Substituted n-phenylbipyrrolidine carboxamides and therapeutic use thereof

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

 

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 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 mannai 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 system. In addition to histamine H3 also modulates the release and/or synthesis of other Natura 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. If this is eduit 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 is 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 is to develop 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 has been unexpectedly found that the compounds of formula (I) can be used as antagonists and/or inverse agonists of H3 receptors. As noted earlier in this document, in U.S. patent No. 7223788 not given specific information that reveals the compounds of 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 of formula (I) exhibit selective activity is ü only in respect of H3 receptors and exhibit low activity in relation to the site of receptor sit-1, moreover, this aspect of the invention become more apparent from the following detailed description.

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

where

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

R4is selected from the group consisting of dimethylaminomethyl, methysulfonylmethane, phenoxymethyl, vinylbenzyl, ethenylbenzene, vinylpyridine, phenyl, benzofuranyl, dihydrobenzofuranyl, oxo-tetrahydrofuranyl, benzodioxolyl, oxo-chromanol, dihydroergotoxine, dioxotetrahydrofuran-1H-benzo[e]diazepine, imidazopyridines, benzotriazolyl, benzoimidazolyl, oxo-dihydrobenzofuranyl, indolyl, indazoles, naphthyridine, chinoline, benzoimidazolyl, pyridinyl, pyrimidinyl, pyrrolyl, triazolyl, thienyl, thiazolyl, tetrahydrofuranyl or pyrrolidinyl;

where specified R4there may be one or more times substituted by the Deputy selected from the group consisting of halogen, hydroxy, methyl, ethyl, isopropyl, propoxyethyl, phenyl, benzoyl, methoxy, deformedarse, CF3, CN, acetyl, methanesulfonyl, sulfamoyl, dimethylamino, N-formylmethionine, 2-hydroxyethylamino, 2-methoxyethylamine, benzyloxy the sludge, carboxyphenoxy, pyrazolyl, 3,5-dimethylpyrazole, imidazole, triazole, oxazolyl, pyridinyl, oxo-dihydropyridines, pyrimidinediamine, N-acetylpiperidine, morpholinyl, morpholinylmethyl or 2-oxo-pyrrolidinyl.

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

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

DETAILED description of the INVENTION

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

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

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

Used in this document the expression(C1-4)-acyl" has the same meaning as "( 1-6-alkanoyl", which may be structurally represented as "R-CO -, where R means (C1-3)-alkyl, in accordance with the herein defined. In addition, (C1-3-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 heptafluoropropyl, nonattribution, undecafluoropentyl and tridecafluorohexyl group. The derived expression(C1-C6)-performace" 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 who's deputies, 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 thiophenyl, pyrrolyl, isopropyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazole and the like. A typical 6-membered heteroaryl radicals include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and similar radicals. Typical examples of bicyclic heteroaryl radicals include benzofuranyl, benzothiophene, indolyl, chinoline, ethenolysis, cannoli, benzimidazolyl, indazoles, perindopril, peridotitic and similar radicals.

Used in this document the terms"heterocycle" includes all known cyclic radicals, containing the 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, such as humans.

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 pharmaceutical composition, i.e., dosage form, which you can enter the patient. One example of such a carrier is a pharmaceutically acceptable oil, commonly used for parenteral administration.

Used in this document, the term "farm is citiesi acceptable salt" means, that salt 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, for example hydrochloric acid, Hydrobromic acid, nitric acid, sulfamic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluensulfonate acid, fumaric acid, maleic acid, hydroxymaleimide acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, propionic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Can also be acidic metal salts, for example manage reactionthat 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 such definition includes pharmacologically inactive chemical substance that, metabolizers or chemically converted under the influence of the biological system such as the system of mammals, converted into a pharmacologically active substance.

The term "stereoisomers" is a General term used for all isomers of individual molecules that differ only in the spatial orientation of their atoms. To them, as a rule, are mirror isomers, which usually exist in the presence of at least one center of asymmetry (enantiomers). If the connection forming the subject this is the first 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, etc. Should be understood that all such isomers and mixtures thereof in any proportions fall within the scope of the present invention.

Used in this document the symbols "R" and "S" are applied as widely used in organic chemistry to indicate the specific configuration of the chiral center. The designation "R" (rectus, right) refers to the configuration of the chiral center with the location of higher rank groups clockwise (from the group with the highest rank to the 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 most the PWM 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 carbon chiral center, and L - isomer, in which it is located to the left.

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

In a broader sense, it is assumed that the term "substituted" is before all permissible substituents of organic compounds. In the herein certain specific implementations, the term "substituted" means substituted by one or more substituents which are independently selected from the group comprising (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-perfluoroalkyl, phenyl, hydroxy, CO2H, ether, amide, (C1-C6)-alkoxy, (C1-C6-thioalkyl, (C1-C6)-perforamce, -NH2, Cl, Br, I, F, -NH-lower alkyl and-N(lower alkyl)2. However, in these implementations can also be used any other suitable substituents known 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) preventing a disease, disorder or condition in a patient who may be predisposed to the disease, disorder and/or condition, however, its presence has not yet been diagnosed;

(ii) suppression of the disease, disorder, or condition, that is, slowing its development; 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 from each other selected from hydrogen, (C1-C4)-alkyl or CF3;

R4is selected from the group consisting of dimethylaminomethyl, methysulfonylmethane, phenoxymethyl, vinylbenzyl, ethenylbenzene, vinylpyridine, phenyl, benzofuranyl, dihydrobenzofuranyl, oxo-tetrahydrofuranyl, benzodioxolyl, oxo-chromanol, dihydroergotoxine, dioxotetrahydrofuran-1H-benzo[e]diazepine, imidazopyridines, benzotriazolyl, benzoimidazolyl, oxo-dihydrobenzofuranyl, indolyl, indazoles, naphthyridine, chinoline, benzoimidazolyl, pyridinyl, pyrimidinyl, pyrrolyl, triazolyl, thienyl, thiazolyl, tetrahydrofuranyl or pyrrolidinyl;

where specified R4there may be one or more times substituted by the Deputy selected from the group consisting of halogen, hydroxy, methyl, ethyl, isopropyl, propoxyethyl, phenyl, benzoyl, methoxy, deformedarse, CF3, CN, acetyl, methanesulfonyl, sulfamoyl, dimethylamino, N-formylmethionine, 2-hydroxyethylamino, 2-methoxyethylamine, benzoyloxymethyl, carboxyphenoxy, pyrazolyl, 3,5-dimethylpyrazole, imidazole, triazole, oxazolyl, pyridinyl, oxo-dihydropyridines, pyrimidinediamine, N-acetyl-piperidinyl, morpholinyl, morpholinylmethyl or 2-oxo-PIR is original.

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

In one implementation of the following specific examples are disclosed compounds of the formula (I) of the present invention, where R is methyl; R2means methyl or CF3; and R1and R3mean hydrogen.

In another implementation of the disclosed compound of formula (I), where R is methyl; R1means methyl or CF3; and R2and R3mean hydrogen.

In another implementation of the disclosed compounds of the formula (I) of the present invention, where R4means phenyl or phenyl substituted with one or more substituents selected from fluorine, chlorine, methyl, isopropyl, propoxyethyl, CF3, CN, methoxy, deformedarse, methanesulfonyl, sulfamoyl, dimethylamino, N-formylmethionine, carboxyphenoxy, oxo-dihydropyridine, pyrimidinediamine, pyrazolyl, 3,5-dim temperatella, imidazolyl, triazolyl, oxazolyl, N-acetylpiperidine, morpholinylmethyl or 2-oxo-pyrrolidinyl.

In another implementation of the present invention are disclosed compounds of the formula (I), where R4is selected from the group consisting of benzofuranyl, dihydrobenzofuranyl, oxo-tetrahydrofuranyl, benzodioxolyl, dihydroergotoxine, dioxotetrahydrofuran-1H-benzo[e]diazepine or oxo-chromanol where the specified R4may have one or more substituents selected from chlorine, methyl or methoxy.

