Substituted n-phenylbipyrrolidine carboxamides and therapeutic use thereof

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

 

The LEVEL of TECHNOLOGY

The scope of the invention

The present invention relates to a group of substituted N-phenylpyrrolidine. 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-phenylpyrrolidine and their intermediates.

Description of the prior art

Histamine is a common molecule-messenger secreted 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 classic antihistaminic drugs (antagonists), such as diphenhydramine and Fexofenadine. Despite the fact that the antagonism of the H1 receptor in IMM is the TES 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. While SL is needs to 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 present invention was to provide a group of substituted N-phenylpyrrolidine as selective ligands of H3 receptors for the treatment of regulated receptor H3 disorders of the Central nervous system.

Also, the present invention was to provide methods of preparation of substituted N-phenylpyrrolidine as specified in this document.

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

BRIEF description of the INVENTION

It was unexpectedly found that the compounds with formula (I) can be used as antagonists and/or inverse agonists of H3 receptors. As noted earlier in this document, in the patent U.S. Patent 7223788 not given specific information that reveals the connection with formula I, no examples, no assumptions about their activity as antagonists/inverse agonists of H3 receptors. Moreover, unexpectedly at present, it was found that the compounds with formula (I) are electivo activity only in respect of H3 receptors and exhibit low activity in relation to the site of receptor sit or absence of any activity, moreover, this aspect of the invention become more apparent from the following detailed description.

Thus, in accordance with the practice of the present invention, it is proposed connection with 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 consisting of cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl; where the specified R4there may be one or more times substituted by the Deputy selected from the group consisting of halogen, methyl, ethyl, pyridinyl, 2-oxo-2H-pyridin-1-yl and CF3.

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

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

Detailed description of the invention

Used in this document Ter the ins 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, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Derivative notations such as "cycloalkane", "cycloalkenyl", "cycloalkenyl", "qi is alkylsulphonyl", 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 hydrogen atoms in the specified alkyl group substituted by fluorine atoms. Specific examples are triptoreline and panafcortelone and linear or branched hepcat acrophilia, 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 that (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 aromatic radicals containing a heteroatom. A typical 5-membered heteroaryl radicals include furanyl, thienyl or t is openil, 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 herein, the term "patient" means warm-blooded animals, for example rats, mice, dogs, cats, Guinea pigs and primates, so the x as a people.

Used in this document the expression "pharmaceutically acceptable carrier" means a non-toxic solvent, a dispersant, a filler, auxiliary or other substance that is mixed with the compound constituting the object of the present invention, to form a drug that is dosed 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 the preparation of compounds in accordance with the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include salts formed by addition of acids, which can be, for example, by mixing the solution of the compounds in accordance with the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfamic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic sour is s, 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 be acidic metal salts, for example, monohydrogenphosphate sodium and potassium hydrosulfate. In addition, the thus obtained salt may be a mono - or disubstituted salts are acidic and can be substantially dehydrated or exist in the form of hydrates. 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" is a common value in this field. One t is some definition includes pharmacologically inactive chemical substance, which, 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 are ketoenamine the tautomers, fenilcetonuria the tautomers, nitrosoamine the tautomers, aminoarabinose the tautomers and other. It should be understood that all such isomers and mixtures thereof in any proportions fall within the scope of the present invention.

Used in this d is the document designations "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 group with the second lowest)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 group with the second lowest)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 that the first carbon atom of 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 ug is erode 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 C1-6alkyl, (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 in the art.

"Therapeutically effective amount" means an amount of compound effective to treat the above mentioned diseases, disorders or conditions.

The term "treatment" means:

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

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

(iii) the elimination of the 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 consisting of cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl; where the specified R4optional one or more times substituted by the Deputy selected from the group consisting of halogen, methyl, ethyl, pyridinyl, 2-oxo-2H-pyridin-1-yl and CF3.

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

In one implementation described below, the disclosed compounds with formula (I), where R is methyl; R2is methyl or CF3; R1and R3- hydrogen.

In another implementation of the present invention features a compound with the formula (I), where R and R1is methyl; R2and R3- hydrogen.

In another implementation of the present invention is disclosed compound with the formula (I), where R4is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl or bicyclo[2,2,1]heptane, which may have one or more times as Deputy methyl.

In another implementation of the present invention features a compound with the formula (I), where R4- tetrahydropyranyl.

In one implementation of the present invention discloses a compound with the formula (I), where R4is selected from the group consisting of furanyl, oxazolyl, isoxazolyl and pyrazolyl, which may have one or more times as Deputy methyl.

In another implementation of the present invention is disclosed compound with the formula (I), where R4is selected from the group containing the th isoxazolyl or isoxazolyl, which may have one or more times as Deputy methyl.

In an additional aspect of the present invention it is possible to list the following compounds included without limitation in the scope of the present invention:

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acids;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-amide cyclopropanecarbonyl acids;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acids;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acids;

[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acids;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acids;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acids;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acids;

[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide cyclopentanecarbonyl acids;

[2-methyl-1-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide cyclohexanecarbonyl acids;

2-cyclopentyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;

2-cyclopentyl-N-[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipyrrole the Il-1'-yl)-phenyl]-ndimethylacetamide;

2-cyclopentyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;

2-cyclopentyl-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;

[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide bicyclo[2.2.1]heptane-2-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide and (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide and (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide and (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;

[3-methyl-4-2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;

[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide, furan-3-carboxylic acid;

[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide, furan-2-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-(2-oxo-2H-pyridin-1-yl)-furan-2-carboxylic acid

[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 2-methoxazole-4-carboxylic acid;

[2-methyl-4-(2S-methyl-[1,3'S]b is pyrrolidinyl-1'-yl)-phenyl]-amide 3-methylisoxazol-5-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 1,5-dimethyl-1H-pyrazole-3-carboxylic acid; and

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-pyridin-4-yl-2H-pyrazole-3-carb is the new 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 included without limitation in the scope of compounds with formula (I) of the present invention:

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acids;

2-cyclopentyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;

[2-methyl-1-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide cyclohexanecarbonyl acids;

[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide bicyclo[2.2.1]heptane-2-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;

[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide, furan-3-carboxylic acid;

[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide 3-methylisoxazol-5-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid; and

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid.

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

In an additional aspect of the present invention it is possible to list the following compounds within the scope of the present invention:

[2-methyl-1-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide cyclohexanecarbonyl acids;

[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide bicyclo[2.2.1]heptane-2-carboxylic acid;

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid; and

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-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, the compound of the present invention may be represented by special stereoisomerism form of formula (II):

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

Compounds of the present invention can be synthesized by any known in the art methods. In particular, some of the original materials used in the preparation of the compounds of this invention are known or commercially available. Connection this is subramania and some 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 that 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 (for example, 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, where R, R1, R2, R3and R4match the definitions given for formula I, unless otherwise indicated.

For example, figure 1 shows an example of obtaining the intermediate [1, 3']-pyrrolopyrimidine with formula (4), in which R is as defined in the present document. First, in stage 1, scheme 1, a suitably protected (for example, tert-butoxycarbonyl (Boc)pyrrolidine with formula (1) is condensed with the desired substituted pyrrolidines with formula (2) by any known means reductive amination for the formation of intermediate compounds with the formula (3). So, like the condensation reaction usually occur in the presence of reducing agents, such as triacetoxyborohydride, in an inert atmosphere, for example under nitrogen atmosphere. The reaction can proceed at temperatures and pressures lower than room temperature, at room values or values above room temperature. Typically, these reactions take place at room temperature and under atmospheric pressure of nitrogen. The reaction mixture was then obrabatyvati care processes, well-known experts in this field, for the isolation of intermediate compounds with the formula (3).

In stage 2, scheme 1, the intermediate compound (3) then removed the protective group for the formation of the desired [1, 3']-pyrrolopyrimidine with formula (4). Such reactions the removal of the protective groups usually occur in an acidic environment, for example, in the presence of hydrochloric acid at a temperature below room temperature up to temperatures above room temperature, for example, in the temperature range from about -10°C to room temperature. However, they may also use other suitable reaction temperature, depending on the nature of the intermediate compounds with the formula (3).

