Substituted n-phenylpyrrolidinyl methylpyrrolidine amides and therapeutic use thereof as modulators of histamine h3 receptor

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

 

PRIOR art

The scope of the invention

The invention relates to a group of substituted N-phenylpropionylamino. The compounds of this invention are modulators of H3 receptors and, therefore, suitable for use as pharmaceuticals, in particular for the treatment and/or prevention of various diseases modulated by H3 receptors, including diseases associated with the Central nervous system. In addition, the present invention also relates to methods for substituted N-phenylpropionylamino and their intermediates.

Description of the prior art

Histamine is a common molecule-messenger released by mastocytoma, enterochromaffin-like cells and neurons. Physiological effects of histamine mediated four pharmacologically defined receptors (H1, H2, H3 and H4). All histamine receptors have seven transmembrane domains and belong to the superfamily of receptors associated with G-protein (GPCR).

The H1 receptor was the first member of the family histamine receptors that have been identified pharmacologically, in the process of developing classical antihistamines (antagonists), such as diphenhydramine and Fexofenadine. Despite the fact that the antagonism is of eceptor N1 in the immune system is commonly used to treat allergic reactions the H1 receptor is also expressed in various peripheral tissues and the Central nervous system (CNS). In the brain H1 is involved in the control of wakefulness, mood, appetite and the secretion of hormones.

The H2 receptor is also expressed in the Central nervous system, where it can modulate several processes, including cognitive function. However, the H2 receptor antagonists were mainly designed to improve the condition when stomach ulcers due to inhibition mediated by histamines secretion of gastric acid parietal granulocyte. To the classical H2 antagonists include cimetidine, ranitidine and famotidine.

It should also be noted that the function of the H4 receptor is still not precisely determined, but it may affect immune regulation and inflammatory processes.

The H3 receptors have also been pharmacologically identified in the Central nervous system, heart, lungs and stomach. The H3 receptor is significantly different from the other histamine receptors, showing low sequence homology (H1: 22%, H2: 21%, H4: 35%). H3 is a presynaptic autoreceptor on histamine neurons in the brain, as well as the presynaptic heteroreceptors in not containing histamine neurons in the Central and peripheral nervous systems. In addition to histamine H3 also modulates the release and/or synthesis of other natrun is smitheram, including acetylcholine, dopamine, norepinephrine and serotonin. It is especially important to note that indirect H3 presynaptic modulation of the release of histamine provides active regulation of receptor H1 and H2 in the brain. Modulating multiple channels of signal transmission of the neurotransmitter, H3 can participate in various physiological processes. In fact, the results of an extensive pre-clinical studies show that H3 plays a role in cognitive functions, the cycle of sleep-wakefulness and energy homeostasis.

Modulators of the function H3 can be used for the treatment of obesity and disorders of the Central nervous system (schizophrenia, Alzheimer's disease, attention deficit disorder with hyperactivity disorder, Parkinson's disease, depression and epilepsy), sleep disorders (narcolepsy and insomnia), cardiovascular disease (acute myocardial infarction), diseases of the respiratory system (asthma), and gastrointestinal disorders. See, in General, Hancock, Biochem. Pharmacol. 2006 Apr. 14;71(8):1103-13 and Esbenshade et al. Mol Interv. 2006 Apr.; 6(2):77-88, 59.

Recently it was found that compounds, which to a certain extent, structurally related to the compounds of the present invention are antagonists of the receptor melaninconcentrating hormone (sit), see, in particular, U.S. patent No. 7223788. Thus is should be noted, what is not disclosed information about the activity of the compounds presented herein, in respect of the site of the H3 receptor.

All these sources are incorporated herein fully by reference.

Thus, the aim of the present invention is to provide a group of substituted N-phenylpropionylamino as selective ligands of H3 receptors for the treatment of regulated receptor H3 disorders of the Central nervous system.

Another objective of the present invention is to provide methods of obtaining substituted N-phenylpropionylamino as disclosed in this document.

Other purposes and other applications of the present invention will become apparent from the detailed description that follows.

BRIEF description of the INVENTION

Was unexpectedly discovered that compounds of the formula (I) can be used as antagonists and/or inverse agonists of H3 receptors. It should also be noted that the compounds of formula I is not covered by the information provided in U.S. patent No. 7223788. Moreover, unexpectedly at present, it was found that the compounds of formula (I) exhibit selective activity only in respect of H3 receptors and exhibit low activity in relation to the site of receptor sit-1, and this aspect of the invention R is camping even more apparent from the following detailed description.

Thus, in accordance with the practice of the present invention features a compound of formula (I):

where R, R1, R2and R3are the same or different and, independently of one another, are selected from hydrogen, (C1-C4)alkyl or CF3;

R4is selected from the group comprising phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, chinoline, naphthyridine, indolyl, benzoimidazolyl, benzofuranyl, bromanil, 4-oxo-4H-chromenes, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxole and 2.5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepine; where the specified R4optional one or more times substituted by the Deputy selected from the group including halogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamine, benzoyloxymethyl, piperidinyl, N-acetylpiperidine, pyrrolyl, imidazolyl and 5-oxo-4,5-dihydropyrazolo.

The present invention also includes various salts of compounds of formula (I), including the various enantiomers or diastereoisomers of the compounds of formula (I).

In other aspects of the present invention also offers a variety of pharmaceutical compositions containing one or more compounds of the formula (I), and their therapeutic use for edema various ill the deposits, partly and/or fully mediated by the H3 receptor.

DETAILED description of the INVENTION

Used in this document, the terms have the following meanings:

Used in this document the expression(C1-C6)alkyl" includes methyl and ethyl groups, and linear or branched through boutelou, pentelow and hexoloy group. Particular alkyl groups are methyl, ethyl, n-sawn, ISO-propyl and tert-bucilina. Derived expressions such as "(C1-4)alkoxy", "(C1-4)thioalkyl", "C1-4)alkoxy (C1-4)alkyl", "hydroxy(C1-4)alkyl", "(C1-4)alkylaryl", "C1-4)alkoxycarbonyl(C1-4)alkyl", "(C1-4)alkoxycarbonyl", "amino(C1-4)alkyl", "(C1-4)alkylamino", "C1-4)allylcarbamate(C1-6)alkyl", "(C1-4)dialkylamino)(C1-4)alkyl", "mono - or di-(C1-4)alkylamino(C1-4)alkyl", "amino(C1-4)alkylaryl", "diphenyl(C1-4)alkyl", "phenyl(C1-4)alkyl", "phenylcarbamoyl(C1-4)alkyl" and "phenoxy(C1-4)alkyl", should be interpreted accordingly.

Used herein, the expression "cycloalkyl" includes all known cyclic radicals. Typical examples of "cycloalkyl" include, without limitation, cyclopropyl, cyclobutyl is, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Derivative notations such as "cycloalkane", "cycloalkenyl", "cycloalkenyl", "cycloalkylcarbonyl", should be interpreted accordingly.

Used in this document the expression(C2-6)alkenyl includes atenilol, as well as linear and branched propenyloxy, butenyloxy, pantanillo and hexenyl group. Similarly, the expression(C2-6)quinil includes etinilnoy and propenyloxy groups, and linear and branched butenyloxy, Punchinello and hexylamino group

Used in this document the expression(C1-4)acyl" has the same meaning as "(C1-6)alkanoyl", which may be structurally represented as "R-CO -, where R - (C1-3)alkyl, in accordance with the herein defined. In addition, (C1-5)alkylsulphonyl" has the same meaning as (C1-4)acyl. In particular, (C1-4)acyl" means a formyl, acetyl or atenolol, propanolol, n-butanoyloxy and other groups. Derived expressions such as "(C1-C4)acyloxy and(C1-C4)aryloxyalkyl", should be interpreted accordingly.

Used here, the expression(C1-C6)perfluoroalkyl" means that all the atoms in the of aroda in the specified alkyl group substituted by fluorine atoms. Specific examples are triptoreline and panafcortelone and linear or branched heptafluoropropyl, nonattribution, undecafluoropentyl and tridecafluorohexyl group. The derived expression(C1-C6)perfluoroalkyl" should be interpreted accordingly.

Used in this document the expression(C6-C10)aryl" means substituted or unsubstituted phenyl or naphthyl. Specific examples of the substituted phenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3-, 1,4-xylyl, 1-methylnaphtho, 2-methylnaphtho etc. "Substituted phenyl" or "substituted naphthyl" also includes any possible substituents, further defined herein or well known to specialists. The derived expression(C6-C10)arylsulfonyl" should be interpreted accordingly.

Used in this document the expression(C6-C10)aryl(C1-C4)alkyl" means (C6-C10)aryl, as defined herein, attached to a (C1-C4)alkyl, in accordance with the herein defined. Typical examples are benzyl, phenylethyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.

Used herein, the expression "heteroaryl" includes all known aromatics is their radicals, containing a heteroatom. A typical 5-membered heteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl, isopropyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazole and the like. A typical 6-membered heteroaryl radicals include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and similar radicals. Typical examples of bicyclic heteroaryl radicals include benzofuranyl, benzothiophene, indolyl, chinoline, ethenolysis, cannoli, benzimidazolyl, indazoles, perindopril, peridotitic and similar radicals.