In another implementation of the present invention are disclosed compounds of the formula (I), where R4is selected from the group consisting of dimethylaminomethyl, methysulfonylmethane, phenoxymethyl, vinylbenzyl, ethenylbenzene or vinylpyridin where the specified R4may be substituted by fluorine one or more times.

In another implementation of the present invention provides compounds of formula (I), where R4means pyridinyl or pyrimidinyl, which may have one or more substituents selected from chlorine, methyl, 2-hydroxyethylamino, 2-methoxyethylamine, benzoyloxymethyl or morpholinyl.

In another implementation of the present invention also provides compounds of formula (I), where R4is selected from the group consisting of imidazopyridine, benzotriazolyl, benzoimidazolyl, oxo-dihydro who benzoimidazolyl, indolyl, indazoles, naphthyridine, chinoline or benzoimidazolyl where the specified R4may have one or more substituents selected from fluorine, chlorine, hydroxy, methyl, isopropyl, methoxy or pyridinyl.

In another implementation of the present invention provides compounds of formula (I), where R4is selected from the group consisting of pyrrolyl, triazolyl, thienyl or thiazolyl where the specified R4may have one or more substituents selected from methyl, phenyl, benzoyl or pyridinyl.

In another implementation of the present invention are disclosed compounds of the formula (I), where R4is selected from the group consisting of tetrahydrofuranyl or pyrrolidinyl, which can be substituted one or more times by acetyl.

It should also be noted that all of the above compounds of various implementations of the present invention may also include, where possible, appropriate salts, including pharmaceutically acceptable salts.

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

where R, R1, R2, R3and R4submitted in accordance with the definitions above.

In one aspect of the present invention several Conques is to maintain connections, included without limitation in the overall scope of the present invention are listed below:

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

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

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

N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-2-phenoxyacetamide;

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

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

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

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

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

(E)-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-3-pyridin-3-ylacrylic;

(E)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-3-pyridin-3-ylacrylic;

(E)-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-3-pyridin-3-ylacrylic;

(E)-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-3-pyridin-3-ylacrylic;

(E)-3-(3-forfinal)-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-acrylamide;

(E)-3-(3-forfinal)-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-acrylamide;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3-phenylprop the new acid;

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

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

2-fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

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

2-fluoro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

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

3-fluoro-N-[2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-benzamide;

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

3-fluoro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

4-fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

4-fluoro-N-[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[2-methyl-4-(2-(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[2-methyl-4-(2(2S)-methyl-[1,3'(3'R)]bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[2-methyl-4-(2(2R)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[2-meth is l-4-(2-(R)-methyl-[1,3'(R)]bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

5-fluoro-2-methyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

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

4-chloro-N-[2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-benzamide;

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

3,5-dichloro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

3,5-dichloro-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

3,5-dichloro-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

3,5-dichloro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

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

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

2,4-dimethyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

4-methanesulfonyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-F. the Nile]-4-(1-propoxyethyl)-benzamide;

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

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

3-methoxy-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

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

4-methoxy-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

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

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

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

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

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

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

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

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

4-cyano-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

2-dimethylamino-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptime ylphenyl]-benzamide;

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

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

3-dimethylamino-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide;

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

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

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

4-{4-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylcarbamoyl]-phenoxy}-benzoic acid;

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

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(1H-pyrazole-3-yl)-benzamide;

4-(3,5-dimethyl-1H-pyrazole-4-yl)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-oxazol-5-yl-benzamide;

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

4-(4,6-dimethylpyrimidin-2-ylamino)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

4-[(4,6-dimethylpyrimidin-2-yl)-methylamino]-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide;

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(6-oxo-1,6-dihydropyridines-3-yl)-benzamide;

4-(1-acetylpiperidine-3-yl)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-the dryer is l]-benzamide;

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

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

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(2-oxo-pyrrolidin-1-yl)-benzamide;

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

2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide;

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

[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide benzofuran-6-carboxylic acid;

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

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-methoxybenzophenone-2-carboxylic acid;

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

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

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 4-oxo-4,5,6,7-tetrahydrofuran-2-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid;

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

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide, imidazo[1,2-a]pyridine-8-carboxylic acid;

[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide, imidazo[1,2-a]pyridine-8-carboxylic acid;

[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-amide, imidazo[1,2-a]pyridine-8-carboxylic acid;

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

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

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

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

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

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

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

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

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

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

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-6-carboxylic acid;

[2-methyl-4-(2(S)-methyl-[1,3'(S)]-bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-6-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-methoxy-1H-indazol-3-carboxylic acid;

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

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-fluoro-2-methylinosine-3-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide [1,6]naphthiridine-2-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 4-hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-chloro-4-oxo-4H-chromen-2-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-methyl-4-oxo-4H-chromen-2-carboxylic acid;

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide benzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid;

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

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

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

N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-nicotinamide;

[2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 6-methylpyridin-2-carboxylic acid is you;

5-chloro-6-(2-hydroxyethylamino)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-nicotinamide;

6-benzoyloxymethyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-nicotinamide;

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

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-6-morpholine-4-iniatiated;

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

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

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

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

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

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

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

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

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

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

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

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

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. Compounds of the present invention and some of the original connection can also be obtained by the methods used to obtain similar compounds, as reported in the literature and as described later in this document. For example, as noted above, some of the compounds with similar structure are disclosed in U.S. patent No. 7223788. Cm. also R.C. Larock, “Comprehensive Organic Transformations,” VCH publishers, 1989.

It is also well known 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 (in the 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 1-4, where R, R1, R2, R3and R4match the definitions given for formula I, unless otherwise indicated.

For example, figure 1 shows an example of obtaining intermediate [1,3']-pyrrolopyrimidine 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 formula (1) is condensed with the desired substituted pyrrolidino formula (2) by any known means is vosstanovitelnogo amination for the formation of intermediate compounds of 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 below ambient, when values of the environment or if the values are above the environment. Typically, these reactions take place at room temperature and under atmospheric pressure of nitrogen. The reaction mixture is then treated using processes known to specialists in this field, for the isolation of intermediate compounds of 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 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 ambient to a temperature above ambient, 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 of formula (3).

Scheme 1

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

In stage 2, scheme 2, the intermediate compound of formula (6) is condensed with the target pyrrolidino formula (7). Such the condensation reaction can also be carried out using any known method to obtain the intermediate compounds of 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 of 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 is ormula (9). It is now established that the intermediate compounds of 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.

Scheme 2

Figure 3 shows an example of obtaining the intermediate aminopropyldimethylamine formula (12), in which R, R1and R2meet the definition in this document. In stage 1 scheme 3 appropriately substituted nitrobenzene of formula (10), in which X denotes acceptable leaving group such as Cl, F, Br or triflate (OTf), is condensed with [1,3']-pyrrolidinylcarbonyl formula (4) to obtain the intermediate compounds of formula (11). Such the condensation reaction can also be carried out using any known in this area of the method. For example, this condensation reaction can be conducted in a polar solvent such as DMSO, in the presence of such a base as potassium carbonate, at ambient temperature or at a temperature exceeding the ambient temperature.

In stage 2, scheme 3, the intermediate compound of formula (11) is restored by g is tiravanija or other known chemical methods, for example by using douglasthe tin in hydrochloric acid, to form a primary intermediate compounds (12).

Scheme 3

Figure 4 shows an example of obtaining compounds of 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 herein, and R3means a hydrogen atom.

In the method And scheme 4, the acid chloride of the formula (13) can react with an intermediate compound (12) in all conditions, known to experts in the field. Generally, such conditions include, among others, the reaction of the acid chloride intermediate compound of formula (12) in a suitable organic solvent, such as dichloromethane, in the presence of a suitable base, for example pyridine. Such reactions are generally conducted at temperatures below ambient, for example about 0°C, but in certain situations can also be carried out at ambient temperature and temperatures above ambient, depending on the nature of the acid chloride and the intermediate (12).