Figure 2 shows an example of obtaining enantiomerically pure isomers [1,3']-pyrrolopyrimidine with formula (9), in which R is as defined in the present document. In stage 1, scheme 2, a suitably protected (for example, Boc) pyrolidine alcohol with formula (5) is treated p-toluensulfonate for the formation of intermediate compounds with the formula (6). This reaction can be carried out using any method known to experts in the field, for example, carrying out the reaction in the presence of a suitable base, such as triethylamine and DMAP in a suitable organic solvent, preferably the proton solvent, for example dichloromethane, at temperatures below the ambient temperature or equal to it.

In stage 2, scheme 2, the intermediate compound with the formula (6) is condensed with the target pyrrolidino with formula (7). Such the condensation reaction can also be carried out using any known method for obtaining an intermediate compound with the formula (8). As a rule, the condensation reaction is conducted in the presence of a base, for example potassium carbonate, in the presence of solvents such as acetonitrile, at ambient temperature or elevated temperature.

At stage 3 scheme 2, the intermediate compound with the formula (8) then reacts with the acid, for example hydrochloric acid, in a suitable solvent, for example dioxane, with the formation of the desired stereospecific isomer of intermediate compounds [1,3']-pyrrolopyrimidine with formula (9). It is now established that the intermediate compound with the formula (9) can easily be obtained in accordance with the process of the present invention with high enantiomeric purity, and specific details of this process are given later in this document in various examples. In General, the enantiomeric purity can be determined by chiral HPLC.

Figure 3 shows an example of gaining the intermediate aminopropyldimethylamine with formula (12), in which R, R1and R2meet the definition in this document. In stage 1 scheme 3 appropriately substituted nitrobenzene with formula (10), in which X denotes acceptable leaving group, for example, Cl, F, Br or triflate (OTf), is condensed with [1,3']-pyrrolidinylcarbonyl with formula (4) to obtain the intermediate compound with the formula (11). Such the condensation reaction can also be carried out using any known in this area of the method. For example, this substitution reaction can be conducted in a polar 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, scheme 3, the intermediate compound with the 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).

Figure 4 contains an example of obtaining compounds with formula (I) of the present invention using method a or method B, 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 in this the m document and R3- the hydrogen atom.

In the method And scheme 4 the acid chloride with 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 with the 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 be carried out at ambient temperature and elevated temperature, depending on the nature of the acid chloride and the intermediate (12).

Similarly, in the method In scheme 4 carboxylic acid with the formula (14) can react with an intermediate compound with the formula (12) at various reaction conditions which are known to experts in the field. For example, the acid with the formula (14) is reacted with an intermediate compound with the formula (12) at low temperature in the presence of suitable reagents, for example, mixtures of N-methylmorpholine, 1-hydroxybenzotriazole and EDC.

As mentioned above herein, the compounds of the present invention can easily turn into salt. In particular, joint the present invention are basic, 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, essentially, is to use the form of the free base. Acids which can be used to prepare 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 pharmaceutical doses of the salts so that 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 the preparation of pharmaceutically acceptable salts by ionoobmennyh processes.

In another aspect of the implementation of the ia of the present invention using the 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 sleeping apnea syndrome, periodic limb movements and restless legs syndrome, excessive sleepiness and drowsiness, which is a side effect of a drug, etc), neurological disorders (among the concrete examples are, among other things, dementia, Alzheimer's disease, multiple sclerosis, epilepsy and neuropathic pain), neuropsychological 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. Also what about 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 antagonists, 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, by assigning the patient a therapeutically effective dose of a compound with formula (I).

For special is the aliste in this area is obvious, what 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 be effectively administered to relieve painful conditions, which fully or partially mediated by H3 receptors.

All the different implementation of the compounds used in the methods of the present invention, as described herein, can be used in methods of 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 may be administered by any known means. In particular, the compounds of the present invention can be assigned to errorline, intramuscularly, subcutaneously, rectally, intratrahealno, intranasal, intraperitoneal or locally.

Finally, in another implementation of the present invention also features a pharmaceutical composition comprising pharmaceutically acceptable carrier and a compound with formula (I), including enantiomers, stereoisomers and tautomers of the compounds and their 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 compositions of the present invention are characterized by inhibiting the action of H3 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 the form of standard dosage forms, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid raspadaemosti, drops, ampoules, autoinjector devices or suppositories intended for oral, intranasal, sublingual or rectal injection or administration by inhalation or insufflation. Alternatively, these drugs can have a shape that is optimal for weekly or monthly use; for example, an insoluble salt of the active compound, such as salt decanoate, can be adapted for cooking depot for intramuscular injection. You can use the collapsing of the polymer containing the active ingredient. To prepare solid preparations such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tablet 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 preliminary composition containing a homogeneous mixture of the compounds constituting the subject matter of this invention, or its pharmaceutically acceptable salt. When such advance preparations are referred to as homogeneous, it is meant that the active ingredient is mixed evenly throughout the composition, and the preparation can be divided into with p the ate performance standard dosage forms, for example, tablets, pills and capsules. Then this solid preliminary drug divided by the standard 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. Flavored standard 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 drug can be coated or otherwise formed to provide a prolonged action dosage forms. For example, the tablet or pill may contain internal and external dosed components when the latter forms a shell comprising a 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 to its introduction has 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 via and is jaczie, include aqueous solutions, syrups with a suitable flavoring, water and oil suspensions, and flavored emulsions with edible oils, such as, cotton, 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, for example, tragakant, Arabian gum, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Drugs of the present invention can be any known in the art methods. In General, the pharmaceutical compounds of the present invention can be administered orally, intramuscularly, subcutaneously, rectally, intratrahealno, intranasal, intraperitoneal or locally. Preferred methods of administration of drugs of the present invention are oral and intranasal routes. Any of the known methods of administration of drugs oral or intranasal route may be used for administration of drugs 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, site is 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)

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- retention rates, "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, DMSO - dimethylsulfoxide, "DMF" - N,N-dimethylformamide, CDI is 1,1'-carbonyldiimidazole, "DHM" or "CH2Cl2" - dichloromethane, "EDC" is 1,2-dichloroethane, "HCl" - hydrochloric acid, "EtOAc" is ethyl, "PBS" phosphate buffered saline "IBMX" - 3-isobutyl-1-methylxanthines, "PEG" is a polyethylene glycol, "MeOH" methanol, "MeNH2" - methylamine, the N 2" is gaseous nitrogen, "iPrOH" - isopropyl alcohol, "Et2O" - ethyl ester, "LAH" - alumoweld lithium, "heptane" - n-heptane, resin "HMBA-AM - aminomethyl resin, 4-hydroxymethylbenzene acid, "PdCl2(dppf)2" complex with dichloromethane dichloride 1,1'-bis(diphenylphosphino)ferienparadies (II), "HBTU" - 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium of hexaflurophosphate, "DIEA" - diisopropylethylamine, "CsF" - cesium fluoride, "MeI" is methyl iodide, "AcN", "MeCN" or "CH3CN - acetonitrile, "TFU" - triperoxonane acid, "THF" is tetrahydrofuran, "DMF - dimethylformamide, "NRM" - 1-methyl-2-pyrrolidinone, "H2O" water, "BOC" - t-butyloxycarbonyl, "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" intraperitoneally, "VV" - 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 - ionization elektrorazpredelenie/mass spectrograph, WOO - time is ariania, M - molecular ion, "~" is about.

The reaction typically is carried out in nitrogen atmosphere. The solvent is dried over magnesium sulfate and evaporated under vacuum on a rotary evaporator. The TLC analyses performed on plates with silica gel EM Science 60 F254 with visualization under UV light. Flash chromatography is performed on columns Alltech, pre-filled with silica gel. Spectra1H NMR gain at the frequency of 300 Hz spectrometer Gemini 300 or Varian Mercury 300 with 5 mm ASW sensor and is usually recorded at room temperature in deuterated solvent, such as D2O, DMSO-D6or CDCl3if not stated otherwise. The magnitude of chemical shift (δ) are quoted in ppm (MD) on tetramethylsilane (TMS) as internal standard.

Experiments on liquid chromatography high pressure and mass spectrometry (GHMC) to determine retention time (RT) and associated mass ions was performed using one of the following methods:

mass spectra (MS) are recorded on a mass spectrometer Micromass. Usually used ionization positive elektrorazpredelenie with scanning mass m/z 100 to 1000. Liquid chromatography was carried out using a binary pump and degasser Hewlett Packard series 1100; as auxiliary detectors used: UV detector is a Hewlett Packard series 1100, wavelength = 220 nm, and evaporative light scattering detector (ELS) Sedere SEDEX 75, detector temperature = 46°C pressure N2=4 bar.