Used in this document the terms "heterocycle" includes all known cyclic radicals containing recovered heteroatom. A typical 5-membered heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophene, pyrrolidine, 2-thiazolyl, tetrahydrofuryl, tetrahydrooxazolo and similar radicals. For exemplary 6-membered heterocyclic radicals include piperidinyl, piperazinil, morpholinyl, thiomorpholine and similar radicals. Various other heterocyclic radicals include, without limitation, aziridinyl, azepane, diazepan, diazabicyclo[2.2.1]hept-2-yl and triazinyl and the like.

"Halogen" or "halo" means chlorine, fluorine, bromine or iodine.

Used here t is pmin "patient" means a warm-blooded animal, for example, rats, mice, dogs, cats, Guinea pigs and primates, such as humans.

Used in this document the expression "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, subsidiary or other substance that is mixed with the compound constituting the object of the present invention, to form a pharmaceutical composition, i.e., dosage form, which you can enter the patient. One example of such a carrier is a pharmaceutically acceptable oil, commonly used for parenteral administration.

Used herein, the term "pharmaceutically acceptable salts" means salts of the compounds of the present invention can be used in medicinal preparations. However, other salts may be useful in producing compounds in accordance with the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include an acid additive salt, which may be formed, for example, by mixing the solution of the compounds in accordance with the present invention with a solution of a pharmaceutically acceptable acid, for example hydrochloric acid, Hydrobromic acid, nitric acid, sulfamic acid is you, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluensulfonate acid, fumaric acid, maleic acid, hydroxymaleimide acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, propionic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Can also form acid salts of metals, such as monohydrogenphosphate sodium and potassium hydrosulfate. In addition, the thus obtained salt may be a mono - or disubstituted salts are acidic and can be essentially anhydrous hydrated. Moreover, if the compounds of the present invention are the acid function, suitable their pharmaceutically acceptable salts can be classified as alkali metal salts, for example sodium or potassium, salts of alkaline earth metals such as calcium salt or magnesium, and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts.

Used herein the term "prodrug" and eat a common value in this field. One such definition includes pharmacologically inactive chemical substance that, metabolizers or chemically converted under the influence of the biological system such as the system of mammals, converted into a pharmacologically active substance.

The term "stereoisomers" is a General term used for all isomers of individual molecules that differ only in the spatial orientation of their atoms. To them, as a rule, are mirror isomers, which usually exist in the presence of at least one center of asymmetry (enantiomers). If the connection forming the subject of the present invention have two or more centers of asymmetry, they may also exist in the form of diastereoisomers, in addition, some individual molecules can exist in the form of geometric isomers (CIS/TRANS). Similarly, the compounds of the present invention may exist in a mixture of two or more structurally distinct forms, which are in rapid equilibrium, commonly known as tautomers. Typical examples of tautomers include keto-enol tautomers, phenol-keto, the tautomers, nitroso-Aksinya the tautomers, imino-enaminone the tautomers, etc. Should be understood that all such isomers and mixtures thereof in any proportion and helped it become the Ute in the scope of the present invention.

Used in this document the symbols "R" and "S" are applied as widely used in organic chemistry to indicate the specific configuration of the chiral center. The designation "R" (rectus, right) refers to the configuration of the chiral center with the location of higher rank groups clockwise (from the group with the highest rank to the other the least), when viewed along the direction of the group, the lowest in seniority. The symbol "S" (sinister, left) refers to the configuration of the chiral center with the location of higher rank groups counterclockwise (from the group with the highest rank to the other the least), when viewed along the direction of the group, the lowest in seniority. The ranking of the groups is determined by the rules of the sequence, with priority primarily based on the atomic number (in descending order of atomic number). A list and discussion of seniority groups is given inStereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York, 1994.

In addition to the system of (R)-(S)herein may also be applied over the old system D-L to denote the absolute configuration, particularly in relation to amino acids. In this system, the formula for the Fischer projection is oriented so the carbon atom number 1 on the main chain was at the top. The prefix "D" is used to describe the absolute configuration of the isomer in which the functional (determines) the group is to the right of carbon chiral center, and L - isomer, in which it is located to the left.

Used herein, the term "MES" means a unit consisting of ion or molecule of the dissolved substance with one or more solvent molecules. Similarly, "hydrate" means a unit consisting of ion or molecule of the dissolved substance with one or more water molecules.

In a broader sense, it is assumed that the term "substituted" includes all permissible substituents of organic compounds. In the herein certain specific implementations, the term "substituted" means substituted by one or more substituents which are independently selected from the group comprising (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perfluoroalkyl, phenyl, hydroxy, CO2H, ether, amide, (C1-C6)alkoxy, (C1-C6)thioalkyl, (C1-C6)perforamce, -NH2, Cl, Br, I, F, -NH lower alkyl and-N(lower alkyl)2. However, in these implementations can also be used any other suitable substituents known to specialists in this field.

"Terap whitesky effective amount" means the amount of coupling, effective for treating the above mentioned diseases, disorders or conditions.

The term "treatment" means:

(i) preventing a disease, disorder or condition in a patient who may be predisposed to the disease, disorder and/or condition, however, its presence has not yet been diagnosed;

(ii) suppression of the disease, disorder, or condition, that is, slowing its development;

(iii) relieving a disease, disorder, or condition, that is, the regression of the disease, disorder and/or condition.

Thus, in accordance with the present invention, it is proposed compound of the formula I:

where

R, R1, R2and R3are the same or different and, independently of one another, are selected from hydrogen, (C1-C4)alkyl or CF3;

R4is selected from the group comprising phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, chinoline, naphthyridine, indolyl, benzoimidazolyl, benzofuranyl, bromanil, 4-oxo-4H-chromenes, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxole, 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepine; where the specified R4optional one or more times substituted by the Deputy selected from the group including halogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, CF3, hydroxymethyl, 2-HYDR is xicillin, methoxyethylamine, benzoyloxymethyl, piperidinyl, N-acetylpiperidine, pyrrolyl, imidazolyl and 5-oxo-4,5-dihydropyrazolo.

The present invention also includes various salts of compounds of formula (I), including the various enantiomers or diastereoisomers of the compounds of formula (I). As noted above and in the specific examples below, all salts that can be formed, including pharmaceutically acceptable salts, are part of the present invention. As was also noted above and in the sequel of this paper, all possible enantiomeric and diastereomeric form compounds of formula (I) are part of the present invention.

In one implementation provides compounds of formula (I) of the present invention, where R and R2represent methyl; R1and R3represent hydrogen.

In another implementation of the present invention are disclosed compounds of the formula (I), where R4represents phenyl which is optionally substituted by one or more groups selected from fluorine, methyl, hydroxymethyl, N-acetylpiperidine, imidazolyl or 5-oxo-4,5-dihydropyrazolo.

In another implementation of the present invention are disclosed compounds of the formula (I), where R4represents pyridinyl, optionally substituted one or more times chloro who, 2-hydroxyethylamino, methoxyethylamine, benzoyloxymethyl or pyrrolidon.

In another implementation of the present invention is also disclosed compounds of the formula (I), where R4is chinoline, naphthyridine, indolyl, benzoimidazolyl or benzofuranyl, and where R4optionally substituted one or more times by chlorine, hydroxy, stands or methoxy.

In another implementation of the present invention are disclosed compounds of the formula (I), where R4represents chromanol, 4-oxo-4H-chromenes or 2,3-dihydrobenzofuranyl where the specified R4optionally substituted by one or more hydroxy or stands.

In another implementation of the present invention discloses a compound of formula (I), where R4represents benzo[1,3]dioxole or 2.5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepine.

In one implementation of the present invention specific compounds of formula (I) are selected without limitation from the group, which includes the following connections:

(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-hydroxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methylpyrrolidine--ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-(1-acetylpiperidine-3-yl)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzamide;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R)-cyclohexanecarbonyl acids;

5-chloro-6-(2-hydroxyethylamino)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;

2-[(2-methoxyethyl)amide] 5-({2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide)pyridine-2,5-dicarboxylic acid;

N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-6-pyrrol-1-iniatiated;

6-benzoyloxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R)-furan-3-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R) - for 3,5-dimethylisoxazol-4-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 7-chloro-4-hydroxyquinolin-3-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 4-hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of 1H-indole-6-carboxylic acid;

{2-methyl-4-[3-(2-metalpro the one-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 5-methoxy-1H-indole-2-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2-methyl-1H-benzoimidazol-5-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 6-methoxybenzophenone-2-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 3,4-dihydroxy-2,2-DIMETHYLPROPANE-6-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 6-methyl-4-oxo-4H-chromen-2-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2,3-dihydrobenzofuran-5-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide benzo[1,3]dioxol-5-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid.

All of the above compounds can also include, where appropriate, the corresponding salts, including pharmaceutically acceptable salts.

In an additional aspect of the present invention it is possible to list the following compounds covered, without limitation, the compound of formula (I) of the present invention:

(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-hydroxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-(1-acetylpiperidine-3-yl)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzamide;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R)-cyclohexanecarbonyl acids;

5-chloro-6-(2-hydroxyethylamino)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;

2-[(2-methoxyethyl)amide] 5-({2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide)pyridine-2,5-dicarboxylic acid;

N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-6-pyrrol-1-iniatiated;

6-benzoyloxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S, 3R)-furan-3-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S, 3R) - for 3,5-dimethylisoxazol-4-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 7-chloro-4-hydroxyquinolin-3-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of 1H-indole-6-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 5-methoxy-1H-indole-2-carboxylic acid;

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2-methyl-1H-benzoimidazol-5-carboxylic acid;

All possible salts of the above compounds, including pharmaceutically acceptable salts, are also part of the present invention.

