 or 3 substituents, each independently from each other selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy;

halogen represents fluorine, chlorine, bromine or iodine.

In the framework of this application, the phrase "compounds in accordance with the present invention" means a compound according to General formula (I), agopermalink acceptable acidic or basic additive salt, its N-oxide form or Quaternary ammonium salt.

The invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient a therapeutically effective amount of a compound in accordance with the present invention, in particular compounds of formula (I), its pharmaceutically acceptable acid or basic additive salts, its N-oxide form, or its Quaternary ammonium salt.

The invention also relates to a method for preventing and/or treating disorders or diseases susceptible to antagonism MCH-receptor, in particular by antagonism of the MCH-1 receptor in a subject in need thereof, comprising the stage of introduction of a specified subject compounds or pharmaceutical compositions of the present invention. In one embodiment of the invention a specified disorder or disease selected from the group including psychiatric disorders, including, but not limited to, anxiety, eating disorders, affective disorders such as bipolar disorder and depression, psychoses, such as schizophrenia, and sleep disorders; obesity; diabetes; sexual disorders and neurological disorders.

The invention also relates to the application with the organisations according to the present invention as a drug and to obtain a medicine for preventing and/or treating disorders or diseases, susceptible to antagonism MCH-receptor, in particular by antagonism of the MCH-1 receptor.

In particular, the invention relates to the use of compounds of the present invention for obtaining a medicinal product for the prevention and/or treatment of psychiatric disorders, including, but not limited to, anxiety, eating disorders, affective disorders such as bipolar disorder and depression, psychoses, such as schizophrenia, and sleep disorders. In addition, the connection can be used for the treatment of obesity, diabetes, sexual disorders and neurological disorders.

Connection in accordance with the present invention, in particular according to formula (I)may also be suitable as an additional treatment or combined treatment and/or prevention of the above diseases, in particular for the prevention and/or treatment of psychiatric disorders in combination with antidepressants, tranquilizers and/or neuroleptic drugs, which are currently available or are under development or which will become available in the future, in particular to improve the efficiency and/or early action. It has been evaluated in rodent models, in which it was shown that antidepressants, tranquilista the s and/or neuroleptic drugs are active. For example, compounds were evaluated in combination with antidepressants, tranquilizers and/or neuroleptic means for weakening induced stress hyperthermia.

The invention therefore also relates to the use of compounds of the present invention in combination with one or more other compounds selected from the group including antidepressants, tranquilizers and neuroleptics, to pharmaceutical compositions comprising the compounds of the present invention and one or more other compounds selected from the group including antidepressants, tranquilizers and neuroleptics, as well as to a method for producing such pharmaceutical compositions.

The invention also relates to the use of compounds of the present invention in combination with one or more other compounds selected from the group of compounds that reduce the level of lipids for the prevention and/or treatment of obesity, to pharmaceutical compositions comprising the compounds of the present invention and one or more other compounds selected from the group of compounds that reduce the level of lipids, as well as to a method for producing such pharmaceutical compositions.

DETAILED description of the INVENTION

In one variant embodiment of the invention relates to soedineniya the present invention, where k, l, m, n, each independently from each other represent an integer equal to 1, 2 or 3, provided that (k+l) and (m+n) is 2, 3 or 4.

In one variant embodiment of the invention relates to the compound of the present invention, where A is selected from the group of radicals (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (c-1), (c-2), (c-3), (c-4), (c-5), (c-6), (c-7), (c-8), (d-1), (d-2), (d-3), (d-4), (d-5), (d-6), (e-1), (e-2), (e-3), (e-4), (e-5), (e-6), (f-1), (f-2), (f-3) and (f-4), as shown below, where one of the-CH2fragments can be replaced by a group O and where each of the-CH2fragments can be replaced by exography.

In the framework of this application, it becomes clear that the above radicals can be introduced in the formula (I) right to left or left to right, i.e. each end of the radical can be attached either to the radical R3or aryl/heteroaryl the radical in the formula (I).

In another variant embodiment of the invention relates to the compound of the present invention, where A is selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (c-2).

In another variant embodiment of the invention, when one of the-CH2fragments in the radical according to formula (II) replaced by-O-, A is a radical according to what armoloy (cc-2), as shown below.

In another variant embodiment of the invention, when one of the-CH2fragments in the radical according to formula (II) is substituted by oxo, A is a radical according to (aa-1) or (bb-1), as shown below.

In another variant embodiment of the invention relates to the compound of the present invention, where R3selected from the group comprising hydrogen, C3-6cycloalkyl and C1-5alkyl, in particular from the group comprising hydrogen, C3-5cycloalkyl and C1-3alkyl, in particular from the group comprising hydrogen, methyl, ethyl, propyl and cyclopropyl.

In another variant embodiment of the invention relates to the compound of the present invention, where X represents CH or nitrogen.

In another variant embodiment of the invention relates to the compound of the present invention, where each of R4and R5independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy.

In another variant embodiment of the invention relates to the compound of the present invention, where p is zero or 1.

In another variant embodiment of the invention relates to the compound of the present invention, where q is equal to zero.

In another embodiment, embodiment and the finding relates to the compound of the present invention, where Y1and Y3each, independently of one another, selected from the group including a simple link and O.

In another variant embodiment of the invention relates to the compound of the present invention, where Y2selected from the group comprising-CH2-, -CH2CH2- and-CH=CH-.

In another variant embodiment of the invention relates to the compound of the present invention, where B is selected from the group comprising phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; in particular, from the group comprising phenyl, pyridinyl and pyridazinyl; in particular, B is phenyl.

In another variant embodiment of the invention relates to the compound of the present invention, where B is substituted by one halogen Deputy, in particular fluorine or halogen.

In another variant embodiment of the invention relates to the compound of the present invention, where the fragment B-Y1-Y2-Y3selected from the radicals (a1-1)to(d1-5), below, optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy; and where r is an integer equal to 1 or 2; or two substituent R6can be combined in the radical-CH2/sub> CH2CH2- or-OCH2O-.

In another variant embodiment of the invention the fragment B-Y1-Y2-Y3choose from the radicals (a1-2), (a1-3) and (a1-5), optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy; and where r is an integer equal to 1 or 2; or two substituent R6can be combined in the radical-CH2CH2CH2- or-OCH2O-.

In another variant embodiment of the invention relates to the compound of the present invention, where applicable one or more, in combination or separately, the following restrictions:

- k, l, m, n, each independently from each other represent an integer equal to 1, 2 or 3, provided that (k+l) and (m+n) is 2, 3 or 4;

And selected from the group of radicals (a-1), (a-2), (a-3), (a-4), (a-5), (6), (7), (8), (9), (10), (11), (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (s-1), (2), (3), (4), (5), (6), (7), (8), (d-1), (d-2), (d-3), (d-4), (d-5), (d-6), (e-1), (e-2), (e-3), (e-4), (e-5), (e-6), (f-1), (f-2), (f-3) and (f-4), where one of the-CH2fragments may be substituted by a group of About; and where each of the-CH2fragments can be replaced by oxopropoxy; or

And selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (C-2); Il-Christ.

- A represents a radical according to formula (SS-2); or

- A represents the radical in accordance with (AA-1) or (bb-1);

- R3selected from the group comprising hydrogen, C3-6cycloalkyl and C1-5alkyl, in particular from the group comprising hydrogen, C3-6cycloalkyl and C1-3alkyl, in particular from the group comprising hydrogen, methyl, ethyl, propyl and cyclopropyl;

- X represents CH;

- each of R4and R5independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy;

p is zero or 1;

- q is zero;

- Y1and Y3each independently of one another, selected from the group including a simple bond and O;

- Y2selected from the group comprising-CH2-, -CH2CH2- and-CH=CH-;

- B is selected from the group comprising phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; in particular from the group comprising phenyl, pyridinyl and pyridazinyl; in particular, B is phenyl;

- B is substituted by one halogen Deputy, in particular fluorine or halogen;

- B-Y1-Y2-Y3selected from the radicals (a1-1)to(d1-5), optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carbon the sludge, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy; and where r is an integer equal to 1 or 2; or two substituent R6can be combined in the radical-CH2CH2CH2- or-OCH2O-; or

- B-Y1-Y2-Y3selected from the radicals (a1-2), (a1-3) and (a1-5), optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C1-3alkyl and C1-3alkyloxy; and where r is an integer equal to 1 or 2; or two substituent R6can be combined in the radical-CH2CH2CH2- or-OCH2O-.

In another variant embodiment of the invention relates to the compound of the present invention, where

A is selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (c-2),

X represents CH or N;

R3selected from the group comprising hydrogen, C3-6cycloalkyl and C1-5alkyl;

R4, R5each independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy;

p is an integer of zero or 1;

q is an integer, equal to zero;

fragment B-Y1/sup> -Y2-Y3selected from the radicals (a1-2), (a1-3) and (a1-5), optionally substituted by r the number of the substituents R6

R6represents a halogen Deputy; and where r is an integer equal to 1 or 2.

In another variant embodiment of the invention relates to the compound of the present invention, where

And selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (C-2),

X represents CH or N;

R3selected from the group comprising hydrogen, C3-6cycloalkyl and C1-3alkyl;

R4, R5each independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy;

p is an integer of zero or 1;

q is an integer, equal to zero;

Y1, Y3each independently from each other selected from the group including a simple link or;

Y2represents a saturated or unsaturated With1-6a hydrocarbon radical straight or branched chain; and

Represents a phenyl, optionally substituted with one halogen Deputy is m R 6.

In another variant embodiment of the invention relates to the compound of the present invention, where

And selected from the group comprising (a-1) or (b-1);

X represents CH;

R3represents methyl;

R4, R5each independently from each other selected from the group comprising hydrogen or halogen;

p is an integer of zero or 1;

q is an integer, equal to zero;

Y1represents a simple bond;

Y3represents About;

Y2represents CH2; and

B represents phenyl.

Under this proposal, the alkyl is a saturated hydrocarbon radical with a straight or branched chain, containing the indicated number of carbon atoms, i.e. when you specify C1-3alkyl, the alkyl radical may contain from 1 to 3 carbon atoms; or when specified C1-5alkyl, the alkyl radical may contain from 1 to 5 carbon atoms. Each radical optionally may be substituted on one or more carbon atoms by one or more substituents selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl. Preferably, the alkyl is a methyl, ethyl, propyl or isopropylene radicals, according to this definition, represents, for example, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, vermeil, deformity and trifluoromethyl.

Under this proposal, C3-6cycloalkyl as a group or part of a group means a cyclic saturated hydrocarbon radicals containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. C3-6cycloalkyl optionally may be substituted on one or more carbon atoms by one or more substituents selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl.

In the framework of this application aryl represents naphthyl or phenyl, each of which is optionally substituted by 1, 2 or 3 substituents, each independently from each other selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, and C1-3alkyloxy.

