3-azabicyclo[3,1,0]hexyl derivatives as modulators of metabotropic glutamate receptors

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, particularly novel pyridinone derivatives of formula (I) or stereochemically isomeric forms thereof, where R1 is C1-6alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 is a halogen, trifluoromethyl, C1-3alkyl or cyclopropyl; X is a covalent bond, O or O-CH2; Ar is an unsubstituted phenyl or phenyl substituted with n radicals R4, where n equals 1, 2 or 3; where each R4 is a halogen; or pharmaceutically acceptable addition salts or solvates thereof. The invention also relates to a pharmaceutical composition, having the activity of positive allosteric modulators of the metabotropic glutamate receptor subtype 2, based on compounds of formula I and use of compounds of formula I to prepare a medicinal agent for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved.

EFFECT: novel compounds which can be useful in treating and preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved are obtained and described.

15 cl, 4 ex, 1 tbl

 

Field of invention the Present invention relates to new derivatives of pyridinone, substituted 3-azabicyclo[3.1.0]hexylene radical, which are positive allosteric modulators of metabotropic glutamate 2 receptor subtype ("mGluR2") and which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases that involve the mGluR2 subtype of metabotropic receptors. The invention also relates to pharmaceutical compositions containing such compounds, to methods of producing such compounds and compositions and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases involving mGIuR2.

Prior art

Glutamate is the main amino acid neurotransmitter in the Central nervous system of mammals. Glutamate plays a major role in numerous physiological functions such as learning and memory, and sensory perception, the development of synaptic plasticity, regulation of motor activity, respiration and regulation of cardiovascular activity. In addition, glutamate is the basis of some various neurological and psychiatric diseases where there is a violation glutamatergic neurotransmission.

Glutamate mediates synaptic neurotransmission through the activation of the channels, ionotropic glutamate receptors (iGluRs) and NMDA(N-methyl-D-aspartate), AMPA-(alpha-amino-3-hydroxy-6-methyl-4-isoxazolidinone acid) and kainite-induced receptors, which are responsible for fast exciting the transmission.

In addition, glutamate activates metabotropic glutamate receptors (mGluRs), which increasingly play a role in modulation, which contributes to the fine adjustment of synaptic efficiency.

Glutamate activates mGluRs by linking with a large extracellular aminocentesis domain of the receptor, referred to in this description orthotricyclen the binding site. This binding causes a conformational change in the receptor that leads to activation of G-proteins and intracellular signal transduction pathways.

The mGluR2 subtype negatively coupled with adenylate cyclase through activation of Gai-protein, and its activation leads to inhibition of the release of glutamate in the synapse. In the Central nervous system (CNS) receptors mGluR2 mainly ubiquitous in the cortex, thalamic region, additional olfactory bulb, hippocampus, amygdala body, the caudate nucleus and adjacent the kernel.

In clinical trials it was shown that activation of mGluR2 is effective for Les is possible anxiety disorders. In addition, it was shown that activation of mGluR2 is effective in various animal models, thereby providing a potentially new therapeutic approach to the treatment of schizophrenia, epilepsy, addiction/drug dependence, Parkinson's disease, pain, sleep disorders and Huntington's disease.

Currently the majority of the available pharmacological means, having as its target mGluRs, are orthotrichaceae ligands, activating some members of this family, as they are structural analogues of glutamate.

A new direction in the development of selective compounds acting on mGluRs, is to identify compounds that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthostereoscopic binding site.

Positive allosteric modulators of mGluRs currently presented as a new pharmacological objects offering this attractive alternative. Describes the various connections as positive allosteric modulators of mGluR2. In WO 2004/092135 (NPS & Astra Zeneca), WO 2004/018386, WO 2006/014918 and WO 2006/015158 (Merck), WO 2001/56990 (Eli Lilly), WO 2007/135527 and WO 2007/135529 (Pfizer), and WO 2006/030031, WO 2007/104783 and WO 2006/030032 (Addex & Janssen Pharmaceutica) are described, respectively, derived is animalfeed, of acetophenone, indanone, pyridylmethyl-sulfonamida, benzimidazole, azobenzenes, thienopyridine/pyrimidine, 3-cyanopyridine and pyridinone as positive allosteric modulators of mGluR2. None of the specifically disclosed in these compounds is not structurally related to the compounds of the present invention.

It was demonstrated that such compounds do not activate the receptor by themselves. Rather, they contribute to the receptor gave a maximum response to the concentration of glutamate, which in itself it induces minimal response. Using mutational analysis, it was clearly shown that there is no binding of positive allosteric modulators of mGluR2 in ortostaticescom the website, but instead it occurs at an allosteric site that is located within the transmembrane segment of the receptor, which consists of seven fragments.

Animal data suggests that positive allosteric modulators of mGluR2 have the same effects in models of anxiety and psychosis, and that the effects obtained with orthotrichaceae agonists. It was shown that allosteric modulators of mGluR2 active in these models of anxiety, as reinforced by the fear of excitation and induced stress hyperthermia. In addition, it was shown that such compounds are active in d is ansirovanie ketamine - or amphetamine-induced hyperlocomotion and reversal of amphetamine-induced disorders preimposed inhibition in models of schizophrenia, representing the acoustic response of fear (J. Pharmacol. Exp.Ther. 2006, 318, 173-185; Psychopharmacology 2005, 179, 271-283).

Recent studies in animals also show that selective positive allosteric modulator of metabotropic glutamate receptors 2 subtype biperiden (BINA) blocks hallucinogenic drug model of psychosis, thereby supporting the strategy of targeting receptors mGluR2 for the treatment of glutamatergic dysfunction in schizophrenia (Mol. Pharmacol. 2007, 72, 477-484).

Positive allosteric modulators enable amplification of the glutamate response, but it was also shown that they enhance the response to orthotrichaceae mGluR2 agonists, such as LY379268 or DCG-IV. These data provide the basis for another new therapeutic approach to the treatment of the above-mentioned neurological and psychiatric diseases involving mGluR2, in which you can using a combination of a positive allosteric modulator mGluR2 together with orthotricyclen mGluR2 agonist.

Detailed description of the invention

The present invention relates to compounds having modulatory activity against metabotropic glutamate 2 receptor subtype having the formula (I)

,

and their stereochemical isomeric forms, where

R1is Soboh the C 1-6alkyl or C1-3alkyl, substituted C3-7cycloalkyl, halogeno, phenyl or phenyl substituted halogeno, trifluoromethyl or triptoreline;

R2represents halogeno, trifluoromethyl, C1-3alkyl or cyclopropyl;

X represents a covalent bond, O, NR3, NR3-CH2or O-CH2;

R3represents hydrogen or C1-3alkyl; and

Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,

where n is 1, 2 or 3;

where each R4independently selected from the group consisting of halogeno, C1-3of alkyl, hydroxys1-3of alkyl, POLYHALOGENATED1-3of alkyl, cyano, hydroxyl, amino, carboxyl, C1-3alkalosis1-3of alkyl, C1-3alkyloxy, polyhalogen1-3alkyloxy, C1-3alkylsulphonyl, mono - and di(C1-3alkyl)amino and morpholinyl; or where

two adjacent radicals R4taken together form a bivalent radical of the formula

-N=CH-NH-(a)

-CH=CH-NH-(b), or

-O-CH2-CH2-NH-(C);

and their pharmaceutically acceptable salts accession and solvate.

Hereinafter the present invention will be described additionally. The following text various aspects of the invention are defined in more detail. Every aspect that is defined in a similar way, can be combined with any other aspect is whether or aspects, unless expressly stated otherwise. In particular, any sign that is specified as preferred or useful, may be combined with any other feature or features indicated as preferred or useful.

In one embodiment of the invention relates to the compound of formula (I) or its stereochemical isomeric form, where

R1represents a C1-6alkyl or C1-3alkyl, substituted C3-7cycloalkyl, phenyl or phenyl substituted halogeno, trifluoromethyl or triptoreline;

R2represents halogeno, trifluoromethyl, C1-3alkyl or cyclopropyl;

X represents a covalent bond, O, NR3, NR3-CH2or O-CH2;

R3represents hydrogen or C1-3alkyl; and

Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,

where n is 1, 2 or 3;

where each R4independently selected from the group consisting of halogeno, C1-3of alkyl, hydroxys1-3of alkyl, POLYHALOGENATED1-3of alkyl, cyano, hydroxyl, amino, carboxyl, C1-3alkalosis1-3of alkyl, C1-3alkyloxy, polyhalogen1-3alkyloxy, C1-3alkylsulphonyl, mono - and di(C1-3alkyl)amino and morpholinyl; or where

two adjacent radicals R4taken together form a bivalent radical of formula-Christ.

-N=CH-NH-(a)

-CH=CH-NH-(b), or

-O-CH2-CH2-NH-(c);

and its pharmaceutically acceptable salts accession and solvate.

In one embodiment of the invention relates to the compound of formula (I) or its stereochemical isomeric form, where

R1represents a C1-6alkyl or C1-3alkyl, substituted C3-7cycloalkyl;

R2represents halogeno;

X represents a covalent bond or-O-CH2; and

Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,

where n is 1, 2 or 3;

where each R4independently selected from the group consisting of halogeno, trifloromethyl, morpholinyl or hydraxis1-3of alkyl;

and its pharmaceutically acceptable salts accession and solvate.

In one embodiment of the invention relates to the compound of formula (I) or its stereochemical isomeric form, where

R1is a 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;

R2represents chloro;

X represents a covalent bond or-O-CH2; and

Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,

where n is 1, 2 or 3;

where each R4independently selected from the group consisting of halogeno, trifloromethyl, morpholinyl is whether hydraxis 1-3of alkyl;

and its pharmaceutically acceptable salts accession and solvate.