In another aspect of the present invention it is possible to list the following compounds included in the scope of the present invention:

(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-hydroxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

4-(1-acetylpiperidine-3-yl)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;

N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzamide;

5-chloro-6-(2-hydroxyethylamino)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;

2-[(2-methoxyethyl)amide] 5-({2-methyl-4-[3-(2-m is tiliroside-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide)pyridine-2,5-dicarboxylic acid;

N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-6-pyrrol-1-iniatiated; and

6-benzoyloxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;

All possible salts of the above compounds, including pharmaceutically acceptable salts, are also part of the present invention.

In another aspect of the present invention, the compound of the present invention may be represented by a specific stereoisomeric form of the formula (II):

where R, R1, R2R3and R4submitted in accordance with the definitions above.

Compounds of the present invention can be synthesized by any of the well-known specialists of ways. In particular, some of the original materials used in the preparation of the compounds of this invention are known or commercially available. Compounds of the present invention and some of the original connection can also be obtained by the methods used to obtain similar compounds, as reported in the literature and as described later in this document. For example, as noted above, some of the compounds with similar structure are disclosed in U.S. patent No. 7223788. Cm. also R. C. Larock, “Comprehensive Organic Transformations,” VCH publishers, 1989.

It is also well known, h is about in various organic reactions may be necessary to protect reactive functional groups, for example, amino groups, to avoid their unwanted participation in the reactions. Conventional protective groups can be used in accordance with standard methods known to experts in the field, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic ChemistryJohn Wiley and Sons, Inc., 1991. For example, suitable aminosidine groups include, without limitation, sulfonyl (e.g., tosyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g., benzyl), which may be subsequently removed by hydrolysis or hydrogenation, depending on the case. Other suitable aminosidine groups include TRIFLUOROACETYL [-C(=O)CF3], which can be removed catalyzed by bases, hydrolysis, or solid-phase polymer-bound benzyl group, such as associated with Merrifield polymer of 2,6-dimethoxybenzyl group (linker Almana) or 2,6-dimethoxy-4-[2-(policyrelease)ethoxy]benzyl, which can be removed by acid-catalyzed hydrolysis, for example with TFA.

More specifically, described herein connections and various predecessors used to them, can be synthesized by the following methods described in schemes 1-3, where R, R1, R2, R3and R4match the definitions given for formula I, unless otherwise indicated.

For example, n the figure 1 shows an example of obtaining the intermediate (8), which is obtained in accordance with the methods described in Bioorg. Med. Chem. 2004, 12 (10), 2603.

Scheme 1

In stage 1 scheme 1 α-aminouksusnoy acid (2) is condensed with butyl acrylate (1) in the presence of formaldehyde to education butyl ether pyrrolidin-3-carboxylic acid (3). This reaction can usually be carried out in a suitable organic solvent, such as toluene, at temperatures of education phlegmy. But can be applied to various other suitable conditions known to the specialists.

In stage 2 scheme 1 the nitrogen atom of the intermediate compound (3) appropriately protect, for example, by reaction with anhydride tert-butylphenol acid for the protection of nitrogen tert-butyloxycarbonyl group with formation of an intermediate compound (4). Similar reactions can also be carried out using methods known to experts in this field. It should be understood that to achieve the same results may be used any known protective groups, allowing you to get properly protected intermediate compound (4).

At stage 3 scheme 1 is the reaction of the intermediate compound (4) with a suitable reagent, such as, for example, a base such as lithium hydroxide, in a suitable solvent, such as methane is, with the formation of the intermediate carboxylic acid (5). This hydrolysis of the ester can be carried out in acidic conditions and/or essentially neutral conditions using a variety of known acids and/or acidic substances, and silyl compounds, known to specialists.

In stage 4 scheme 1 acid intermediate compound (5) is reacted with substituted pyrrolidino formula (6), where R corresponds to the definition in this document. This reaction mix can be carried out in the presence of such reagents, as a combination of N-methylmorpholine, 1-hydroxybenzotriazole and EDC hydrochloride in the presence of a suitable organic solvent, such as dichloromethane. However, it may be used any other way to perform this transformation.

On stage 5 of scheme 1 with the intermediate compound (7) removes the protective group with the formation of intermediate compounds (8), for example using hydrochloric acid in the presence of a suitable solvent, such as methanol. Again, at this stage it is possible to use any known in the art methods and/or reagents that will allow you to remove the protective group.

Finally, in stage 6 of scheme 1, the intermediate compound (8) is subjected to reductive conditions to obtain the desired intermediate (). At this stage you can apply various methods of recovery that allows you to convert the carbonyl group to a methylene. For example, the intermediate compound (8) is subjected to reductive conditions in the presence of socialogical in an organic solvent, such as tetrahydrofuran, and receive the intermediate compound (9).

Similarly, enantiomerically pure form intermediate compound (9) can be obtained using the appropriate starting materials in accordance with the methods shown in scheme 1. Specific examples of enantiomerically enriched compounds that are the subject of the present invention, is shown below.

Figure 2 shows an example of obtaining the intermediate aminopropyldimethylamine formula (12), where R, R1and R2meet the definition in this document.

Scheme 2

In stage 1 scheme 2 appropriately substituted nitrobenzene of formula (10), where X denotes acceptable leaving group, for example, Cl, F, Br or triflate (OTf), is condensed with [1,3']-pyrrolidinylcarbonyl formulas (9) to obtain the intermediate compounds of formula (11). Such reactions repair can also be carried out using any known in the field of fashion. For example, this substitution reaction can be carried out in p is lannom solvent, such as DMSO, in the presence of such a base as potassium carbonate, at room temperature or at a temperature exceeding room temperature.

In stage 2 of scheme 2, the intermediate compound of formula (11) is recovered by hydrogenation or other known chemical methods, for example by using douglasthe tin in hydrochloric acid, to form a primary intermediate compounds (12).

Scheme 3 shows an example of obtaining compounds of formula (I) of the present invention by using method a or method, depending on the availability of the appropriate carboxylic acid of formula R4-CO2H, either in the form of the acid or its acid chloride, where R, R1, R2and R4described herein, and R3- the hydrogen atom.

In the method And scheme 3, the acid chloride of the formula (13) can react with an intermediate compound (12) in all conditions, known to experts in the field. Generally, such conditions include, among others, the reaction of the acid chloride intermediate compound of formula (12) in a suitable organic solvent, such as dichloromethane, in the presence of a suitable base, for example pyridine. Such reactions are generally conducted at low temperatures, for example about 0°C, but in certain situations can also apply the Xia ambient temperature and elevated temperature, depending on the nature of the acid chloride and the intermediate (12).

Scheme 3

Similarly, in the method of scheme 3 carboxylic acid of formula (14) can react with an intermediate compound of formula (12) at various reaction conditions which are known to experts in the field. For example, the acid of formula (14) is reacted with an intermediate compound of formula (12) at low temperature in the presence of suitable reagents such as a mixture of N-methylmorpholine, 1-hydroxybenzotriazole and EDC.

As mentioned above herein, the compounds of the present invention can easily be turned into salt. In particular, the compounds of the present invention are basic, and such compounds are useful in the free base form or in the form of a pharmaceutically acceptable acid additive salts of such compounds. Acid additive salts can be more convenient form for use, and in practice the use of salt is essentially reduced to the form of the free base. Acids which can be used to obtain the acid additive salts include preferably those which when reacted with the free base form of pharmaceutically acceptable salts, i.e. salts, the anions of which are not toxic to the patient in the pharmacy is practical doses of the salts, so positive inhibitory effects inherent in the free bases are not destroyed side effects attributed to the anions. Although pharmaceutically acceptable salts of the specified basic compounds are preferred, all acid additive salts are useful as sources of the free base forms, even if the particular salt per se is only necessary as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as intermediate compounds in obtaining pharmaceutically acceptable salt by ion-exchange processes.

In another aspect of implementation of the present invention, by using compounds of the present invention it is possible to treat a particular disease, disorder or condition, including, among other things, sleep disorders (specific examples include, among other things, narcolepsy, disruption of circadian rhythm sleep, obstructive sleep apnea syndrome, periodic limb movements and restless legs syndrome, excessive sleepiness and drowsiness, which is a side effect of medicines, etc), neurological disorders (among the concrete examples are, among other things, dementia, Alzheimer's disease, multiple sclerosis, epilepsy and europalaces pain), neuropsychologische and cognitive disorders (specific examples include, without limitation, schizophrenia, hyperactivity, attention deficit, Alzheimer's disease, depression, seasonal affective disorder and cognitive impairment).

As shown below in the specific examples of the present document, the compounds of formula (I) bind to receptors H3 and show reverse agonism in relation to the functional activity of the H3. Therefore, compounds of the present invention can be used for the treatment of diseases or conditions that are alleviated by ligands of the receptor H3. More specifically, the compounds of the present invention are ligands of the receptor H3, which modulate the function of the H3 receptor, acting as antagonists of the activity of the receptor. In addition, the compounds of the present invention can act as inverse agonists, which inhibit the basal activity of the receptor, or can act as antagonists, which completely block the action of agonists that activate the receptor. Moreover, the compounds of the present invention may also be partial agonists, which are partially blocked, or partially activate the receptor H3, or can be agonists that activate the receptor. Thus, the compounds of the present invention can act as an the agonists, inverse agonists and/or partial agonists depending on the functional result of histamine-induced tone and/or condition of the tissue. Accordingly, the differential activity of these compounds may allow their use to facilitate a variety of pathological conditions that were specifically listed above.