Under this proposal represents a halogen Deputy, selected from the group comprising fluorine, chlorine, bromine and iodine. Preferably the halogen is a fluorine, chlorine or bromine.

Within this application, unless otherwise specified, the connection may be any connection, including covalent bond, common bond, double bond, triple bond, coordination bond and hydrogen bond.

On the other hand, this form of acid additive salts can be converted in the form of a free base by treatment with a suitable base.

The compound in accordance with formula (I)containing an acidic proton may also be converted to therapeutically active form of salt accession by non-toxic metal is a or amine (primary additive salt) by treatment with appropriate organic and inorganic base. Suitable forms ό salts include, for example, ammonium salts, salts of alkali and alkaline earth metals, in particular lithium salts, sodium, potassium, magnesium and calcium, salts with organic bases, for example benzathine, N-methyl-D-glucamine, germinoma salts and salts with amino acids such as arginine and lysine.

On the other hand, the salt form can be converted into a free form using a suitable acid.

The term "additive salt"as used within this application also includes the MES, which can form the compound of formula (I)and its salt. Such solvate represent, for example, hydrates and alcoholate.

N-oxide form of a compound of formula (I) include the compounds of formula (I)in which one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or several tertiary nitrogen atoms (for example, piperazinilnom or piperidinyl radical) are N-oxidized. Such N-oxides can be obtained by specialists in this field without any inventive skills, and they are the obvious alternative for the compounds of formula (I), since these compounds are metabolites that are formed by oxidation in the body after they are received. the AK is well-known, the oxidation is usually the first stage of the metabolism of drugs (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, p.70-75). Also, it is commonly accepted that the form of the metabolite compounds can also be administered to the person instead of the connection itself, in fact, with the same effect.

The compound of formula (I) can be converted to the corresponding N-oxide forms following the procedures known in the art for converting a trivalent nitrogen into its N-oxide. This reaction N-oxidation, as a rule, can be carried out by reacting the compounds of formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene or halogensubstituted benzonorbornadiene, for example 3-chlorobenzalmalononitrile, paracalanidae acid, for example paracoccus acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones, e.g. the 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Quaternary ammonium salts of the compounds of formula (I) determines a specific connection, which may be formed by reaction between a basic nitrogen of compounds of formula (I) and suitable quaternization agent such as, for example, optionally substituted alkylhalogenide, aryl halides or arylalkylamine, in particular, methyliodide and benzylated. Can also be used with other reagents with easy atmasamyama groups, such as, for example, alkylarylsulfonate, alkylarylsulfonate and alkyl-para-toluensulfonate. Quaternary ammonium salt contains at least one positively charged nitrogen. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triftoratsetata and acetate ions.

The invention also includes a derived (usually called the "prodrug") pharmacologically active compounds of the present invention, in particular, in accordance with formula (I), which degrades in vivo to form compounds of the present invention. Prodrugs are usually (but not always) more low-activity on the target receptor than the connection on which they decompose. Prodrugs are particularly useful when the desired compound has a chemical or physical the properties, which makes his introduction is difficult or ineffective. For example, the desired compound may be only slightly soluble, it can poorly transported across the mucosal epithelium, or it may have undesirable short half-life in plasma. A more detailed discussion of prodrugs can be found in Stella, V.J. et al., "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176 and Drugs, 1985, 29, pp. 455-473.

The form of the prodrugs of the pharmacologically active compounds of the present invention basically is a compound of formula (I), its pharmaceutically acceptable acid or basic additive salt, N-oxide or Quaternary ammonium salt containing an acid group which is esterified or amidinophenoxy. Such esterified acid group include groups of the formula-COORXwhere RXrepresents a C1-6alkyl, phenyl, benzyl or one of the following groups:

Amidarone groups include groups of formula - CONRyRzwhere Ryrepresents H, C1-6alkyl, phenyl or benzyl, and Rzrepresents-OH, H, C1-6alkyl, phenyl or benzyl. The compound of the present invention containing the amino group can be modified using a ketone or aldehyde, such as formaldehyde, with the formation of the Foundation Manichee base will be either hydrolyzed with first order kinetics in aqueous solution.

In the framework of this application, the compound of the present invention essentially includes all stereochemical isomeric form. The term "stereochemical isomeric form"as used in this application, determines all possible stereochemical isomeric form, which compound of formula (I) may have. If not mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, said mixtures containing all diastereomers and enantiomers of basic molecular structure. More specifically, stereogenic centers may have the R - or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the CIS-or TRANS-configuration. Compounds containing double bonds, can be of E or Z stereochemistry at the specified double bond. Thus, all stereochemical isomeric forms of the compounds of formula (I) is included in the scope of the present invention.

Following the nomenclature CAS, when the molecule contains two stereogenic center is known absolute configuration, the designation ofRorSgiven (based on the rules of the sequence Cahn-Ingold-Prelog) chiral center with the smallest sequence number, a reference center. The configuration of the second stereogenic center indicated using the m relevant designations [ R*,R*] or [R*,S*], where R* is always defined as a reference center, and [R*,R*] specifies the centers with the same chirality, and [R*,S*] specifies the centers with different chirality. For example, if a chiral center with the smallest sequence number in the molecule has aSthe configuration and the second center isR-configuration, stereobitrate will be presented as S-[R*,S*]. When using the "α" and "β", the situation of the most high-priority substituent on the asymmetric carbon atom in the ring system, containing the least number of rings, random is always in the "α" the position of the mean plane defined by the ring system. The situation of the most high-priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in the compound of formula (I)) relative to the position of the most high-priority substituent on the reference atom is designated as "α", if it is on the same side of the mean plane defined by the ring system, or "β", if it is on the other side of the mean plane defined by the ring system.

In the framework of this application, the compound of the present invention essentially includes all isotopic combinations of the chemical elements. Under this proposal, a chemical element, in particular when it is specified in connection with the soybean is inanam formula (I), includes all isotopes and isotopic mixture of this element occurring naturally or obtained synthetically, with a natural abundance of the isotope or isotope-enriched form. In particular, when specified hydrogen, it should be clear that it refers to1H,2H,3H and their mixtures; when specified carbon, it should be clear that it refers to11C,12C,13C,14C and their mixtures; when specified nitrogen, it should be clear that it refers to13N14N15N and their mixtures; when specified oxygen, it should be clear that it refers to14O,15O,16O,17O,18O and their mixtures; and when specified fluorine, it should be clear that it refers to18F,19F and their mixtures.

Therefore, the connection of the present invention essentially includes a connection to one or more isotopes of one or more elements and their mixtures, including radioactive compound, also called a compound labeled with a radioactive isotope, in which one or more non-radioactive atoms have been replaced by one of its radioactive isotopes. As regards the term "connection, radiolabelled," he means any compound of formula (I), its pharmaceutically acceptable acid or basic additive salt, N-oxide form, or its Quaternary AMM is nieuwy salt, which contains at least one radioactive atom. For example, the connection can be observed by positron or gammaglutamyl radioactive isotopes. For ways of linking with radioligand (analysis of membrane receptors)3H-atom, or125I-atom is an atom selected for replacement. To obtain images of the most widely used positionspussy radioactive isotopes (PET) is a11C,18F,15O and13N, all of which are obtained by using the accelerator and have half-lives of 20, 100, 2 and 10 minutes respectively. Because the half-lives of these isotopes are very short, their use is practically possible only in institutions that have the accelerator to receive them, and it is, therefore, limits their application. The most widely used of these isotopes are18F,99mTc201Tl and123I. dealing with such radioactive isotopes, the reception, selection and introduction into the molecule is well known to specialists in this field of technology.

In particular, the radioactive atom is selected from the group including hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, the radioactive atom is selected from the group including hydrogen, carbon and halogen.

In particular, a radioactive isotope SEL is given from the group include3H,11C,18F,122I123I125I131I75Br,76Br,77Br and82Br. Preferably, a radioactive isotope selected from the group including3H,11C and18F.

GETTING

The compound of the present invention, as a rule, can be obtained by consistent implementation stages, each of which is well known to specialists in this field of technology. In particular, pyridinone derivative can be obtained in accordance with one or more of the following methods to retrieve.

Scheme 1A

The reaction mix with the use of copper was carried out in the presence of a salt of copper, such as Cu(OAc)2in an aprotic solvent such as DCE, in the presence of amine or N-oxide amine, such as pyridine or NMO, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 15 minutes at 180°C under microwave irradiation. The reaction mix using palladium was carried out in an aprotic solvent such as toluene, in the presence of a palladium catalyst such as Pd(AcO)2and in the presence of tert-BuOK as a base and a ligand, such as BINAP, at a suitable temperature or PU is eating traditional heating, or using microwave irradiation, for a period of time sufficient to complete the reaction, usually 24 hours at 100°C for conventional heating.

When A-R3is an amide, the reaction mix is carried out in an aprotic solvent such as dioxane or DMF, in the presence of CuI, N,N-dimethylethylenediamine and K3PO4as grounds, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 20 minutes at 175°C under microwave irradiation.

When the amino group protected by a protective group, the reaction of removing the protective groups carry out well-known methods of synthesis. Converting the amino group into various derivative can be accomplished by using the synthesis methods, well known to specialists in this field.

In addition, pyridinone derivative can be obtained in accordance with the procedure described in scheme 1B.

Scheme 1B

The reaction mix with the use of copper is carried out in an aprotic solvent such as dioxane or DMF, in the presence of CuI, N,N-dimethylethylenediamine as ligand and inorganic bases, such as K3RHO4when the right temperature is for by traditional heating or using microwave irradiation, for a period of time sufficient to complete the reaction, usually 20 minutes at 175°C under microwave irradiation.

Orthotamine phenyl derivatives can be obtained in accordance with scheme 2.

Hal-radical is a halogen such as Br or I. XAndcan be a HE, Br or I. the Reaction mix with the use of copper is carried out in an aprotic solvent such as dioxane or DMF, in the presence of CuI, N,N-dimethylethylenediamine as ligand and inorganic bases, such as K3RHO4under suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 20 minutes at 175°C under microwave irradiation.

OH-activation can be done through triflate, in the presence of triftormetilfullerenov anhydride or 1,1,1-Cryptor-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide, in an aprotic solvent such as DCM or THF, at a temperature suitable for completion of the reaction. The reaction mix using palladium carried out in an aprotic solvent such as toluene or triptorelin, in the presence of a palladium catalyst such as Pd(AO) 2and in the presence of a base, such as tert-BuOK or CS2CO3and does not necessarily require the presence of a ligand such as BINAP or Xanthos, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 24 hours at 100°C for conventional heating.

Compounds of the present invention with substituents other than benzyloxy receive in accordance with the diagram 3A diagram 3B.