Similarly, in the method In scheme 4 carboxylic acid of formula (14) can takes the diamonds in the reaction with intermediate compound of formula (12) at various reaction conditions, which well-known experts in the field. For example, the acid of formula (14) is reacted with an intermediate compound of formula (12) at a temperature below ambient in the presence of suitable reagents such as a mixture of N-methylmorpholine, 1-hydroxybenzotriazole and EDC.

Scheme 4

As mentioned above herein, the compounds of the present invention can easily turn into salt. In particular, the compounds of the present invention are basic, and such compounds are useful in the free base form or in the form of a pharmaceutically acceptable acid additive salts of such compounds. Salts formed by addition of acids, 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 the e salt 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 implementation of the present invention, by using compounds of the present invention it is possible to treat a particular disease, disorder or condition, including, without limitation, sleep disorders (specific examples include, without limitation, 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), and cognitive neuropsychologische disorders (specific examples include, without limitation, schizophrenia, hyperactivity, attention deficit, Alzheimer's disease, depression, seasonal affective Rosstroy the VA and cognitive impairment).

As shown below in the specific examples of the present document, the compounds of formula (I) bind to receptors H3 and show reverse agonism in relation to the functional activity of the H3. Therefore, compounds of the present invention can be used for the treatment of diseases or conditions that are alleviated by ligands of the receptor H3. More specifically, the compounds of the present invention are ligands of the receptor H3, which modulate the function of the H3 receptor, acting as antagonists of the activity of the receptor. In addition, the compounds of the present invention can act as inverse agonists, which inhibit the basal activity of the receptor, or can act as antagonists, which completely block the action of agonists that activate the receptor. Moreover, the compounds of the present invention may also be partial agonists, which are partially blocked or partially activate the receptor H3, or can be agonists that activate the receptor. Thus, the compounds of the present invention can act as 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 the surveillance of many pathological conditions, which 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 introducing the patient a therapeutically effective dose of the compounds of formula (I).

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

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

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

Finally, in another implementation of the present invention also features a pharmaceutical composition comprising pharmaceutically acceptable carrier and a compound of 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 differ 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 preferred assests is 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 spray solutions, 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 who and pharmaceutical diluents, such as water, to form a solid pre-composition comprising a homogeneous mixture of the compounds constituting the subject matter of this invention, or its pharmaceutically acceptable salt. When such prior compositions referred to as homogeneous, it is meant that the active ingredient is mixed evenly throughout the composition, and the composition can be divided into with equal efficiency standard dosage forms such as tablets, pills and capsules. Then this solid pre-composition 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 to intact with the standing to get into the duodenum, or that 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 acetylcellulose.

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

The pharmaceutical compositions of the present invention can be any known in the art methods. In General, the pharmaceutical compounds of the present invention can be administered orally, intramuscularly, subcutaneously, rectally, intratrahealno, intranasal, intraperitoneal or locally. Preferred methods of administration of medicinal p is aparatow of the present invention are oral and intranasal routes. Any of the known routes of administration of pharmaceutical compositions (oral or intranasal route) can be used for the introduction of the compositions of the present invention.

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

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

Examples (General part)

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." - conc the bath, "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, N2" 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, "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" - high performance liquid chromatography, "MVR" - mass spectrum with high resolution, "PPV" loss on drying, "the CCI" - microcurie, "/b" is 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, user. broadened, LC - liquid chromatography, MS = mass spectrograph, ESI/MS - ionization elektrorazpredelenie/mass spectrograph, WU - retention time, M is the 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 MHz 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 (ppm) relative to 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 the th of the following methods.

Mass spectra (MS) 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 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 33×2 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 minutes)

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

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 minutes)

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-metile is alidina (1,95 g, to 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 (ESI) m/z 255 and 199 ([M+H]+and [[M+H]-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. N2 was passed through the solution in the mixing process. The exit stream was passed through a solution of KOH for 30 minutes 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 below. LC/MS: RT=0,35 minutes, 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 (users).

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 carb is NAT potassium), was 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): 8,10 (d, 9 Hz, 1H), 6,36 (userd, 9 Hz, 1H), 6,28 (users, 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 compound (iv)

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

A solution of 2-methyl-1'-(3-methyl-4-nitrophenyl)-[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 with further drying under a 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-(R)-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 the peak of 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 (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 minutes to absorb the HCl. The solvent was removed by evaporation until dry to obtain absorbent resin is 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. JHMS: RT=0,35 minutes, 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 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 85°C 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): 8,10 (d, 9 Hz), 6,36 (userd, 9 Hz), 6,28 (users), 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']b is pyrrolidinyl-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 with 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 pass through the layer of celite and washed with methanol. The filtrate was concentrated until dry with further drying under high vacuum to obtain the desired compound in the form of liquid reddish-brown color after drying under high vacuum, 2,02 g (yield 100%). This material was used in the next stage without additional purification. MS: 260 (M+H+).

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 subsequent removal of the protective groups hydrochloride in dioxane.

JHMS: RT=0,36 minutes, MS: 155 (M+H).

1H NMR (CDCl3, 300 MHz): 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)-(that is Wal-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. The TLC analysis (5% MeOH in DHM) showed that the reaction was completed. The reaction mixture was suppressed by addition of the amine on the polymer carrier (8 g), was stirred for 30 minutes 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), 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): 7,80 (d, 9.0 Hz, 2H), 7,35 (d, 7.8 Hz, 2H), 5,04 (users, 1H), of 3.45 (m, 4H), 2,46 (users, 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 connection of the group of (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 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/MS showed 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%). JHMS: RT=1,27 minutes, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3): 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'-carbon is 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). JHMS: RT=1,05 minutes, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3): 3,30 (m, 1H), 3,14 (users, 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 ether 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), was stirred for 30 minutes, was added 50 ml DHM and filter the Ali. 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 purified prodct, 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 (basic).

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

The intermediate compound (xiii)

Tert-butyl 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 80°C for 24 h Analysis TLC (3% MeOH in DHM for THEM, to 7.5% MeOH in DHM product showed that it was from Ashdown almost completely. 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. JHMS: RT=1,14 minutes, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3): 3,30 (m, 1H), 3,14 (users, 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 (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). JHMS: RT=1,09 minutes, MS: 255 (M+H).

1H NMR (300 MHz, CDCl3): 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 to obtain the desired compound 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: (D2O, 300 MHz): 11,6 (users, 1H), 9,1 (users, 1H) 4,12 (m, 1H) to 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).

JHMS: RT =0,37 minutes, MS: 155 (M+H).

1H NMR: (D2O, 300 MHz): 11,6 (users, 1H), 9,1 (users, 1H) 4,12 (m, 1H) to 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 of the tert-butyl ester 2-(2R)-methyl-[1,3'(3'R)]bipirimidiny-1'-carboxylic acid (intermediate compound (xiv)obtained above). MS: 155 (M+H).

1H NMR: (D2O, 300 MHz): 11,6 (users, 1H), 9,1 (users, 1H), 4,12 (m, 1H) to 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 m is, 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. JHMS: RT=1,38 minutes, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3): 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 (square, 8,1 Hz, 1H), 2,31 (m, 2H), 2,11 (m, 2H,), to 1.87 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Conditions analytical chiral HPLC: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm.

Results: RT=10,92 minutes; AI 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 similar to getting ex is knogo compounds (xix), by condensation of 2-(2S)-methyl-[1,3'(3'S)]piperadine and 5-fluoro-2-nitrotoluene. JHMS: RT=1,43 minutes, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3): 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), up to 1.98 (m, 2H), 1,45 (m,1H), 1,08 (d, 6.2 Hz, 3H).

Conditions analytical chiral HPLC: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm.

Results: RT=8,16 minutes; AI 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. JHMS: RT=1,41 minutes, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3): 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 (square, 8,1 Hz, 1H), 2,31 (m, 2H), 2,11 (m, 2H,), to 1.87 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Conditions analytical chiral HPLC: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm.

Results: RT=11,93 minutes; AI 100%.