In one embodiment of the invention relates to the compound of formula (I) or its stereochemical isomeric form, where

R1is a 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;

R2represents chloro;

X represents a covalent bond or-O-CH2; and

Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,

where n is equal to 2;

where each R4independently selected from the group consisting of halogeno;

and its pharmaceutically acceptable salts accession and solvate. In one embodiment of the invention relates to the compound of formula (I) or its stereochemical isomeric form, where

R1is a 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;

R2represents chloro;

X represents a covalent bond or-O-CH2; and

Ar is an unsubstituted phenyl or 2,5-dichlorophenyl;

and its pharmaceutically acceptable salts accession and solvate. In one embodiment of the invention relates to the compound of formula (I) or its stereochemical isomeric form, where

R1is a 1-butyl or (cyclopropyl)methyl;

R2presented yet a chloro;

X represents a covalent bond or-O-CH2; and

Ar is an unsubstituted phenyl or 2,5-dichlorophenyl;

and its pharmaceutically acceptable salts accession and solvate. In an additional embodiment of the invention relates to compounds according to any of the other embodiments, where R1represents a C1-6alkyl or C1-3alkyl, substituted C3-7cycloalkyl, fluorescent, phenyl or phenyl substituted halogeno, trifluoromethyl or triptoreline.

In an additional embodiment of the invention relates to compounds according to any of the other embodiments, where R1represents a C1-6alkyl or C1-3alkyl, substituted by one or more than one Deputy, selected from the group consisting of C3-7cycloalkyl, halogeno, phenyl and phenyl substituted by one or more than one Deputy, selected from the group consisting of halogeno, trifloromethyl, triptoreline.

In an additional embodiment of the invention relates to compounds according to any of the other embodiments, where R1represents a C1-6alkyl or C1-3alkyl, substituted by one Deputy, selected from the group consisting of C3-7cycloalkyl, halogeno, phenyl or phenyl substituted by one or more than one Deputy, selected from the group consisting of GoLoG is but trifloromethyl, triptoreline.

In one embodiment of the invention relates to the compound of formula (I)where the specified connection selected from:

(2α,3β,3α)-1-butyl-3-chloro-4-[6-[(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-it;

(2α,3α,3α)-1-butyl-3-chloro-4-[6-[(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-it;

(2α,3α,3α)-1-butyl-3-chloro-4-(6-phenyl-3-Aza-bicyclo[3.1,0]Gex-3-yl)-1H-pyridine-2-it;

(2α,3α,3α)-3-chloro-1-cyclopropylmethyl-4-(6-phenyl-3-Aza-bicyclo[3.1.0]Gex-3-yl)-1H-pyridine-2-it;

including any stereochemical isomeric form,

and its pharmaceutically acceptable salts accession and solvate.

Wherever the term "substituted" used in the present invention, it is intended to indicate that one or more than one hydrogen atom, preferably from 1 to 3 hydrogen atoms, more preferably 1 hydrogen atom on the atom indicated in the expression as "substituted", replaced with a selection from the indicated group, provided that the principal valence of the specified atom is not exceeded, and that the substitution leads to a chemically stable compound, i.e. the compound which is sufficiently stable to retain its properties after isolation from the reaction mixture to a suitable purity and preparation in the form of a therapeutic agent. For example, when phenyl substituted halogeno, this is means, the specified phenyl substituted by one or more than one Deputy, selected from halogeno.

The notation C1-3alkyl as a group or part of a group defines a saturated straight or branched hydrocarbon radical having from 1 to 3 carbon atoms, such as methyl, ethyl, 1-propyl and 1-methylethyl.

The notation C1-6alkyl as a group or part of a group defines a saturated straight or branched hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl and the like.

The notation C3-7cycloalkyl defines a saturated cyclic hydrocarbon radical having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Designation of halogen or halogen as a group or part of a group is generic for fluorescent, chloro, bromo, iodo.

The notation C1-3alkyloxy as a group or part of a group refers to a radical having the formula-ORbwhere Rbrepresents a C1-3alkyl. Non-limiting examples of suitable alkyloxy include metiloksi, acyloxy, propyloxy, isopropoxy.

Designation polyhalogen1-3alkyloxy as a group or part of a group refers to a radical Csub> 1-3alkyloxy having values, as defined above, where more than one hydrogen atom substituted by a halogen atom as defined above. Non-limiting examples of such radicals, polygalacturonic include deformations, cryptometrics, 1,1,1-cryptometrics and the like.

When any variable occurs more than one time in any constituent, each definition is independent.

For therapeutic use of salts of compounds of formula (I) are salts where the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are not pharmaceutically acceptable may also find use, for example in obtaining or purification of pharmaceutically acceptable compounds. All salts, pharmaceutically acceptable or not included in the scope of the present invention.

Pharmaceutically acceptable salts are defined as including therapeutically active non-toxic form of salts accession acids, which are capable of forming compounds of formula (I). These salts can be obtained by processing the basic form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example halogenoalkane acids, in particular hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric KIS the Auteuil and phosphoric acid; organic acids, for example acetic acid, hydroxyoctanoic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, econsultancy acid, benzosulfimide acid, para-toluensulfonate acid, reklamowa acid, salicylic acid, para-aminosalicylic acid and pambou acid. Conversely, the salt form can be converted into the free base by treatment appropriate basis.

The compounds of formula (I)containing acidic protons may also be converted into a therapeutically active non-toxic form of basic salts by treatment with appropriate organic and inorganic bases. Appropriate forms basic salts include ammonium salts, alkali and alkaline earth metals, in particular lithium salts, sodium, potassium, magnesium and calcium salts of organic bases, such as salt, benzathine, N-methyl-D-glucamine, hydramine, and salts of amino acids such as arginine and lysine. Conversely, the salt form can be converted into a form of free acids by treatment with the tried acid.

The term "MES" includes the forms of the accession of the solvent, as well as their salts, which are capable of forming compounds of formula (I). Examples of such forms of connection of the solvent are, for example, hydrates, alcoholate and the like.

It should be understood that some of the compounds of formula (I) and their pharmaceutically primemix salts connection and stereoisomeric forms may contain one or more than one center of chirality and exist as stereoisomeric forms.

The term "stereochemical isomeric forms"as used here, defines all the possible isomeric forms, which may be of the compounds of formula (I). If not specified, or is not otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of basic molecular structure. The invention also includes each of the individual isomeric forms of the compounds of formula (I) and their salts and solvate, essentially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2%, and most preferably less than 1% of other isomers. Thus, when the compound of formula (I) is defined, for example, as (R), this means that the compound is essentially free of (S) isomer. Stereogenic centers can the be R - or S-configuration; the substituents on bivalent cyclic (partially) saturated radicals may have either the CIS-or TRANS-configuration.

Following the rules of nomenclature CAS, when two stereogenic center is known absolute configuration are present in the compound, R or S descriptor assign (rule-based sequence Kanna-Ingold-Prelog) chiral center with the lowest number, the starting point. The configuration of the second stereogenic center indicate if you use a relative descriptors [R*,R*] or [R*,S*], where R* always take as their starting point, and [R*,R*] denotes the centers with the same chirality, and [R*,S*] denotes the centers with different chirality. For example, if the connection chiral center has the lowest number is S-configuration, and the second center is R-configuration, streetscapes will be designated as S-[R*,S*]. If you use "α" and "β": the position with the highest ranking substituent on the asymmetric carbon atom in the ring system, with the lowest number in the ring, is always relative to "a" position to the Central plane defined by the ring system. The position having the greatest seniority of Deputy differently the asymmetric carbon atom in the ring system (hydrogen atom in the compounds of formula (I)in relation to the position with the largest one hundred is the most substituent on the atom, which begins the countdown, referred to 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.

Within this application the item, particularly when referred to in relation to the compounds of formula (I)includes all isotopes and mixtures of isotopes of this element, either natural or artificially synthesized or natural composition, or in isotopically enriched form. Radiolabelled compounds of formula (I) may contain a radioactive isotope selected from the group3H,11C,18F,122I123I125I131I75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group3H,11C and18F.

Thus, the connection according to the invention essentially includes a connection to one or more than one isotope of one or more than one element, and mixtures thereof, including radioactive compound, also called a compound labeled with radioactive isotopes, where one or more than one non-radioactive atom is replaced by one of its radioactive isotopes. The term "compound labeled with radioactive isotopes" refers to any compound of the formula (I) or its pharmaceutically acceptable salt, containing p is at least one radioactive atom. For example, the connection can be marked by emitting a positron or gamma rays emitted by radioactive isotopes. For methods radioligand binding3H-atom, or125I-atom is preferred atoms for substitution. To visualize the most commonly used positron emitting (PET) radioactive isotopes are11C,18F,15O and13N, all of which are generated by accelerators and have half-lives of 20, 100, 2 and 10 minutes (min), respectively. Because the half-lives of these isotopes is so short, the only possibility is to use them in institutions that have the accelerator to generate them in place, which limits their use. The most widely used of them are18F,99mTc201TI and123I. Manipulation of these radioactive isotopes, their generation, selection and introduction into the molecule known to the person skilled in the technical field.

In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen, and halogen. In particular, a radioactive isotope selected from the group3H,11C,18F,122I123I125I131I75Br,76Br,77Br and82Br.

In one embodiment of radiolabelled compounds in this image is the shadow can be used as a radio in positron emission tomography (PET) for imaging metabotropic glutamate 2 receptor subtype (mGluR2). Radionuclides commonly used in PET are, for example,11C,18F,15O and13N, in particular18F.

When used in the description and the attached claims, the singular number also include the plural meanings, unless the context clearly requires otherwise. For example, "connection" means 1 or more connection than 1 connection.

The terms described above, and other, used in the description, understandable to experts in this field of technology.

Getting

Compounds according to the invention can usually be obtained through a sequence of stages, each of which are known to a person skilled in the art. In particular, the compounds can be obtained according to the following synthesis methods.

The compounds of formula (I) can be synthesized in the form of racemic mixtures of enantiomers which can be separated from each other, following the methods of separation known in the art. Racemic compounds of the formula (I) can be converted into the corresponding diastereomeric salt form by reacting with a suitable chiral acid. These diastereomeric salt forms are then separated, for example through election or fractional crystallization, and the enantiomers extracted with alkali. An alternative way redelineation forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric forms may also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the interaction proceeds stereospetsifichno.

A. obtain the final compounds

Experimental methods 1

The compounds of formula (I), where R2relates solely to halogeno called so (I-a)can be obtained by reacting the intermediate compounds of formula (II) with N-halogenating, such as, for example, N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, according to the reaction scheme (1). This interaction can be carried out in a suitable reaction-inert and aprotic solvent such as, for example, dichloromethane or 1,2-dichloroethane. The reaction mixture is stirred at a suitable temperature, typically at room temperature, over a period of time necessary to achieve completion of the reaction, typically 1 hour (h). In the reaction scheme (1) all other variables are defined as in formula (I).