Scheme 3A

The reaction mix with the use of copper is carried out in the presence of a salt of copper, such as Cu(OAc)2in an aprotic solvent such as DCE, in the presence of amine or N-oxide amine, such as pyridine or NMO, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 15 minutes at 180°C under microwave irradiation.

Halogenoalkane carried out in the presence of oxybromide or phosphorus oxychloride, in an aprotic solvent such as DCE, at a temperature suitable for completion of the reaction, typically 150°C under microwave irradiation.

The alkylation is carried out in the presence of organic or inorganic based what I such as NaH or 1,8-diazabicyclo[5.4.0]undecen-7, in an aprotic solvent such as DME, CH3CN or DMF, at a temperature suitable to complete the reaction, usually 120oC for 10 minutes under microwave irradiation. The reaction mix using palladium carried out in an aprotic solvent such as toluene or dioxane, in the presence of a palladium catalyst such as Pd(AcO)2or Pd(PPh3)4and in the presence of a base, such as tert-BuOK, or inorganic aqueous base, such as Na2CO3and sometimes you want a ligand, such as BINAP, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 24 hours at 100°C for conventional heating.

Other compounds synthesized by following scheme 3B.

Scheme 3B

The reaction mix with the use of copper is carried out in the presence of a salt of copper, such as Cu(OAc)2in an aprotic solvent such as DCE, in the presence of amine or N-oxide amine, such as pyridine or NMO, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 15 minutes is ri 180°C under microwave irradiation.

The reduction is carried out in a protonic solvent, such as MeOH, and in the presence of a reducing agent such as sodium borohydride at room temperature and over a period of time sufficient to complete the reaction, usually for 30 minutes at room temperature.

The reaction type of reaction, Mitsunobu can be done in the presence of a phosphine, such as triphenylphosphine, azodicarboxylate derivative, such as diethylazodicarboxylate, in an aprotic solvent such as THF, at a suitable temperature and for a period of time sufficient to complete the reaction, for example, at 100°C for 5 minutes under microwave irradiation.

The reaction mix using palladium was carried out in an aprotic solvent such as toluene, in the presence of a palladium catalyst such as Pd(AcO)2and in the presence of tert-BuOK as a base and a ligand, such as BINAP, at a suitable temperature, either by conventional heating or under microwave irradiation, for a period of time sufficient to complete the reaction, usually 24 hours at 100°C for conventional heating.

PHARMACOLOGY

It has been unexpectedly found that the compound of the present invention, in particular compound of formula (I), its pharmaceutically acceptable acid - or jus the additive salt, its N-oxide form or Quaternary ammonium salts have affinity binding against MCH-receptor, in particular in relation to MCH-1 receptor, in particular as antagonists.

Taking into account the above activity, the compounds of the present invention are suitable for the prevention and/or treatment of diseases, where the antagonism MCH-receptor, in particular antagonism MCH-1 receptor is therapeutically useful. In particular, the compound of the present invention may be suitable for treatment and/or prevention of psychiatric disorders, including, but not limited to:

- a state of anxiety, including, but not limited to, agoraphobia, generalized anxiety; compulsive urge; obsessive-compulsive disorder; panic disorder; social phobia; and stress, such as post-traumatic stress disorder;

- a disorder associated with attention deficit/hyperactivity disorder;

- autism;

- dysthymia;

- eating disorder, including, but not limited to, anorexia; compulsive overeating and nervous bulimia;

- disorder of control of impulses;

- mental retardation, including, but not limited to, transient syndrome X;

- mood disorder, including, but not exhaust anievas this, anxiety; bipolar disorder, such as bipolar affective disorder, bipolar disorder (I), bipolar disorder (II), hypomanic state and manic syndrome; depression, such as severe depression and suicidal depression; seasonal mood disorders; suicide;

- premenstrual syndrome, including, but not limited to, restlessness;

- psychosis, including, but not limited to, aggressiveness; drug psychosis; schizoaffective disorder; schizophrenia, such as delusions, catatonic syndrome, catatonic schizophrenia, destructive schizophrenia, paranoid schizophrenia, residual schizophrenia and schizophreniform disorder; and dyssomnia, such as secondary dyssomnia;

- a sleep disorder, including, but not limited to, disorders of circadian rhythm; hypersomnia; insomnia; narcolepsy syndrome and sleep apnea;

- stuttering and

- attacks of rage.

In addition, the compound of the present invention can be used for the treatment of sexual disorders, neurological disorders, especially obesity and diabetes.

The invention, therefore, relates to the compound of General formula (I), its pharmaceutically acceptable acid or basic additive salts, its N-oxide form or Quaternary ammonium salt, for use in ka is este medicines.

The invention also relates to the use of compounds of the present invention for obtaining a medicinal product for the prevention and/or treatment of diseases, where the antagonism MCH-receptor, in particular antagonism MCH-1 receptor is therapeutically useful.

The invention also relates to the use of compounds of the present invention for obtaining a medicinal product for the prevention and/or treatment state anxiety, eating disorders, affective disorders such as bipolar disorder and depression, psychoses, such as schizophrenia, and sleep disorders. In addition, the compound of the present invention can be used for the treatment of sexual disorders and neurological disorders, particularly obesity and diabetes.

COMBINED TREATMENT

The compound of the present invention, in particular according to formula (I), it is possible to enter as additional treatment and/or prevention of the above diseases.

In particular, the compound of the present invention, in particular according to formula (I), it is possible to enter in combination with antidepressants, tranquilizers and/or neuroleptic drugs, which are currently available or are under development or caloriesmart available in the future, in particular to improve the efficiency and/or early action. Is appropriate when the connection of the present invention and one or more other funds may be present in the form of a combined preparation for simultaneous, separate or sequential use for the prevention and/or treatment of depression and/or a state of anxiety. Such a combination of drugs can, for example, be in the form of double packaging. Is also suitable when the connection of the present invention and one or more other tools you can enter as separate pharmaceutical compositions, either simultaneously or sequentially.

The invention therefore relates to pharmaceutical compositions of the present invention, characterized in that it further includes one or more other compounds selected from the group including antidepressants, tranquilizers and neuroleptics.

Suitable classes of antidepressant drugs include inhibitors of reuptake of norepinephrine, selective inhibitors of reuptake of serotonin (SSRI), monoamine oxidase inhibitors (MAOI), reverse inhibitors of monoamine oxidase (RIMA), inhibitors of reuptake of serotonin and norepinephrine (SNRI), noradrenergic and specific serotonergic antidepressants (NaSSA), antagonist factor release corticotropin (CRF), antagonists of α-adrenergic receptors and atypical antidepressants.

Suitable examples of inhibitors of reuptake of norepinephrine include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, reboxetine and their pharmaceutically acceptable salts.

Suitable examples of selective inhibitors of reuptake of serotonin include fluoxetine, fluvoxamine, paroxetine, sertraline, and their pharmaceutically acceptable salts.

Suitable examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranilcipromin, selegiline and their pharmaceutically acceptable salts.

Suitable examples of reverse monoamine oxidase inhibitors include moclobemide and its pharmaceutically acceptable salts.

Suitable examples of inhibitors of reuptake of serotonin and norepinephrine include venlafaxine and its pharmaceutically acceptable salts.

Suitable atypical antidepressants include bupropion, lithium, nefazodone, trazodone, viloxazine, sibutramine and their pharmaceutically acceptable salts.

Other suitable antidepressants include adinazolam, alaproclate, amineptine, the combination of amitriptyline/chlordiazepoxide, atipamezole, asamaseen, basinin, Buturlin, bifemelane, bendalin, biphenol, brofaromine, bupropion, sa is occason, cericlamine, cyanopropyl, cinoxate, citalopram, climara, clovoxamine, datapanel, deanol, deoxidation, dibenzepin, dothiepin, droxidopa, anatexis, estazolam, etoperidone, femoxetine, fengbin, Ptolemy, footrace, idazoxan, indalpine, indeloxazine, iprindole, lipoprotein, litoxetine, lofepramine, modificatin, metabromine, metralindol, mianserin, milnacipran, minupren, mirtazapine, Meireles, nebracetam, nefopam, nialamide, nomifensine, noruoxetine, retiredin, oxaprozin, pinazepam, pelingon, pizotyline, ritanserin, rolipram, sermorelin, setiptiline, sibutramine, sulbutiamine, sulpirid, danilochkin, totaline, toolbarin, tianeptine, diplocarpon, ciencin, tofisopam, toloxatone, tomoxetin, veralipride, Vikulin, zimelidine and somethin and their pharmaceutically acceptable salts, and St. John's wort herb or Hypericum perforatum or their extracts.

Suitable classes of anti-anxiety include benzodiazepines and agonists or antagonists of 5-HT1Areceptor, in particular a partial agonist at 5-HT1Aantagonists of the factor in the release of corticotropin (CRF), compounds having muscarinic cholinergic activity, and compounds acting on ion channels. In addition to benzodiazepines, other classes of anti-anxiety include dibenzodiazepine sedative-hypnotic drug environments is TBA, such as zolpidem; stabilizing mood medicines, such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol and vigabatrin; and barbiturates.

Suitable neuroleptic drugs chosen from the group comprising acetophenazine, in particular, maleato salt; alenamy, in particular, hydrobromide salt; Albertin; azaperone; batelaan, in particular, maleato salt; benperidol; benzindopyrine, in particular, cleaners containing hydrochloride salt; propoxy; bromperidol; butaclamol, in particular, cleaners containing hydrochloride salt; butaperazine; cartensen, in particular, maleato salt; carvacrol, in particular, cleaners containing hydrochloride salt; chlorpromazine; chlorprothixene; zinderen; contramid; Clamaran, in particular, the phosphate salt; clopenthixol; clupeoid; clappison, in particular, mesilate salt; chloroiron, in particular, cleaners containing hydrochloride salt; clotiapine; clohexane, in particular, maleato salt; clozapine; cyclogenesis, in particular, cleaners containing hydrochloride salt; droperidol; Etisalat, in particular, cleaners containing hydrochloride salt; benemid; Lucinda; flumezapine; fluphenazine, in particular, decanoate, enanthate and/or cleaners containing hydrochloride salt; flumeturon; fluspirilene; lutropin; Genotropin, in particular, cleaners containing hydrochloride salt; gallopamil; haloperidol; haloperidol; imidogen, in particular, cleaners containing hydrochloride salt; lebaron; loxapine; motaparthy,in particular, succinate salt; mesoridazine; mediabin; milanian; militarty; molindone, in particular, cleaners containing hydrochloride salt; narinol, in particular, cleaners containing hydrochloride salt; niflumic, in particular, cleaners containing hydrochloride salt; ocaperidone; olanzapine; oxepanone; penfluridol; pentaen, in particular, maleato salt; perphenazine; pimozide; pinoxaden, in particular, cleaners containing hydrochloride salt; pipamperone; piperacetazine; pipotiazin, in particular, palmitate salt; piquante, in particular, cleaners containing hydrochloride salt; prochlorperazine, in particular, edisylate salt; prochlorperazine, in particular, maleato salt; promisin in particular, cleaners containing hydrochloride salt; quetiapine; remoxipride; risperidone; rimcazole, in particular, cleaners containing hydrochloride salt; seberida, in particular, cleaners containing hydrochloride salt; sertindole; setoperone; spiperone; sulpiride; thioridazine; thiothixene; Chorazin; tiapride, in particular, cleaners containing hydrochloride salt; tiospirone, in particular, cleaners containing hydrochloride salt; trifluoperazine, in particular, cleaners containing hydrochloride salt; trifluperidol; triflupromazine; ziprasidone, in particular, cleaners containing hydrochloride salt; and mixtures thereof.