Thus, one aspect of the present invention is a method of treating disease in a patient, and the disease is selected from the group including violation associated with a sleep disorder, dementia, Alzheimer's disease, multiple sclerosis, cognitive disorder, hyperactivity disorder attention deficit and depression, including introduction this patient a therapeutically effective amount of the compounds of formula (I).

For the person skilled in the art it is obvious that the pathology and pathological conditions expressly set forth in this document are designed not to restrict, but rather to illustrate the effectiveness of the compounds that are the subject of the present invention. So, you need to understand that the compounds of the present invention can be used to facilitate any disease caused by the effects of H3 receptors. In other words, as noted above, the compounds of the present invention are modulators of H3 receptors and can effectively centuries which help to relieve painful conditions, which is completely or partially mediated by H3 receptors.

All the different implementation of the compounds of the present invention can be used in the treatment of various pathological conditions, as described herein. As stated herein, the compounds used in the method of the present invention, is able to counteract the effects of H3 receptor and, thus, to attenuate and/or condition caused by the activity of the H3 receptor.

In yet another implementation of the method of the present invention compounds of the present invention can be administered by any known means. In particular, the compounds of the present invention can be administered orally, intramuscularly, subcutaneously, rectally, intratrahealno, intranasal, intraperitoneal or locally.

Finally, in another implementation of the present invention also features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I, including enantiomers, stereoisomers and tautomers of the specified compound and its pharmaceutically acceptable salt, solvate or derivative, with the specified connection has the General structure shown in formula I as described herein.

As described herein, the pharmaceutical composition and the present invention differ inhibiting H3 action and, thus, applicable in the treatment of any disease, condition or disorder caused by the patient the effects of H3. Again, as described above, all of the preferred embodiment of the compounds of the present invention, as disclosed herein, can be used to obtain pharmaceutical compositions, as described herein.

Preferably, the pharmaceutical compositions of the present invention are presented in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid spray solutions, drops, ampoules, autoinjector devices or suppositories intended for oral, intranasal, sublingual or rectal injection or administration by inhalation or insufflation. Alternatively, these compositions may be optimal for injection 1 time a week or 1 time a month; for example, an insoluble salt of the active compound, such as salt decanoate, may be adapted for receiving depot for intramuscular injection. You can use the collapsing of the polymer containing the active ingredient. For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, is for example common for tablets ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water, to form a solid pre-composition comprising a homogeneous mixture of the compounds constituting the subject matter of this invention, or its pharmaceutically acceptable salt. When such prior compositions referred to as homogeneous, it is meant that the active ingredient is mixed evenly throughout the composition, and the composition can be divided into with equal efficiency unit dosage forms such as tablets, pills and capsules. Then this solid pre-composition is divided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient constituting the object of the present invention. Scented unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg of active ingredient. Pills and tablets new composition can be coated or otherwise formed to provide a dosage form with prolonged action. For example, the tablet or pill may contain internal and external dosed components when the latter forms a shell comprising a lane the first component. Two components can be separated enteric layer, which prevents the destruction in the stomach and permits the inner component in the intact condition to get into the duodenum, or that his release had been delayed. As such enteric layers or coatings can be used a variety of substances, including a number of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compounds forming the subject of the present invention may be administered orally or by injection include aqueous solutions, syrups with a suitable flavoring, water and oil suspensions, and flavored emulsions with edible oils such as cottonseed, sesame, coconut or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspenders agents for aqueous suspensions include synthetic and natural resins, such as tragakant, Arabian gum, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical compositions of the present invention can be any known in the art methods. In General, the pharmaceutical compositions of the us is Vashego of the invention can be administered orally, intramuscularly, subcutaneously, rectally, intratrahealno, intranasal, intraperitoneal or locally. Preferred routes of administration of the pharmaceutical compositions of the present invention are oral and intranasal routes. Any of the known methods of administration of drugs oral or intranasal route can be used to introduce the pharmaceutical compositions of the present invention.

In the treatment of various pathological conditions described herein, a suitable dose is from about 0.01 to 250 mg/kg / day, preferably from about 0.05 to 100 mg/kg / day, and in particular from about 0.05 to 20 mg/kg / day. Connections may be entered in accordance with the scheme 1-4 times a day.

The present invention is further illustrated by the following examples which are given for purposes of explanation and not in any way limit the scope of the present invention.

Examples (General part)

The reaction typically is carried out in nitrogen atmosphere. The solvent is dried over magnesium sulfate and evaporated under vacuum on a rotary evaporator. Tests run on TLC plates with silica gel EM Science 60 F254 with visualization by UV radiation. Flash chromatography is performed on columns Alltech, pre-filled with silica gel. Spectra1H NMR write what I at the frequency of 300 MHz spectrometer Gemini 300 or Varian VXR 300 and determined in deuterated solvent, such as DMSO-D6or CDCl3if not stated otherwise. The magnitude of the chemical shift is indicated in ppm (MD) on tetramethylsilane (TMS) as internal standard. LC/MS is recorded on a Micromass Platform LCZ.

Used in the examples and the subsequent preparations terms shall have the following specified meanings: "kg" refers to kilograms, "g" - grams, "mg" (milligrams, "μg" - micrograms, "PG" PG, "f" pound, "" oz, "mol" - moles, "mmol" - millimoles, "umol" - micromoles, "nmol" - nanomoles, "l" is a liter, "ml - milliliters, "μl" - microliter, "Gal" - gallon, "°C" degrees Celsius, "Rf" is the coefficient of retention, "TP" or "other" melting point, "decomp." - decomposition, "TC" or "as" boiling point, "mm of Hg" is the pressure in millimeters of mercury, "cm" cm "nm - nanometers, "abs." absolute, "conc." - concentrated, "C" is the concentration in g/ml, "THF" is tetrahydrofuran, "DMF - dimethylformamide, "NRM" - 1-methyl-2-pyrrolidinone, "saline" - saturated aqueous sodium chloride solution, "M" - both molarity, "mm" - millionares, "μm" - mikrokosmos, "nm" - nanoelement, "N" normality, "TLC" - thin layer chromatography, "HPLC" is a high - performance liquid chromatography, "MVR" - mass spectrum with high resolution, "PPV" loss on drying, "µci - microcurie, "/b" nutribase is but "centuries" - intravenous, bezw. - anhydrous, water. water, min - minute, h - hour, d - day, us. - rich, s - singlet, d - doublet, t - triplet, Quartet, m - multiplet, DD - doublet of doublets, sh. - wide, LC - liquid chromatography, MS = mass spectrograph, ESI/MS - electrospray ionization/mass spectrograph, WU - retention time, M is the molecular ion.

The intermediate compound (i)

Tert-butyl ester (2S,3S)-3-(2-methylpyrrolidine-1-carbonyl)pyrrolidin-1-carboxylic acid

1-tert-butyl ether (3S)-pyrrolidine-1,3-dicarboxylic acid (purchased in Astatech, Inc, 0.5 g, 2.3 mmol) was dissolved in DHM (20 ml) and the resulting solution was cooled in an ice bath. To this solution was added sequentially a solution of (S)-2-methylpyrrolidine (purchased in Advanced Asymmetric, Inc., 235 mg, was 2.76 mmol, 1.2 equiv.) in 1 ml DHM, N-methylmorpholin (700 mg, 6,9 mmol, 3 equiv.), 1-gynocentrism (HOBT) (404 mg, 3 mmol, 1.3 equiv.) and then EDC.HCl (576 mg, 3 mmol, 1.3 equiv.). The obtained clear solution is light brown in color and was stirred at room temperature overnight. The TLC analysis (10% MeOH in DHM) and LC/MS showed a peak product at retention time 3,238 min with MS 227 (M-t-Bu). The reaction mixture was extinguished saturated aqueous sodium bicarbonate (10 ml) and 10 ml DHM. Two layers were separated, and the aqueous layer was extracted with dichloromethane (15 ml × 2). Joint the United extracts DHM washed successively with sodium bicarbonate (10 ml) and brine (10 ml), was dried (anhydrous potassium carbonate), filtered and concentrated under vacuum to obtain the desired compound, 0.65 g (100% yield), as a thick oily liquid.

LC/MS: Tr=3,238 minutes; MS: 227 (M-tBu).

1H NMR (300 MHz, CDCl3), δ (DM): and 4.40 (m, 1H), 3.95 to 3,20 (m, 6H), 2,65 is 2.00 (m, 5H), of 1.95 (m, 1H), 1,65 (s, 9H), of 1.35 (m, 2H).

The intermediate compound (ii)

(2S,3S) (2 methylpyrrolidine-1-yl)pyrrolidin-3-ylmethanone

Tert-butyl ester (2S, 3S)-3-(2-methylpyrrolidine-1-carbonyl)pyrrolidin-1-carboxylic acid, obtained as described above (~ 2.3 mmol) was treated with 3 ml of 4M HCl in dioxane at a temperature in the range from 0°C to room temperature over night. Analysis of LC/MS showed a peak of product at t=1,219 with MS 183. The peak of the source material has not been detected. Excess reagent was removed by purging the reaction mixture with dry nitrogen passing through the column with potassium hydroxide to absorb hydrogen chloride for 1 hour. The solvent drove by evaporation under high vacuum. The remainder continued to dry under high vacuum for 2 h to obtain cleaners containing hydrochloride salt of the desired compound in the form of semi-solid substances, 0.85 grams, with an indefinite number of hydration. LC/MS: T=1,219 min, MS: 183 (M+H).