Experimental methods 2

Alternatively, the compounds of formula (I) can be obtained by reacting the intermediate compounds of formula (III) with an intermediate compound of formula (IV), which can be synthesized SPO is Obama, well known to the person skilled in the art according to the reaction scheme (2). This interaction can be carried out in a suitable reaction-inert solvent such as, for example, toluene. The interaction may be carried out in the presence of a suitable base, such as, for example, mpem-piperonyl sodium. The interaction may be carried out in the presence of a catalyst based on a metal, in particular palladium catalyst such as palladium(II)acetate. The interaction may be carried out in the presence of a suitable ligand, such as, for example, [1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine] (BINAP). The reaction mixture can be heated for a suitable period of time that allows you to complete the reaction, for example at 100°C for 16 hours in a sealed tube. In the reaction scheme (2) Zarepresents a group suitable for Pd catalyzed combination with amines, such as, for example, halogen or triflate. All other variables are defined as in formula (I).

Such intermediate compounds (II), (III) and (IV) can be obtained according to reaction schemes (3)-(14) (see below). Transformation of various functional groups present in compounds with other functional groups of the formula (I) can be carried out by synthesis methods well known is time specialist in this field of technology.

C. Obtaining intermediates

Experimental methods 3

Intermediate compounds of formula (II) can be obtained by reacting the intermediate compounds of formula (V) with an intermediate compound of formula (IV) according to reaction scheme (3). This interaction can be carried out in a suitable reaction-inert solvent such as, for example, toluene. This interaction can usually be carried out in the presence of a suitable base, such as, for example, tert-piperonyl sodium. The interaction may be carried out in the presence of a catalyst based on a metal, in particular palladium catalyst such as palladium(II)acetate, and a suitable ligand, such as, for example, [1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine] (BINAP). This mixture can be heated for a suitable period of time that allows you to complete the reaction, for example at 100°C for 16 hours in a sealed tube. In the reaction scheme (3) all variables are defined as in formula (I).

Experimental methodology 4

Intermediate compounds of formula (III), where Zarelates solely to halogeno called thus (111-a), and the intermediate compounds of formula (V) can be obtained by reacting the intermediate compounds of formula (VI-a) or (VI-b), where Y is predstavljaet a H or R 2(as defined in the formula (I), with a suitable halogenation agent such as, for example, oxybromide phosphorus. The interaction can be performed in a suitable reaction-inert solvent such as, for example, DMF (dimethylformamide). The interaction may be carried out at moderately elevated temperatures, such as, for example, 110°C, for a suitable period of time, for example 1 hour, allowing you to complete the reaction. In reaction scheme (4) Y is the same as specified, and all other variables are defined as in formula (I).

Experimental methods 5

Intermediate compounds of formula (III), where Zarepresents triftorbyenzola called thus (III-b), can be obtained by reacting the intermediate compounds of formula (VI-b) with triplicates anhydride (also called triftormetilfullerenov anhydride). The interaction can be performed in a suitable reaction-inert solvent such as, for example, dichloromethane. The interaction can usually be carried out in the presence of a base, such as pyridine, at a low temperature, such as, for example, -78°C, for a suitable period of time that allows you to complete the reaction. In the reaction scheme (5) all variables are defined as in formula (I).

Experimental methodology 6

Intermediate compounds of formula (VI-a), intermediate compounds of formula (VI-b), where R2(and thus also Y) refers exclusively to CF3called thus (VI-b1), intermediate compounds of formula (V1-b), where R2(and thus also Y) is restricted to C1-3the alkyl or cyclopropyl called so (VI-b2)can be obtained by hydrogenolysis of the corresponding intermediate compounds of formula (VII-a), (VII-b1) or (VII-b2), where Y represents N or R2(as defined in the formula (I). The interaction can usually be carried out in a suitable reaction-inert solvent such as, for example, ethanol. The interaction may be carried out in the presence of a catalyst, such as, for example, 10% palladium on charcoal, in a period of time to ensure completion of the reaction, typically at room temperature and a pressure of 1 atmosphere of hydrogen gas (101.3 kPa) for 2 hours. In the reaction scheme (6) all variables are defined as in formula (I), unless otherwise indicated in the reaction scheme (6).

Experimental methodology 7

Alternatively, intermediate compounds of formula (VI), where R2relates solely to halogeno called so (VI-b3)can be obtained by the EOI is to interact the intermediate compounds of formula (VII-b3) in a mixture of acetic acid and Hydrobromic acid. The mixture can be heated at an elevated temperature over a period of time necessary to complete the reaction, typically at 130°C for 30 minutes under microwave irradiation. In the reaction scheme (7) all variables are defined as in formula (I).

Experimental methods 8

Intermediate compounds of formula (VII-a) can be obtained by methods known in the art, by reacting commercially available 4-benzyloxy-1H-pyridin-2-one with commercially available alkylating agent of the formula (VIII)in which Zbrepresents a suitable leaving group, such as, for example, halogeno. The interaction may be carried out using a base, such as, for example, K2CO3and possibly salt of iodine, such as, for example, KI. Interaction typically can be carried out in an inert solvent, such as, for example, acetonitrile or DMF, at a moderately high temperature such as, for example, 80-120°C, for a suitable period of time, which allows you to complete the reaction, for example 16 hours. In the reaction scheme (8) Zbrepresents a suitable leaving group, such as, for example, halogen and all other variables are defined as in formula (I).

Experimental methodology 9

Intermediate soy is inane formula (VII-b1) can be obtained by reacting the intermediate compounds of formula (VII-c) with commercially available methyl-2,2-debtor-2-(persulfonic)acetate. The interaction can be performed in a suitable reaction-inert solvent such as, for example, DMF. The interaction may be carried out in the presence of a suitable copper salt such as copper iodide(1). The reaction mixture can be heated for a suitable period of time that allows you to complete the reaction, for example at 100°C for 5 hours. In the reaction scheme (9) all variables are defined as in formula (I).

Experimental methods 10

Intermediate compounds of formula (VII-b3) can be obtained by reacting the intermediate compounds of formula (VII-a) with a commercially available N-halogenating, such as, for example, N-chloro-(NCS), N-bromo- (NBS) or N-iodosuccinimide (NIS). The interaction can be performed in a suitable reaction-inert solvent such as, for example, DMF, dichloromethane or acetic acid, typically at room temperature over a period of time from 1 to 24 hours. In reaction scheme (10) all variables are defined as in formula (I).

Experimental methods 11

Intermediate compounds of formula (VII-b2) can be obtained by reacting the intermediate compounds of formula (VII-b3) derived from C1-3alkyl - or cyclopropylboronic acid, such as cyclopropylboronic acid or meta baronova acid. The interaction can be performed in a suitable reaction-inert solvent such as, for example, 1,4-dioxane. The interaction may be carried out in the presence of a suitable palladium complex catalyst such as, for example, the complex [1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-DHM (dichloromethane), and in the presence of a suitable base, such as sodium bicarbonate. The reaction mixture can be heated for a suitable period of time that allows you to complete the reaction, for example, at 175°C for 20 minutes under microwave irradiation. In the reaction scheme (11) all variables are defined as in formula (I).

Experimental methods 12

Intermediate compounds of formula (IV) can be obtained by removing the protection of the nitrogen atom of pyrrolidine in the intermediate compound of formula (IX), where L represents a suitable protective group for the nitrogen atom pyrolidine derivative, such as, for example, tert-butoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, benzyl and methyl, according to the reaction scheme (12) using methods known in the art.

For example, when L represents a benzyl, then the reaction of removing the protection can be carried out in a suitable solvent or mixture of solvents, such as, for example, a mixture of the of ethanol and 1,4-cyclohexadiene. The interaction may be carried out in the presence of a suitable catalyst, such as palladium on charcoal, at a moderately high temperature such as, for example, 100°C.

For example, when L is a mpem-butoxycarbonyl, the reaction of removing the protection can be carried out by reacting with a suitable acid, such as, for example, hydrochloric acid. This interaction can usually be carried out in a suitable solvent, such as, for example, 1,4-dioxane. In the reaction scheme (12) all variables are defined as in formula (I).

Experimental methods 13

Intermediate compounds of formula (IV), where X represents O-CH2called thus (IV-a), can be obtained by removing the protection of the nitrogen atom of pyrrolidine in the intermediate compound of formula (IX-a), where L represents a suitable protective group for the nitrogen atom pyrolidine derivative, such as, for example, tert-butoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, benzyl and methyl, according to the reaction scheme (13) using methods known in the art.

For example, when L represents a benzyl, then the reaction of removing the protection can be carried out in a suitable solvent or mixture of solvents, such as, for example, a mixture of methanol and 1,4-cyclohexadiene Interaction can be carried out in the presence of a suitable catalyst, such as, for example, palladium on charcoal, at a moderately high temperature such as, for example, 100°C.

For example, when L is a tert-butoxycarbonyl, the reaction of removing the protection can be carried out by reacting with a suitable acid, such as, for example, hydrochloric acid. This interaction can be carried out in a suitable solvent, such as, for example, 1,4-dioxane. In the reaction scheme (13) all variables are defined as in formula (I).

Experimental methods 14

Intermediate compounds of formula (IX-a), where X represents O-CH2can be obtained by reacting the intermediate compounds of formula (X), where L represents a suitable protective group for the nitrogen atom pyrrolidinone groups, such as, for example, tert-butoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl, benzyl and methyl, with an aromatic alcohol represented by the formula Ar-OH, under the reaction conditions, Mitsunobu. Interaction in such reaction conditions, Mitsunobu occur, for example, in the presence of a suitable tertiary phosphine and dialkyldithiocarbamate in an organic solvent, such as THF (tetrahydrofuran) or dichloromethane, at a temperature, which allows to happen this interaction, usually from 0°C to 60°C. Typical conditions for reakcionizma described in Tetrahedron. Letters., 31, 699, (1990); The Mitsunobu Reaction, D.L Hughes, Organic Reactions, 1992, Vol.42, 335-656 and Progress in the Mitsunobu Reaction, D.L. Hughes, Organic Preparations and Procedures International, 1996, Vol.28, 127-164, and well known to the person skilled in the art. In the reaction scheme (14) all variables are defined as in formula (I).