The intermediate compound (xxii)

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

ISCO is the second compound was obtained by way essentially the same as the intermediate compound (xix), by condensation of 2-(2R)-methyl-[1,3'(3'R)]piperadine and 5-fluoro-2-nitrotoluene. JHMS: RT=1,43 minutes, MS: 290 (M+H).

1H NMR (300 MHz, CDCl3): 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), up to 1.98 (m, 2H), 1,45 (m, 1H), 1,08 (d, 6.2 Hz, 3H).

Conditions analytical chiral HPLC: isocratic 100% isopropanol with 0.5% IP-amine and 5 ml/min, outlet pressure 150 bar, 200 nm.

Results: RT=8,95 minutes; AI 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-nitrophenyl)-[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): 0,3 Rf.

This material is ial group used directly without storage and/or further purification.

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-nitrophenyl)-[1,3'(3'S)]piperadine. LC/MS: 260, TLC (10% MeOH/DHM): 0,3 Rf.

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): 0,3 Rf.

The intermediate compound (xxvi)

2-methyl-4-(2-(2R)-methyl-[1,3'(3'R)]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'R)]piperadine. LC/MS: 260, TLC (10% MeOH/DHM): 0,3 Rf.

Example 1

4-fluoro-N-[2-methyl-4-(2(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-benzamide

2-methyl-4-(2-(2S)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine (200 mg, 0.77 mmol) was dissolved in DHM (10 ml). In this solution the PE eneli a solution of 4-fluoro-benzoyl chloride (Alfa Aesar, 222 mg, 1.4 mmol) in DHM (2 ml) followed by addition of pyridine (1 ml) at 0°C. the Solution was stirred at 0°C for 30 minutes After removing the ice bath, the reaction mixture was stirred at room temperature for 1.5 h, when TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed, and were detected peak product (396). The reaction mixture was extinguished polimersvarka Diethylenetriamine (4 mmol/g, 0.25 g), stirring at room temperature for 30 minutes, then filtered and washed DHM. The solvent is evaporated to the dry state was re-dissolved in DHM and washed with an aqueous solution of sodium bicarbonate. The two phases were separated and the aqueous phase was extracted with dichloromethane (5 ml × 2). The combined extracts DHM repeatedly washed with sodium bicarbonate solution (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 sequentially 2%, 7.5% and 10% MeOH in DHM, to obtain the desired compound in the form of a solid yellow-brown in free base form. This material was dissolved in DHM and ether (1:1 vol./about., 5 ml) and was treated with 1N HCl (1 ml) at 0°C. the Solvent is evaporated and dried under high vacuum to obtain the desired compound in the form of a solid brown color.

W the MS: R T=2.26 and minutes, MS: 382 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): of 8.06 (m, 1H), 7,89 (m, 1H), 7,47 (m, 1H), 7,15 (m, 1H), 7,06 (m, 1H), to 6.43-6,46 (m, 2H), of 3.56 (m, 2H), 3,42 (m, 2H), 3,30 (m, 2H), of 3.07 (m, 1H), 2,78 (m, 1H), and 2.27 (s, 3H), of 2.21 (m, 2H), 2.05 is and 1.80 (m, 3H), of 1.65 (m, 1H), 1,29 (d, 6.3 Hz, 3H).

Example 2

Triptorelin 5-fluoro-2-methyl-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(3-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 5-fluoro-2-methylbenzothiazol (from Alfa Aesar). MS: 396,3 (M+H).

Example 3

5-fluoro-2-methyl-N-[2-methyl-4-(2(2S)-methyl-[1,3'(3'R)]bipirimidiny-1'-yl)-phenyl]-benzamide

2-methyl-4-(2-(2S)-methyl-[1,3'(3'R)]bipirimidiny-1'-yl)-phenylamine (200 mg, 0.77 mmol) was dissolved in DHM (10 ml). To this solution was added a solution of 5-permitidentifier (from Alfa Aesar, 242 mg, 1.4 mmol) in DHM (2 ml) followed by addition of pyridine (1 ml) at 0°C. the Solution was stirred at 0°C for 30 minutes After removing the ice bath, the reaction mixture was stirred at room temperature for 1.5 h, when TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed, and were detected peak product (396). The reaction mixture was extinguished polimersvarka Diethylenetriamine (4 mmol/g, 0.25 g), stirring at room temperature for 30 minutes, ZAT is filtered and washed DHM. The solvent is evaporated to the dry state was re-dissolved in DHM and aqueous sodium bicarbonate solution. 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 × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira sequentially 2%, 7.5% and 10% MeOH in DHM, to obtain the desired compounds in the free base form in a solid yellow-brown color. This material was dissolved in DHM and ether (1:1 vol./about., 5 ml) and was treated with 1N HCl (1 ml) at 0°C. the Solvent is evaporated and dried under high vacuum to obtain the desired compound in the form of a solid, yellowish-brown.

JHMS: RT=1,61 minutes, MS: 396 (M+H).

1H NMR (DMSO-d6, 300 MHz), δ (ppm): 10,8 (users, 1H), 9,59 (users, 1H), 7,32 (m, 2H), 7,14 (m, 1H), 7,17 (m, 2H), 6,51 (m, 2H), 4,15 (m, 1H), of 3.56 (m, 4H), of 3.48 (m, 1H), 3,39 (m, 1H), 3,23 (m, 2H), 2,5-2,4 (m, 3H), of 2.38 (s, 3H), 2,22 (s, 3H), of 1.95 (m, 2H), of 1.66 (m, 1H), 1,45 (d, 6.4 Hz, 3H).

Example 4

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

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-trif what normativetechnical. MS: 418,2 (M+H).

Example 5

5-fluoro-2-methyl-N-[2-methyl-4-(2(2R)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenyl]-benzamide

2-methyl-4-(2-(2R)-methyl-[1,3'(3'S)]bipirimidiny-1'-yl)-phenylamine (200 mg, 0.77 mmol) was dissolved in DHM (10 ml). To this solution was added a solution of 5-fluoro-2-methylbenzonitrile (from Alfa Aesar, 242 mg, 1.4 mmol) in DHM (2 ml) followed by addition of pyridine (1 ml) at 0°C. the Solution was stirred at 0°C for 30 minutes After removing the ice bath, the reaction mixture was stirred at room temperature for 1.5 h, when TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed, and were detected peak product (396). The reaction mixture was extinguished polimersvarka Diethylenetriamine (4 mmol/g, 0.25 g), stirring at room temperature for 30 minutes, then filtered and washed DHM. The solvent is evaporated to the dry state was re-dissolved in DHM and aqueous solution of NaHCO3. 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 × 2), dried (anhydrous potassium carbonate), filtered and concentrated under vacuum. The crude product was purified on silikagelevye column, elwira sequentially 2%, 7.5% and 10% MeOH in DHM, to obtain the desired compound in the form of a solid yellow is brown in free base form. This material was dissolved in DHM and ether (1:1 vol./about., 5 ml) and was treated with 1N HCl (1 ml) at 0°C. the Solvent is evaporated and dried under high vacuum to obtain the desired compound in the form of a solid, yellowish-brown. JHMS: RT=1,59 minutes, MS: 396 (M+H).

1H NMR (DMSO-d6, 300 MHz), δ (ppm): 10,8 (users, 1H), 9,59 (users, 1H), 7,32 (m, 2H), 7,14 (m, 1H), 7,17 (m, 2H), 6,51 (m, 2H), 4,15 (m, 1H), of 3.56 (m, 4H), of 3.48 (m, 1H), 3,39 (m, 1H), 3,23 (m, 2H), 2,5-2,4 (m, 3H), of 2.38 (s, 3H), 2,22 (s, 3H), of 1.95 (m, 2H), of 1.66 (m, 1H), 1,45 (d, 6.4 Hz, 3H).