LCT: gradient (AcN+0.05% of TFA):(H2O+0.05% of TFA)=5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3 min). Column: YMC Jsphere 33x2 4 micron, 1 ml/min

MUX: Column: YMC Jsphere 33×2, 1 ml/min

gradient (AcN+0.05% of TFA):(H2O+0.05% of TFA)=5:95 (0 min) to 95:5 (by 3.4 min)to 95:5 (4,4 min)

LCT2: YMC Jsphere 33×2 4 microns, (AcN+0.05% of TFA):(H2O+0.05% of TFA)=5:95 (0 min) to 95:5 (by 3.4 min)to 95:5 (4,4 min)

QU: YMC Jsphere 33×2 1 ml/min, (AcN+0,08% formic acid):(H2O+0.1% of formic acid)=5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3,0 min)

The following examples describe the methods used to obtain various raw materials used to prepare the compounds of the present invention.

INTERMEDIATE COMPOUNDS

The intermediate compound (i)

Tert-butyl ester 2-methyl-[1,3']bipirimidiny-1'-carboxylic acid

To a solution of N-BOC-3-pyrrolidinone (4,22 g is 22.9 mmol) and 2-methylpyrrolidine (1,95 g is 22.9 mmol) (HCl salt obtained by adding to 22.9 ml of 1 M HCl in ether to a solution of 2-methylpyrrolidine in DHM with subsequent evaporation) in EDC (60 ml) was slowly added powdered triacetoxyborohydride sodium current of the N2at room temperature. Opaque yellowish solution was stirred at room temperature overnight. LC/MS - m/z 255 and 199 (foundations of the Oh peak and peak M-tBu).

The reaction mixture was extinguished in an aqueous solution of NaHCO3. The two phases were separated, and the aqueous phase was extracted with dichloromethane (20 ml × 2). The combined extracts DHM washed with sodium bicarbonate (10 ml) and brine (5 ml × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira DHM and 7.5% MeOH in DHM, to obtain the desired compound in the form of liquid, 5.50 g (yield: 94%). MS: 255 (M+H+); TLC: 0,5 (10% MeOH in DHM).

The intermediate compound (ii)

Hydrochloride of 2-methyl-[1,3']piperadine

Tert-butyl ester 2-methyl-[1,3']bipirimidiny-1'-carboxylic acid (intermediate compound (i)obtained above, 5.50 g, 21,62 mmol) was treated with 20 ml of 4 M HCl in dioxane at 0°C. the Solution was stirred in nitrogen atmosphere at room temperature overnight. The TLC analysis (10% MeOH in DHM) showed no presence of starting material. N2was passed through the solution in the mixing process. The exit stream was passed through a solution of KOH for 30 min to absorb the HCl. The solvent was removed by evaporation until dry to obtain the desired compound in the form of hygroscopic resinous substance, of 5.3 g (~100%). This material was used without additional purification in the following stages, as shown the lower is. LC/MS: RT=0,35 min, MS: 155 (M+H).

1H NMR (D2O, 300 MHz): 4,30 (m), 3,85 (m)3,76 (C), 3.5mm (m)of 3.46 (m), 3,32 (m)2,66 (m) 2,28 (m), 2,10 (m), 1,46 (SHS).

The intermediate compound (iii)

2-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3']bipirimidiny

Hydrochloride of 2-methyl-[1,3']piperadine (intermediate compound (ii)obtained above, 5,3 g, 21.6 mmol, 1,12 equiv.) was dissolved in anhydrous DMSO (30 ml). To this solution was added 5-fluoro-2-nitrotoluene (3.00 g, 18,78 mmol, 1 equiv.), then add powdered potassium carbonate (8,9 g, 65 mmol). The suspension was heated in an oil bath to 85°C for 4 h, when the source material was consumed, as shown by TLC analysis (5% MeOH in DHM) and LC/MS. To the suspension was added 20 ml of water and 50 ml DHM. The two phases were separated, and the aqueous phase was extracted with dichloromethane (20 ml × 2). The combined extracts DHM washed with sodium bicarbonate (20 ml) and brine (15 ml × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira 5% MeOH in DHM, to obtain the desired compound in the form of a solid yellow color after drying, vs. 5.47 g (100%). MS: 290 (M+H+).

1H NMR (300 MHz, CDCl3), δ (MD): 8,10 (d, 9 Hz, 1H), 6,36 (sm, 9 Hz, 1H), 6,28 (SHS, 1H), 3,4-3,2 (m, 5H), 3.00 and-2,78 (m, 2H), 2,64 (s, 3H), 1.7 to 2.2 (m, 6H), 1.5 a (m, 1H), 1.06 a (m, 3H).

The intermediate connection of the group (iv)

4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine

A solution of 2-methyl-1'-(3-methyl-4-nitro-phenyl)-[1,3']piperadine (intermediate compound (iii)obtained above, of 2.23 g, 7.7 mmol) in MeOH was wearisomely and nadowli nitrogen. To this solution was added Pd-C (10%). This mixture was stirred under pressure H2at room temperature for 8 hours TLC Analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed. The mixture was passed through a layer of celite and washed with methanol. The filtrate was concentrated until dry and further dried under high vacuum to form a liquid reddish-brown color after drying under high vacuum to obtain the desired compound in the form of a resinous liquid black, 1.73 g (86%). This material was used in the next stage without additional purification and storage. MS: 260 (M+H+).

The intermediate compound (v)

Hydrochloride of 2-(2R)-methyl-[1,3']piperadine

To a solution of N-BOC-3-pyrrolidinone (1.26 g, 6,83 mmol) and 2-(R)-methylpyrrolidine (0,83 g, 6,83 mmol) in EDC (20 ml) was slowly added powdered triacetoxyborohydride sodium current of the N2at room temperature. Opaque yellowish solution was stirred at room temperature overnight. Analysis of LC/MS showed m/z 255 and 199 (main peak and peak-tBu).

The reaction mixture was extinguished in an aqueous solution of NaHCO3. The two phases were separated, and the aqueous phase was extracted with dichloromethane (10 ml × 2). The combined extracts DHM washed with sodium bicarbonate (10 ml) and brine (5 ml × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira DHM and 7.5% MeOH in DHM, to obtain a liquid, 1.29 g (yield: 74%). This thick liquid obtained above (1.29 g, 5.08 mmol), was treated with 16 ml of 4M HCl in dioxane at 0°C. the Solution was stirred in nitrogen atmosphere at room temperature overnight. The TLC analysis (10% MeOH in DHM) showed no presence of starting material.

N2was passed through the solution in the mixing process. The exit stream was passed through a solution of KOH for 30 min to absorb the HCl. The solvent was removed by evaporation until dry to obtain absorbent resin substances (salt and hydrate HCl, the exact composition unknown), 1,32 g (~100%). This material was used without additional purification in the following stages, as shown below. LC/MS: RT=0,35 min, MS: 155 (M+H).

The intermediate compound (vi)

2-(2R)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3']bipirimidiny

5-fluoro-2-nitrotoluene (1.55 g, 10 mmol) was dissolved in anhydrous DMSO. To this the solution was added the hydrochloride of 2-(2R)-methyl-[1,3']piperadine (2.30 g, 15 mmol), followed by the addition of powdered potassium carbonate. The suspension was heated in an oil bath to 85oC for 3 h, when the source material was consumed, as shown by TLC analysis (5% MeOH/DHM) and LC/MS. To the suspension was added 20 ml of water and 50 ml DHM. The two phases were separated, and the aqueous phase was extracted with dichloromethane (20 ml × 2). The combined extracts DHM washed with sodium bicarbonate (20 ml) and brine (15 ml × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira 5% MeOH in DHM, to obtain the desired compound in the form of a solid yellow color after drying, 2.70 g (93%). MS: 290 (M+1).

1H NMR (CDCl3, 300 MHz), δ (MD): 8,10 (d, 9 Hz), 6,36 (sm, 9 Hz), 6,28 (SHS), 3,4-3,2 (m)3,00-2,78 (m), 2,64 (C), 1,7-2,2 (m)1,5 (m)of 1.06 (d, 6.6 Hz), 1.14 in (d, 6.6 Hz).