The intermediate compound (iii)

(2S,3S)-2-methyl-1-pyrrolidin-3-iletilenlerin

To a solution of (2S, 3S)-(2-methylpyrrolidine-1-yl)pyrrolidin-3-ylmethanone (2.3 mmol, obtained as described above ) in dry THF (6 ml) was added dropwise a solution of 2M BH3SMe2in THF (2M in THF, 5 ml, 10 mmol, 4 equiv.). The mixture was heated at the boil under reflux for 2 hours. After cooling the solution to room temperature was added 5 ml of methanol and was stirred for 2 h at room temperature. The solvent is evaporated until dry to obtain the desired product in the form of semi-solid substances. Analysis of LC/MS showed molecular ion peak of the desired compound 169 (M+H) with retention time 1,742 minutes

The intermediate compound (iv)

(2S,3R)-2-methyl-1-[1-(3-methyl-4-nitrophenyl)pyrrolidin-3-ylmethyl]pyrrolidin

(2S,3S)-2-methyl-1-pyrrolidin-3-iletilenlerin (2 mmol) was dissolved in anhydrous DMSO (10 ml). To this solution was added 5-fluoro-2-nitrotoluene (620 mg, 4 mmol, 2 equiv.), then add powdered potassium carbonate (1.1 g, 8 mmol, 4 equiv.). The suspension was heated on an oil bath to 85oC (bath temperature) for 4 h, when the source material was consumed, as shown by the analysis of LC/MS. MS showed 304 (main peak).

To this suspension was added 5 ml of water and 10 ml DHM. Two layers were separated, and the aqueous layer ekstragirovaniem (10 ml × 2). The combined extracts DHM then washed with sodium bicarbonate (10 ml) and brine (10 ml × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira 0-2% MeOH in DHM, to obtain the desired compound in the form of a solid yellow color after drying. MS: 304 (M+1).

1H NMR (300 MHz, CDCl3), δ (MD): 8,08 (D., and 9.2 Hz, 1H), 6,36 (DD, of 9.2 and 2.8 Hz, 1H), 6,28 (d, 2.2 Hz, 1H), 3,6 (m, 1H), 3,4 (m, 2H), 3,20 (m, 1H), 3,05 (m, 1H), 2,78 (m, 2H) 2,62 (s, 3H), 2.40 a is 1.60 (m, 8H), of 1.45 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

The intermediate compound (v)

(2S,3R)-2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine

A solution of (2S, 3R)-2-methyl-1-[1-(3-methyl-4-nitrophenyl)pyrrolidin-3-ylmethyl]pyrrolidine (0.3 g, 1 mmol) in MeOH (15 ml) was wearisomely and pressurized with nitrogen. To this solution was added Pd-C (10%, 30 mg). This mixture was stirred under pressure H2at room temperature over night. The TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed and the peak of the product was observed at t=1,458 min, m/z: 274 (M). The mixture was passed through a layer of celite and washed with methanol. The filtrate was concentrated until dry with further drying under high vacuum to obtain the desired compound in the form of liquid reddish-brown color after drying under high vacuum.

P is the iMER 1

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2-methyl-1H-benzoimidazol-5-carboxylic acid

2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine (27 mg, 0.1 mmol) and 2-methyl-1H-benzoimidazol-5-carboxylic acid (17.6 mg, 0.1 mmol) was dissolved in a mixture containing 3 ml of dichloromethane and 1 ml dimethylformamide. To this solution was then added N-methylmorpholine (33 μl, 0.3 mmol), 1-hydroxybenzotriazole (17.6 mg, 0.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22 mg, 0,123 mmol). The reaction mixture was stirred at room temperature for 20 hours In the evaporation and HPLC-PF received 25 mg of the desired compound with triperoxonane acid in the form of salt (46%). MS: 432,5 (M+H).

Example 2

5-Chloro-6-(2-hydroxyethylamino)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 5-chloro-6-(2-hydroxyethylamino)nicotinic acid. MS: 472,3 (M+H).

Example 3

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 7-chloro-4-hydroxyquinolin-3-carboxylic acid

The desired compound was obtained by method, su is estu similar to example 1, through a combination of 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 7-chloro-4-hydroxyquinolin-3-carboxylic acid. MS: 479,2 (M+H).

Example 4

N-{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-6-pyrrol-1-iniatiated

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 6-pyrrol-1-lincocinbuy acid. MS: 444,5 (M+H).

Example 5

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2,3-dihydrobenzofuran-5-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 2,3-dihydrobenzofuran-5-carboxylic acid. MS: 420,3 (M+H).

Example 6

6-Benzoyloxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 6-benzyloxypyridine acid. MS: 499,3 (M+H).

Example 7

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide benzo[1,3]dio the Sol-5-carboxylic acid

The desired compound was obtained by a method essentially similar to example 1 by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with benzo[1,3]dioxol-5-carboxylic acid. MS: 422,5 (M+H).

Example 8

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of 1H-indole-6-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 1H-indole-6-carboxylic acid. MS: 417,5 (M+H).

Example 9

4-Imidazol-1-yl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 4-imidazol-1-eventing acid. MS: 444,3 (M+H).

Example 10

4-(1-Acetylpiperidine-3-yl)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 4-(1-acetylpiperidine-3-yl)benzoic acid. MS: 503,3 (M+H).

Example 11

4-Hydroxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 4-hydroxymethylbenzene acid. MS: 408,5 (M+H).

Example 12

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 5-methoxy-1H-indole-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 5-methoxy-1H-indole-2-carboxylic acid. MS: 447,5 (M+H).

Example 13

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(3-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 2.5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid. MS: 476,3 (M+H).

Example 14

2-[(2-Methoxyethyl)amide] 5-({2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide) pyridine-2,5-dicarboxylic acid

The search link is received by way essentially the same as the example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 2-[(2-methoxyethyl)amide] pyridine-2,5-dicarboxylic acid. MS: 480,3 (M+H).

Example 15

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 6-methoxybenzophenone-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 6-methoxybenzophenone-2-carboxylic acid. MS: 448,5 (M+H).

Example 16

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 3,4-dihydroxy-2,2-DIMETHYLPROPANE-6-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 3,4-dihydroxy-2,2-DIMETHYLPROPANE-6-carboxylic acid. MS: 494,6 (M+H).

Example 17

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 4-hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 4-hydroxy-7-methyl-[1,8]naphthyridin-carboxylic acid. MS: 460,6 (M+H).

Example 18

N-{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzamid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzoic acid. MS: 474,6 (M+H).

Example 19

{2-Methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 6-methyl-4-oxo-4H-chromen-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 6-methyl-4-oxo-4H-chromen-2-carboxylic acid. MS: 460,3 (M+H).

Example 20

(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

(2S,3R)-2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine (92 mg, 0.34 mmol) was dissolved in DHM (4 ml) and pyridine (1 ml). The solution was cooled in an ice bath. To this solution was added a solution of 5-fluoro-2-methylbenzonitrile (from Alfa Aesar, of 0.48 g, 2.77 mmol, 1.6 equiv.) in DHM (2 ml). The solution was stirred at room temperature for 2 hours the Reaction was considered complete when TLC analysis (10% MeOH in DHM) and the X/MS did not detect THEM at 274, but he said only the peak of the product under 410,2 and retention time to 3.02 minutes To the mixture was added polimerobetonie Diethylenetriamine (4 mmol/g, 0.12 g) and stirred at room temperature for 30 min, then filtered and washed DHM. The solvent is evaporated to the dry state was re-dissolved in DHM and aqueous solution of NaHCO3. Two layers were separated, and the aqueous layer was extracted with dichloromethane (10 ml × 2). The combined extracts DHM washed successively with sodium bicarbonate (5 ml) and brine (5 ml × 2), dried (anhydrous potassium carbonate)was passed through a layer of silica gel (samoupravlenie, ~10 g), washed DHM (without product) and then 10% MeOH in DHM (in the presence of the product). The solution was concentrated under vacuum to obtain the crude product, which was purified on silikagelevye column, elwira from 0 to 10% MeOH in DHM, to obtain 48 mg (34% yield) of the desired compound in the form of semi-solid substances. LC/MS: T=3,020 min, MS: 410,2.

1H NMR (300 MHz, CDCl3), δ (MD): 7,49 (m, 1H), 7.23 percent (m, 1H), 7,11 (m, 2H), 6,41 (m, 1H), 3,70 (m, 2H), 3,57 (t, 6.2 Hz, 1H), 3,39 (m, 2H), 3,32 (m, 1H), and 3.16 (m, 1H), 3,06 (m, 1H), 2.95 and (m, 2H), 2,65 (m, 1H), 2,62 (s, 1H), 2,61 (s, 3H), 2.49 USD (m, 1H), of 2.38 (s, 3H), of 2.05 (m, 2H), 1,90 (m, 2H), 1,80 (m, 1H), 1,40 (d, 6.5 Hz, 3H).

Example 21

(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide

The desired compound was obtained method is m, essentially analogous to example 20, by a combination of (2S, 3R)-2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 3-tormentilla at exit 39%.

JHMS: RT= 2,949 min, MS: 396,20 (M+H).