Educt of the formula (X) are either commercially available or can be obtained according to the conventional methods of interaction, in General, well-known specialists in this field of technology.

Intermediate compounds of formula (IX), other than (IX-a)can be obtained according to methods known to a person skilled in the art. Typical reaction conditions for this type of interaction is described in:

Synthesis of aza-, oxa-, and thiabicyclo[3.1.0]hexane heterocycles from a common synthetic intermediate. Renslo, Adam R.; Gao, Hongwu; Jaishankar, Priyadarshini; Venkatachalam, Revathy; Gordeev, Mikhail F. Organic Letters (2005), 7(13), 2627-2630;

Synthesis of (1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexane, a novel achiral diamine. Brighty, Katherine E.; Castaldi, Michael J. Synlett(1996), (11), 1097-1099;

Construction of the (1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexane ring system. Braish, Tamim F.; Castaldi, Michael; Chan, Samantha; Fox, Darell E.; Keltonic, Tom; McGarry, James; Hawkins, Joel M.; Norris, Timothy; Rose, Peter R.; et al. Synlett (1996), (11), 1100-1102;

Diastereoselective syntheses of N-protected derivatives of 1α,5α,6β-6-amino-3-azabicyclo[3.1.0]hexane. A route to trovafloxacin, 6β-diastereomer. Vilsmaier, Elmar; Goerz, Torsten, Synthesis (1998), (5), 739-744.

Pharmacology

Compounds proposed in this invention are positive allosteric modulator of the mi metabotropic glutamate receptors, in particular they are positive allosteric modulators of mGluR2. It turns out that the compounds of the present invention do not bind to glutamate-recognizing site, orthotricyclen the binding site of the ligand, but instead contact an allosteric site located within the transmembrane segment of the receptor, which consists of seven fragments. In the presence of glutamate or mGluR2 agonist compounds of this invention increase the response mGluR2. Expect that the compounds proposed in this invention will have an impact on mGluR2 due to its ability to enhance the response of these receptors to glutamate or mGluR2 agonists, thereby enhancing the response of the receptor. Therefore, the present invention relates to the compound of the present invention for use as a medicine, as well as to the use of compounds according to the invention or pharmaceutical compositions according to the invention for the manufacture of a medicine for treatment or prevention, in particular treatment, of the condition in a mammal, including humans, for treatment or prevention of which is affected by the neuromodulatory effect of allosteric modulators of mGluR2, in particular their positive allosteric modulators, or treatment or prevention of which he contributes. The present izobreteniya refers to the connection of the present invention or pharmaceutical compositions according to the invention for use in the manufacture of a medicine for treatment or prevention, in particular treatment, of the condition in a mammal, including humans, for treatment or prevention of which is affected by the neuromodulatory effect of allosteric modulators of mGluR2, in particular their positive allosteric modulators, or treatment or prevention of which he contributes. The present invention also relates to the compound of the present invention or pharmaceutical compositions according to the invention for the treatment or prevention, in particular treatment, of the condition in a mammal, including humans, for treatment or prevention of which is affected by the neuromodulatory effect of allosteric modulators of mGluR2, in particular their positive allosteric modulators, or treatment or prevention of which he contributes.

Also the present invention relates to the use of compounds according to the invention or pharmaceutical compositions according to the invention for the manufacture of medicinal products for the treatment, prevention, improvement, regulation or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including humans, for treatment or prevention of which is affected by the neuromodulatory effect of positive allosteric modulators of mGluR2, or treatment or prevention of which he SPO is obstet.

Where indicated, the invention relates to the use of compounds or compositions according to the invention for the manufacture of a medicinal product, for example, for treatment of a mammal, it is clear that this application should be interpreted in some applications as a way, for example, treatment of a mammal, comprising the administration to a mammal in need of such treatment, an effective amount of a compound or composition according to the invention.

In particular, neurological and psychiatric disorders associated with glutamate dysfunction, include one or more of the following conditions or diseases: acute neurological and psychiatric disorders, such as cerebral disorders after cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive disorders, idiopathic and induced with drugs for Parkinson's disease, muscle spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, mi is the Renu (including migraine headache), incontinence, tolerance to the substance, withdrawal of substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, sleeping pills, and so on), psychosis, schizophrenia, anxiety (generalized anxiety disorder, panic disorder and obsessive-compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic condition, severe pain, uncontrollable pain, neuropathic pain and post-traumatic pain), late dyskinesia, sleep disorders (including narcolepsy), attention deficit disorder with hyperactivity and conduct disorder.

In particular, the condition or disease is a disorder of the Central nervous system selected from the group consisting of anxiety disorders, psychotic disorders, personality disorders, disorders caused by the admission of substance use, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, disorders of childhood, cognitive disorders, neurodegeneration, neurotoxicity and ischemia.

Prepact the strong disorder of the Central nervous system is an anxiety disorder, selected from the group consisting of agoraphobia, generalized anxiety disorder (Gad), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia and other phobias.

Preferably the disorder of the Central nervous system is an anxiety disorder selected from the group consisting of agoraphobia, generalized anxiety disorder (Gad), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD) and social phobia.

Preferably the disorder of the Central nervous system is a psychotic disorder selected from the group consisting of schizophrenia, crazy disorder, schizoaffective disorder, schizophreniform disorders and psychotic disorders, caused by taking psychoactive substances.

Preferably the disorder of the Central nervous system is a personality disorder selected from the group consisting of obsessive-compulsive personality disorder and schizoid disorders, schizotypical disorders.

Preferably the disorder of the Central nervous system is a disorder caused by taking substance in the substance, selected from the group consisting of alcoholism, alcohol addiction, alcohol withdrawal, delirium during alcohol withdrawal, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal symptoms.

Preferably the disorder of the Central nervous system is an eating disorder selected from the group consisting of nerve neurogenic anorexia and bulimia.

Preferably the disorder of the Central nervous system is a mood disorder selected from the group consisting of bipolar disorder (type I and II), cyclothymic disorder, depression, estimatesare disorder, major depressive disorder and mood disorders, caused by taking psychoactive substances.

Preferably the disorder of the Central nervous system is a migraine.

Preferably the disorder of the Central nervous system represents epilepsy or convulsive disorder selected from the group consisting of generalized non-convulsive epilepsy, generalized convulsive epilepsy, small epileptic fit great epileptic seizure, partial epilepsy with clouding or without clouding of consciousness, infantile spasms, continuous partial epilepsy other forms of epilepsy.

Preferably the disorder of the Central nervous system is a syndrome of attention deficit hyperactivity disorder.

Preferably the disorder of the Central nervous system is a cognitive disorder selected from the group consisting of delirium, persisting delirium, caused by taking psychoactive substances, dementia, dementia with HIV disease, dementia in Huntington's disease, dementia in Parkinson's disease, dementia in medical literature type, persistent dementia, caused by taking psychoactive substances and mild cognitive impairment.

Of the above-mentioned disorders treatment of anxiety, schizophrenia, migraine, depression and epilepsy is particularly important.

The present invention also relates to compounds of formula (I) for use in the treatment or prevention of diseases or conditions mentioned herein above.

The present invention also relates to compounds of formula (I) for use in the treatment of diseases or conditions mentioned herein above.

The present invention also relates to compounds of formula (I) for treating or preventing diseases or conditions, mentioned the x here above.

The present invention also relates to compounds of formula (I) for treating diseases or conditions mentioned herein above.

Currently in the fourth edition of the manual of diagnostic and statistical of mental diseases (DSM-IV) American psychiatric Association Dan diagnostic tool for the identification of the disorders described herein. Specialist in the art knows that there are alternative nomenclatures, nosology and classification system neurological and psychiatric disorders described herein, and that they have evolved with advances in medicine and science.

Since such positive allosteric modulators of mGluR2, including the compounds of formula (I)increase the response mGluR2 on glutamate, the advantage of these methods is the use of endogenous glutamate.

As positive allosteric modulators of mGluR2, including the compounds of formula (I)increase the response on mGluR2 agonists, it is obvious that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction, by introducing an effective amount of a positive allosteric modulator of mGluR2, including the compounds of formula (I), in combination with mGluR2-agonist. Examples of mGluR2 agonist include, for example, LY-379268; DCG-I; LY-354740; LY-404039; LY-544344; LY-2140023; LY-181837; LY-389795; LY-446433; LY-450477; telegrammed; MGS0028; MGS0039; (-)-2-oxa-4-aminobutyl[3.1.0]hexane-4,6-in primary forms; (+)-4-amino-2-sulfonylurea[3.1-0]hexane-4,6-dicarboxylic acid; (+)-2-amino-4-formello-[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,3R,5S,6S-2-amino-3-formello-[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybutyl[3.1 -0]hexane-2,6-dicarboxylic acid; (+)-4-amino-2-sulfonylurea[3.1.0]hexane-4,6-dicarboxylic acid; (+)-2-amino-4-formello[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybutyl[3.1,0]hexane-2,6-dicarboxylic acid; 1S,2R,3R,5S,6S-2-amino-3-formello[3.1.0]hexane-2,6-dicarboxylic acid or 1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybutyl[3.1.0]-hexane-2,6-dicarboxylic acid. More preferred mGluR2 agonists include LY-379268; DCG-IV; LY-354740; LY-404039; LY-544344 or LY-2140023.

Compounds of the present invention can be used in combination with one or more than one drug in the treatment, prevention, regulation, improvement or reduction of risk of diseases or conditions in which the compounds of formula (I) or one of the others is their medicines can be used, where the combination drug is safer or more effective than each drug separately. The pharmaceutical composition

The invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of the compounds according to the invention, in particular compounds of formula (I), its pharmaceutically acceptable salt, MES or stereochemical isomeric form.

Compounds according to the invention, in particular compounds of formula (I), their pharmaceutically acceptable salt, solvate or a stereochemical isomeric forms, or any subset or combination can be prepared in the form of various pharmaceutical forms for entry. As appropriate compositions can be cited all compositions usually employed for systemically injected drugs.