The intermediate compound (vii)

2-methyl-4-(2-(2R)-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine

A solution of 2-(2R)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3']piperadine (2 g, 6,9 mmol) in MeOH (15 ml) was wearisomely and nadowli nitrogen. To this solution was added Pd-C (10%, 0.20 g). The nitrogen was replaced by hydrogen, and the 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. The mixture was passed through a layer of celite and washing is whether methanol. The filtrate was concentrated until dry and further dried under high vacuum to obtain the desired compound in the form of liquid reddish-brown color after drying under high vacuum, 2,02 g (yield 100%).

The intermediate compound (viii)

Hydrochloride of 2-(2S)-methyl-[1,3']piperadine

The desired compound was obtained by a method essentially the same as the intermediate compound (v), by condensation of N-BOC-3-pyrrolidinone (1.26 g, 6,83 mmol) and 2-(S)-methylpyrrolidine, with the subsequent removal of the protective groups hydrochloride in dioxane.

LC/MS: RT=0,36 min, MS: 155 (M+H).

1H NMR (CDCl3, 300 MHz), δ (MD): 4,16 (m)of 3.77 (m), 3,61 (m), 3,13 (m), and 3.31 (m), 2,53 (m)2,41 (m)to 1.98 (m), 1,67 (m)1,31 (m).

The intermediate compound (ix)

Tert-butyl ether 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid

In a round bottom flask was placed n-toluensulfonate (16,01 g, 83,98 mmol, 1.5 equiv.) and 150 ml of anhydrous DHM. The solution was cooled in an ice bath, was evacuated and purged with nitrogen. To this solution was added a solution of (3R)-(-)-N-BOC-3-hydroxypyrrolidine (supplied by Aldrich) (10,47 g, 55,99 mmol) in 50 ml DHM, followed by the addition of DMAP (0.66 g) and triethylamine (16.2 ml). The solution was stirred in nitrogen atmosphere overnight from 0°C to room temperature. Analysis of the SH (5% MeOH in DHM) showed that reaction was completed. The reaction mixture was suppressed by addition of the amine on the polymer carrier (8 g), stirred for 30 min and was added 100 ml DHM. The organic fraction was washed H3PO4(1M, 2×50 ml), then NaHCO3(50 ml), brine (50 ml), dried (K2CO3), was filtered through a layer of silica gel and concentrated to obtain the desired compound in the form of liquid, 15,82 g (82,8 %). MS: 363 (M+Na+); TLC (DHM) Rf=0,3.

1H NMR (CDCl3, 300 MHz), δ (MD): 7,80 (d, 9.0 Hz, 2H), 7,35 (d, 7.8 Hz, 2H), 5,04 (SHS, 1H), of 3.45 (m, 4H), 2,46 (CL, 3H), of 2.05 (m, 2H), USD 1.43 (s, 9H).

The intermediate compound (x)

Tert-butyl ester 2-(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-carboxylic acid

Tert-butyl ether 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid (intermediate compound (ix)obtained above, 15,82 g of 46.4 mmol, 1 equiv.) and S-(+)-2-methylpiperidin (obtained from Advanced Asymmetrics), (7,88 g, 92,79 mmol, 2 equiv.) was dissolved in anhydrous CH3CN (150 ml). To this colorless solution was added powdered K2CO3(powder, 325 mesh, 98+%, 14,11 g, 102,08 mmol, 2.2 equiv.) at room temperature. The suspension was heated in an oil bath at a temperature of 80°C for 24 h Analysis TLC (3% MeOH in DHM for the source material (IM) and 7.5% MeOH in DHM product showed that it was almost totally spent. LC/Spousal a small number of THEM at m/z 363 and product at 255.

The suspension was concentrated until dry. The residue is stirred in water (25 ml) and DHM (80 ml). Two phases were fractionally, and the aqueous phase was extracted with dichloromethane (20 ml × 2). The combined extracts DHM washed with sodium bicarbonate (25 ml) and brine (25 ml), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira MeOH in DHM (from 0 to 7.5%), to obtain the desired compound in the form of a resinous substance, to $ 7.91 g (67%). LC/MS: RT=1,27 min, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 3.15 in (m, 2H), 3,3 (m, 3H), of 2.97 (m, 1H), 2,71 (m, 1H), 2,47 (m, 1H), up to 1.98 (m, 2H), 1,96-to 1.67 (m, 4H), of 1.46 (s, 9H), 1.06 a (d, 6.2 Hz, 3H).

The intermediate compound (xi)

Tert-butyl ester 2-(2R)-methyl-[1,3'(3'S)]bipirimidiny-1'-carboxylic acid

The desired compound was obtained by a method essentially the same as the intermediate compound (x)by condensing tert-butyl ester 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid (intermediate compound (ix)obtained above) and R-(-)-2-methylpiperidine (obtained from Advanced Asymmetrics). LC/MS: RT=1,05 min, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 3,30 (m, 1H), 3,14 (CL, 2H), 2.91 in (m, 1H), 2,75 (m, 1H), of 2.51 (m, 1H), 2,07 was 1.69 (m, 6H), of 1.46 (s, 9H), 1,10 (d, 6.0 Hz, 3H).

The intermediate compound (xii)

Tert-butyl EPE is 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid

In a round bottom flask was placed 80 ml of anhydrous DHM. The solvent was evacuated and purged with nitrogen. To this solvent was added (3S)-1-BOC-3-pyrrolidinone (obtained from Astatech), (16,32 g, 33.8 mmol), DMAP (0.4 g). The solution was cooled in an ice bath. To this chilled solution was added a solution of p-toluensulfonate (9,67 g, 50,87 mmol, 1.5 equiv.) in 20 ml of DHM. After removing the ice bath and the mixture was stirred in nitrogen atmosphere overnight. The TLC analysis (5% MeOH in DHM for THEM, rendering I2; DHM for a product, UV) showed that the reaction was completed. The reaction mixture was suppressed by addition of the amine on the polymer carrier (4.5 g), stirred for 30 min, was added 50 ml DHM and filtered. The filter is washed with DCM. The organic fraction was washed H3PO4(1M, 2×50 ml), then NaHCO3(50 ml), brine (50 ml), dried (K2CO3), filtered and concentrated to obtain liquid. The obtained product was purified on silikagelevye column (110 g) on Analogix using 0-2% MeOH in DHM, to obtain the pure product, 8,82 g (yield: 77%).

TLC (DHM) Rf=0,3. LC: Rt=3,55 min, 100% purity according to molecular ion, MS: 363 (M+Na); 342, 327, 286 (main peak).

1H NMR (300 MHz, CDCl3), δ (MD): 7,81 (d, 8.7 Hz, 2H), 7,37 (d, 8.7 Hz, 2H), 5,04 (SHS, 1H), of 3.45 (m, 4H), to 2.46 (s, 3H), of 1.44 (s, 9H).

The intermediate compound (xiii)

Tert-Hotelowy ester 2-(2S)-methyl-[1,3'(3'R)]bipirimidiny-1'-carboxylic acid

Tert-butyl ether 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid (intermediate compound (xii)obtained above, 6,82 g, 19,97 mmol, 1 equiv.) and S-(+)-2-methylpiperidin (obtained from Advanced Asymmetrics), (3,40 g, 40 mmol, 2 equiv.) was dissolved in anhydrous CH3CN (65 ml). To this colorless solution was added powdered K2CO3(powder, 325 mesh, 98+%, 6,10 g, a 44.2 mmol, 2.2 equiv.) at room temperature. The suspension was heated in the mixing process in a nitrogen atmosphere over an oil bath at a temperature of 80°C for 24 h Analysis TLC (3% MeOH in DHM for THEM, to 7.5% MeOH in DHM product showed that it was almost totally spent. LC/MS showed a small number of THEM at m/z 363.

The suspension was concentrated until dry. The residue was dissolved in water (25 ml) and DHM (80 ml). The two phases were separated, and the aqueous phase was extracted with dichloromethane (20 ml × 2). The combined extracts DHM washed with sodium bicarbonate (25 ml) and brine (25 ml), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column (70 g) at Analogix, elwira MeOH in DHM (from 0 to 7.5%), to obtain 4,08 g (80,3%) of the desired compound in the form of a resinous substance. LC/MS: RT=1,14 min, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 3,30 (m, 1H), 3,14 (CL, 2H), 2.91 in (the, 1H), a 2.75 (m, 1H), of 2.51 (m, 1H), 2,07 was 1.69 (m, 6H), of 1.46 (s, 9H), 1,10 (d, 6.2 Hz, 3H).