1H NMR (CDCl3, 300 MHz), δ (MD): 7,87 (d, 7.7 Hz, 1H), 7.62mm (m, 2H), 7,45 (m, 2H), 7,20 (m, 1H), 6,39 (m, 1H), to 3.73 (m, 1H), 3,57 (t, 6.2 Hz, 1H)and 3.59 (m, 1H), 3,40-3,19 (m, 3H), of 3.07 (m, 2H), 2,82 of 2.68 (m, 3H), 2,36 (m, 1H, in), 2.25 (s, 3H), of 2.15 (m, 2H), 2,11 and 1.80 (m, 3H), USD 1.43 (d, 6.4 Hz, 3H).

Example 22

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R)-furan-3-carboxylic acid

The desired compound was obtained by a method essentially similar to example 20, by a combination of (2S, 3R)-2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with 3-forargliga at exit 35%.

JHMS: RT=2,502 min, MS: 368,2 (M+H).

1H NMR (CD3OD, 300 MHz), δ (MD): 8,16 (SHS, 1H), to 7.61 (SHS, 1H), was 7.08 (d, 8,4 Hz, 1H), 6.90 to (CL, 1H), of 6.49 (m, 2H), to 3.58 (m, 2H), 3,55-of 3.27 (m, 3H), is 3.08 of 2.92 (m, 2H), 2,70 (m, 1H), 2,35 (m, 3H), of 2.28 (s, 3H), of 2.15 (m, 2H,), of 2.08 (m, 2H), 1,87 (m, 1H), 1,70 (m, 1H), 1,40 (d, 6.4 Hz, 3H).

Example 23

{2-methyl-4-[3-(2-methylpyrrolidine-1-yl-methyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R) - for 3,5-dimethylisoxazol-4-carboxylic acid

The desired compound was obtained by a method essentially similar to example 20, by a combination of (2S, 3R)-2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with a 3.5-dimetil oxazol-4-carbonylchloride when the output is 50%.

JHMS: RT=2,521 min, MS: 397,3 (M+H).

1H NMR (CD3OD, 300 MHz), δ (MD): 7,46 (W, 1H), 6,92 (W, 1H), 6,39 (m, 1H), of 3.56 (m, 1H), 3,38 (m, 2H), 3,03 (m, 2H), 2,70 (m, 1H), 2,65 (s, 3H), of 2.44 (s, 3H), of 2.25 (s, 3H), 2,68 (m, 3H), of 2.15 (m, 3H), of 2.08 (m, 2H,), to 1.87 (m, 1H), 1,70 (m, 1H), 1,30 (d, 6.4 Hz, 3H).

Example 24

{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R)-cyclohexanecarbonyl acid

The desired compound was obtained by a method essentially similar to example 20, by a combination of (2S, 3R)-2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamine with cyclohexanecarbonitrile at exit 45%.

JHMS: RT=2,972 min, MS: 384,2 (M+H).

Biological examples

Example 25

In the present example demonstrates the effectiveness of the compounds of the present invention as ligands of H3 receptors. It is known that the compounds of the present invention displace radioligand [3H]-methylhistamine that is associated with the membranes of mammalian cells expressing the receptor H3 rhesus monkeys (Macacca Mulatta). These compounds have affinity constants (Ki) to H3 of resursov in the range from 1 μm to <1 nm. In addition, through the analysis of binding radioligand GTPγS was shown that the compounds of the present invention inhibit the constitutive functional activity of rhesus H3 in cell membranes. This ingabire is the W binding of radioactive ligand GTPγS, mediated basal H3 of resursov shows that the compounds of the present invention can be used as inverse agonists. These compounds reduce the level of binding of the radioactive ligand GTPHγS H3 receptors of resursov at 0-40% below basal levels.

Membrane N3 of resursov received from the cell line Flp-In T-REx 293 (Invitrogen)stably transtitional pcDNA5/FRT/TO (Invitrogen)containing the receptor H3 rhesus macaques (Macacca Mulatta) of 445 amino acids. (Genbank #AY231164). Stable transfetsirovannyh culture amplified in flasks for culturing tissues using standard methods of cultivation of tissues and induced for expression of H3 RH by exposure to 500 ng/ml tetracycline (Cellgro) within 24 hours. After induction the cells were detached from flasks using Cell Stripper (Cellgro). Cells were centrifuged (1000 × g, 5 min) and the precipitate was frozen in a bath of ethanol-dry ice, in order to destroy the cell membrane. Frozen sediment cells resuspendable in 5 mm HEPES (pH of 7.4, Invitrogen) at a concentration of collected cells 10 ml/1000 cm2. Cell suspension was aspirated with a needle 18 size (2-3x), and then the needle 23 size (2-3x)in order to destroy the cell membrane. Cell suspension was centrifuged (40 000 × g, 30 min). Sediment cell membranes resuspendable in 5 mm HEPES (pH of 7.4, Invitrogen) at a final protein concentration of 10 mg/ml IU the gap H3 RH was kept under liquid nitrogen until use for analysis of binding of [3H]-methylhistamine and radioactive ligand GTPγS.

Analysis of the binding of radioactive ligand H3 RH was performed using a membrane receptor H3 RH (obtained as described above), [3H]-methylhistamine (Perkin Elmer) and pellets WGA SPA (scintillation analysis of convergence using agglutinin from wheat germ) (Amersham). The analysis was carried out in 96-cell tablet Opti-Plates (Packard). Each reaction used 50 μl of membranes H3 RH (20-30 µg of total protein), 50 μl of the pellet WGA SPA (0.1 µg) and 50 μl of 83 CI/mmol [3H]-methylhistamine (final concentration 2 nm) and 50 μl of the compounds. Compounds of the present invention and/or the media was diluted with binding buffer from the source solution 10 mm in DMSO. Tablets for analysis was sealed TopSeal (Perkin Elmer) and mixed on a shaker (25°C, 1 hour). Tablets for analysis read on TopCount scintillation counter (Packard). Analysis of the results was performed by transforming the hill, and Ki values were determined by the equation of Cheng-Prusoff. The observed data linking for several representative compounds of the present invention are shown in table 1.

Table 1
# exampleAffinity: ki in the membrane H3 RH-binding ki (nm)Reverse agonism: % is ingibirovaniya basal GTPγS binding in rhesus H3
115,7-
251,2-
394,7-
439,3-
540,4-
695,4-
734,2-
818,0-
93,1-
1029,8-
1162,1-
1261,5-
139,3-
1432,3-
15 66,7-
1667,6-
1719,2-
18to 59.4-
1926,5-

Example 26

This example illustrates the selective affinity compounds of the present invention receptor H3 and shows low activity in respect of the site of the sit-1 receptor.

The affinity H3 compounds of the present invention was measured in accordance with the methods described in example 25.

The activity of the compounds of the present invention in the website of the MCH receptor-1, if any, was measured in accordance with the methods described below.

Test compounds: the Compounds of the present invention were stored in 96-cell tablets for micrometrology (1 μl, 10 mm in 100% DMSO). Each of the test samples were diluted 249 μl of 100% DMSO (dilution 1:250). The test compounds was further diluted 1:4 in (0.1% DMSO) during analysis, resulting in the final concentration of test compounds was 10 μm.

Negative control: 40 μm MCH-1 analytical journal is the first buffer with 0.4% DMSO was transferred into tablets, micrometrology for dilution to control, that provided a final concentration of 10 μm.

Idle control: Analytical buffer containing 0.4% DMSO, transferred to the tablets of micrometrology for dilution, in order to hold the idle experience.

The procedure of analysis: Filter plates with 250 ml of 0.5% solution of PEI in the cell incubated 2 hours at room temperature. PEI was removed by vacuum filtration before selecting a pipette (Univac Polyfiltronic/Whatman). A solution of the compound prepared above (50 µl), or MCH-1 (negative control) or buffer/DMSO (positive control) were added to 96-round bottom cell tablet for micrometrology. Then added 50 μl of a solution of the ligand with [125J], after which was added 100 μl of membrane suspension. Cells were covered with lids and incubated for 60 min at 25°C. the Sample was transferred to a filter plate GF/B. the Reaction mixture was removed by vacuum filtration, washed 4 × with 300 μl proryvnym buffer, cooled to freezing temperature, and the solution after washing was removed by vacuum filtration. Rubber-like layer on the bottom of the tablet was then removed, and the filters were dried overnight at room temperature. Added 25 μl of scintillation mixture, and the tablets were sealed, and then added a frame for tablets and incubated for 1 hour at room temperature. Then measured the level of radioactivity, the hundred and the standard settings for the 125J, 30 s per cell. Based on this determined the percent inhibition of ligand binding.

Results: generally, the compounds of the present invention demonstrated the value of ki for binding to the receptor H3 RH in the range of from about 100 nm to less than 5 nm, whereas the percentage of inhibition of binding of the ligand to the receptor, MCH-1 was less than 35% at a concentration of 10 μm. This comparative example shows that the compounds of the present invention can be more than a thousand times more selective on the website of the H3 receptor, the receptor of the sit-1.

Example 27

This example illustrates a study of the effectiveness of the compounds of the present invention to increase wakefulness in animal models.

Male rats Sprague-doli (Charles River, France) weighing 250 ± 10 g were obtained anesthesia ZoletilR50 (60 mg/kg/b) and were fixed in a stereotactic device. Cortical electrodes (small screw electrodes from stainless steel with a diameter of 0.9 mm) was screwed into the bone over the sensorimotor part of the cerebral cortex (1.5 mm lateral relative to the medial seam and 1.5 mm for frontal-parietal suture), the visual part of the crust (1.5 mm lateral to medial seam and 1.5 mm in front of the occipital-parietal suture), and cerebellum (reference electrode). Cortical electrodes were connected to the connector (Winchester, 7-conductors) fiksirovalis dental cement to the skull.