For the manufacture of pharmaceutical compositions according to this invention, an effective amount of a particular compound may in salt form, as active ingredient together in a homogeneous mixture with a pharmaceutically acceptable carrier or diluent, which may have a wide variety of forms depending on the form of preparation desired for introduction the Oia. These pharmaceutical compositions are suitable in a standard dosage form suitable, in particular, for administration orally, rectally, transdermally, by parenteral injection or by inhalation. For example, in the preparation of compositions in a dosage form for oral administration can be any of the usual pharmaceutical media, such as, for example, 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 the introduction oral administration is preferred, and tablets and capsules represent the most convenient standard oral dosage forms, in which case of course use solid pharmaceutical carriers. For parenteral compositions, the carrier will typically include sterile water, at least largely, though may include other ingredients, for example to increase the solubility. Can be prepared, for example, injectable solutions, in which the carrier comprises saline solution, actor glucose or a mixture of saline and glucose solution. Can also be prepared injectable suspension, in which case can be used appropriate liquid carriers, suspendresume agents and the like. Also included preparations of solid forms that are designed for turning, immediately prior to use, in preparations liquid forms. In the compositions suitable for percutaneous administration, the carrier may include an agent that improves the penetration and/or a suitable wetting agent may combined in minor proportions with suitable auxiliary substances of any nature, which does not have a significant negative effect on the skin. These excipients can facilitate the introduction on the skin and/or may be useful for the preparation of the required compositions. These compositions can be introduced in various ways, for example in the form of a transdermal patch, in the form of the drug spot it, in the form of ointment.

It is particularly convenient to prepare the above-mentioned pharmaceutical compositions in the form of a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form, which is used here, refers to physically discrete units suitable as single doses, each unit contains a defined amount of the active ingredient, R is shitennou so, to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, packets of powder, pills, suppositories, injectable solutions or suspensions and the like, and their individual multiples.

The exact dosage and frequency of administration depends on the specific compounds of formula (I), a specific condition, which are treated, the severity of the condition being treated, age, weight, sex, extent of disorder and General physical condition of the particular patient, and other medical treatment, which may receive the subject, and also well-known to specialists in this field of technology. Moreover, it is clear that the effective daily amount may be reduced or increased depending on the response of the subject, which is treated and/or depending on a doctor prescribing the compounds of the present invention.

Depending on the method of administration of the pharmaceutical composition will contain from 0.05 to 99 wt.%, preferably from 0.1 to 70 wt.%, more preferably from 0.1 to 50 wt.%, active ingredient and from 1 to 99.95 wt.%, preferably from 30 to 99.9 wt.%, more preferably from 50 to 99.9 wt.%, farmacevtichesky acceptable carrier, all percentage concentrations are calculated on the total weight of the composition.

As already mentioned, the invention also relates to pharmaceutical compositions containing the compounds according to the invention and one or more than one medicine for treating, preventing, managing, improvement or reduction of risk of diseases or conditions in which the compounds of formula (I) or other drugs can be useful, and also to the use of such compositions for the manufacture of a medicinal product. The present invention also relates to combinations of compounds of the present invention and orthostereoscopic mGluR2 agonist. The present invention also relates to such a combination for use as a drug. The present invention also relates to a product containing (a) compound of the present invention, its pharmaceutically acceptable salt or MES, and (b) ortostaticeski mGluR2 agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including humans, for treatment or prevention of which is affected by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators, mGluR, or treatment or prevention of which he sposobstvuyuschie medicines such combination or product can be combined in one preparation, together with pharmaceutically acceptable carriers or diluents, or they may, individually, be placed in a separate drug together with pharmaceutically acceptable carriers or diluents.

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

Chemical experiments

Some methods for producing compounds according to this invention is illustrated in the following examples. Unless otherwise noted, all source materials received from suppliers and used without further purification.

Hereinafter in the description of "THF" means tetrahydrofuran; "DMF" means N,N-dimethylformamide; "EtOAc" means ethyl acetate; "CHM" means dichloromethane; "DME" means 1,2-dimethoxyethane; "DCE" means 1,2-dichloroethane; "DIPE" means diisopropyl ether; "DMSO" means dimethyl sulfoxide; "BINAP" means [1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine]; "DBU" means 1,8-diaza-7-bicyclo[5.4.0]undecen.

ISOLUTE® SCX2 is a strong cation exchange sorbent based on silica with chemically bound to functional groups propylsulfonyl acid. This sorbent can be used in the cartridge SOLUTE® SCX2 to separate the products of a chemical reaction from excess reagents and by-products.

Interaction with microwave irradiation was performed in a single reactor: a microwave reactor Initiator™ Sixty EXP (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).

Description 1

4-Benzyloxy-1-cyclopropylmethyl-1H-pyridine-2-he (O1)

(Methyl bromide)cyclopropane (3,68 g; 27,33 mmol) and potassium carbonate (10.3 g; 74,52 mmol) was added to a solution of 4-benzyloxy-1H-pyridin-2-she (5.0 g; 24.84 mmol) in acetonitrile (200 ml) and the mixture was heated at the temperature of reflux distilled for 16 hours. Then this reaction mixture was filtered through diatomaceous earth and concentrated under vacuum. The crude residue is then triturated with diethyl ether to obtain pure 01 (6,32 g; 98%) as a white solid.

Description 2

1-Cyclopropylmethyl-4-hydroxy-1H-pyridine-2-he (O2)

A mixture of intermediate compound O1 (2.0 g; 7,83 mmol) and a catalytic amount of 10% palladium on charcoal in ethanol (300 ml) was stirred in hydrogen atmosphere for two hours. This mixture was filtered through diatomaceous earth and the solvent evaporated under vacuum to obtain the intermediate O2 (1.3 g; 100%)which was used as is without further purification.

Description 3

4-Bromo-1-cyclopropylmethyl-1H-pyridine-2-he (O3)

Xibrom the d phosphorus (5,4 g; of 18.9 mmol) was added to a solution of intermediate compound O2 (1.42 g; 8.6 mmol) in DMF (140 ml) and the mixture was heated at 110°C for 1 hour. After cooling in an ice bath, the solution was distributed between water and EtOAc. After three extraction using EtOAc the combined organic fractions were dried (Na2SO4), filtered and the solvent evaporated under vacuum. The crude product was purified by column chromatography (silica gel; DHM as eluent). The desired fractions were collected and evaporated under vacuum to obtain the intermediate O3 (1,82 g; 93%).

Description 4

4-Benzyloxy-1-butyl-1H-pyridine-2-on (04)

1-Rambutan (3.75 g; 27,33 mmol) and potassium carbonate (10.3 g; 74,52 mmol) was added to a solution of 4-benzyloxy-1H-pyridin-2-she (5.0 g; 24.84 mmol) in acetonitrile (200 ml) and the mixture was heated at the temperature of reflux distilled for 16 hours. Then this reaction mixture was filtered through diatomaceous earth and concentrated under vacuum. The crude residue is then triturated with diethyl ether to obtain pure O4 (6,26 g; 98%) as a white solid.

Description 5

1-Butyl-4-hydroxy-1H-pyridine-2-he (O5)

A mixture of intermediate compounds O4 (2,01 g; 7,83 mmol) and a catalytic amount of 10% palladium on charcoal in ethanol (300 ml)was stirred in hydrogen atmosphere for two hours. This mixture was filtered through diatomaceous earth and the solvent evaporated under vacuum to obtain intermediate compound 05 (1.3 g; 100%)which was used without further purification in the next reaction stage.

Description 6

1-Butyl-3-chloro-4-hydroxy-1H-pyridine-2-he (O6)

N-Chlorosuccinimide (1.6 g; 11,96 mmol) was added to a solution of intermediate compound O5 (2.0 g; 11,96 mmol) in DMF (30 ml). This reaction mixture was stirred over night at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography (silica gel; 0-5% methanol/DHM as eluent) to give the intermediate compound 06 (2.0 g; 83%).

Description 7

4-Bromo-1-butyl-1H-pyridine-2-he (O7)

The intermediate connection O7 received from the intermediate O5, following the same methodology used for the synthesis of O3.

Description 8

1-Butyl-3-chloro-2-oxo-1,2-dihydropyridines-4-silt ether triftormetilfullerenov acid (O8)

Pyridine (1.60 ml; for 19.8 mmol) was added to a solution of intermediate compound 06 (2.0 g; 9,92 mmol) in DHM (80 ml), cooled to -78°C. the resulting solution was stirred for 10 minutes, after which was added triftormetilfullerenov anhydride (1,90 ml, 10.9 mmol). The floor is built the solution was stirred at -78°C for 3 hours. Then this mixture was heated to room temperature and was suppressed by addition of an aqueous saturated solution of ammonium chloride. This mixture was diluted with water and was extracted with DHM. The separated organic layer was dried (Na2SO4), filtered and the solvent evaporated under vacuum to obtain intermediate compound 08 (of 3.31 g; 100%) as a crude product, which was used as is for the next reaction stage without further purification.

Description 9

(2α,3α,3α)-1-Cyclopropylmethyl-4-(6-phenyl-3-Aza-bicyclo[3,1 .0]Gex-3-yl)-1H-pyridine-2-he (O9)

6-Phenyl-3-Aza-bicyclo[3.1.0]hexane (0,188 g; 1,184 mmol) (obtained according to the procedure described Renslo, Adam R. et al, Organic Letters (2005), 7(13), 2627-2630), palladium acetate(And) (0,0089 g; 0,0395 mmol), tert-piperonyl sodium (0,1896 g; 1,973 mmol) and BINAP (0,0368 g; 0,0592 mmol) was added to a solution of intermediate compound O3 (0.18 g; 0,789 mmol) in toluene (2 ml). This reaction mixture was heated at 100°C for 16 hours in a sealed tube, after which it was cooled to room temperature. Then the mixture was diluted with water (5 ml) and was extracted with EtOAc (3×5 ml). The combined organic fractions were dried (Na2SO4), filtered and the solvent evaporated under vacuum. The crude product was purified by column chromatography (silica gel; 0-3% methanol/DHM is as eluent). The desired fractions were collected and evaporated under vacuum to obtain the intermediate connection 09 (0,170 g; 58%) as a brown solid.