The intermediate compound (xiv)

Tert-butyl ester 2-(2R)-methyl-[1,3'(3'R)]bipirimidiny-1'-carboxylic acid

The desired compound was obtained by a method essentially the same as the intermediate compounds (xiii), by condensing tert-butyl ester 3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid (intermediate compound (xiii)obtained above) and R-(-)-2-methylpiperidine (obtained from Advanced Asymmetrics). LC/MS: RT=1,09 min, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 3.15 in (m, 2H), 3,3 (m, 3H), of 2.97 (m, 1H), 2,71 (m, 1H), 2,47 (m, 1H), up to 1.98 (m, 2H), 1,96-to 1.67 (m, 4H), of 1.46 (s, 9H), 1.06 a (d, 6.2 Hz, 3H).

The intermediate compound (xv)

Getting 2-(2S)-methyl-[1,3'(3'R)]piperadine

Tert-butyl ester 2-(2S)-methyl-[1,3'(3'R)]bipirimidiny-1'-carboxylic acid (to $ 7.91 g, 31,14 mmol) was treated with a 28.8 ml of HCl in dioxane at 0°C. the Solution was stirred in nitrogen atmosphere at room temperature overnight. The TLC analysis (10% MeOH in DHM) and LC/MS showed no presence of starting material. The reaction was deemed complete.

N2was passed through the solution in the mixing process. The exit stream was passed through a solution of KOH for 1 h to absorb the HCl. The solvent was removed by evaporation until dry DL is obtaining the required connection in the form of hygroscopic very dense resinous substances (2HCl salt, hydrate - the exact composition unknown), 8,07 g (~100%). MS: 155 (M+H).

1H NMR (300 MHz, D2O), δ (MD): 11,6 (SHS, 1H), 9,1 (SHS, 1H), 4,12 (m, 1H) 3,5 (m, 2H), 3,3-3,1 (m, 3H), 2,4-2,1 (m, 4H), 2,4 (m, 2H), 1,6 (m, 1H), 1,4 (d, 6.0 Hz, 3H).

The intermediate compound (xvi)

2-(2S)-methyl-[1,3'(3'S)]bipirimidiny

The desired compound was obtained by a method essentially the same as the intermediate compound (xv)by acid hydrolysis of the tert-butyl ester 2-(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-carboxylic acid (intermediate compound (x)obtained above).

LC/MS: RT=0,37 min, MS: 155 (M+H).

1H NMR (300 MHz, D2O), δ (MD): 11,6 (SHS, 1H), 9,1 (SHS, 1H), 4,12 (m, 1H) 3,5 (m, 2H), 3,3-3,1 (m, 3H), 2,4-2,1 (m, 4H), 2,4 (m, 2H), 1,6 (m, 1H), 1,4 (d, 6.0 Hz, 3H).

The intermediate compound (xvii)

Getting 2-(2R)-methyl-[1,3'(3'S)]piperadine

The desired compound was obtained by a method essentially the same as the intermediate compound (xv)by acid hydrolysis of the tert-butyl ester 2-(2R)-methyl-[1,3'(3'S)]bipirimidiny-1'-carboxylic acid (intermediate compound (xi)obtained above).

The intermediate compound (xviii)

2-(2R)-methyl-[1,3'(3'R)]bipirimidiny

The desired compound was obtained by a method essentially the same as the intermediate compound (xv)by acid hydrolysis tre the-butyl ester 2-(2R)-methyl-[1,3'(3'R)]bipirimidiny-1'-carboxylic acid (intermediate compound (xiv), obtained above). MS: 155 (M+H).

1H NMR (300 MHz, D2O), δ (MD): 11,6 (SHS, 1H), 9,1 (SHS, 1H), 4,12 (m, 1H) 3,5 (m, 2H), 3,3-3,1 (m, 3H), 2,4-2,1 (m, 4H), 2,4 (m, 2H), 1,6 (m, 1H), 1,4 (d, 6.0 Hz, 3H).

The intermediate compound (xix)

2-(2S)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3'(3'R)]bipirimidiny

2-(2S)-methyl-[1,3'(3'R)]bipirimidiny (to 0.23 g, 1.2 mmol) was dissolved in anhydrous DMSO (5 ml) in a flask. To this solution was added 5-fluoro-2-nitrotoluene (223 mg, 1.44 mmol), followed by the addition of powdered potassium carbonate (662 mg, 4.8 mmol). The suspension was heated in an oil bath to 85°C for 4 h, when the source material was consumed, as shown by TLC analysis (5% MeOH/DHM) and LC/MS. MS: 290 (main peak).

To the suspension was added 2 ml of water and 5 ml DHM. The two phases were separated, and the aqueous phase was extracted with dichloromethane (10 ml × 2). The combined extracts DHM washed with sodium bicarbonate (5 ml) and brine (5 ml × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira 5% MeOH in DHM, to obtain the desired compound in the form of a solid yellow color after drying. LC/MS: RT=1,38 minutes, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 8,10 (d, 9.1 Hz, 1H), 6,36 (DD, of 9.2, 2.5 Hz, 1H), 6,28 (d, 2.4 Hz, 1H), 3,654 (m, 2H), 3,37 (m, 3H), 2,99 (dt, 3,7 Hz and 8.8 Hz, 1H), 2,84 (sextet, and 6.6 Hz, 1H), 2,65 (s, 3H), 2,56 (K, 8,1 Hz, 3H), 31st (m, 2H), 2,11 (m, 2H) to 1.87 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC was spent in the following conditions: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm. The following results were obtained: RT=10,92 min; EE 100%.

The intermediate compound (xx)

2-(2S)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3'(3'S)]bipirimidiny

The desired compound was obtained by a method essentially the same as the intermediate compound (xix), by condensation of 2-(2S)-methyl-[1,3'(3'S)]piperadine and 5-fluoro-2-nitrotoluene. LC/MS: RT=1,43 min, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 8,10 (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, 2H), 3,3 (m, 3H), 3.00 and-2,78 (dt, 3.5 Hz, 8,8 Hz, 2H), and 2.79 (m, 1H), 2,64 (s, 3H), of 2.56 (m, 1H), 2,03 (m, 2H) to 1.98 (m, 2H,), a 1.45 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC was spent in the following conditions: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm. The following results were obtained: RT= 8,16 min; EE 100%.

The intermediate compound (xxi)

2-(2R)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3'(3'S)]bipirimidiny

The desired compound was obtained by a method essentially the same as the intermediate compound (xix), by condensation of 2-(2R)-methyl-[1,3'(3'S)]piperadine and 5-fluoro-2-nitrotoluene. LC/MS: RT=1,41 min, MS: 90 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 8,10 (d, 9.1 Hz, 1H), 6,36 (DD, of 9.2, 2.5 Hz, 1H), 6,28 (d, 2.4 Hz, 1H), 3,654 (m, 2H), 3,37 (m, 3H), 2,99 (dt, 3,7 Hz and 8.8 Hz, 1H), 2,84 (sextet, and 6.6 Hz, 1H), 2,65 (s, 3H), 2,56 (K, 8,1 Hz, 1H), 2,31 (m, 2H), 2,11 (m, 2H) to 1.87 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC was spent in the following conditions: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm. The following results were obtained: RT= 11,93 min; EE 100%.

The intermediate compound (xxii)

2-(2R)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3'(3'R)]bipirimidiny

The desired compound was obtained by a method essentially the same as the intermediate compound (xix), by condensation of 2-(2R)-methyl-[1,3'(3'R)]piperadine and 5-fluoro-2-nitrotoluene. LC/MS: RT=1,43 min, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 8,10 (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, 2H), 3,3 (m, 3H), 3.00 and-2,78 (dt, 3.5 Hz, 8,8 Hz, 2H), and 2.79 (m, 1H), 2,64 (s, 3H), of 2.56 (m, 1H), 2,03 (m, 2H) to 1.98 (m, 2H,), a 1.45 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Analytical chiral HPLC was spent in the following conditions: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm. The following results were obtained: RT=8,95 min; EE 100%.

The intermediate compound (xxiii)

2-methyl-4-(2-(2S)-methyl-[1,3'(3'R)]bipirimidiny-1'-yl)-phenylamine

A solution of 2-(2S)-methyl-1'-(3-methyl-4-nor is Ravenel)-[1,3'(3'R)]piperadine (2,02 g, 6,98 mmol) in MeOH (40 ml) was wearisomely and nadowli nitrogen. To this solution was added Pd-C (10%, 0.2 g). This mixture was stirred under H2at room temperature for 4 hours TLC Analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed and the product was detected by MS 261. The mixture was passed through a layer of celite and washed with methanol. The filtrate was concentrated until dry, with further drying to obtain the desired compound in the form of liquid reddish-brown color after drying under high vacuum, of 1.81 g (yield 100%). LC/MS: 260, TLC (10% MeOH/DHM): Rf of 0.3.