The compound of the present invention, in particular according to formula (I)can also be used in combination with other reducing lipid levels tool, thus leading to a so-called combination for reducing the level of lipid therapy for the treatment of obesity Specified additional lowering lipid levels tool can be a, for example, a well-known remedy traditionally used for the treatment of hyperlipidemia, such as, for example, resin, amplifying secretion of bile acids, derived fibrin acid or nicotinic acid as described above under “Background of the invention”. Suitable additional reduce the level of lipids tools also include other inhibitors of the biosynthesis of cholesterol and inhibitors of cholesterol absorption, in particular inhibitors of HMG-CoA reductase and inhibitors of HMG-CoA synthase, inhibitors of gene expression of HMG-CoA reductase inhibitors, CETP inhibitors, ACAT inhibitors, inhibitors stvalentines antagonists CB-1, inhibitors of cholesterol absorption, such as ezetimibe etc.

Any inhibitor of HMG-CoA reductase can be used as the second compound in the aspect of the present invention relating to combination therapy. The term "inhibitor of HMG-CoA reductase inhibitor", as used in this application, unless otherwise specified, refers to a compound that inhibits the biotransformation hydroxymethylglutaryl-coenzyme A to mevalonic acid under the catalytic action of the enzyme HMG-CoA reductase. Such inhibitors of HMG-CoA reductase" represents, for example, lovastatin, simvastatin, fluvastatin, pravastatin, mevastatin and atorvastatin.

Any inhibitor of HMG-CoA synthase can be used as a second connection is made aspect of the present invention, related to combination therapy. The term "inhibitor of HMG-CoA synthase", as used in this application, unless otherwise specified, refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A catalytic action of the enzyme HMG-CoA synthase.

Any inhibitor gene expression of HMG-CoA can be used as the second compound in the aspect of the present invention relating to combination therapy. Such means may be an inhibitor of transcription of HMG-CoA reductase inhibitors, which block the transcription of DNA, or inhibitors broadcast HMG-CoA reductase, which prevents the translation of mRNA that encodes a HMG-CoA reductase protein. Such inhibitors can affect the transcription or translation directly, or can biopreservatives in connection with the above properties, using one or more enzymes in the cascade of the biosynthesis of cholesterol, or can lead to accumulation of the metabolite having the above activities.

Any CETP inhibitor can be used as the second compound in the aspect of the present invention relating to combination therapy. The term "CETP inhibitor", as used in this application, unless otherwise specified, refers to the connection of the structure, which inhibits mediated protein-carrier cholesterolemia of ester (CETP) was different cholesterolemic esters and triglycerides from HDL to LDL and VLDL.

Any ACAT inhibitor can be used as the second compound in the aspect of the present invention relating to combination therapy. The term "the ACAT inhibitor", as used in this application, unless otherwise specified, refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoA:cholesterylester.

Any inhibitor stvalentines can be used as the second compound in the aspect of the present invention relating to combination therapy. The term "inhibitor scaledcontents", as used in this application, unless otherwise specified, refers to a compound that inhibits the condensation of two molecules of farnesylpyrophosphate with the formation of squalene in the catalytic action of the enzyme stvalentines.

The PHARMACEUTICAL COMPOSITION

The invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient a therapeutically effective amount of the compounds of the present invention, in particular compounds of formula (I), its formats whitesky acceptable acidic or basic additive salt, its N-oxide form, or its Quaternary ammonium salt.

The compound of the present invention, in particular compound of formula (I), its pharmaceutically acceptable acid or basic additive salt, N-oxide form or Quaternary ammonium salt, or any subset or combination can be formulated in various pharmaceutical forms intended for insertion. As appropriate compositions can be stated all compositions usually employed for systemic administration of drugs.

To obtain pharmaceutical compositions of the present invention an effective amount of a particular compound, optionally in the form of its salt additive, as an active ingredient together in a close mixture with a pharmaceutically acceptable carrier, such carrier may take a wide variety of forms depending on the form of preparation desired for administration. Such pharmaceutical compositions it is desirable to obtain a standard dosage form suitable, in particular, for oral, rectal, percutaneous injection, parenteral administration by injection or administration by inhalation. For example, to obtain compositions in oral dosage form can be any of the commonly used pharmaceutical environment, such as, for example the EP, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like, in the case of powders, pills, capsules and tablets. Because of the simplicity of their administration tablets and capsules represent the most advantageous standard dosage forms for oral administration, in this case, it is evident the use of solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least for the most part, although it may include other ingredients, for example, contributing to the dissolution. Can be obtained, for example, solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Suspension for injection can also be obtained, in this case, you can use the appropriate liquid carriers, suspendresume substances, etc. Also included are solid form preparations intended to convert, immediately before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally includes an agent that enhance the penetration and/or appropriate Simachev the substance abuser, optionally combined with suitable additives of any nature in small quantities, such additives should not have any significant adverse effect on the skin. These additives can contribute to the introduction on the skin and/or may be useful to obtain the desired compositions. Such compositions can be entered in various ways, for example in the form of transdermal patches, by applying the spot, in the form of ointment.

Especially advantageous to formulate the above pharmaceutical composition in a standard dosage form for ease of their introduction and uniform dosing. Standard dosage form, as used in this application, refers to physically discrete units suitable as standardized doses, with each unit contains a predetermined quantity of active ingredient calculated to provide the desired therapeutic effect, in Association with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated), capsules, pills, sachets of powder, pills, suppositories, solutions or suspensions for injection and the like, and such forms are divided into multiple parts. Since the compounds of the present invention are active and oral input antagonists of dopamine, pharmaceutical compositions comprising these compounds intended for oral administration, are particularly preferred.

As mentioned, the invention also relates to pharmaceutical compositions comprising a compound of the present invention and one or more other compounds selected from the group including antidepressants, tranquilizers, neuroleptics and means for reducing the level of lipids, and the use of such compositions for obtaining medicines.

The following examples are intended to illustrate but not to limit the scope of the present invention.

EXPERIMENTAL PART

In all sections of this application "THF" means tetrahydrofuran; "DMF" means N,N-dimethylformamide; "EtOAc" means ethyl acetate; "DCM" means dichloromethane; "DME" means 1,2-dimethoxyethane; "DCE" means 1,2-dichloroethane; "DIPE" means diisopropyl ether; "DMSO" means dimethyl sulfoxide; "DIPEA" means diisopropylethylamine; "DIAD" means diisopropylperoxydicarbonate; "TEMPO" means 2,2,6,6-tetramethylpiperidine-1-oxyl Free Radical; "BINAP means 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; "TFUK" means triperoxonane acid; "Xantphos" means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; "BOC" means tert-butyloxycarbonyl; "NMO" means N-methylmorpholin is-N-oxide.

Reactions carried out using microwave irradiation was carried out in onemodule reactor: Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currently Biotage) or Initiator™ Sixty (Biotage). Description both units can be found atwww.biotage.com. And in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.). Description of the machine can be found atwww.milestonesci.com.

A. the production of intermediate compounds

A1. Obtaining an intermediate compound I-1

To a solution of 4-benzyloxy-2(lH)-pyridone (1 g, 5.0 mmol) in DCE (20 ml) was added 4-brompheniramine acid (2 g, 12,0 mmol), Cu(OAc)2(1,82 g, 10.0 mmol), pyridine (1,51 ml, 20.0 mmol) and molecular sieves (4Å) (2 g). The reaction mixture was heated under microwave irradiation at 180°C for 15 minutes. The solid was filtered. The filtrate was treated with aqueous solution of NH4OH. The organic layer was separated, dried (Na2SO4) and the solvent evaporated. The obtained residue was purified using column chromatography in DCM 100 to DCM/EtOAc 4:1 to obtain an intermediate compound I-1 (230 mg, 13%).

A2. Obtaining an intermediate compound I-2

A mixture of 4-benzyloxy-2(1H)-pyridone (0.5 g, 0,0025 mol), 4-bromo-2-methoxyphenol (0,67 g, 0,0033 mol), CuI (0,48 g 0,0025 mol), N,N'-dimethylethylenediamine (of 0.53 ml, 0,0050 mol) and K3PO4(1.06 g, 0,0050 mol) in sm is si dioxane/DMF (4/1; 10 ml) was heated for 15 minutes at 180°C in a microwave reactor. Then heating was repeated again for 15 minutes in a microwave reactor. The solid was filtered and the filter was washed using DCM. To the filtrate was added a solution of NH4OH (32%). The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated. The residue was purified using flash column-chromatography. The desired fractions were collected and the solvent evaporated. The residue was besieged by using DIPE with obtaining an intermediate compound I-2 (31%).

A3. Obtaining an intermediate compound I-3

A mixture of intermediate compound I-2 (0,76 g, 0,0033 mol), 1,1,1-Cryptor-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1.18 g, 0,0033 mol) and K2CO3(to 1.38 g, 0.01 mol) in THF (20 ml) was heated in a microwave reactor at 120°C for 15 minutes. The solid was filtered and washed using DCM. The filtrate was evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM/EtOAc 100/0, 9/1 and 4/1). The desired fractions were collected and the solvent evaporated. Yield: 0.9 g of intermediate compound I-3 (60%).

Intermediate compound I-3 can also be obtained by adding at 0°C triftormetilfullerenov anhydride (1.1 EQ.) to a mixture of intermediate compound I-2, Et3N and DCM is as a solvent. In this case, the mixture is stirred for 2 hours at room temperature to complete the reaction.

A4. Obtaining an intermediate compound I-4

A mixture of compound I-1 (534 mg, 0,0015 mol) and POBr3(1,72 g 0,006 mol) in 1,2-DCE (7.5 ml) was stirred in a microwave reactor at 150°C for 20 minutes. Then added Na2CO3(saturated aqueous solution), DCM and MeOH. The reaction mixture was stirred until then, until the solution mixture became transparent. Then the organic layer was separated, dried (Na2SO4) and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/EtOAc; 9/1). Then the residue was processed using DIPE with getting 0.375 g of intermediate compound I-4 (76%) as a solid.