After three weeks of postoperative recovery, animals were placed in Plexiglas cylinders (60 cm diameter) with free access to food and water. The room temperature was maintained at a constant level (21 ± 1°C)and lighting supported from 07.00 h to 19.00 h Registration readings in rats conducted from 10.00 h to 16.00 h for three consecutive days: the control day (D1), day of taking the medicine (D2) and day after taking the medicine (D3). Media (D1 and D3) or drug (D2) were administered 15 min prior to registration.

The activity of sensorimotor and visual parts of the cortex were recorded by comparing with a standard electrode placed over the cerebellum. Identified three stages:

- Wake (B), which was characterized by rapid electrical cortical activity with low voltage (ECoG);

- sleep NBDG (slow eye movement or medlennovolnovoj sleep: MBC), which was characterized by the growth of cortical electrical activity; formation of slow waves of high amplitude, with bursts sleepy spindle;

- REM sleep (rapid eye movement or paradoxical sleep: COP), which was characterized by hypersynchronization theta rhythm in the visual field.

Analysis of the ECoG signal was performed automatically by a computer system that recognizes the different phases of sleep with serial Spa is Central to the analysis of the ten-second periods (software Deltamed “Coherence”).

Compounds of the present invention was dissolved in 0.6% of MTC twin and administered orally (p/o). The volume of injection was 0.5 ml/100 g body weight.

Two types of analysis used to quantify the effects of compounds of the present invention to variables sleep-wakefulness: an analysis of the one-hour period and analysis of a six-hour period.

The results are expressed in minutes (the time period of analysis) or as a percentage of control values (100%). Statistical analysis was performed using t-student test for paired values, in order to determine significant deviations from control values.

Example 28

Test stress-induced ultrasonic vocalizations in adult rats

This example illustrates a study of the effectiveness of the compounds of the present invention as antidepressants in animal models.

The used procedure was adapted on the basis of the methodology described in Van Der Poel AM, Noach E.J.K, Miczek K.A (1989) Temporal patterning of ultrasonic distress calls in the adult rat: effects of morphine and benzodiazepines.Psychopharmacology97:147-8. Rats during the training session were placed in a cage with slatted floors, stainless steel (MED Associates, Inc., St. Albans, VT). Four electric shock (0.8 mA, 3 s) was made every 7 s, and then recorded the ultrasonic signals (UV, 22 kHz) using the system of the s Ultravox (Noldus, Wageningen, The Netherlands) for 2 minutes a Modified ultrasonic detector (model Mini-3 bat), associated with the microphone, used for converting the ultrasonic signal into audible sound. Then the signal was filtered and transmitted to the computer where the software Ultravox registered every burst of UV, which lasted for more than 10 MS. Rats were selected for the duration of their UV (> 40), and perform the test within 4 h after training. For the test rats were placed in the same cage, where they spent training. Made one electric shock (0.8 mA, 3 s), and then recorded the UV (duration and frequency) for 2 min using system Ultravox. Compounds of the present invention has introduced the p/o for 60 min before testing.

Example 29

Test the forced swimming in rats

This example additionally illustrates a study of the effectiveness of the compounds of the present invention as antidepressants in animal models.

The procedure is a modification of the approach described by Porsolt et al. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730-2. Rats were placed in separate glass cylinder (40 cm high, 17 cm in diameter)containing water (21°C), particular object sticking its bloated up to a height of 30 cm was Performed two sessions of swimming (15-minute training session followed after 24 hours, 6 minutes to the Estai). After each session of swimming rats were placed under a heating lamp to avoid hypothermia. The duration of a state of immobility was measured during a 6-minute test. Compounds of the present invention was administered p/o twice (15 min after training session and for 60 min before the test).

Although the present invention is illustrated by some of the examples above, they should not be construed as limiting its scope, but on the contrary, as noted earlier herein, the invention extends to a related field. There are various modifications and implementation, not deviating from the basic idea and scope of the present invention.

1. The compound of formula (I)

where R, R1, R2and R3are the same or different and independently from each other selected from hydrogen, (C1-C4)alkyl or CF3;
R4is selected from the group comprising phenyl, cyclohexyl, pyridine, furanyl, isoxazolyl, chinoline, naphthyridine, indolyl, benzoimidazolyl, benzofuranyl, bromanil, 4-oxo-4H-chromenes, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxole and 2.5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepine; where the specified R4optional one or more times substituted by the Deputy chosen from the group comprising halogen, Hydra is XI, (C1-C4)alkyl, (C1-C4)alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamine, benzoyloxymethyl, piperidinyl, N-acetylpiperidine, pyrrolyl, imidazolyl and 5-oxo-4,5-dihydropyrazolo; or its pharmaceutically acceptable salt or enantiomer or diastereoisomer.

2. The compound according to claim 1, where
R and R2represent methyl;
R1and R3represent hydrogen; and
R4represents phenyl which is optionally substituted by one or more groups selected from fluorine, methyl, hydroxymethyl, N-acetylpiperidine, imidazolyl or 5-oxo-4,5-dihydropyrazolo;
or
R4represents pyridinyl, optionally substituted one or more times by chlorine, 2-hydroxyethylamino, methoxyethylamine, benzoyloxymethyl or pyrrolidon; or
R4is chinoline, naphthyridine, indolyl, benzoimidazolyl or benzofuranyl, and where R4optionally substituted one or more times by chlorine, hydroxy, stands or methoxy; or
R4represents chromanol, 4-oxo-4H-chromenes or 2,3-dihydrobenzofuranyl where the specified R4optionally substituted by one or more hydroxy or stands; or
R4represents benzo[1,3]dioxole or 2.5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepine.

3. The compound according to claim 1, in which bireme from the group which includes:
(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;
(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;
4-hydroxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;
4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;
4-(1-acetylpiperidine-3-yl)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}benzamide;
N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzamide;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide (23,3R)-cyclohexanecarboxylic acid;
5-chloro-6-(2-hydroxyethylamino)-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1 - yl]phenyl}nicotinamide;
2-[(2-methoxyethyl)amide] 5-({2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide)pyridine-2,5-dicarboxylic acid;
N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}-6-pyrrol-1-iniatiated;
6-benzoyloxymethyl-N-{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}nicotinamide;
{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide of (2S,3R)-furan-3-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide (23,3R) - for 3,5-dimethylisoxazol-4-carboxylic acid;
{2-IU the Il-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 7-chloro-4-hydroxyquinolin-3-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 4-hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenylamide 1H-indole-6-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 5-methoxy-1H-indole-2-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2-methyl-1H-benzoimidazol-5-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 6-methoxybenzophenone-2-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 3,4-dihydroxy-2,2-DIMETHYLPROPANE-6-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 6-methyl-4-oxo-4H-chromen-2-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2,3-dihydrobenzofuran-5-carboxylic acid;
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]-phenyl}amide benzo[1,3]dioxol-5-carboxylic acid; and
{2-methyl-4-[3-(2-methylpyrrolidine-1-ylmethyl)pyrrolidin-1-yl]phenyl}amide 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid
or their pharmaceutically acceptable salt.

4. Pharmaceutical composition having modulating activity against receptor H3 histamine containing the compound of formula (I) is of any one of claims 1 to 3, or its pharmaceutically acceptable salt or enantiomer or stereoisomer, in combination with at least one pharmaceutically acceptable excipient, diluent or carrier.

5. The use of the compounds of formula (I) according to any one of claims 1 to 3 optionally in combination with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition for the treatment of diseases selected from the group including violation associated with a sleep disorder, dementia, Alzheimer's disease, multiple sclerosis, cognitive disorder, hyperactivity disorder attention deficit and depression.

6. The use according to claim 5, where the sleep disorder is selected from the group including narcolepsy, disruption of circadian rhythm sleep, obstructive sleep apnea syndrome, periodic limb movements and restless legs syndrome, excessive sleepiness and drowsiness caused by a side effect of the drug.

7. The use according to claim 5, where the disorder is a cognitive disorder.

8. The use according to claim 5, where the disease is Alzheimer's disease.

9. The use according to claim 5, where the disease is depression.

10. The use according to claim 5, where the disease is dementia.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of imidazo[4,5-c]chinoline of general formula or to its pharmaceutically acceptable salts, where R1 represents straight-chained C1-C6alkyl, possibly substituted with one substituent, selected from C1-C3alkoxy; Z1 represents C2-C6alkylene; X1 represents NR5 or >NCOR5; Y1 represents C1-C6alkylene; R3 represents C1-C6alkyl, possibly substituted with C1-C6alkoxy; R5 represents hydrogen, piperidinyl, possibly substituted by piperidinyl nitrogen with group R10, group C1-C6alkyl, where the last group is possibly substituted with one substituent, independently selected from NR7R8 or R9; or R5 represents C1-C6alkylene, which can be bound with carbon atom in C2-C6alkylene group Z1 with formation of piperidine ring; each of R7 and R8 independently represents tetrahydropyranyl, piperidinyl, possibly substituted by piperidinyl nitrogen atom with group R10a, C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR12; or R7 and R8 together with nitrogen atom, to which they are bound, form 4-7-membered saturated heterocyclic ring, selected from asetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-oxazepanyl and 1,4-diazepanyl, where heterocyclic ring is possibly substituted with one or two substituents, independently selected from S(O)qR15, OR15, CO2R15, COR15, CONR15R16, NR15CO2R16, pyrimidinyl and C1-C6alkyl, where the last group is possibly substituted with one group, independently selected from OR18 and CO2R18; R9 represents S(O)qR20; R10 and R10a independently represent COR2 or group C1-C6alkyl; each of R12, R15, R16, R18, R20 and R24 independently represents hydrogen or C1-C6alkyl; q equals 2; m and n both equal 0; and A represents phenyl. Invention also relates to method of obtaining formula (I) compound, based on it pharmaceutical composition, and to method of treating said pathological conditions.