The intermediate compound (xxiv)

2-methyl-4-(2-(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine

The desired compound was obtained by a method essentially the same as the intermediate compound (xxiii), by hydrogenation of 2-(2S)-methyl-1'-(3-methyl-4-nitro-phenyl)-[1,3'(3'S)]piperadine. LC/MS: 260, TLC (10% MeOH/DHM): Rf of 0.3.

The intermediate compound (xxv)

2-methyl-4-(2-(2R)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine

The desired compound was obtained by a method essentially the same as the intermediate compound (xxiii), by hydrogenation of 2-(2R)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3'(3'S)]piperadine. LC/MS: 260, TLC (10% MeOH/DHM): Rf of 0.3.

The intermediate compound (xxvi)

2-methyl-4-(2-(2R)-methyl-[1,3'(3'R)]bipyrrole dinil-1'-yl)-phenylamine

The desired compound was obtained by a method essentially the same as the intermediate compound (xxiii), by hydrogenation of 2-(2R)-methyl-1'-(3-methyl-4-nitrophenyl)-[1,3'(3'R)]piperadine. LC/MS: 260, TLC (10% MeOH/DHM): Rf of 0.3.

Example 1

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid

2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine (330 mg, 1.15 mmol) was dissolved in DHM (6 ml) and DMF (2 ml) and the resulting solution was cooled in an ice bath. To this solution was added sequentially powdered 3,5-dimethyl-isoxazol-4-carboxylic acid (168,9 mg, 1.38 mmol, 1.2 equiv.), N-methylmorpholin (280 mg, 3 equiv.), 1-gynocentrism (HOBT) (rate £ 0.162 g, 1,19 mmol, 1.3 equiv.) and then EDC.HCl (0,228 g, 1,19 mmol, 1.3 equiv.). The obtained transparent brown solution was stirred at room temperature overnight. The TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed, and were detected peak product (368). The reaction mixture was extinguished saturated aqueous sodium bicarbonate (3 ml) and 3 ml DHM. The two phases were separated, and the aqueous phase was extracted with dichloromethane (5 ml × 2). The combined extracts DHM washed with sodium bicarbonate (5 ml) and brine (5 ml), dried (anhydrous potassium carbonate), filtered and koncentrira is whether under vacuum to obtain the crude product, which was purified on silikagelevye column (25 g silica gel) on Analogix, to obtain the desired compound in the form of a solid substance of a brownish color, 200 mg (49% yield).

JHMS: RT=1,54 min, MS: 383 (M+H).

1H NMR (CDCl3, 300 MHz), δ (MD): 7,44 (m, 1H), 6,92 (SHS, 1H), 6,40 (SHS, 1H), 6,39 (SHS, 1H), 3,50 (m, 1H), 3,4-3,2 (m, 4H), to 3.00 (m, 1H), 2,78 (m, 1H), 2,66 (CL, 3H), 2,48 (CL, 3H), 2,5 (m, 1H), and 2.26 (s, 3H), 2,18 (m, 1H), 2,00 (m, 2H), 1,79 (m, 2H), 1,48 (m, 1H), 1.14 in (d, 6.3 Hz, 3H).

Example 2

Triptorelin [2-methyl-1-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide cyclohexanecarbonyl acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine with cyclohexanecarbonyl acid. MS: 370,41 (M+H).

Example 3

Triptorelin [2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide bicyclo[2.2.1]heptane-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine with bicyclo[2.2.1]heptane-2-carboxylic acid. MS: 382,24 (M+H).

Example 4

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid

2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine (330 mg, 1.15 mm in the l) was dissolved in DHM (6 ml) and DMF (2 ml) and the resulting solution was cooled in an ice bath. To this solution was added sequentially powder tetrahydropyran-4-carboxylic acid (179,6 mg, 1.38 mmol, 1.2 equiv.), N-methylmorpholin (280 mg, 3 equiv.), 1-gynocentrism (HOBT) (rate £ 0.162 g, 1,19 mmol, 1.3 equiv.) and then EDC.HCl (0,228 g, 1,19 mmol, 1.3 equiv.). The obtained transparent brown solution was stirred at room temperature overnight. The TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed, and was detected peak product (372). The reaction mixture was extinguished saturated aqueous sodium bicarbonate (3 ml) and 3 ml DHM. The two phases were separated, and the aqueous phase was extracted with dichloromethane (5 ml × 2). The combined extracts DHM washed with sodium bicarbonate (5 ml) and brine (5 ml), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum to obtain the crude product, which was purified on silikagelevye column (25 g silica gel) on Analogix, to obtain the desired compound in the form of a solid substance of a brownish color, 210 mg (49% yield).

LC/MS: RT=1,46 min, MS: 372 (M+H).

1H NMR (CDCl3, 300 MHz), δ (MD): 7,34 (d, 8.2 Hz, 1H), 6,79 (s, 1H), to 6.39 (s, 1H), 6,36 (s, 1H), 4,06 (m, 2H), 3,51-3,19 (m, 7H), to 3.00 (m, 1H), 2,78 (m, 1H), 2,53 (m, 2H), 2,19 (s, 3H), 2,13-of 1.73 (m, 10H), 1,47 (m, 1H), to 1.14 (d, 6.0 Hz, 3H).

Example 5

Triptorelin [2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide 3-methylisoxazol-5-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine with 3-methylisoxazol-5-carboxylic acid. MS: 369,21 (M+H).

Example 6

Triptorelin [2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide, furan-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine with furan-3-carboxylic acid. MS: 354,21 (M+H).

Example 7

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 3.5-dimethylisoxazol-4-carboxylic acid. MS: 383,22 (M+H).

Example 8

Triptorelin 2-cyclopentyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2-cyclopentyloxy acid. MS: 370,23 (M+H).

Example 9

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydro the Piran-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with tetrahydropyran-4-carboxylic acid. MS: 358,23 (M+H).

Example 10

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with cyclopropanecarbonyl acid. MS: 328,22 (M+H).

Example 11

Triptorelin [3-methyl-4-2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with tetrahydropyran-4-carboxylic acid. MS: 372,27 (M+H).

Example 12

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid. MS: 382,28 (M+H).

Example 13

Triptorelin [4-2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 1H-pyrazole-4-carboxylic acid. MS: 340,22 (M+H).

Example 14

[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid

2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine (330 mg, 1.15 mmol) was dissolved in DHM (6 ml) and DMF (2 ml) and the resulting solution was cooled in an ice bath. To this solution was added sequentially powdered 5-methyl-1H-pyrazole-3-carboxylic acid (174,6 mg, 1.38 mmol, 1.2 equiv.), N-methylmorpholin (280 mg, 3 equiv.), 1-gynocentrism (HOBT) (rate £ 0.162 g, 1,19 mmol, 1.3 equiv.) and then EDC.HCl (0,228 g, 1,19 mmol, 1.3 equiv.). The obtained transparent brown solution was stirred at room temperature overnight. The TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed, and was detected peak product (368). The reaction mixture was extinguished saturated aqueous sodium bicarbonate (3 ml) and 3 ml DHM. The two phases were separated, and the aqueous phase was extracted with dichloromethane (5 ml × 2). The combined extracts DHM washed with sodium bicarbonate (5 ml) and brine (5 ml), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum to obtain untreated the i.i.d. product, which was purified on silikagelevye column (25 g silica gel) on Analogix, to obtain the desired compound in the form of a solid substance of a brownish color, 207 mg (49% yield).

LC/MS: RT=1,61 min, MS: 368 (M+H).

1H NMR (300 MHz, CDCl3), δ (MD): 8,3 (SHS, 1H), 7,65 (d, 9.6 Hz, 1H), only 6.64 (s, 1H), to 6.43-to 6.39 (m, 2H), 3,52 (m, 1H), 3,39 (m, 1H), 3,26 (m, 2H), to 3.02 (m, 1H), 2,78 (m, 1H), 2,53 (K, 8,1 Hz, 1H), is 2.37 (s, 3H), of 2.28 (s, 3H), 2,12 (m, 1H), up to 1.98 (m, 2H), 1,78 (m, 2H)and 1.51 (m, 2H).