A5. Obtaining an intermediate compound I-5

To 60% solution of NaH (55 mg, 0,00136 mol) in DME (1.5 ml) dropwise at 0°C was added 4-tormentingly alcohol (0,149 ml, 0,00136 mol). The reaction mixture was stirred at room temperature for 15 minutes. Then was added compound I-4 (225 mg, 0,00068 mol) in DME (1.5 ml). The reaction mixture was stirred in a microwave reactor at 120°C for 10 minutes. Then added NH4Cl (10%) and DCM. The organic layer was separated, dried (Na2SO4) and the solvent of viparita is I. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/EtOAc 9/1 and 4/1) to obtain the rate of 0.193 g of intermediate compound I-5 (76%).

A6. Obtaining an intermediate compound I-6

A mixture of 2-hydroxy-4-pyridinecarboxamide (123 mg, 0.001 mol), 4-brompheniramine acid (400 mg, 0.002 mol), Cu(OAc)2(18 mg, 0.0001 mol), pyridine (162 ml, 0.002 mol), TEMPO (172 mg, 0,0011 mol) and molecular sieves in DCM (2 ml) was stirred at room temperature for 24 hours. Then the solids were filtered through a layer of celite and the filtrate was treated with the help of Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using column chromatography (eluent: DCM and DCM/EtOAc; 9/1) to obtain the 0,180 g of intermediate compound I-6 (65%).

A7. Obtaining an intermediate compound I-7

To a mixture of intermediate compound I-6 (180 mg, 0,00065 mol) in methanol (5 ml) at 0°C was added sodium borohydride (30 mg, 0,00078 mol). The reaction mixture was stirred at room temperature for 30 minutes. Then added NH4Cl (saturated aqueous solution). The mixture was extracted using DCM. The organic layer was separated, dried over Na2SO4and the solvent evaporated. Estato is besieged by using DIPE with getting 0,170 g of intermediate compound I-7 (93%).

A8. Obtaining an intermediate compound I-8

A mixture of compound I-7 (170 mg, 0,00061 mol), phenol (87 mg, 0,00092 mol), DIAD (181 ml, 0,00092 mol) and triphenylphosphine (241 mg, 0,00092 mol) in THF (2 ml) was stirred in a microwave reactor at 100°C for 10 minutes. The solvent is evaporated and the residue was purified using column chromatography (eluent: DCM and DCM/EtOAc 9/1). Then the residue was processed using DIPE with getting 0,151 g of intermediate compound I-8 (70%).

A9. Obtaining an intermediate compound I-9

A mixture of compound I-4 (150 mg, 0,00045 mol), TRANS-2-vanilinovoi acid (66 mg, 0,00045 mol) and Pd(PPh3)4(27 mg, 0,000023 mol) in deoxygenating dioxane (1 ml) and a saturated aqueous solution of Na2CO3(1 ml) was stirred in a microwave reactor at 150°C for 10 minutes. Then was added DCM and H2O. the Organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/EtOAc; 9/1 and 4/1) to obtain 0,040 g of intermediate compound I-9 (25%).

A10. Obtaining an intermediate compound I-10

A mixture of 2,5-dibromopyridine (474 mg, is 0.0002 mol), 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 500mg, 0,00019 mol), DIPEA (2 ml) in acetonitrile (1 ml) was heated at 175°C under microwave irradiation for 10 minutes. Then was added DCM and Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4was filtered and the filtrate was concentrated. The residue was purified using flash chromatography (eluent: DCM and DCM/EtOAc 4:1) to give 375 mg of intermediate compound I-10 (52%).

A11. Obtaining an intermediate compound I-11

A mixture of 4-benzyloxy-2(lH)-pyridone (50 mg, 0,0025 mol), 2-bromo-5-iodotoluene (1.13 g, 0,0038 mol), CuI (0,238 g 0,0015 mol), N,N-dimethylethylenediamine (0,266 ml 0,0025 mol) and K3PO4(1.06 g, of 0.005 mol) in a mixture of dioxane/DMF 9:1 (75 ml) was stirred at 180°C in a microwave reactor for 15 minutes. Then was added DCM. The solid was filtered through dicalite and the filtrate was washed using a 32% solution of NH4OH. The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using column chromatography (eluent: DCM). The desired product were collected and evaporated. The resulting product was besieged by using DIPE with getting 0,737 g of intermediate compound I-11 (80%).

B. obtain the final compounds

B1. The resulting compound I-5

To a mixture of PR the intermediate compound I-1 (0,000561 mol) in toluene (3 ml) in an atmosphere of N 2added 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 0,00078 mol), Pd(OAc)2(0,0000267 mol), BINAP (0,000042 mol) and at the end of thetBuONa (0,00168 mol). The mixture was heated at boiling under reflux in a sealed tube overnight. Then to the mixture was added H2O and was extracted using DCM. The organic layer was filtered, dried over Na2SO4and concentrated. The residue was purified using flash column-chromatography on silica gel (10 g cartridge; eluent: DCM and DCM/(CH3OH/NH3); from 10% to 30%) to obtain the 0,189 g BOC-protected compound (67%). This compound (0,00717 mol) was dissolved in TFOC (14 ml) and DCM (28.8 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated and the residue was neutralized with 50% NaOH solution while cooling in an ice bath. The organic phase was extracted using DCM, dried over Na2SO4and was evaporated. The residue was purified using chromatography on silica gel short column (eluent: DCM/CH3OH; a 9.5/0.5) and DCM/(CH3OH(NH3); 9.5/0.5 to 9/1) to obtain 1.08 g of compound 1-5 (49%).

B2. The resulting compounds 1-11

A mixture of intermediate compound I-1 (0,00084 mol), tert-butyl ester 1-oxo-2,7-diazaspiro[3,5]nonan-7-carboxylic sour is s (024 g, 0,0010 mol), CuI (0.16 g, 0,00084 mol), N,N-dimethylethylenediamine (0,0016 mol) and K3PO4(0.35 g, 0,0016 mol) in a mixture of dioxane/DMF 9:1 (75 ml) was stirred at 175°C in a microwave reactor for 20 minutes. Then was added DCM. The solid was filtered through dicalite and the filtrate is washed with the help of NH4Cl (saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated to obtain 0,433 g BOC-protected compound. This crude product (0,000969 mol) was dissolved in TFOC (2 ml) and DCM (4 ml). The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction mixture was neutralized with the help of Na2CO3(saturated aqueous solution) in terms of cooling in an ice bath. The organic phase was extracted using DCM, dried over Na2SO4and was evaporated. The residue was purified using chromatography on a short column of silica gel (5 g) and washed with ethyl ether to obtain 0,270 g of compound 1-11 (67%).

B3. The final connection 2-1

A mixture of intermediate compound I-11 (185 mg, of 0.0005 mol), 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 171 mg, 0,00065 mol), Pd(OAc)2(11 mg, 0,00005 mol), BINAP (23 mg, 0,0375 mmol), andtBuONa (144 mg, 0,0015 mol) in toluene (25 ml) was stirred in an atmosphere of N 2and heated at 100°C for 24 hours. Added excessive amounts of Pd(OAc)2and BINAP by heating the reaction mixture for 24 hours. Then was added DCM. The solids were filtered off through celite and the filtrate was evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/EtOAc; 9/1 and DCM/acetone 9/1 and 4/1) to obtain 0,175 g BOC-protected compound. This compound was dissolved in TFOC (1 ml) and DCM (2 ml) and the reaction mixture was stirred at room temperature for 2 hours. Then added Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM/MeOH 95/5 and DCM/(CH3OH/NH3); 95/5). The residue was treated with ethyl ether to obtain 0,089 g of compound 2-1 (62%).

B4. The final connection 2-2

A mixture of intermediate compound I-3 (228 mg, of 0.0005 mol), 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 171 mg, 0,00065 mol), Pd(OAc)2(11 mg, 0,00005 mol), Xantphos (58 mg, 0.0001 mol) and Cs2CO3(407 mg, 0,00125 mol) in triptoreline (3.0 ml) was stirred in an atmosphere of N2and heated at 100°C for 24 hours. Then was added DCM. Solids of otherthrow the Wali through celite and the filtrate evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/EtOAc; 9/1 and DCM/acetone 9/1 and 4/1) to obtain 0,130 g BOC-protected compound. This compound was dissolved in TFOC (1 ml) and DCM (2 ml) and the reaction mixture was stirred at room temperature for 2 hours. Then added Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM(MeOH) 95/5 and DCM/(CH3OH/NH3); 95/5). The residue was treated with ethyl ether to obtain 0,0366 g of compound 2-2 (35%).

B5. The final connection 3-2

A mixture of intermediate compound I-5 (0,190 g, 0,00051 mol), 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 0,177 g, 0,00066 mol), Pd(OAc)2(58 mg, 0,000026 mol), BINAP (24 mg, 0,000038 mol) andtBuONa (147 mg, 0,00153 mol) in deoxygenating toluene (4 ml) was heated overnight at 100°C. Then was added DCM. The solid was filtered and the filtrate was evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/acetone; 9/1 and 4/1) to obtain 0,202 g BOC-protected compound. This compound (0,202 g, 0,00039 mol) was dissolved in TFOC (2 ml) and DCM (4 ml) and stirred at room themes is the temperature value within 2 hours. Then added Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM(MeOH) 95/5 and DCM/(CH3OH/NH3); 9/1). Then the residue was processed using DIPE with getting 0,098 g of compound 3-2 (60%).

B6. The final connection 3-1

A mixture of intermediate compound I-9 (0,040 g, 0,00011 mol), 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 0.037 g, 0,00014 mol), Pd(OAc)2(12 mg, 0,0000055 mol), BINAP (5 mg, 0,0000083 mol) andtBuONa (0,00033 mol) in toluene (1 ml) was stirred in an atmosphere of N2and heated overnight at 100°C. Then was added DCM. The solid was filtered through celite and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (eluent: DCM and DCM/acetone 9/1) to obtain the 0,050 g BOC-protected amine (91%). This product was dissolved in a mixture of TFOC (0.5 ml) and DCM (1 ml), stirring the reaction mixture at room temperature for 2 hours. Then added Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using flash column-chromatography on silica gel (Elya is NT: DCM(CH 3OH) 95/5 and DCM/(CH3OH/NH3); 1/1). The residue was processed using DIPE with the receipt of 0.017 g of compound 3-1 (43%).