Description 10

(2α,3α,3α)-1-Butyl-4-[6-(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-he (O10)

6-(2,5-Dichloro-benzyl)-3-Aza-bicyclo[3.1.0]hexane (0,323 g; 1,251 mmol) (obtained according to the method described in WO 2007135529 A2 20071129 and Brighty, Katherine E. et al. in Synlett (1996), (11), 1097-1099), palladium(II) acetate (0,0109 g; 0,0481 mmol), tert-piperonyl sodium (0,231 g; 2,406 mmol) and BINAP (0,045 g; 0,0722 mmol) was added to a solution of intermediate compounds 07 (0,221 g; 0,962 mmol) in toluene (5 ml). The reaction mixture was heated at 100°C for 16 hours in a sealed tube, after which it was cooled to room temperature, filtered through diatomaceous earth and washed with dichloromethane. The solvent is evaporated under vacuum. The crude product was purified by column chromatography (silica gel; 0-1% mixture of methanol/7.NH3)/DHM as eluent). The desired fractions were collected and evaporated under vacuum to obtain the intermediate 010 (0,063 g; 16%) as a brown oil.

Description 11

(2α,3β,3α)-1-Butyl-4-[6-(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-he (O11)

6-(2,5-Dichloro-benzyl)-3-Aza-bicyclo[3.1.0]hexane (0,323 g; 1,251 m is ol) (obtained according to the method described in WO 2007135529 A2 20071129 and Brighty, Katherine E. et al. in Synlett (1996), (11), 1097-1099), palladium(II) acetate (0,0109 g; 0,0481 mmol), mpem-piperonyl sodium (0,231 g; 2,406 mmol) and BINAP (0,045 g; 0,0722 mmol) was added to a solution of intermediate compound 08 (0,221 g; 0,962 mmol) in toluene (4 ml). This reaction mixture was heated at 100°C for 16 hours in a sealed tube, after which it was cooled to room temperature, filtered through diatomaceous earth and washed with dichloromethane. The solvent is evaporated under vacuum. The crude product was purified by column chromatography (silica gel; 0-1% mixture of methanol/7.NH3)/DHM as eluent). The desired fractions were collected and evaporated under vacuum to obtain the intermediate 011 (0.1 g; 25%) as a brown oil.

Example 1

(2α,3α,3α)-3-Chloro-1-cyclopropylmethyl-4-(6-phenyl-3-Aza-bicyclo[3.1.0]Gex-3-yl)-1H-pyridine-2-on (compound E1)

A solution of intermediate compounds 09 (0.17 g; 0,444 mmol) and N-chlorosuccinimide (0,059 g; 0,444 mmol) in DHM (2 ml) was stirred at room temperature for 10 minutes. This reaction mixture is washed with saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, evaporated under vacuum and the crude product was purified by column chromatography (silica gel; 0-2% methanol/DHM in which the quality of eluent). The desired fractions were collected, evaporated under vacuum and the resulting solid was purified again by column chromatography (silica gel; 0 to 10% mixture of EtOAc/DHM as eluent) to obtain the compound E1 (of 0.085 g; 56%) as a white solid.

Melting point: 172,2°C.

1H NMR (500 MHz, CDCl3) δ million10.32-0.40 (m, 2H), 0.54-0.62 (m, 2H), 1.18-1.30 (m, 1H), 1.86 (broadened t, J=3.3 Hz, 1H), 1.93 (broadened s, 2H), 3.74 (broadened d, J=10.4 Hz, 2H), 3.76 (d, J=7.2 Hz, 2H), 4.23 (d, J=10.4 Hz, 2H), 5.86 (d, J=7.8 Hz, 1H), 7.03-7.08 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.24-7.31 (m, 2H).

Example 2

(2α,3α,3α)-1-Butyl-3-chloro-4-[6-[(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl-1H-pyridine-2-on (compound E2)

A solution of intermediate 010 (0,063 g; 0,155 mmol) and N-chlorosuccinimide (0,0206 g; 0,155 mmol) in DHM (3 ml) was stirred at room temperature for 15 minutes. This reaction mixture is washed with saturated aqueous NaHCO3. The organic layer was separated, dried (Na2SO4), filtered, evaporated under vacuum and the crude product was then purified by reverse-phase HPLC. The desired fractions were collected and evaporated under vacuum to obtain compound E2 (0,012 g; 17%) as a white solid.

1H NMR (500 MHz, CDCl3) δ million10.93 (t, J=7.4 Hz, 3H), 1.28-1.39 (m, 3H), 1.63-1.74 (m, 2H), 1.76 (broadened s, 2H), 3.63 (broadened d, J=101 Hz, 2H), 3.87 (t, J=7.4 Hz, 2H), 3.97 (d, J=6,7 Hz, 2H), 4.13 (d, J=10.1 Hz, 2H), 5.80 (d, J=7.8 Hz, 1H), 6.87-6.92 (m, 2H), 6.96 (d, J=7.8 Hz, 1H), 7.28 (d, J=8,4 Hz, 1H).

Example 3

(2α,3β,3α)-1-Butyl-3-chloro-4-[6-[(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-on (compound E3)

A solution of intermediate compound 011 (0.1 g; 0,245 mmol) and N-chlorosuccinimide (0,0327 g; 0,245 mmol) in DHM (3 ml) was stirred at room temperature for 15 minutes. This reaction mixture is washed with saturated aqueous NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated under vacuum. The crude product was purified by radial chromatography (chromatotron®) on silica gel using 0-1% mixture (methanol/7.NH3)/DHM as eluent. The desired fractions were collected and evaporated under vacuum to obtain compound E3 (0,038 g; 35%) as a white solid.

1H NMR (500 MHz, CDCl3) δ million10.92 (t, J=7.4 Hz, 3H), 1.27-1.38 (m, 2H), 1.47-1.56 (m, 1H), 1.63-1.72 (m, 2H), 1.91-1.97 (m, 2H), 3.77-3.83 (m, 2H), 3.84 (t, J=7.4 Hz, 2H), 4.05 (d, J=10,7 Hz, 2H), 4.10 (d, J=7.5 Hz, 2H), 5.77 (d, J=7,8 Hz, 1H), 6.83-6.88 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 7.26 (d, J=8,1 Hz, 1H).

Example 4

(2α,3α,3α)-1-Butyl-3-chloro-4-(6-prenyl-3-Aza-bicyclo[3.1,0]Gex-3-yl)-1H-pyridine-2-on (compound E4)

A mixture of 6-phenyl-3-Aza-bicyclo[3.1.0]hexane (0.1 g; 0,628 mmol) (obtained according to met the dick, described Renslo, Adam R. et al, Organic Letters (2005), 7(13), 2627-2630), the intermediate connection 08 (0,139 g; 0,419 mmol) and diisopropylethylamine (0,146 ml; 0,837 mmol) in acetonitrile (2 ml) was heated at 180°C for 5 minutes under microwave irradiation. After cooling to room temperature the solvent is evaporated under vacuum. The crude residue was purified by column chromatography (silica gel; 0-20% mixture of EtOAc/DHM as eluent) and then by ion exchange chromatography using an ISOLUTE cartridge® SCX2 (elution Meon). The desired fractions were collected and evaporated under vacuum to obtain compound E4 (0,130 g; 91%) as a cream solid.

Melting point: 185,9°C.

1H NMR (400 MHz, CDCl3) δ million10.94 (t, J=7.4 Hz, 3H), 1.29-1.41 (m, 2H), 1.65-1.76 (m, 2H), 1.86 (broadened t, J=3,4 Hz, 1H), 1.90-1.96 (m, 2H), 3.68-3.77 (m, 2H), 3.88 (t, J=7,3 Hz, 2H), 4.22 (d, J=10.4 Hz, 2H), 5.83 (d, J=7.9 Hz, 1H), 6.98 (d,, J=7.9 Hz, 1H), 7.03-7.08 (m, 2H), 7.15-7.21 (m, 1H), 7.24-7.31 (m, 2H).

Physico-chemical data of

Liquid chromatography/mass spectrometry (IHMS)

Measurement using HPLC was performed using a chromatograph HP 1100 company Agilent Technologies include four-channel pump with degasser, auto sampler, column thermostat, diode matrix detector (DMD) and a column as specified below. Flow from the column to the MS-spectrometer was divided. The MS detector was equipped with a light source is com ionization elektrorazpredelenie. As a gas atomizer used nitrogen. The source temperature was maintained at 140°C. data acquisition was performed using the software MassLynx-Openlynx.

Reversed-phase HPLC was carried out on the cartridge XDB-C18 (1,8 μm, and 2.1×30 mm) of the company Agilent, with a flow rate of 1 ml/min, at 60°C. under the conditions Used in the gradient consisted of the following: 90% A (0.5 g/l solution of ammonium acetate), 5% B (acetonitrile), 5% C (methanol) to 50% b and 50% for 6.5 minutes, to 100% In 7 minutes and equilibrated to initial conditions over the interval from 7.5 minutes until 9.0 minutes. The volume of injected sample was 2 µl. Mass spectra of a high-resolution time-of-flight, TOF) was obtained in the positive mode ionization by scanning from 100 to 750 in 0.5 seconds using a time delay of 0.1 seconds. The voltage on the capillary needle was 2.5 kV, and the voltage at the cone was 20 Century Leucine-enkephalin was a standard substance used for internal calibration mass.

The melting point

For a number of compounds, melting points were determined in open capillary tubes on the instrument Mettler FP62. The melting point was measured at the temperature gradient of 3 or 10°C/min. The maximum temperature was 300°C. the melting Point was read from a digital display and was obtained with the experimental errors that are typically associated with these the analytical method.

Nuclear magnetic resonance (NMR)

Spectra1H NMR were recorded either on a spectrometer Bruker DPX400 or Bruker AV-500 with standard pulse sequences, operating at 400 and 500 MHz, respectively. All presents chemical shifts (b) are expressed in ppm (m-1in weak fields from tetramethylsilane (TMS), which was used as an internal standard.

Table 1 lists the compounds of formula (I)obtained according to one of the above examples.

Table 1

No. ConnArXR1StereochemistryMelting point (°C)MH+Retention time (min)
E1phenyllink(2α,3α,3α)172,23434,71
E22,5-dichloro-phenyl (2α,3α,3α)n/a4415,24
E32,5-dichloro-phenyl(2α,3β,3α)n/a4415,12
E4phenyllink(2α,3α,3α)185,93434,71
No. Conn. indicates the connection number; n/a means "not determined".