Example 15

Hydrochloride [2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 1,5-dimethyl-1H-pyrazole-3-carboxylic acid

The desired compound was obtained by a method essentially similar to example 16, by a combination of 2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine with 1,5-dimethyl-1H-pyrazole-3-carboxylic acid. The obtained product was dissolved in DHM and was treated with 1N HCl in ether at a temperature of 0oC to obtain cleaners containing hydrochloride salt of the desired compound in the form of a solid brown color. LC/MS: RT=1,76 min, MS: 382 (M+H).

1H NMR (DMSO-d6, 300 MHz), δ (MD): 11,31 (SHS), 9,15 (SHS), 7,26 (d, 8,76 Hz, 1H), 6,50 (m, 3H), USD 5.76 (s, 1H), 4,11 (m, 1H), 3,81 (s, 3H), up 3.6-3.7 (m, 5H), 3,20 (m, 2H), a 2.36 (m, 2H), of 2.21 (m, 1H), a 2.36 (s, 3H), 2,17 (s, 3H), of 1.95 (m, 2H), 1,67 (m, 1H), 1,47 (d, 6.2 Hz, 3H).

Example 16

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenylamine with 2,2,3,3-tetramethylcyclopropanecarboxylate acid. MS: 384,3 (M+H).

Example 17

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2,2,3,3-tetramethylcyclopropanecarboxylate acid. MS: 384,3 (M+H).

Example 18

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 3.5-dimethylisoxazol-4-carboxylic acid. MS: 383,3 (M+H).

Example 19

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide, furan-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenylamine with furan-2-carboxylic acid. MS: 354,3 (M+H).

Example 20

Triptorelin [2-m is Tyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 5-methyl-1H-pyrazole-3-carboxylic acid. MS: 368,2 (M+H).

Example 21

Triptorelin 2-cyclopentyl-N-[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenylamine with 2-cyclopentyloxy acid. MS: 370,3 (M+H).

Example 22

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 5-methyl-1H-pyrazole-3-carboxylic acid. MS: 368,3 (M+H).

Example 23

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid. MS: 382,3 (M+H).

Example 24

Triptorelin [2-m is Tyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with tetrahydropyran-4-carboxylic acid. MS: 372,3 (M+H).

Example 25

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2,2,3,3-tetramethylcyclopropanecarboxylate acid. MS: 370,3 (M+H).

Example 26

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 3.5-dimethylisoxazol-4-carboxylic acid. MS: 369,2 (M+H).

Example 27

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2,2,3,3-tetramethylcyclopropanecarboxylate acid. MS: 384,3 (M+H).

Example 28

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 2-methoxazole-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenylamine with 2-methoxazole-4-carboxylic acid. MS: 369,2 (M+H).

Example 29

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid. MS: 368,2 (M+H).

Example 30

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-amide cyclopropanecarbonyl acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline with cyclopropanecarbonyl acid. MS: 382,2 (M+H).

Example 31

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipyrrole the Il-1'-yl)-phenylamine with 5-methyl-1H-pyrazole-3-carboxylic acid. MS: 354,2 (M+H).

Example 32

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-(2-oxo-2H-pyridin-1-yl)-furan-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 5-(2-oxo-2H-pyridin-1-yl)-furan-2-carboxylic acid. MS: 447,2 (M+H).

Example 33

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 1H-pyrazole-4-carboxylic acid. MS: 354,2 (M+H).

Example 34

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 1H-pyrazole-4-carboxylic acid. MS: 354,3 (M+H).

Example 35

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-amide 5-methyl-1H-pyrazole-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3 bipirimidiny-1'-yl)-2-triptoreline 5-methyl-1H-pyrazole-3-carboxylic acid. MS: 422,2 (M+H).

Example 36

Triptorelin 2-cyclopentyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with cyclopentyloxy acid. MS: 356,2 (M+H).

Example 37

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-pyridin-4-yl-2H-pyrazole-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 5-pyridin-4-yl-2H-pyrazole-3-carboxylic acid. MS: THAT AMOUNT TO 431,3 (M+H).

Example 38

Triptorelin 2-cyclopentyl-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with cyclopentyloxy acid. MS: 370,2 (M+H).

Example 39

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide cyclopentanecarbonyl acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenylamine cyclopentanecarbonyl acid. MS: 356,3 (M+H).

Example 40

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acid

The desired compound was obtained by a method substantially similar to example 1, by combining 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with cyclopropanecarbonyl acid. MS: 314,2 (M+H).

Example 41

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acid

The desired compound was obtained by a method essentially similar to example 1 by combining 3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with cyclopropanecarbonyl acid. MS: 328,2 (M+H).

Biological examples

Example 42

In the present example 42 demonstrated 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) for retusum H3 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 actively the th rhesus H3 in cell membranes. This inhibition of binding of radioactive ligand GTPγS-mediated basal resuse H3, 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 GTPγS receptors of resursov H3 at 0-40% below basal levels.

Membrane resursov H3 were obtained from cell line Flp-In T-REx 293 (Invitrogen), which has been steadily transactionalist with pcDNA5/FRT/TO (Invitrogen)containing the receptor H3 rhesus macaques (Macacca Mulatta) of 445 amino acids (Genbank #AY231164). Stable transfection culture amplified in mattresses for the cultivation of tissues using standard methods of cultivation of tissues and induced for expression of rhesus H3 by exposure to 500 ng/ml tetracycline (Cellgro) within 24 hours. After induction the cells were separated from mattresses with Cell Stripper (Cellgro). Cells were centrifuged (1000 x 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 (40000 × g, 30 min). The precipitate cellular membranes of the Republic who was Bandarawela in 5 mm HEPES (pH 7,4, Invitrogen) at a final protein concentration of 10 mg/ml Membrane H3 RH was kept under liquid nitrogen, before they can be used for analysis of binding of [3H]-methylhistamine and radioactive ligand GTPγS.

Analysis of the binding of radioactive ligand rhesus H3 was performed using a membrane receptor H3 RH (prepared 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 rhesus H3 (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
# exampleki in the membrane rhesus H3 (nm)Reverse agonism: % inhibition of basal GTPγS binding in rhesus H3
61,8-17
363,14-33

Example 43

This example illustrates the selective affinity of the compounds of the present invention receptor H3 and shows low activity in respect of the site of the sit receptor and (or) the absence of any activity.

The affinity H3 compounds of the present invention was measured in accordance with the methods set forth in example 42 and are shown in table 2.

The activity of the compounds of the present invention in the website of the MCH receptor, 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 is: 40 μm MCH analytical 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 spend 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 (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, STD is bound parameters for 125J, 30 seconds per cell. Based on this determined the percentage of inhibition of binding of the ligand, as shown in table 2.

-7,2
Table 2
# exampleki in the membrane rhesus H3 (nm)% inhibition of MCH at 10 µm
10,40,7
20,4of-2.1
30,6-0,8
41,0-1,6
51,13,1
61,8-6,9
73,25,0
88,41,4
98,7-2,8
109,64,0
11of 17.02,7
12to 19.9-2,8
1322,14,8
14the 4.728,3
1510,810,3
160,85,8
1737,311,5
182,6-2,0
19a 3.96,0
2030,924,3
210,91,9
22the 17.35,6
23130,311,2
246,88,6
25 143,815,0
262,19,4
2765,536,0
284,67,0
2915,711,4
3014,71,2
3144,530,5
3233,310,9
3324,7the 9.7
34125,616,8
35307,023,5
363,10,7
3714,234,4
3810,73,7
390,5
40the 9.7-3,4
4117,7-1,3

Example 44

This example illustrates a study of the effectiveness of the compounds constituting the subject matter of this invention, to improve sleep quality in model animals.

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) and fixed with 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 show and 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:

wakefulness (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;

sleep REM (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 consistent spectral analysis 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-bokstaven the I: analysis time period and the six-hour analysis 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 45

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 sec) were made every 7 seconds, and then recorded the ultrasonic signals (UV, 22 kHz) using system 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 more than 10 MCE is. Rats were selected for the duration of their UV (> 40 sec) 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 sec), 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 46

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.Nature266:730-2. 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-minute test). 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 proillyustrirovano 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 means (C1-C4)-alkyl;
R1and R2are the same or different and independently from each other selected from hydrogen, (C1-C4)-alkyl or CF3;
R3means hydrogen;
R4is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2,2,1]heptyl, cyclopentylmethyl, tetrahydropyranyl, furanyl, oxazolyl, isoxazolyl and pyrazolyl;
where specified R4optional one or more times substituted by the Deputy selected from the group consisting of methyl, ethyl, pyridinyl and 2-oxo-2H-pyridin-1-yl; or their pharmaceutically acceptable salt, enantiomer or diastereoisomer.