B7. The final connection 3-3

A mixture of intermediate compound I-8 (304 mg, 0,00085 mol), 1,1-dimethylethylene ether 2,7-diazaspiro[3,5]nonan-7-carboxylic acid (CAS: 896464-16-7, 289 mg, 0,0011 mol), Pd(OAc)2(10 mg, 0,000043 mol), BINAP (40 mg, 0,000064 mol) andtBuONa (245 mg, 0,00255 mol) in toluene (5 ml) was heated at 100°C for 24 hours. Then was added DCM. The solid was filtered through a layer of celite. The filtrate is evaporated, dried over MgSO4and the residue was purified using column chromatography (eluent: DCM and DCM/acetone; 9/1) to obtain the 0,430 g BOC-protected amine. This compound was dissolved in TFOC (2 ml) and DCM (4 ml) and the mixture was shaken at room temperature for 2 hours. Then added Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was treated with ethyl ether to obtain 0,278 g of compound 3-3 (81%).

B8. The final connection 4-1

A mixture of 4-benzyloxy-2(1H)-pyridone (187 mg, of 0.93 mmol), intermediate I-10 (375 mg, of 0.93 mmol), copper iodide (177 mg, of 0.93 mmol), N,N-dimethylethylenediamine (0,198 ml of 1.86 mmol), potassium phosphate (395 mg, of 1.86 mmol) in a mixture of di is Xan:DMF 4:1 (4 ml) was heated at 180°C for 15 minutes under microwave irradiation. Then was added DCM. The solid was filtered through a layer of celite. The filtrate was treated with a solution of NH4OH (30%). The organic layer was separated, dried (Na2SO4) and the solvent evaporated to obtain 600 mg of the BOC-protected compound. This compound was dissolved in TFOC (3 ml) and DCM (6 ml) and the mixture was shaken at room temperature for 1 hour. Then added Na2CO3(saturated aqueous solution). The organic layer was separated, dried over Na2SO4and the solvent evaporated. The residue was purified using column chromatography (eluent: DCM/CH3OH 98/5 and DCM/CH3OH(NH3) 9/1). The desired fractions were collected and the solvent evaporated. The residue was treated with ethyl ether to obtain 0,238 g of compound 4-1 (64%).

B9. The resulting compounds 1-9

A mixture of compound I-5 (0.5 g, 1.25 mmol) and 1-ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (is 0.260 ml, 0,0013 mol) in MeOH (methanol; 6 ml) and acetic acid (0.2 ml) was stirred at room temperature for 30 minutes. Then add cyanoborohydride sodium (0,113 g, 0,0018 mol). The reaction mixture was heated at 80°C for 24 hours. Then added NaHCO3(saturated aqueous solution) and NH4OH (30%). The mixture was extracted using DCM. The separated organic layer was dried (Na2SO4) and the solvent viparis the Lee. The residue was purified using flash column-chromatography on silica gel (eluent: DCM/MeOH 95/5 and DCM/(MeOH/NH3) 95/5. The desired fractions were collected and the solvent evaporated. The residue was treated with simple ethyl ether to obtain 0,470 g of compound 1-9 (86%).

B10. The resulting compounds 2-4

Reductive methylation was carried out overnight at 50°C in a mixture of compound 2-3 (2.1 g, of 0.005 mol) and paraform (0.5 g) in methanol (100 ml), with Pt/C 5% (0.5 g) as catalyst in the presence of a solution of thiophene (0.5 ml; 4% in DIPE). After absorption of H2(1 equivalent), the catalyst was filtered and the filtrate was evaporated. The residue was led out of CH3CN. Yield: 1.6 g of compound 2-4 (71%).

B11. The resulting compounds 1-15

A mixture of intermediate compound I-1 (7,80 g of 0.022 mol), 1,1-dimethylethylene ether 2,8-diazaspiro[4,5]decane-8-carboxylic acid (6 g, of 0.025 mol), Pd(OAc)2(0.25 g, 0,0011 mol), BINAP (1.12 g, 0,0018 mol) andtBuONa (2.4 g, 0,025 mol) was stirred overnight in an atmosphere of N2at an oil bath at 100°C. Then the reaction mixture was cooled to room temperature and filtered on Dicalite. The filter was washed with toluene (200 ml). The filtrate was evaporated and obtained 6 g of the crude residue. The filter was washed with hot DCM (300 ml). RA is the solvent evaporated to obtain 12 g of a white solid. The combined residues were led out of CH3CN. Got to 8.3 g of BOC-protected compound (73%). This BOC-protected compound (8,3 g to 0.016 mol) is suspended in 2-propanol (200 ml). Then was added a mixture of HCl/2-propanol (50 ml, 6 N) and received the solution. This solution was heated, and there was a formation of sludge. The mixture was heated at the boil under reflux for 3 hours, after which it was cooled in an ice bath. The product was filtered. Yield: 8.0 g of the compound 1-15 (99%; 2HCl.0,8 H2O).

B12. The resulting compounds 1-14

The first connection 1-15 were converted into the free base (which corresponds to the compound 1-13) by methods well known to specialists in this field. Then carried out the reaction of reductive methylation over night at 50°C in a mixture of compounds 1-13 (1.5 g, 0,0036 mol) and paraform (1 g) in methanol (150 ml), using Pt/C 5% (0.5 g) as catalyst in the presence of a solution of thiophene (1.0 ml; 4% in DIPE). After absorption of H2(1 EQ.) the catalyst was filtered and the filtrate was evaporated. The residue was led out of CH3CN. The desired compound was filtered. Yield: 1.2 g of the compound 1-14 (78%).

Tables 1-4 present the compounds of formula (I), which were obtained in accordance with one of the above examples.

Table 1

Table 2

Table 3

Table 4

The ANALYTICAL PART

IHMS the Basic procedure A

HPLC analysis was performed using a HP 1100 from the company Agilent Technologies, which included a pump (four - or two-component) with degasser, an automatic device for input samples, and a column oven, a diode detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to lead in MS spectrometer. The configuration of the MS detector included source ionization electrospray. Nitrogen was used as the spray gas. The source temperature was maintained at 140°C. data acquisition was performed using the MassLynx program-Openlynx.

IHMS the Basic procedure B

HPLC analysis was performed using the systems Alliance HT 2790 (Waters), which includes four pump with degasser, an automatic device for input samples, and a column oven (set at 40°C, unless otherwise noted), a diode detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to lead in MS spectrometer. The configuration of the MS detector included source ionization electrospray. Mass spectra were obtained by scanning from 100 to 1000 within 1 time use rest of 0.1 C. The voltage on the capillary needle was 3 kV and the source temperature was maintained at 140°C. Nitrogen was used as the spray gas. Data collection was performed using data systems Waters-Micromass MassLynx-Openlynx.

IHMS the Basic procedure C

LC analysis was performed using the system Acquity UPLC (Waters), including a two-part pump, a device for introducing samples, column heater (set at 55°C), a diode detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to lead in MS spectrometer. The configuration of the MS detector included source ionization electrospray. Mass spectra were obtained by scanning from 100 to 1000 for 0,18 with using resting time of 0.02 C. Voltage on the capillary needle was 3.5 kV and the source temperature was maintained at 140°C. Nitrogen was used as the spray gas. The data were collected by using the system data.

IHMS - Procedure 1

In addition to primary procedure A: Reversed phase HPLC was carried out on a column of ACE-C18 (3.0 mm, and 4.6×30 mm) from Advanced Chromatography Technologies, a flow rate of 1.5 ml/min, at 40°C. Used the following gradient conditions: 80% A (0.5 g/l solution of ammonium acetate), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to 100% B for 7 minutes and balanced to start at the conditions to 7.5 minutes until 9.0 minutes. The volume of injected sample 5 ál. Mass high resolution spectra (time of flight, TOF) received only positive mode ionization by scanning from 100 to 750 in 0.5 s using time rest of 0.1 C. the Voltage on the capillary needle was 2.5 kV for positive mode ionization and the voltage at the cone was the 20th Century Leucine-Enkephalin used as a standard substance for calibration of a fixed mass.

IHMS - Procedure 2

In addition to primary procedure B: Reversed phase HPLC was carried out on a column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/minute. Used three mobile phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) to implement the terms of the gradient of 100% A to 1% A, 49% B and 50% C for 6.5 minutes, up to 1% A 99% B in 1 minute and withstand these conditions for 1 minute and again balanced 100% A for 1.5 minutes. Used the volume of injected sample is 10 ál. The voltage at the cone was 10 for positive mode ionization and 20 for negative ionization mode.

IHMS - Procedure 3

In addition to primary procedure B: Column heater was set at 60°C. Reverse-phase HPLC was performed on a column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min. Use the three mobile phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; the mobile phase B: acetonitrile; mobile phase C: methanol) to implement the terms of the gradient of 100% A to 50% B and 50% C for 6.5 minutes, to 100% B for 0.5 minutes and withstand these conditions for 1 minute and again balanced 100% A for 1.5 minutes. Used the volume of injected sample is 10 ál. The voltage at the cone was 10 for positive mode ionization and 20 for negative ionization mode.

IHMS - Procedure 4

In addition to primary procedure C: Reversed-phase SWASH (stocks large quantity of liquid chromatography) was performed on C18 column (1.7 mm, and 2.1×50 mm; Waters Acquity) with an associated hybrid bridge etisalats/silica gel(BEH) with a flow rate of 0.8 ml/min. Used two mobile phases (mobile phase A: 0.1% of formic acid in H2O/methanol 95/5; mobile phase B: methanol) to implement the terms of the gradient of 95% A and 5% B to 5% A and 95% B for 1.3 minutes and keeping within 0.2 minutes. Used the volume of injected sample of 0.5 µl. The voltage at the cone was 10 for positive mode ionization and 20 for negative ionization mode.

The melting point

For some compounds was determined by the melting point (TPL) using DSC823e (Mettler-Toledo). The melting point was measured using a temperature gradient of 30°C/min. The maximum temperature was 400°C. Values represent the Wallpaper and maximum values.

For some compounds was determined by the melting point (TPL) using DSC822e (Mettler-Toledo). The melting point was measured using a temperature gradient of 10°C/min. The final temperature was set at 300°C. Values represent maximum values.

For some compounds was determined by the melting point in open capillary tubes in the apparatus Mettler FP62. The melting point was measured using a temperature gradient of 10°C/min. The maximum temperature was 300°C. the melting Point was read from the digital display.

Data were obtained from experimental errors, which are usually associated with this analytical method.

C. Pharmacological examples

The interaction of the compounds of formula (I) with MCH-1 receptor was assessed in in vitro assays temporary mobilization (Ca2+in the fluorometric format tablet reader (FLIPR) (Sullivan et al. 1999, Methods Mol Biol 114:125-133). In General, the natural agonist (MCH) were incubated with cells expressing MCH-1 receptor that was dependent on the concentration of the temporary mobilization of Ca2+from internal reserves. The interaction of test compounds with the receptor was evaluated in competitive analyses. Various concentrations of the test compounds were added to incubation mixtures containing expressing receptor cells and submaximal concentrations of MCH. The test connection is proportional to its antagonistic activity and its concentration inhibited MCH-induced mobilization of Ca2+.