EFFECT: obtained are novel derivatives of imidazo[4,5-c]chinoline, useful modulation of TLR7 activity.

17 cl, 18 dwg, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heterocyclic amide compound of formula I: or a pharmaceutically acceptable salt thereof. Described also is a pharmaceutical composition containing said compound, having protein kinase inhibitor, regulator or modulator properties, which is acceptable in treating or preventing a proliferative disease, an anti-proliferative disorder, inflammation, arthritis, neurologic or neurodegenerative disease, cardiovascular disease, hair loss, neural disease, ischemic disorder, viral disease or fungal disease.

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-aza-bicyclo[3.3.0]octane derivatives of formula , where R1 and R2 are hydrogen, C1-4alkyl or fluorine; R3 is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl, trifluoromethoxy group and halogen; 2,3-dihydrobenzofuranyl; 2,3-dihydrobenzo[1,4]dioxynyl; or isoxazolyl, pyridyl, indazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyrrolo[2,1b]thiazolyl, imidazo[ 1,2-a]pyridinyl or imidazo[2,1-b]thiazolyl, where said groups are unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, halogen and trifluoromethyl; A is or ; R4 is C1-4alkyl or -NR6R7; R6 is hydrogen or C1-4alkyl; R7 is hydrogen or C1-4alkyl; and D is a phenyl which is unsubstituted, mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, C1-4alkoxy group, trifluoromethyl and halogen; or a pharmaceutically acceptable salt of such a compound. 3-aza-bicyclo[3.3.0]octane derivatives or a pharmaceutically acceptable salt thereof are used as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where R denotes (C1-C4)-alkyl; R1 and R2 are identical or different and independently denote H, (C1-C4)-alkyl, CF3; R3 denotes H; R4 denotes cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl; where R4 is optionally substituted one or more times by a substitute selected from methyl, ethyl, pyridinyl, 2-oxo-2H-pyridin-1-yl; or a pharmaceutically acceptable salt thereof, an enantiomer or a diastereomer thereof.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof to prepare a pharmaceutical composition for treating central nervous system diseases.

10 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to (R)-4-(heteroaryl)phenyl compounds of formula ,

where X represents heteroatom, selected from -S or O, Y represents H or residue, selected from group, consisting of - linear or branched C1-C4-alkyl, halogen-C1-C3-alkyl; Z represents heteroaryl ring, selected from group, consisting of unsubstituted tetrazole and triazole, pyrazole, thiazole, isoxazole, isothiazole, thiadiazole and oxadiazole, substituted with one hydroxyl group and optionally additionally substituted with linear C1-C4-alkyl. (R)-4-(heteroaryl)phenylethyl derivatives of formula (I), which can be used for application in treatment of diseases, into which C5a-induced human PMN-chemotaxis is involved. Formula (I) compounds, where Z represents tertazole, is obtained by interaction of formula

compound with trimethylsililazide.

EFFECT: obtaining (R)-4-(heteroaryl)phenylethyl derivatives, possessing high selectivity and activity in inhibition of C5a-induced chemotaxis of neutrophils.

7 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A, J, R1, R4, X, Z are given in claim 1, and to a pharmaceutical composition containing such compounds, which modulate activity of store-operated calcium (SOC) channels. The present invention also describes methods of using such SOC channel modulators to treat diseases or conditions where inhibition of activity of SOC channels can be beneficial.

EFFECT: improved method.

17 cl, 5 tbl, 2 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) , where Ar denotes each of R2, R3, R4, R5, R4' and R5' denote hydrogen; A denotes C(O); D denotes oxygen or NR8; E denotes CR63R64CR65R66; R63 and R64 denote hydrogen; R65 and R66 independently denote hydrogen or C1-4alkyl; k equals 0; m equals 1; R6 denotes a group -(X)p-Y-(Z)q-R10, or R6 denotes α- or β-branched C3-6alkyl (optionally substituted with C6cycloalkyl); X and Z independently denotes a C1-4alkylene group; p and q are independently equal to 0 or 1; Y denotes a bond; R8 denotes hydrogen; R10 denotes hydrogen or a saturated 5-7-member ring system; R7 denotes a 6-member aromatic ring, optionally substituted with a halogen, carboxyl, C1-6alkyl, C1-2alkoxy or a 5-member heteroaromatic ring (which is optionally substituted with C1-6alkyl); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) or a pharmaceutically acceptable salt thereof are used to produce a medicinal agent for treating respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis.

EFFECT: high efficiency of using said compounds.

7 cl, 1 tbl, 102 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to formula 1 compounds, possessing properties of Xa factor inhibitors, their pharmaceutically acceptable salts and based on them pharmaceutical compositions. In formula 1 cycle A stands for residue, selected from group, including the following structures: R1-R12 independently represents H, (C1-C7)alkyl or (C3-C7)cycloalkyl, R3 and R4 form cycle by binding (C3-C5)alkylene, alkylene carbon atom can be substituted with carbonyl; R13 stands for H, (C1-C7)alkyl or formyl.

EFFECT: obtaining compounds, possessing properties of Xa factor inhibitors.

8 cl, 5 ex, 3 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: in claimed invention described is compound of general formula 1, or its pharmaceutically acceptable salt, where in each case independently on each other m equals 0, 1; p equals 1 or 2; R1 is selected from group, including -OH, -OC(O)NHMe, -OC(O)NMe2, -OC(O)NH(CH2)2Ph and OC(O)NH(CH2)2NMe2; R2 stands for -OH, -OC(O)Me, -OCH2CO2H, -OCH2CO2Et, -N3, -N=C(NMe2)2, -NH2, -NMe2, -NHC(O)Me, -NHC(O)CF3, - NHC(O)Ph, -NHC(O)NHPh, -NHC(O)CH2CH2CO2H, -NHC(O)CH2CH2CO2Me, - NHCH2Ph, -NHCH2(4-pyridyl), -NHCH2(2-pyridyl), -NHCH2(4-(CO2H)Ph), - NHCH2(3-(CO2H)Ph), -NHEt, -NHCHMe2, -NHCH2CHMe2, -N(CH2CHMe2)2, - NHCH2(cyclopropyl) or -NHC(O)CH2CH2NMe2; R3 stands for -OMe, -OEt, - OCH2(cyclopropyl), F, -O(CH2)2NMe2 or -O(CH2)2(4-morpholino); R4 stands for -NMe2, -NEt2, -NHEt, -NHCH2CHMe2, -N(Me)CH2CHMe2, - N(Me)CH2CH2NHS(O)2Me, -N(Me)CH2CH2NHS(O)2CF3, -NHCH2CH2OH, - N(Me)CH2CH2OH, -N(Me)CH2CO2H, -N(Me)CH2C(O)NH2, N(Me)CH2C(O)NHMe, -N(Me)CH2C(O)NMe2, -NHC(O)Me, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, -NH2, -NO2, Br, CI, F, -C(O)Me or -CH2NH2; R5 stands for -OH or -N(R17)(R18); R17 and R18 independently in each case stand for H, (C1-C6)-alkyl, (C5-C7)-aryl-(C1-C6)-alkyl, where said aryl contains from zero to two heteroatoms, (C1-C6)-alkoxy or -[C(R19)(R20)]P-R21 R19 and R20 independently in each case represent H, (C1-C6)-alkyl, (C1-C6)-alkoxy, amino-(C1-C6)-alkyl, acylamino, sulfonylamino, (C5-C7)-aryl, (C5-C7)-aryl-(C1-C6)-alkyl or 3-10-membered heterocyclyl-(C1-C6)-alkyl, containing in ring from one to two heteroatoms; R21 independently in each case represents H, 3-10-membered heterocyclyl, containing in ring one heteroatom, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonamido or amido; R22 stands for halogen; R23 stands for methyl; R24 stands for methyl and R25 stands for methyl, where said aryl stands for 5-7-membered ring, containing from zero to two heteroatoms, and said aryl or said heterocyclyl can be non-substituted or substituted halogen, (C1-C6)-alkyl or amino. Also described is pharmaceutical composition, possessing inhibiting activity with respect to Bcl-2 and/or Bcl-XL proteins, which includes said compound, also described is method of treating disorder, mediated by Bcl-2 and/or Bcl-XL proteins, which lies in introduction of said compound to patient, who needs such treatment, in therapeutically efficient amount.

EFFECT: increased efficiency of compound application.

41 cl, 6 dwg, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where R denotes (C1-C4)-alkyl; R1 and R2 are identical or different and independently denote H, (C1-C4)-alkyl, CF3; R3 denotes H; R4 denotes cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl; where R4 is optionally substituted one or more times by a substitute selected from methyl, ethyl, pyridinyl, 2-oxo-2H-pyridin-1-yl; or a pharmaceutically acceptable salt thereof, an enantiomer or a diastereomer thereof.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof to prepare a pharmaceutical composition for treating central nervous system diseases.

10 cl, 46 ex

Up!