Example 6

2-fluoro-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine (1.52 g, of 5.84 mmol) was dissolved in DHM (30 ml). This solution was transferred a solution of 2-tormentilla in DHM (2 ml) followed by addition of pyridine (7.5 ml). The solution was stirred at room temperature for 2 h when TLC analysis (10% MeOH in DHM) and LC/MS showed that the reaction was completed. The reaction mixture was extinguished polimersvarka Diethylenetriamine (4 mmol/g, 1.5 g) and the suspension was stirred for 30 minutes and Then the suspension was added 10 DHM and was filtered through a layer of celite followed by washing DHM and 10% MeOH in DHM. The crude product was purified on silikagelevye column, elwira 2%, 5% and 7.5% MeOH in DHM, to obtain the desired compound in the form of a solid yellow color, 1,79 g (80%). JHMS: RT =1,53 minutes, MS: 382 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): there were two sets of signals in a ratio of about 1:1.2, and the spectra significantly overlap. Was observed following chemical shifts: compared to 8.26 (m), 7,78 (m), 7,65 (m), 7.5 (m), and 7.3 (m), 7,15 (m), 6.4 (m), 3,5-3,2 (m)3,00 (m)2,80 (m)to 2.55 (m), 2,3 (m), 2,10-1,6 (m)2,45 (m)1,08 (d).

Example 7

4-fluoro-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-tormentilla. JHMS: RT=1,54 minutes, MS: 382 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): there were two sets of signals and spectra significantly overlap. Was observed following chemical shifts: 1,86 (m)of 7.48, 7,13 (m), 7,11 (m)6,41 (m), 3,53-3,34 (m)to 2.29 (m), 2,89 (m), 2,62 (m)2,60-1,77 (m)of 1.57 (m)to 1.21 (d, 6,1 Hz), 1,20 (d, 5.8 Hz).

Example 8

2-fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(R)-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2-tormentilla. JHMS: RT=1,70 minutes, MS: 382 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): there were two sets of signals in a ratio of about 1:1.2 and mean spectra is Ino overlap. Was observed following chemical shifts: 12,5 (users), compared to 8.26 (m)8,00 (m), 7,78 (m), 7,60 (m), and 7.3 (m), 6,55 (m)4,2 (users), 3,98 (users), 3,68-3,34 (m)to 2.29 (m), 2,89 (m), 2,62 (m)1,90 (m)1,6 (m).

Example 9

4-fluoro-N-[2-methyl-4-(2-(2R)-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(R)-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 4-tormentilla. JHMS: RT=1,57 minutes, MS: 382 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): there were two sets of signals in a ratio of about 1:3, and the spectra significantly overlap. Was observed following chemical shifts: 12,8 (users), 7,86 (m)of 7.48, 7,13-6,95 (m), 6,45 (m), 4,2, 3,9, 3,85-3,10 (m), 2,6-2,0 (m), 2,62 (m)2,0-1,57 (m).

Example 10

5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-fluoro-2-methylbenzothiazol (from Alfa Aesar). JHMS: RT=1,56 minutes, MS: 396 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): of 7.48 (d, 7.4 Hz, 1H), 7.23 percent (m, 2H),? 7.04 baby mortality (m, 1H), 6.42 per (m, 2H), 3,53 was 3.05 (m, 6H), of 2.81 (m, 1H), 2,54 (m, 1H), 2.49 USD (users, 3H), 2,28 (users, 3H), 2,2-of 1.95 (m, 3H), of 1.70 (m, 4H)and 1.15 (d, 6.0 Hz, 3H).

Example 11

5-fluoro-2-methyl-N-[2-methyl-4-(2-(2S)-methyl-[1,3'(3'S)]BIP is rollitini-1'-yl)-phenyl]-benzamide

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 5-fluoro-2-methylbenzothiazol (from Alfa Aesar).

JHMS: RT=2,14 minutes, MS: 396 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): of 7.48 (d, 7.4 Hz, 1H), 7.23 percent (m, 1H),? 7.04 baby mortality (m, 2H), 6.42 per (m, 2H), 3,53 (m, 1H), 3,40-of 3.27 (m, 4H), 3,05 (m, 1H), 2,81 (m, 1H), 2,54 (m, 1H), 2.49 USD (users, 3H), 2,28 (users, 3H), 2,2-of 1.95 (m, 3H), to 1.70 (m, 4H)and 1.15 (d, 6.0 Hz, 3H).

Example 12

Hydrochloride 5-fluoro-2-methyl-N-[2-methyl-4-(2-(R)-methyl-[1,3'(R)]bipirimidiny-1'-yl)-phenyl]-benzamide

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-(R)-methyl-[1,3'(R)]bipirimidiny-1'-yl)-phenylamine with 5-fluoro-2-methylbenzothiazol (from Alfa Aesar).

JHMS: RT=1,61 minutes, MS: 396 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): of 7.48 (d, 7.4 Hz, 1H), 7.23 percent (m, 1H),? 7.04 baby mortality (m, 2H), 6.42 per (m, 2H), 3,53 (m, 1H), 3,40-of 3.27 (m, 4H), 3,05 (m, 1H), 2,81 (m, 1H), 2,54 (m, 1H), 2.49 USD (users, 3H), 2,28 (users, 3H), 2,2-of 1.95 (m, 3H), to 1.70 (m, 4H)and 1.15 (d, 6.0 Hz, 3H).

Example 13

3-fluoro-N-[2-methyl-4-(2-(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-benzamide

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 3-fermenting acid. JHMS: R =2.26 and minutes, MS: 382 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): the 7.65 (m, 2H), 7,47 (m, 2H), 7.23 percent (m, 1H), 6,45-6.42 per (m, 2H), 3,54 (t, 7.5 Hz, 1H), 3,39 (m, 3H), and 3.31 (m, 1H), 3,10 (m, 1H), 2,88 (m, 1H), 2,60 (sq., and 8.4 Hz, 1H), 2,28 (s, 3H), 2.23 to-1,71 (m, 5H), of 1.53 (m, 1H), 1,19 (d, 6.3 Hz, 3H).

Example 14

4-chloro-N-[2-methyl-4-(2-(S)-methyl-[1,3' (S)]bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-chlorobenzylchloride. JHMS: RT=3,96 minutes, MS: 398 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): 8,19 (m, 1H), 7,94 (m, 1H), 7,46 (d, 7.2 Hz, 1H), 7.23 percent (m, 1H), to 6.43-6,46 (m, 2H), of 3.56 (m, 2H), 3,53 (m, 1H), 3,40-3,24 (m, 3H), 3,1 (m, 1H), 2,78-of 2.50 (m, 3H), and 2.27 (s, 3H), of 2.21 (m, 2H), 2.05 is and 1.80 (m, 3H), of 1.75 (m, 1H), 1,50 (m, 1H), 1,17 (d, 6.3 Hz, 3H).

Example 15

5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 5-fluoro-2-triftoratsetilatsetonom. JHMS: RT=2,53 minutes, MS: 450 (M+H).

1H NMR (CDCl3, 300 MHz), δ (ppm): 7,78 (DD, 5,1 Hz and 8.4 Hz, 1H), 7,49 (d, 8,4 Hz, 1H), 7,74 (DD, 2,7 Hz and 8.4 Hz, 1H), 7,06 (s, 1H), 6,46-6.42 per (m, 2H), 3,55 (m, 1H), 3.43 points (m, 2H), and 3.31 (m, 2H), 2,92 (m, 1H), 2,64 (m, 1H), 2,28 (, 3H), 2,24-is 1.51 (m, 7H), 1,22 (d, 6.6 Hz, 3H).

Example 16

[2-methyl-4-(2(2S)-methyl-[1,3'('S)]bipirimidiny-1'-yl)-phenyl]-amide 2,3-dihydrobenzofuran-5-carboxylic acid; triperoxonane 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 2,3-dihydrobenzofuran-5-Carboni chloride. JHMS: RT=1,19 minutes, MS: 406,2 (M+H).

Example 17

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

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 4-methysulfonylmethane. MS: 442,2 (M+H).

Example 18

Triptorelin 2-fluoro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 2 tormentilla. MS: 436,2 (M+H).

Example 19

4 deformedarse-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-diftormetilirovaniya. MS: 430,2 (M+H).

Example 20

Three is corzett 3-fluoro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-tormentilla. MS: 368,2 (M+H).