Example C1: Analysis of binding to MCH-1

Cell culture and membrane preparation. Cells Chinese hamster ovary (CHO)stably expressing MCH-1 receptor human, were grown in 1:1 mixture of the modified Dulbecco eagle medium (DMEM) and environment HAM F12 containing Glutamax™ (Invitrogen), supplemented with 10% thermoactivation fetal bovine serum and 400 μg/ml of geneticin.

Analysis of the mobilization of Ca2+for the MCH-1 receptor. Twenty-four hours before the experiment expressing MCH-1 receptor CHO cells were sown in 20 ál (5000 cells per well) in 384-well microtiter tablets with dark walls and a transparent bottom (Costar). On the day of the experiment were added 20 μl per well containing calcium test kit containing 10 mm probenecid (Molecular Devices). Cells were loaded for 90 minutes at 37°C and 5% CO2in the incubator for cell culture. After the load was added 20 μl of serial dilutions of the test compound and the cells further incubated for 20 minutes at room temperature in the dark. After 20 minutes was added 20 μl of a submaximal concentration of MCH and record the changes of intracellular calcium directly in the apparatus FLIR III (Molecular devices).

Data analysis and results. Data analysis in the presence of the compounds was calculated as a percentage of the total Ca2+responses measured in the absence of the test compound. Curves of inhibition, representing the percentage of the total Ca2+responses against log concentrations of the test compounds were received automatically and sigmoidal inhibition curves were obtained using the method of nonlinear regression. Values pIC50for test compounds were received on the basis of individual curves.

All the compounds of formula (I) provided the inhibition of more than 50% (pIC50) at test concentrations ranging from 10-6M to 10-9M dependent on concentration.

For a selected number of compounds covering a greater part of the various variants of the embodiments of formula (I),in vitrostudies are presented in table 6.

Table 6
Data pharmacological studies for compounds
according to the present invention
Connection # MCH-1 pIC50
1-127,6
1-6 7,6
2-17,6
2-37,6
3-47,6
1-147,5
1-47,5
1-57,5
2-47,5
2-27,4
3-27,4
1-27,3
1-117,2
1-77,2
1-87,2
3-17,2
4-17,2
1-17,1
1-107,1
1-97,0
1-36,9
3-36,3

Example C.2: is the definition of reducing hERG

The potential effects of the compounds of the present invention on the hERG-mediated membrane K+the current was investigated at the level of individual cells using the whole cell configuration of the patch-clamp method with one electrode (Hamill, O.P., Marty, A., Neher, E., Sakmann, B. &Sigworth, F.J. (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflϋgers Archiv. 391: 85-100).

HERG (ether-à-go-go-related human gene) encodes a potassium channel with biophysical properties similar to those of fast-activated K+a current of the detained straightening (IKrin cardiac myocytes (Snyders, D.J. & Director, A. (1996). High affinity open channel block by dofetilide of HERG expressed in a human cell line. Molecular Pharmacology 49, 949-955 and Smith, P.L., Baukrowitz, T. & Yllen, G. (1996). The adopts inward rectification mechanism of the HERG cardiac potassium channel. Nature 379, 833-836). This IKrcurrent contributes to the K+current responsible for the repolarization phase of the potential cardiac action. Blocking this current may prolong the duration of action potential and cause long QT syndrome. The development of QT prolongation may lead to bouts of ventricular arrhythmias, such as Pointes de Pointes, which can lead to sudden death.

Automatic patch-clamp analysis using the PatchXpress 7000A (Axon Instruments) was used to assess the effect of the test substances on HERG residual current.

Cells: Used a cell line kidney Embry is per person (HEK293) with stable transfection of HERG (Mohammad, S., Zhou, Z., Gong, Q. & January, C.T. (1997). Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. American Journal of discrimination 273, H2534-H2538 and Zhou, Z., Gong, Q., Ye, B., Fan, Z., Makielski, J.C., Robertson, G.A. & January, C.T. (1998). Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophysical Journal 74, 230-241). Cells were constantly in culture. Before using the received cell suspension and immediately before the experiment the cells were centrifuged at 1000 rpm./min for 1 minute, the supernatant was decanted and the cells are again suspended in 150 μl of solution baths 1.5-ml Eppendorf tube.

Solutions: The solution in the bath contained 137 mm NaCl, 4 mm KCl, 10 mm glucose, 10 mm HEPES, 1.8 mm CaCl2and 1 mm MgCl2(a pH of 7.4 using NaOH). Vnutrimatocny the solution contained 130 mm KCl, 5 mm EGTA, 10 mm HEPES, 5 mm MgATP, and 1 mm MgCl2(pH to 7.2 using KOH). Test compounds were dissolved in DMSO to obtain the original solution from the 10-2M to 3×10-1M (final concentration of DMSO: 0,3, 0.1 or 0.03 percent). Control (= solution baths + DMSO) and test solution (= solution baths + DMSO + test compound) consisted of 0.3% or 0.1% DMSO.

The registration system: PatchXpress poured (primiraly) solution bath and vnutrimatocny solution. 16-hole chip for filling (Sealchip 16, Aviva Biosciences Corp.) was introduced into the system and primiraly to obtain a suspension of cells in solution in the bath. Tube Append the FA, filled with cells were placed in a certain position and started the procedure with the grinding and dispersion of cells in each recording chamber (pit) chip. System PatchXpress followed the General principles of the conventional patch-clamp analysis configuration “whole cell”.

Measurement: HERG current was determined as the maximum residual current -50 mV after 4,8-with depolarization to +20 mV, since the source potential of -80 mV. Each value represents the average current of 4 consecutive voltage pulses. To determine the duration of blocking the residual current was compared with pre-treatment by the media. The effect of test compounds on HERG current was measured after 5 minutes after making medicines. If you watched more than 5% reduction in HERG current, the test substance was considered to be (partially) blocking HERG current.

Control experiments: Simultaneously performed control experiments using media in a similar situation. Astemizole was used as control compounds known as inhibiting HERG - mediated current at nanomolar concentrations.

Table 7
Comparison of reduction in hERG
ConnectionStructureReduction of hERG
(%) at 3 μm
The connection of the prior art (Banyu 2005/085200)38,9%
The connection of the prior art (Banyu 2005/085200)42,6%
Connection 1-7-1,8%
Connection 1-120,7%
Connection 2-115,6%

D. Examples of compositions

"Active ingredient" (A.I.)as used in all the examples, refers to the final compound of formula (i), its pharmaceutically acceptable acid or basic additive salt, its stereochemical isomeric forms, its N-oxide form, its Quaternary ammonium salt and its prodrug.

Example D.1: drops for oral administration

500 g of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l for which etilenglikola at 60-80°C. After cooling to 30-40°C was added 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then was added a solution of 1750 g of sodium saccharin in 2.5 liters of distilled water and with stirring was added 2.5 l of cocoa flavor and polyethylene glycol (as required) up to a volume of 50 l, to obtain the solution drops for oral administration, containing 10 mg/ml of A.I. the resulting solution was filled in suitable containers.

Example D.2: solution for oral administration

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate was dissolved in 4 l of boiling distilled water. In 3 l of this solution were dissolved first 10 g of 2,3-dihydroxybutanedioate acid and then 20 g of the A.I. the latter the resulting solution was combined with the remaining part of the first resulting solution was added to 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of sodium saccharin were dissolved in 0.5 l of water was added 2 ml of raspberry essences and 2 ml essences gooseberry. This last obtained solution was combined with the previous solution was added water (as required) up to a volume of 20 l with obtaining a solution for oral administration, comprising 5 mg of the active ingredient on a teaspoon (5 ml). The resulting solution was filled in suitable containers.

Example D.3: tablets film coated

Obtain core tablets

A mixture of 100 g of the A.I., 570 g is actoz and 200 g starch are thoroughly mixed, and then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture was sieved through a sieve, dried and again sieved through a sieve. Then was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All this was thoroughly mixed and extruded into pellets to obtain 10,000 tablets each containing 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose in 150 ml of DCM. Then added 75 ml of DCM and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was melted and dissolved in 75 ml of DCM. This last obtained solution was added to the first resulting solution was then added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye and everything is homogenized. Core tablets were coated thus obtained mixture in the apparatus for applying the coating.

Example D.4: solution for injection

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate was dissolved in about 0.5 l of boiling water for injection. After cooling to about 50°C was added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of the A.I. the Solution was cooled to room temperature and added to water for injection (as necessary) to 1 liter with obtaining a solution comprising 4 mg/ml of A.I. the Solution sterilized is whether by filtration and filled them sterile container.

1. The compound of formula (I)

its pharmaceutically acceptable acid or basic additive salt,
where a represents a radical of the formula (II)

where k, l, m, n, each independently from each other represent an integer of 0, 1, 2, 3, or 4, provided that (k+l) and (m+n) is 2, 3, 4 or 5; where one of the-CH2fragments can be replaced by an atom About; and where each of the-CH2fragments can be replaced by oxopropoxy;
X represents CH or N;
R3selected from the group comprising hydrogen, C1-5alkyl and C3-6cycloalkyl;
R4, R5each independently of one another, selected from the group
comprising hydrogen, halogen, oxo, C1-3alkyl and C1-3alkyloxy;
p is an integer of zero, 1, 2 or 3;
q is an integer of zero, 1, 2 or 3;
Y1, Y3each independently from each other selected from the group including a simple link and About;
Y2represents a saturated or unsaturated With1-6a hydrocarbon radical with a straight chain;
In selected from the group comprising phenyl, optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from halogen; and where r is an integer of zero, 1 or 2;
alkyl performance, which provides a saturated hydrocarbon radical with a straight or branched chain, contains the specified number of carbon atoms; where the specified radicals optionally may be substituted on one or more carbon atoms by one or more radicals selected from the group comprising halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl; and
halogen represents fluorine, chlorine, bromine or iodine.

2. The compound according to claim 1, wherein k, l, m, n, each independently from each other represent an integer equal to 1, 2 or 3, provided that (k+l) and (m+n) is 2, 3 or 4.

3. The compound according to claim 1, wherein a is selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (C-2)

4. The compound according to claim 1, characterized in that a represents a radical of the formula (SS-2)

5. The compound according to claim 1, characterized in that a represents a radical of the formula (AA-1) or (bb-1).

6. The compound according to claim 1, wherein each of R4and R5independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy.

7. The compound according to claim 1, wherein p is zero or 1.

8. The compound according to claim 1, characterized in that q R is UPE zero.

9. The compound according to claim 1, characterized in that Y2selected from the group including
-CH2-, -CH2CH2- and-CH=CH-.