The drugs examples

Connections proposed in the present invention are positive allosteric modulators of mGluR2. It turns out that these compounds enhance glutamate responses through binding to an allosteric site, and not with the glutamate-binding site. Answer mGluR2 on the concentration of glutamate is increased in the presence of compounds of the formula (I). Expect the compounds of formula (I) are the order effect essentially on mGluR2 due to its ability to enhance the functioning of the receptor. The behavior of positive allosteric modulators tested against mGluR2 by using the method of analysis based on the binding of [35S]γS described below, and which is suitable for the identification of such compounds, and more specifically, compounds of formula (I)shown in table 2.

Analysis of the binding of [35S]γS

Analysis of the binding of [35S]γS represents a function, based on the use of membranes analysis used to study the functioning associated with G-protein receptor (GPCR), in accordance with which the measure adherence neytralinogo analogue of GTP, [35S]γS (guanosin-5'-triphosphate, labeled with gamma-emitting35S). the α-Subunit of G-protein catalyzes the exchange of guanosine-5'-diphosphate (GDF) guanosin-5'-triphosphate (GTP), and upon activation of GPCR agonist [35S]γS attached and cannot be split for the continuation of the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.). The number of attached radioactive [35S]γS is a direct measure of the activity of a G protein, and hence can be used to determine the activity of the agonist. Receptors mGluR2, as shown, preferably paired with Gαl-protein, preferred pairing for this method, and therefore it is widely used to study receptor activity receptor mGluR2 lines, recombinant cells, and in tissues (Schaffhauser et al 2003, Pinker-ton et al, 2004, Mutel et al (1998) Journal of Neurochemistry. 71:2558-64; Schaffhauser et al (1998) Molecular Pharmacology 53:228-33). Here the authors describe the use of analysis of binding of [35S]γS when using membranes of cells transfected with the human mGluR2 receptor, and adapted, as in the work Schaffhauser et al ((2003) Molecular Pharmacology 4:798-810)for detection of properties of the compounds according to this invention in terms of positive allosteric modulation (PAM). Preparation of membranes

SNO-cells (cells Chinese hamster ovary) were cultured until reaching incomplete confluently and stimulated with 5 mm butyrate for 24 hours before washing in PBS (phosphate buffered saline) and then collected by scraping in the buffer for homogenization (50 mm Tris-HCl buffer, pH of 7.4, 4°C). Cell lysates quickly homogenized (15 seconds) using a homogenizer (Ultra-Turrax. The homogenate was centrifuged at 23500 on for 10 minutes and supernatant was discarded. Sediment resuspendable in 5 mm Tris-HCl, pH 7.4 and centrifuged again (30000 l; 20 min, 4°C). The final precipitate resuspendable in 50 mm HEPES (hydroxyethylpiperazine-N'-2-econsultancy acid), pH 7.4 and stored at -80°C in the appropriate aliquot to use. The protein concentration was determined by the method of Bradford (Bio-Rad, USA) with bovine serum is albumin as the standard.

Analysis of the binding of [35S]γS

Measurement of positive allosteric modulatory activity mGluR2 test compounds in membranes containing human mGluR2 receptors was performed using frozen membranes were thawed and quickly homogenized prior to incubation in 96-well microplate (15 µg/well for analysis, 30 minutes, 30°C) in buffer for analysis (50 m HEPES pH of 7.4, 100 mm NaCl, 3 mm MgCl2, 50 μm (GDF), 10 μg/ml saponin,) with increasing concentrations of positive allosteric modulator (from 0.3 nm to 50 μm) and either glutamate in the minimum pre-determined concentration (FRAME analysis), or without the addition of glutamate. For FRAMES-analysis of membranes pre-incubated with glutamate at a concentration of EU25, i.e. the concentration that gives 25% of the maximum glutamate response, and in line with published data (Pin et al. (1999) Eur. J. Pharmacol. 375:277-294). After addition of [35S]γS (0.1 nm, final concentration) to obtain the total volume of the reaction mixture, 200 μl, the microplate was shaken for a short time and then incubated, making possible the accession of [35S]γS when activated (30 minutes, 30°C). The reaction was stopped by rapid vacuum filtration through glass fiber filter place the ins (96-well filter plates GF/B, Unifilter, Perkin-Elmer, Downers Grove, USA) microplate using a harvester to collect cells for 96-hole tablet (Filtermate, Perkin-Elmer, USA), and then by three times washing with 300 μl chilled on ice wash buffer (Na2PO4·2H2O 10 mm, NaH2PO4·H2O 10 mm, pH=7,4). The filters were then air-dried and added to each well 40 μl of liquid scintillation mixture (Microscint-O) and the number of contacting membranes [35S]γS was measured in a scintillation tablet reader for 96-well plates (Top-Count, Perkin-Elmer, USA). Nonspecific binding of [35S]γS determined in the presence of cold 10 μm GTP. Each curve built at least once using a double sampling on one result and 11 concentrations.

Data analysis

The curves of the concentration-response for representative compounds of the present invention in the presence of added mCluR2-agonist of glutamate at a concentration corresponding EC25to determine the positive allosteric modulation (PAM), was obtained when using the software GraphPad Prism (Graph Pad Inc., San Diego, USA). Curves were approximatively in accordance with the four-parameter logistic equation (Y=bottom value+(the upper value-lower value)/(1+10^((LogEC50-X)*hill coefficient), enabling determination of ve is icin EU 50. EC50represents the concentration that causes half of the maximum amplification of the glutamate response. It calculates by subtracting the maximum of glutamate responses in the presence of fully saturated concentration of positive allosteric modulator of the glutamate response in the absence of a positive allosteric modulator. The concentration that causes half-maximal effect, then count as EC50.

Table 2: pharmacological data of the compounds according to the invention

All compounds were tested in the presence of mCluR2-agonist of glutamate at a predefined concentration EU25to determine the positive allosteric modulation (γS-PAM). Shown values are average values simultaneously measured values on the curve concentration-response 11 concentrations of at least one experiment. All the tested compounds showed the value of pEC50(-logEC50) more than 5,0, from 6,56 to 7,05. It is estimated that the error in the determination of the values of pEC50for an individual experiment is approximately 0.3 log units.

No. of connectionsγS-hR2 FRAMES, pEC50
E1 6,56
E26,91
E36,90
E47,05

Examples of compositions

The term "active ingredient"as used throughout these examples relates to the final compound of formula (I), its pharmaceutically acceptable salt, solvate and stereochemical isomeric forms.

Typical examples of recipes of preparation according to the invention are as follows:

1. Tablets

The active ingredient5-50 mg
Phosphate calcium20 mg
Lactose30 mg
Talc10 mg
Magnesium stearate5 mg
Potato starchup to 200 mg

In this example, the active ingredient may be replaced by the same quantity of any of the compounds of the present invention, in particular the same amount of any of compounds according to the examples.

2. Suspension

Aqueous suspension is prepared for peroral the th introduction thus, to each 1 ml contains from 1 to 5 mg of one of the active compounds, 50 mg of carboxymethylcellulose sodium, 1 mg sodium benzoate, 500 mg of sorbitol and water up to 1 ml

3. Injectable composition

Parenteral composition is prepared by mixing 1.5 percent (by weight) of active ingredient according to the invention in 10% (by volume) solution of propylene glycol in water.

4. Ointment

The active ingredient5-1000 mg
Stearyl alcohol3 g
Lanolin5 g
White petrolatum15 g
Waterto 100 g

In this example, the active ingredient may be replaced by the same quantity of any of the compounds of the present invention, in particular the same amount of any of compounds according to the examples.

Reasonable changes should not be considered as going beyond the scope of the invention. It is obvious that the described thus the invention can be modified by experts in the field of technology in various ways.

1. The compound having the formula (I)

or stereochemical and Amarna form, where
R1represents a C1-6alkyl or C1-3alkyl, substituted C3-7cycloalkyl;
R2represents halogeno, trifluoromethyl, C1-3alkyl or cyclopropyl;
X represents a covalent bond, O, or O-CH2;
Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,
where n is 1, 2 or 3;
where each R4is a halogen;
or
its pharmaceutically acceptable salt or accession or MES.

2. The compound according to claim 1 or its stereochemical isomeric form, where
R1is a 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
R2represents chloro;
X represents a covalent bond or-O-CH2;
Ar represents unsubstituted phenyl or phenyl substituted by n radicals R4,
where n is 1, 2 or 3;
where each R4represents halogeno;
or its pharmaceutically acceptable salt or accession or MES.

3. The compound according to claim 1 or its stereochemical isomeric form, where
R1is a 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
R2represents chloro;
X represents a covalent bond or-O-CH2;
Ar represents an unsubstituted who enyl or phenyl, substituted by n radicals R4,
where n is equal to 2;
where each R4represents halogeno;
or its pharmaceutically acceptable salt or accession or MES.

4. The compound according to claim 1 or its stereochemical isomeric form, where
R1is a 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
R2represents chloro;
X represents a covalent bond or-O-CH2;
Ar is an unsubstituted phenyl or 2,5-dichlorophenyl;
or its pharmaceutically acceptable salt or accession or MES.

5. The compound according to claim 1, chosen from:
(2α,3β,3α)-1-butyl-3-chloro-4-[6-[(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-it;
(2α,3α,3α)-1-butyl-3-chloro-4-[6-[(2,5-dichloro-phenoxymethyl)-3-Aza-bicyclo[3.1.0]Gex-3-yl]-1H-pyridine-2-it;
(2α,3α,3α)-1-butyl-3-chloro-4-(6-phenyl-3-Aza-bicyclo[3.1.0]Gex-3-yl)-1H-pyridine-2-it;
(2α,3α,3α)-3-chloro-1-cyclopropylmethyl-4-(6-phenyl-3-Aza-bicyclo[3.1.0]Gex-3-yl)-1H-pyridine-2-it;
or its pharmaceutically acceptable salt or accession or MES.

6. Pharmaceutical composition having activity positive allosteric modulators of metabotropic glutamate 2 receptor subtype and containing a therapeutically effective amount of a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excep the UNT.

7. The compound according to any one of claims 1 to 5 for use as a drug with activity positive allosteric modulators of metabotropic glutamate 2 receptor subtype.