Example 21

Triptorelin (E)-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-3-pyridin-3-alacrimia

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-pyridine-3-eracriliola. MS: 377,3 (M+H).

Example 22

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2.5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-carboxylic acid. MS: 462,3 (M+H).

Example 23

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

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 4-cyanobenzaldehyde. MS: 389,2 (M+H).

Example 24

Triptorelin 3-fluoro-N-[3-METI the-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-tormentilla. MS: 382,2 (M+H).

Example 25

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide tetrahydrofuran-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 tetrahydrofuran-2-carboxylic acid. MS: 358,2 (M+H).

Example 26

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-chloroimidazo[1,2-a]pyridine-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 6 chloroimidazo[1,2-a]pyridine-2-carboxylic acid. MS: 438,4 (M+H).

Example 27

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

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-triftoratsetilatsetonom. MS: 432,2 (M+H).

Example 28

Tripto the acetate [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide thiophene-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 thiophene-2-carboxylic acid. MS: 370,2 (M+H).

Example 29

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 4-oxo-4,5,6,7-tetrahydrofuran-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 4-oxo-4,5,6,7-tetrahydrofuran-2-carboxylic acid. MS: 422,4 (M+H).

Example 30

4-isopropyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-3-sulfamoylbenzoic

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 4-isopropyl-3-sulfamoylbenzoic acid. MS: 485,3 (M+H).

Example 31

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(1H-pyrazole-3-yl)-benzamide

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 4-(1H-pyrazole-3-yl)-benzoic acid. MS: 430,3 (M+H).

Example 32

[2-methyl-4-(2-methyl-[1,3']bi is pirrolidone-1'-yl)-phenyl]-amide benzofuran-5-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 benzofuran-5-carboxylic acid. MS: 404,4 (M+H).

Example 33

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-methoxybenzophenone-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 6-methoxybenzophenone-2-carboxylic acid. MS: 434,2 (M+H).

Example 34

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2-pyridin-3-yl-1H-benzoimidazol-5-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 2-pyridin-3-yl-1H-benzoimidazol-5-carboxylic acid. MS: 481,3 (M+H).

Example 35

[2-methyl-4-(2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-chloro-4-oxo-4H-chromen-2-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 6-chloro-4-oxo-4H-chromen-2-carboxylic acid. MS: 466,2 (M+H).

Example 36

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

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 pyridine-3-carboxylic acid. MS: 365,22 (M+H).

Example 37

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-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 1H-indole-2-carboxylic acid. MS: 389,22 (M+H).

Example 38

5-chloro-6-(2-hydroxyethylamino)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-nicotinamide

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-chloro-6-(2-hydroxyethylamino)-nicotinic acid. MS: 458,4 (M+H).

Example 39

6-benzoyloxymethyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-nicotinamide

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 6-benzoyloxymethyl is kotikovay acid. MS: 485,5 (M+H).

Example 40

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2-pyridin-4-iltiazem-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 2-pyridine-4-iltiazem-4-carboxylic acid. MS: USD 448,2 (M+H).

Example 41

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide thiophene-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 thiophene-2-carboxylic acid. MS: 370,2 (M+H).

Example 42

4-(4,6-dimethylpyrimidin-2-ylamino)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-(4,6-dimethylpyrimidin-2-ylamino)-benzoic acid. MS: 485,3 (M+H).

Example 43

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

The desired compound was obtained by a method substantially similar to example 1, by combin is of 4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 1-acetylpyrrolidine-2-carboxylic acid. MS: 385,3 (M+H).

Example 44

Triptorelin 5-fluoro-2-methyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 5-fluoro-2-methylbenzoic acid. MS: 382,3 (M+H).

Example 45

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-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 1H-indole-2-carboxylic acid. MS: 403,3 (M+H).

Example 46

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

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-dimethylaminobenzoyl acid. MS: 407,3 (M+H).

Example 47

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

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-Fenox is acetic acid. MS: 394,2 (M+H).

Example 48

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

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 4-methysulfonylmethane acid. MS: 442,2 (M+H).

Example 49

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methoxybenzophenone-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-methoxybenzophenone-2-carboxylic acid. MS: 434,2 (M+H).

Example 50

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 4-hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 4-hydroxy-7-methyl-[1,8]naphthiridine-3-carboxylic acid. MS: 446,5 (M+H).

Example 51

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

The desired compound was obtained by a method substantially similar is the example 1, through a combination of 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2-pyridin-2-yl-1H-benzoimidazol-5-carboxylic acid. MS: 481,3 (M+H).

Example 52

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-5-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 1H-indole-5-carboxylic acid. MS: 403,4 (M+H).

Example 53

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide benzo[1,3]dioxol-5-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 benzo[1,3]dioxol-5-carboxylic acid. MS: 408,4 (M+H).

Example 54

4-(formylmethylene)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-(formylmethylene)-benzoic acid. MS: 421,3 (M+H).

Example 55

4-(1-acetylpiperidine-3-yl)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

The claim is e connection received by way essentially the same as the example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 4-(1-acetylpiperidine-3-yl)-benzoic acid. MS: 489,3 (M+H).

Example 56

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

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-fermenting acid. MS: 368,2 (M+H).

Example 57

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(6-oxo-1,6-dihydropyridines-3-yl)-benzamide

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 4-(6-oxo-1,6-dihydropyridines-3-yl)-benzoic acid. MS: 457,3 (M+H).

Example 58

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

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 4-morpholine-4-ylmethylamino acid. MS: 463,4 (M+H).

Example 59

Triptorelin (E)-3-(3-forfinal)-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-acrylamide

/p>

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 (E)-3-(3-forfinal)-acrylic acid. MS: 394,2 (M+H).

Example 60

Triptorelin (E)-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-3-pyridin-3-alacrimia

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 (E)-3-pyridin-3-elkrylova acid. MS: 445,2 (M+H).

Example 61

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1-acetylpyrrolidine-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 1-acetylpyrrolidine-2-carboxylic acid. MS: 399,2 (M+H).

Example 62

2-[(2-methoxyethyl)-amide] 5-{[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide} pyridine-2,5-dicarboxylic 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-methoxyethyl)-amide] pyridine-2,5-dicarboxylic acid. MS: 466,3 (M+H).

Example 63

2,dimethyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamid

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 2,4-dimethylbenzylamine. MS: 446,2 (M+H).

Example 64

4-(3,5-dimethyl-1H-pyrazole-4-yl)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-(3,5-dimethyl-1H-pyrazole-4-yl)-benzoic acid. MS: 458,3 (M+H).

Example 65

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(2-oxo-pyrrolidin-1-yl)-benzamide

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 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid. MS: 447,5 (M+H).

Example 66

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-6-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenylamine with 1H-indole-6-carboxylic acid. MS: 403,4 (M+H).

Example 67

Triptorelin [4-(2-methyl-1,3']bipirimidiny-1'-yl)-phenyl]-amide, imidazo[1,2-a]pyridine-8-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 imidazo[1,2-a]pyridine-8-carboxylic acid. MS: 390,3 (M+H).

Example 68

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

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 4-cyanobenzoic acid. MS: 389,2 (M+H).

Example 69

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide, imidazo[1,2-a]pyridine-8-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 imidazo[1,2-a]pyridine-8-carboxylic acid. MS: 404,3 (M+H).

Example 70

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-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 1H-indole-2-carboxylic acid. MS: 403,2 (M+H).

Example 71

Triptorelin 2-metasolv the Nile-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-methanesulfonylaminoethyl acid. MS: 380,2 (M+H).

Example 72

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-fluoro-2-methylinosine-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 6-fluoro-2-methylinosine-3-carboxylic acid. MS: 447,4 (M+H).

Example 73

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide benzofuran-6-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 benzofuran-6-carboxylic acid. MS: 404,2 (M+H).

Example 74

Triptorelin (E)-3-(3-forfinal)-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-acrylamide

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 (E)-3-(3-forfinal)-acrylic acid. MS: 408,2 (M+H).