2. The compound according to claim 1, where
R means methyl;
R2means hydrogen, methyl or CF3;
R1means hydrogen or methyl;
R3means hydrogen; and
R4is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl or bicyclo[2,2,1]heptane, which optionally one or more times C is medeni the stands, or R4means tetrahydropyranyl; or R4is selected from the group consisting of furanyl, oxazolyl, isoxazolyl and pyrazolyl that optional one or more times substituted stands; or
R4is selected from the group consisting of isoxazolyl or isoxazolyl, which optionally one or more times substituted stands.

3. The compound according to claim 1, selected from the group which includes:
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-trifluoromethyl-phenyl]-amide cyclopropanecarbonyl acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide cyclopropanecarbonyl acid;
[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,2,3,3-tetramethylcyclopropanecarboxylate acid;
[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide cyclopentanecarbonyl acid;
[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide cyclohexanecarbonyl the acid;
2-cyclopentyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;
2-cyclopentyl-N-[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;
2-cyclopentyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;
2-cyclopentyl-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-ndimethylacetamide;
[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide bicyclo[2.2.1]heptane-2-carboxylic acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide and (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide and (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide and (1S,4R)-bicyclo[2.2.1]heptane-2-carboxylic acid;
[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide tetrahydropyran-4-carboxylic acid;
[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide, furan-3-carboxylic acid;
[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide, furan-2-carboxylic acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-(2-oxo-2H-pyridin-1-yl)-furan-2-carbon is acid;
[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 2-methoxazole-4-carboxylic acid;
[2-methyl-4-(2S-methyl-[1,3'S]bipirimidiny-1'-yl)-phenyl]-amide 3-methylisoxazol-5-carboxylic acid;
[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3,5-dimethylisoxazol-4-carboxylic acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1H-pyrazole-4-carboxylic acid;
[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;
[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;
[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-trifluoromethyl-phenyl]-amide 5-methyl-1H-pyrazole-3-carboxylic acid;
[2-methyl-4-(2(2S)-IU the Il-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-amide 1,5-dimethyl-1H-pyrazole-3-carboxylic acid; and
[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-pyridin-4-yl-2H-pyrazole-3-carboxylic acid;
or their pharmaceutically acceptable salt.

4. The compound according to claim 1, which corresponds to the formula (II):

where R, R1, R2R3and R4presented according to claim 1.

5. Pharmaceutical composition having activity to bind to the H3 ligand containing compound of the formula (I) according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, or enantiomer, or diastereoisomer in combination with at least one pharmaceutically acceptable excipient, diluent or carrier.

6. The use of compounds with formula (I) according to any one of claims 1 to 4 optionally in combination with a pharmaceutically acceptable carrier for the preparation of pharmaceutical compositions 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.

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

8. The use according to claim 6, wherein the disorder is a cognitive disorder.

9. The use according to claim 6, wherein the disease is Alzheimer's disease.

10. The use according to claim 6, wherein the disorder is depression or dementia.



 

Same patents:

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 novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

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: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or pharmaceutically acceptable salts thereof, where W is where each R4 independently denotes H or CN; R2 denotes a cycloalkyl which can be independently substituted with two of the following substitutes: C(1-3)alkyl; Z denotes H; J denotes CH or N; X denotes or ; where R1 denotes -ORa, -CN, -NA1A2, -SO2CH3, -COORa, -CO2CH3, -CH2-NA1A2, -CONA1A2, -CH2ORa, -NHCH2CH2ORa, -OC(1-4)alkylNA1A2, OCH2CO2Ra and tetrazolyl; Rz and Ry independently denotes H or -C(1-4)alkyl, where both Rz may have syn or anti stereochemistry; alternatively both Rz in syn interaction may be taken together to form -(CH2)n-, where n equals 2; R3 denotes C(1-3)alkyl-CF3 or -COCH3; A1 denotes H or -C(1-4)alkyl; A2 denotes H or -C(1-4)alkyl; alternatively, A1 and A may be taken together with a nitrogen atom with which they are bonded to form a heterocyclic ring selected from: , where Ra denotes H or C(1-4)alkyl; Rbb denotes H, -C(1-4)alkyl, and -CH2CO2H, where cycloalkyl relates to a partially unsaturated ring with 6 carbon atoms. The invention also relates to specific compounds of formula I, a pharmaceutical composition based on the compound of formula I and methods of treating inflammation and autoimmune diseases.

EFFECT: novel compounds of formula I which are useful as c-fms inhibitors are obtained.

10 cl, 2 tbl, 44 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: medicine, pharmaceutics.

SUBSTANCE: invention refers to a benzazepin compound of general formula (1) possessing the property of vasopressin antagonist, and to a based pharmaceutical composition. In general formula (1) R1 means a group (1-1) or (1-3) to (1-7): (1-1) represents a group -CO-(CH2)n-COR2 wherein n means an integer 1 to 4, R2 means (2-1) hydroxyl group; (2-2) lower alkoxy group if necessary substituted by hydroxyl group, lower alkanoyl group, lower alkanoyloxy group, lower alkoxycarbonyloxy group, cycloalkyloxycarbonyloxy group or 5-methyl-2-oxo-1,3-dioxol-4-yl; or (2-3) amino group if necessary substituted by hydroxyl lower alkyl; (1-3) represents a group -CO-(CH2)p-O-CO-NR5R6 wherein p means an integer 1 to 4, R5 means lower alkyl group, and R6 means a group of lower alkoxycarbonyl lower alkyl; (1-4) represents a group -CO-(CH2)q-X-R7 wherein q means an integer 1 to 4, X means an oxygen atom, a sulphur atom or a sulphonyl group, and R7 means a group of carboxy lower alkyl or a group of lower alkoxycarbonyl lower alkyl; (1-5) represents a group -CO-R8, (wherein R8 means (8-1) alkyl group if necessary substituted by a halogen atom, lower alkanoyloxy group or phenyl group (substituted by dihydroxyphosphoryloxy group wherein hydroxyl groups may be substituted by benzyl groups, and lower alkyl group), a (8-2) lower alkoxy group substituted by a halogen atom, lower alkanoyloxy group or dihydroxyphosphoryloxy group, (8-3) pyridyl group or (8-4) lower alkoxyphenyl group; (1-6) represents a lower alkyl group substituted by a group consisting of a lower alkylthio group, a dihydroxyphosphoryloxy group and a lower alkanoyloxy group; and (1-7) represents a peptide residue if necessary substituted by one or more protective groups.

EFFECT: compound of formula (1) is able to maintain the blood tolvaptan level for a long period of time that enables providing the desired pharmaceutical effects.

FIELD: chemistry.

SUBSTANCE: compound, represented by formula

,

or its pharmaceutically acceptable salt, where Y1 represents nitrogen atom or group, represented by CRA, Y2 represents nitrogen atom or group, represented by CRB, Y3 represents nitrogen atom or group, represented by CRC, RA, RB and RC, which can be similar or different, each represents hydrogen atom, etc. (except in the case, when Y1 is CRA, Y2 is CRB and Y3 is CRC), X represents oxygen atom, etc., R1 represents C1-C6alkyl group, etc., R3 represents optionally substituted phenyl group, etc., R4 represents hydrogen atom, etc., and R5 represents optionally substituted phenyl group, etc.), possesses inhibiting action with respect to S1P binding with its receptor Edg-1(SlP1).

EFFECT: obtaining composition, which can be used as therapeutic medication in case of autoimmune diseases, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis or age-related macula lutea degeneration, etc.

13 cl, 9 ex, 1 tbl, 4 dwg

FIELD: chemistry.

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

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

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 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: medicine.

SUBSTANCE: invention refers to a new compound of formula or to its pharmaceutically acceptable salt. What is prepared and described is the new compound applicable as a modulator of ATP-binding cartridge (ABC) transporter or their fragments including a cystic fibrosis transmembrane regulator (CFTR).

EFFECT: higher efficacy.

1 cl, 422 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 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

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