8. The use of compounds according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6 for the manufacture of a medicinal product for the treatment or prevention of a condition in a mammal, the treatment or prevention of which is affected by the neuromodulatory effect of positive allosteric modulators of metabotropic glutamate receptor 2 subtype (mGluR2), or the treatment or prevention of which he contributes.

9. The use of compounds according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6 for the manufacture of a medicinal product for the treatment or prevention of Central nervous system disorders selected from the group consisting of anxiety disorders, psychotic disorders, personality disorders, disorders caused by the admission of substance use, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, disorders of childhood, cognitive disorders, neurodegeneration, neurotoxicity and ischemia.

10. The use according to claim 9, where the disorder of the Central nervous system is an anxiety disorder is selected from the group consisting of agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, social phobia and other phobias.

11. The use according to claim 9, where the disorder of the Central nervous system is a psychotic disorder selected from the group consisting of schizophrenia, crazy disorder, schizoaffective disorder, schizophreniform disorders and psychotic disorders, caused by taking psychoactive substances.

12. The use according to claim 9, where the disorder of the Central nervous system is a mood disorder selected from the group consisting of bipolar disorder (type I and II), cyclothymic disorder, depression, estimatesare disorder, major depressive disorder and mood disorders, caused by taking psychoactive substances.

13. The use according to claim 9, where the disorder of the Central nervous system selected from the group consisting of anxiety, schizophrenia, migraine, depression and epilepsy.

14. The use of compounds according to any one of claims 1 to 5 in combination with orthotricyclen mGluR2 agonist for the manufacture of a medicinal product for treating or preventing the condition described in any of PP-13.

15. Product br/> a) compound according to any one of claims 1 to 5; and
b) ortostaticeski mGluR2 agonist,
as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, the treatment or prevention of which is affected by the neuromodulatory effect of allosteric modulators of mGluR2, or treatment or prevention of which he contributes.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a non-hydratable crystal form (polymorph A) of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-[4-cyano-2-methyl-6-[(methylamino)-carbonyl]phenyl]-1H-pyrazole-5-carboxamide (compound 1), which is characterised by an X-ray diffraction pattern having reflection angle peaks given in the claim. According to the invention, the method involves heating a hydratable crystal form of compound 1 (polymorph B), having X-ray diffraction characteristics given in the claim, at temperature from about 40°C to the boiling point of the solvent of the mixture, which contains a solvent selected from a group consisting of water, n-heptane, 1-chlorobutane, toluene, 1-butanol and 1-pentanol.

EFFECT: obtaining a stable polymorph A of compound 1, which enables to obtain stable solid insecticide compositions.

15 cl, 2 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 4-(4-cyano-2-thioaryl)- dihydropyrimidin-2-one derivatives of formula (I), a method for preparing and using them. In formula , , both A and E mean C-R7, wherein R7 mean hydrogen, Z means O, n means the number 0,1 or 2, R1 means (C1-C6)-alkyl which may be substituted by the group hydroxy, (C1-C4)-alkoxy,(C3-C6)-cycloalkyl, phenyl or 5- or 6-member heteroaryl with two heteroatoms specified in nitrogen or sulphur, or may be substituted up to three times by fluorine, or means (C3-C6)-cycloalkyl or phenyl, R2 means hydrogen, R3 means cyano or a group of formulas -C(=O)-R8, -C(=O)-O-R8 or -C(=O)-NH2, wherein R8 means (C1-C6)-alkyl or (C3-C6)-alkenyl, R4 means methyl or ethyl, or R3 and R4 are linked to each other and together form an annulated group of formula (II), R9 means hydrogen, (C1-C6)-alkyl or (C3-C6)-cycloalkyl with (C1-C6)-alkyl may be substituted by a hydroxy group, aminocarbonylamino or (C1-C4)-acylamino, R5 means hydrogen or (C1-C6)-alkyl. The other group and radical values are specified in the patent claim.

EFFECT: compounds possess the properties of a neutrophil elastase (HNE) inhibitor and can find application in treating and/or preventing pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary emphysema, mediated by neutrophil elastase (HNE) activity.

16 cl, 4 tbl, 10 dwg, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely neurology, and concerns treating multiple sclerosis. That is ensured by administering a pharmaceutical composition containing an activated-potentiated form of human gamma-interferon (IFN-γ) antibodies and an activated-potentiated form of brain-specific protein S-100 antibodies.

EFFECT: drug provides the effective treatment of multiple sclerosis ensured by the synergetic action of the ingredients of the composition.

11 cl, 2 ex, 1 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to oxime derivatives of 3,5-seco-4-nor-cholestane of formula (I) use thereof as medicinal agents, having cytoprotective, specifically neuroprotective, cardioprotective and/or hepatoprotective action, as well as pharmaceutical compositions based thereon. In formula (I) R1 is -CH3, R2 is C1-C8 alkyl group, optionally substituted with 1-4 substitutes selected from a halogen atom, a hydroxyl group or a group of formula Rc-Q-(CH2)n- (A), in which (i) n is an integer which can assume any value from 1 to 4; and (ii) Q is an oxygen atom or a -NRa group, in which Ra is selected from a hydrogen atom or a C1-C6 alkyl group, and Rc is a hydrogen atom or a group of one of the formulae (C) or (D) or (iii) Q is a -O-C(O)- group or a -NRa-C(O)- group, in which Ra is as defined earlier, and Rc is a hydrogen atom or C1-C6 alkyl, aryl, heteroaryl group, heterocycle, R3 is a hydrogen atom; R4 is a hydrogen atom; R5 is a hydrogen atom or hydroxylamino group (-NH2-OH); or R4 and R5 togethr form an additional carbon-carbon bond between carbon atoms to which they are bonded; R6 is a hydrogen atom; R7 is a group selected from (G1, G2, G3, G4, G5 or G6) optionally substituted with a halogen atom or hydroxyl group.

EFFECT: improved properties of compounds.

22 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to veterinary and medicine and specifically to compositions which include one or more long-chain polyunsaturated fatty acids, one or more compounds which release nitrogen monoxide, and one or more medium-chain triglycerides, and methods of using such compositions to enhance cognitive function, reduce or prevent deterioration of social behaviour, reduce or prevent age-related behavioural changes, enhance learning capability, maintain optimum brain functioning, facilitate learning and memory, reduce memory loss, slow down brain ageing, prevent or treat stroke and prevent or treat dementia in humans and pets.

EFFECT: group of inventions improves effectiveness of enhancing cognitive function.

113 cl, 5 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel medication possessing antidepressant, anxiolytic and nootropic activity, which represents compound of general formula where: X is NH or 1,4-piperasino; R1=H or CH3; R2=H, OCH3 or N(CH3)2.

EFFECT: on experimental models in vivo compounds, possessing original spectrum of psychotropic action, exceed medications of different pharmacological groups - aphobazolum, melipramin, phenotropil, diazepam in complex of useful qualities, and can be applied in treatment of patients with anxiety and depressive disorders.

4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel medication, possessing nootropic and antihypoxic activity, which represents arylamides of 2-[4-oxo-3(4H)quinazolinyl]acetic acid of general formula where R=o-CH3, n-CH3 or 2,3-phenylene. Compounds demonstrated original spectrum of psychotropic action, exceeding in complex of useful properties medications of different pharmacological groups - piracetam, phenibut, phenotropil, mexidol, on experimental models in vivo.

EFFECT: compounds can be widely applied in treatment of patients with organic affection of brain.

3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology and neurophysiology, therapy and gerontology, and concerns treating chronic cerebral ischemia. That is ensured by adding the food ration with the foodstuff 'Samarskiy Zdorovyak' in a daily dose of 180 g, three times a day 60 g per one intake - with breakfast, lunch and dinner with underlying common ethiopathogenetic drug therapy .

EFFECT: method provides higher clinical effectiveness in chronic cerebral ischemia ensured by better pharmacodynamics and pharmacokinetics of the drug preparations used in treating the given disease that in turn promotes normalising the vasoactive, neurometabolic and neuroprotective brain functions.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacology and clinical medicine, and describes a pharmaceutical composition in the form of tablets containing a S1P receptor modulator representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or a pharmaceutically acceptable salt thereof, and additive substances: microcrystalline cellulose, sodium carboxymethyl starch, calcium stearate or magnesium stearate in the following proportions.

EFFECT: composition is more stable and has less side effects.

3 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I where A is such as given in the invention formula, R is selected from the group consisting of H and C1-6 alkyl, n and p each is independently selected from 0, 1 and 2, on condition that n + p = 2; Y represents -O- or -S-; R1, R2, R3, R4 in each position are independently selected from H and C1-6 alkyl; R5 is selected from the group consisting of -C(O)-CH2-indol-3-yl, -C(O)-(CH2)2-indol-3-yl, -C(O)-(CH2)3-indol-3-yl, trans -C(O)-(CH=CH)-indol-3-yl, -SO2-4-fluorophenyl, -C(O)-CH(n-propyl)2, -C(O)-(4-hydroxy-3,5-di-tert-butylphenyl), -C(O)-CH(NH2)-CH2-indol-3-yl and -C(O)-CH2CH3; and R6 represents H. Invention also relates to pharmaceutical composition for modulation of muscarinic receptor M1, containing formula I compounds, and methods of treating disease or state, curable by modulator of muscarinic receptor M1.

EFFECT: formula I compounds as modulators of muscarinic receptor M1.

33 cl, 1 tbl, 27 ex

FIELD: medicine.

SUBSTANCE: what is described is N-(4-acetoxybenzoyl)glycine lithium salt of formula I: .

EFFECT: higher tranquilising and nootropic action.

4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula

or a pharmaceutically acceptable salt thereof, where: R1 is O or F; R3 is H, Me, Et, OH, MeO, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, HOCH2CH2-, , , , , or ; R7 is cyclopropyl-CH2- or C1-C4alkyl, where said alkyl is optionally substituted with one or more F; R8 is Br, I or SMe; and R9 is CH3, CH2F, CHF2, CF3, F or Cl. The invention also discloses use of said compound in preparing a medicinal agent for treating a hyperproliferative disorder or an inflammatory condition, as well as a MEK inhibiting pharmaceutical composition.

EFFECT: novel compounds are obtained and described, which are MEK inhibitors and can useful in treating hyperproliferative diseases such as cancer and inflammation in mammals and inflammatory conditions.

13 cl, 25 ex, 8 tbl, 15 dwg

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