10. The compound according to claim 1, characterized In that represents phenyl.

11. The compound according to claim 1, characterized in that the fragment B-Y1-Y2-Y3selected from the radicals (a1-2), (a1-3) and (a1-5), optionally substituted by r the number of the substituents R6, each of which is independently from each other selected from the group comprising halogen; and where r is an integer equal to 1 or 2;

12. The compound according to claim 1, its pharmaceutically acceptable acid or basic additive salt, where
k, l, m, n, each independently from each other represent an integer equal to 1, 2 or 3, provided that (k+l) and (m+n) is 2, 3 or 4; where one of the-CH2fragments can be replaced by an atom About; and where each of the-CH2fragments can be replaced by oxopropoxy;
X represents CH or N;
R3selected from the group comprising hydrogen, C3-6cycloalkyl and C1-5alkyl;
R4, R5each independently of one another, selected from the group
comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy;
p is an integer of zero or 1;
q is an integer, aunoe zero;
Y1, Y3each independently from each other selected from the group including a simple link or;
Y2represents a saturated or unsaturated With1-6a hydrocarbon radical straight or branched chain; and
Represents a phenyl, optionally substituted by one
halogen substituent R6.

13. The compound according to claim 1, its pharmaceutically acceptable acid or basic additive salt, where
And selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (C-2),


X represents CH or N;
R3selected from the group comprising hydrogen, C3-6cycloalkyl and C1-5alkyl;
R4, R5each independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy;
p is an integer of zero or 1;
q is an integer, equal to zero;
fragment B-Y1-Y2-Y3selected from the radicals (a1-2), (a1-3) and (a1-5), optionally substituted by r the number of the substituents R6

R6represents a halogen Deputy; and where r is an integer equal to 1 or 2.

14. The compound according to claim 1, its pharmaceutically acceptable acid or basic additive salt, in which
And selected from the group comprising (a-1), (b-1), (b-3), (b-5) and (C-2),


X represents CH or N;
R3selected from the group comprising hydrogen, C3-5cycloalkyl and C1-3alkyl;
R4, R5each independently from each other selected from the group comprising hydrogen, halogen, C1-3alkyl and C1-3alkyloxy;
p is an integer of zero or 1;
q is an integer, equal to zero;
Y1, Y3each independently from each other selected from the group including a simple link or;
Y2represents a saturated or unsaturated With1-6a hydrocarbon radical straight or branched chain; and
Represents a phenyl, optionally substituted with one halogen substituent R6.

15. The compound according to claim 1, its pharmaceutically acceptable acid or basic additive salt, where
And selected from the group comprising (a-1) or (b-1);

X represents CH;
R3represents methyl;
R4, R5each independently on the UGA, selected from the group comprising hydrogen or halogen;
p is an integer of zero or 1;
q is an integer, equal to zero;
Y1represents a simple bond;
Y3represents About;
Y2represents CH2and
Represents a phenyl.

16. The compound according to any one of claims 1 to 15 for use as a drug for prevention and/or treatment of a disease where antagonism of the sit-1-receptor is therapeutically useful.

17. Pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 15 for obtaining a medicinal product for the prevention and/or treatment of psychiatric disorders, including, but not limited to, anxiety, an eating disorder, and affective disorders such as bipolar disorder and depression, psychoses, such as schizophrenia, and sleep disorders; obesity; diabetes; sexual disorders and neurological disorders.

18. A method of obtaining a pharmaceutical composition according to 17, wherein the pharmaceutically acceptable carrier is thoroughly mixed with a therapeutically effective amount of a compound according to any the mu one of claims 1 to 15.

19. The use of compounds according to any one of claims 1 to 15 or a pharmaceutical composition according to 17, to obtain drugs for the prevention and/or treatment of psychiatric disorders, including, but not limited to, anxiety, an eating disorder, and affective disorders such as bipolar disorder and depression, psychoses, such as schizophrenia, and sleep disorders; obesity; diabetes; sexual disorders and neurological disorders.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to indole-3-yl-carbonyl-spiro-piperidine derivatives which have an effect of Vla-receptor antagonists and are presented by Formula I: where a tail spiropiperidine group A and residual R1, R2 and R3 are such as specified in the patent claim.

EFFECT: higher efficiency of applying the compounds in drugs effective in dysmenorrhea, hypertension, chronic heart failure, inadequate vasopressin secretion, hepatic cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxious and depressive disorders.

22 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

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

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

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel derivatives of spiro{indeno[1,2-6]quinoline-6,3'-pyrroles} of formula where R=CH2Ph, Ph; X=H, Me, OMe. The invention also relates to a method for synthesis of the said compounds.

EFFECT: novel compounds, having analgesic activity, which can be used for synthesis of novel heterocyclic compounds, are obtained.

4 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula in which R1 denotes a) adamantyl, hydroxyadamantyl or trifluoromethylphenyl; R2 denotes hydrogen, methyl, ethyl or cyclopropyl; one of R3 and R4 denotes alkyl, cycloalkyl, haloalkyl or is absent, and the other denotes a) hydrogen, alkyl, pyridinyl, cycloalkyl, cycloalkylalkyl or haloalkyl; b) phenyl or phenyl substituted with one to three substitutes independently selected from fluorine, chlorine, bromine, haloalkyl and alkoxy group; c) phenylalkyl, where the phenylalkyl is optionally substituted with one to three halogens; e) naphthyl or tetrahydronaphthyl; f) phenylalkoxyalkyl; g) hydroxyalkyl; or h) pyridinyloxyalkyl or pyridinyloxyalkyl substituted with an cyano group; or R3 and R4 together with a carbon atom with which they are bonded form a cycloalkane or piperdine, where the cycloalkyl and piperidine are optionally substituted with one to three substitutes independently selected from aryl and arylalkyl; one of R5 and R6 denotes hydrogen, isopropyl, isobutyl or haloalkyl, and the other denotes hydrogen or is absent; and to pharmaceutically acceptable salts thereof, under the condition that 1,3-dihydro-4-phenyl-1-(3-(trifluoromethyl)phenyl)-2H-imidazol-2-one is excluded, and if one of R3 and R4 denotes methyl, ethyl, n-propyl or n-butyl, and the other denotes hydrogen or is absent, then R2 denote hydrogen or methyl. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 11-beta-hydroxysteroid dehydrogenase 1 (11-beta-HSDI) inhibiting activity.

15 cl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: where X is selected from a group consisting of hydrogen, halogen, cyano, nitro, ethenyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl; Y denotes hydrogen or fluorine; R4 and R5 denote hydrogen or lower alkyl; one of R1 and R8 is selected from a group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl, and the other denotes hydrogen; one of R6 and R7 is selected from a group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl, and the other denotes hydrogen, cyano group or lower alkyl; R2 is selected from a group consisting of hydrogen, lower alkyl and substituted lower alkyl; R3 is selected from a group consisting of oxygen, sulphur and NNH(C=O)OR9; R9 denotes lower alkyl or substituted lower alkyl; where the term "substituted" denotes substitution with 1-5 substitutes independently selected from a group consisting of lower alkyl, lower alkenyl, lower alkynyl, dioxo-lower alkenyl, halogen, hydroxy, -CN, -CF3, -NH2, -N(H, lower alkyl), N(lower alkyl)2, aminocarbonyl, carboxy, -NO2, lower alkoxy, thio-lower alkoxy, lower alkylsulphonyl, aminosulphonyl, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, lower alkylcarbonyl-NH, fluoro-lower alkyl, fluoro-lower alkoxy, lower alkoxy-carbonyl-lower alkoxy, carboxy-lower alkoxy, carbamoyl-lower alkoxy, hydroxy-lower alkoxy, -NH2-lower alkoxy, -N(H, lower alkyl)-lower alkoxy, -N(lower alkyl)2-lower alkoxy, benzyloxy-lower alkoxy, mono or di-lower alkyl, substituted with aminosulphonyl or lower alkyl, which can optionally be substituted with a halogen, hydroxy, -NH2, -N(H, lower alkyl) or -N(lower alkyl)2; the term "heteroaryl" denotes an aromatic heterocyclic ring system containing up to two rings; and the term "heterocycle" denotes a substituted or unsubstituted 5-8-member mono- or bicyclic, aromatic or non-aromatic hydrocarbon, where 1-3 carbon atoms are replaced with a heteroatom selected from a nitrogen, oxygen or sulphur atom; and pharmaceutically acceptable salts thereof or esters. The invention also relates to a pharmaceutical composition, use of compounds in claims 1-31, as well as to methods of producing compounds of formulae II and III.

EFFECT: obtaining novel biologically active compounds which inhibit interaction of MDM2 protein with a p53-like peptide.

38 cl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to indole-3-yl-carbonyl-spiro-piperidine derivatives which have an effect of Vla-receptor antagonists and are presented by Formula I: where a tail spiropiperidine group A and residual R1, R2 and R3 are such as specified in the patent claim.

EFFECT: higher efficiency of applying the compounds in drugs effective in dysmenorrhea, hypertension, chronic heart failure, inadequate vasopressin secretion, hepatic cirrhosis, nephrotic syndrome, obsessive-compulsive disorder, anxious and depressive disorders.

22 cl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel indol-3-yl-carbonyl-asaspiro-derivatives of formula I: where R1 represents H,-(CH2)m-Ra, where Ra represents NRiRii, phenyl, possibly substituted by one or more than one B, -(CH2)n-(CO)-Rb , where Rb represents NRiRii; there exists one or more than one R2 , where each R2 is the same or different and represents one or more than one H, in halogen way; R3 represents H, C1-6-alkyl; B represents in halogen way; Ri and Rii each independently represents H, C1-6-alkyl, C1-6alkyl-NRiiiRiv; Riii and Riv each independently represents C1-6alkyl; m equals 1-6; n equals 1-4; A represents group : where R4 represents H or C1-6alkyl; R5 represents phenyl, possibly substituted in halogen way; or its pharmaceutically acceptable salt; on condition that 1-(1H-indol-3-yl-carbonyl)-4-(1,3-dioxolan-2-yl)pyperidine is excluded.

EFFECT: compounds demonstrate antagonistic activity with respect to Via vasopressin receptor, which makes it possible to apply them for obtaining pharmaceutical composition.

22 cl, 4 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to indol-3-yl-carbonyl-spiro-piperadine derivatives used as V1a receptor antagonists and which have formula I: , where the spiro-piperadine A head group and residues R1, R2 and R3 are as defined in claim 1 of the invention. The invention also pertains to pharmaceutical compositions which contain such compounds and use thereof in preparing medicines with V1a receptor antagonist activity.

EFFECT: high activity of derivatives.

37 cl, 1 tbl, 285 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely therapy and endocrinology, and may be applicable as a lipid, carbohydrate and protein normalising drug in treating type II diabetes mellitus, atherosclerosis and metabolic syndrome. That is ensured by adding the integrating therapy with the drug Uglanex.

EFFECT: invention provides effective treatment of said pathological conditions ensured by reducing a cholesterol level, an atherogenicity index, blood sugar, insulin resistance and albuminuria.

3 tbl

Up!