Example 75

Tripto the acetate 2-methanesulfonyl-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 2-methanesulfonylaminoethyl acid. MS: 380,2 (M+H).

Example 76

Triptorelin [2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1-acetylpyrrolidine-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 1-acetylpyrrolidine-2-carboxylic acid. MS: 399,3 (M+H).

Example 77

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

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 4-chlorobenzylchloride. MS: 398,2 (M+H).

Example 78

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-5-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-indole-5-carboxylic acid. MS: 403,3 (M+H).

Example 79

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]4-oxazol-5-ylbenzene

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 4-oxazol-5-eventorganizer. MS: THAT AMOUNT TO 431,3 (M+H).

Example 80

Triptorelin 3-methoxy-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 3-methoxybenzylamine. MS: USD 448,2 (M+H).

Example 81

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

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 4-chlorobenzylchloride. MS: 398,2 (M+H).

Example 82

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

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 4-dimethylaminobenzoyl acid. MS: 393,2 (M+H).

Example 83

2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid [2-methyl-4-(2-methyl-[1,3']bipirimidiny-'-yl)-phenyl]-amide

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 2,3-dihydrobenzo[1,4]dioxin-6-carboxylic acid. MS: 422,4 (M+H).

Example 84

Triptorelin 5-fluoro-2-methyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 5-fluoro-2-methylbenzothiazol. MS: 450,2 (M+H).

Example 85

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

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-dimethylaminobenzoyl acid. MS: TO 393.3 (M+H).

Example 86

Triptorelin [2-methyl-4-(2(S)-methyl-[1,3'(S)]bipirimidiny-1'-yl)-phenyl]-amide 6-methylpyridin-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 6-methylpyridin-2-carboxylic acid. MS: TO 379.2 (M+H).

Example 87

Triforce is at 4-methoxy-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-methoxybenzylamine. MS: 394,2 (M+H).

Example 88

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2-pyridin-3-iltiazem-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 2-pyridine-3-iltiazem-4-carboxylic acid. MS: USD 448,2 (M+H).

Example 89

Triptorelin 3,5-dichloro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 3.5-dichlorobenzotrifluoride. MS: 486,1 (M+H).

Example 90

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2-methyl-1H-benzoimidazol-5-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 2-methyl-1H-benzoimidazol-5-carboxylic acid. MS: 418,3 (M+H).

Example 91

Triptorelin 3,5-di the ENT-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-dichlorobenzotrifluoride. MS: 418,1 (M+H).

Example 92

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

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-triftoratsetilatsetonom. MS: 432,2 (M+H).

Example 93

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

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-tormentilla. MS: 382,2 (M+H).

Example 94

Triptorelin [3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 3-phenylpropionic 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-phenylpropionic acid. MS: 388,2 (M+H).

Example 95

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-methyl-4-oxo-4H-chromen-2-carbon is howling 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 6-methyl-4-oxo-4H-chromen-2-carboxylic acid. MS: KZT 446.4 (M+H).

Example 96

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide [1,6]naphthiridine-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 [1,6]naphthiridine-2-carboxylic acid. MS: 416,4 (M+H).

Example 97

3-methanesulfonyl-4-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-methanesulfonyl-4-methylbenzothiazol. MS: 456,2 (M+H).

Example 98

4-{4-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylcarbamoyl]-phenoxy}-benzoic 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 4,4'-bicarboxylic ether. MS: 500,3 (M+H).

Example 99

Triptorelin 2-dimethylamino-N-[4-(2-what ethyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 2 dimethylaminobenzoyl acid. MS: 461,3 (M+H).

Example 100

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-6-morpholine-4-iniatiated

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 6-morpholine-4-lincocinbuy acid. MS: 450,5 (M+H).

Example 101

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 5-methyl-2-phenyl-2H-[1,2,3]triazole-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 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid. MS: 445,4 (M+H).

Example 102

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

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 2,3-dihydrobenzofuran-5-carboxylic acid. MS: TO 406.4 (M+H).

Example 103

Three is corzett [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide thiophene-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 thiophene-2-carboxylic acid. MS: 356,2 (M+H).

Example 104

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

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 4-methysulfonylmethane. MS: 428,2 (M+H).

Example 105

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 4-benzoyl-1H-pyrrole-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 4-benzoyl-1H-pyrrole-2-carboxylic acid. MS: 457,4 (M+H).

Example 106

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 1-isopropyl-1H-benzotriazol-5-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 1-isopropyl-1H-benzotriazol-5-carboxylic acid. MS: 447,3 (M+H).

Example 107

Triptorelin 2-methanesulfonyl--[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-ndimethylacetamide

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 2-methanesulfonylaminoethyl acid. MS: OF 434.1 (M+H).

Example 108

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

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-dimethylaminobenzoyl acid. MS: TO 393.3 (M+H).

Example 109

Triptorelin 3-fluoro-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 3-tormentilla. MS: 436,2 (M+H).

Example 110

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

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 4-chlorobenzylchloride. MS: 384,2 (M+H).

Example 111

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide a quinoline-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 quinoline-3-carboxylic acid. MS: OF 415.3 (M+H).

Example 112

4-imidazol-1-yl-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-imidazol-1-eventing acid. MS: 430,5 (M+H).

Example 113

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide of 1H-indole-6-carboxylic acid

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 1H-indole-6-carboxylic acid. MS: 403,3 (M+H).

Example 114

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 6-methoxy-1H-indazol-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 6-methoxy-1H-indazol-3-carboxylic acid. MS: 434,3 (M+H).

Example 115

Triptorelin 2-methanesulfonyl-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 2-methanesulfonylaminoethyl acid. MS: 366,2 (M+H).

Example 116

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

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 2-dimethylaminoethanol acid. MS: 399,3 (M+H).

Example 117

Triptorelin 4-cyano-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 4-cyanobenzylidene. MS: 443,2 (M+H).

Example 118

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

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 nicotinic acid. MS: 351,2 (M+H).

Example 119

Triptorelin [4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-amide, imidazo[1,2-a]pyridine-8-carboxylic to the slots

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 imidazo[1,2-a]pyridine-8-carboxylic acid. MS: 458,2 (M+H).

Example 120

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

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 phenoxyalkanoic acid. MS: 380,2 (M+H).

Example 121

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

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 4-methoxybenzylamine. MS: 380,2 (M+H).

Example 122

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-amide 2-oxo-2,3-dihydro-1H-benzoimidazol-5-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 2-oxo-2,3-dihydro-1H-benzoimidazol-5-carboxylic acid. MS: 420,3 (M+H).

Example 123

Triptorelin N-[3-methyl-4-(2-methyl-[1,3']bipyrrole dinil-1'-yl)-phenyl]-4-morpholine-4-iletilmesine

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 4-morpholine-4-imlivinthedream. MS: 463,3 (M+H).

Example 124

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-(1-propoxyethyl)-benzamide

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 4-(1-propoxyethyl)-benzoic acid. MS: 463,3 (M+H).

Example 125

Triptorelin N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-nicotinamide

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 nicotinic acid. MS: 419,2 (M+H).

Example 126

4-[(4,6-dimethylpyrimidin-2-yl)-methylamino]-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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 4-[(4,6-dimethylpyrimidin-2-yl)-methylamino]-benzoic acid. MS: 499,5 (M+H).

Example 127

Triptorelin 3,5-dichloro-N-[3-is ethyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-dichlorbenzene acid. MS: 432,2 (M+H).

Example 128

Triptorelin 3-dimethylamino-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 3-dimethylaminobenzoyl acid. MS: 461,3 (M+H).

Example 129

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

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-methoxybenzoic acid. MS: 394,2 (M+H).

Example 130

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

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 4-dimethylaminobenzoyl acid. MS: 407,3 (M+H).

Example 131

Triptorelin 2,4-dimethyl-N-[4-(2-methyl-[1,3']bier olidine-1'-yl)-phenyl]-benzamide

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 2,4-dimethylbenzylamine. MS: 378,2 (M+H).

Example 132

Triptorelin 4-methanesulfonyl-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 4-methysulfonylmethane acid. MS: 496,2 (M+H).

Example 133

Triptorelin N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-2-phenoxyacetamide

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 phenoxyalkanoic acid. MS: USD 448,2 (M+H).

Example 134

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

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 2,4-dimethylbenzylamine. MS: 392,2 (M+H).

Example 135

[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-the ID benzo[d]imidazo[2,1-b]thiazole-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 benzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid. MS: 460,4 (M+H).

Example 136

Triptorelin 4-methoxy-N-[4-(2-methyl-[1,3']bipirimidiny-1'-yl)-2-triptoreline]-benzamide

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 4-methoxybenzoic acid. MS: USD 448,2 (M+H).

Example 137

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

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 phenoxyalkanoic acid. MS: 394,3 (M+H).

Example 138

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

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-methoxybenzoic acid. MS: 380,2 (M+H).

Example 139

Triptorelin (E)-N-[3-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl-3-pyridin-3-alacrimia

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-pyridine-3-elkrylova acid. MS: 391,3 (M+H).

Example 140

Triptorelin (E)-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-3-pyridin-3-alacrimia

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-pyridine-3-elkrylova acid. MS: 391,3 (M+H).

Example 141

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

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 2,4-dimethylbenzylamine. MS: 392,3 (M+H).

Example 142

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-4-[1,2,4]triazole-1-ylbenzene

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 4-[1,2,4]triazole-1-eventing acid. MS: THAT AMOUNT TO 431,3 (M+H).

Example 143

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

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-tormentilla. MS: 382,2 (M+H).

Example 144

Triptorelin 3,5-dichloro-N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-benzamide

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-dichlorobenzotrifluoride. MS: 432,2 (M+H).

Example 145

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

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 nicotinic acid. MS: 365,2 (M+H).

Example 146

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

The desired compound was obtained by a method substantially similar to example 1, by combining 2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenylamine with 5-methoxy-1H-indole-2-carboxylic acid. MS: 433,2 (M+H).

Example 147

N-[2-methyl-4-(2-methyl-[1,3']bipirimidiny-1'-yl)-phenyl]-6-pyrazole-1-iniatiated

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 6-pyrazole-1-lincocinbuy acid. MS: 431,4 (M+H).

Biological examples

Example 148

In the present example demonstrates the effectiveness of the compounds of the present invention as ligands of H3 receptors. It is known that the compounds of the present invention displace radioligand [3H]-methylhistamine that is associated with the membranes of mammalian cells expressing the receptor H3 rhesus monkeys (Macacca Mulatta). These compounds have affinity constants (Ki) 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 activity of 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 × 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 (2-3×), and then the needle 23 size (2-3×), to an even greater extent to destroy the cell membrane. Cell suspension was centrifuged (40000 × g, 30 minutes). Sediment cell membranes resuspendable in 5 mm HEPES (pH of 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). Analysis of PR who drove 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
# exampleAffinity: ki in the membrane rhesus H3 (nm)Reverse agonism: % inhibition of basal GTPγS binding in rhesus H3
7to 2.06-31
520,77-17
730,78-15
861,42-18

Example 149

This example shows that the stereochemistry of the compounds of the present invention has an effect on biological activity. Several representative compounds of the present invention used in this example to demonstrate this difference in biological activity on the basis of stereoisomeric forms. All connections in this example was tested for the activity of the receptor ligand H3 in accordance with the methods described in example 148. The results are summarized in table 2.

Table 2
# exampleAffinity: ki in the membrane rhesus H3 (nm)
37,3
5120,8
112,5
12to 147.2

Example 150

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

The affinity H3 compounds this is part II of the invention was measured in accordance with the methods shown in example 148.

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

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

Negative control: 40 μm MCH-1 in the 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-1 (negative control) or buffer/DMSO (positive control) were added to 96-round bottom cell tablet for micrometrology. Then added 50 μl of a solution of the ligand with [ 125J], after which was added 100 μl of membrane suspension. Cells were covered with lids and incubated for 60 minutes at 25°C. the Sample was transferred to a filter plate GF/B. the Reaction mixture was removed by vacuum filtration, washed 4 × with 300 μl proryvnym buffer, cooled to freezing temperature, and the solution after washing was removed by vacuum filtration. Rubber-like layer on the bottom of the tablet was then removed and the filters were dried overnight at room temperature. Added 25 μl of scintillation mixture and the tablets were sealed, and then added a frame for tablets and incubated for 1 hour at room temperature. Then measured the level of radioactivity, the default settings for the125J, 30 sec. on the cell. Based on this determined the percent inhibition of ligand binding.

Results: generally, the compounds of the present invention demonstrated the value of ki for binding to the receptor H3 RH in the range of from about 400 nm to less than 1 nm, whereas the percentage of inhibition of binding of the ligand to the receptor, MCH-1 was less than 40% at a concentration of 10 μm. This comparative example shows that the compounds of the present invention can be more than a thousand times more selective on the website of the H3 receptor, the receptor of the sit-1.

Example 151

This example illustrates the research the Finance effectiveness of the compounds of the present invention with the support of wakefulness in animal models.

Male rats Sprague-doli (Charles River, France) weighing 250±10 g were obtained anesthesia ZoletilR50 (60 mg/kg/b) and were fixed in a stereotactic device. Cortical electrodes (small screw electrodes from stainless steel with a diameter of 0.9 mm) was screwed into the bone over the sensorimotor part of the cerebral cortex (1.5 mm lateral relative to the medial seam and 1.5 mm for frontal-parietal suture), the visual part of the crust (1.5 mm lateral to medial seam and 1.5 mm in front of the occipital-parietal suture), and cerebellum (reference electrode). Cortical electrodes were connected to the connector (Winchester, 7-conductors) 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 conducted from 10.00 h to 16.00 h for three consecutive days: the control day (D1), day of taking the medicine (D2) and day after taking the medicine (D3). Media (D1 and D3) or drug (D2) was administered 15 minutes before 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:

- baud is the existence of (B), which was characterized by rapid electrical cortical activity with low voltage (ECoG);

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

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

Analysis of the ECoG signal was performed automatically by a computer system that recognizes the different phases of sleep with 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-wakefulness: 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 ntalnyh values.

Example 152

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.) produced every 7 sec., and then was detected 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 for more than 10 msec. 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.), then recorded the UV (will continue lnost and frequency) for 2 minutes using system Ultravox. Compounds of the present invention has introduced the p/o for 60 min before testing.

Example 153

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 minutes after the training session and for 60 min before the test).

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

1. The compound of formula (I):

where R, R1, R2and R3are the same or different and independently from each other selected from hydrogen, (C1-C4)-alkyl or CF3;
R4is selected from the group consisting of dimethylaminomethyl, methysulfonylmethane, phenoxymethyl, vinylbenzyl, ethenylbenzene, vinylpyridine, phenyl, benzofuranyl, dihydrobenzofuranyl, oxo-tetrahydrofuranyl, benzodioxolyl, oxo-chromanol, dihydroergotoxine, dioxotetrahydrofuran-3-H-benzo[e]diazepine, imidazopyridines, benzotriazolyl, benzoimidazolyl, oxo-dihydrobenzofuranyl, indolyl, indazoles, naphthyridine, chinoline, benzoimidazolyl, pyridinyl, pyrrolyl, triazolyl, thienyl, thiazolyl, tetrahydrofuranyl or pyrrolidinyl; where the specified R4optional one or more times substituted by the Deputy selected from the group consisting of halogen, hydroxy, methyl, ethyl, isopropyl, propoxyethyl, phenyl, benzoyl, methoxy, deformedarse, CF3, CN, acetyl, methanesulfonyl, sulfamoyl, dimethylamino, N-formylmethionine, 2-hydroxyethylamino, 2-methoxyethylamine, carboxyphenoxy, pyrazolyl, 3,5-dimethylpyrazole, imidazole, triazole, oxazolyl, pyridinyl, oxo-dihydropyridine, N-acetylpiperidine, morph is lineal, morpholinylmethyl and 2-oxo-pyrrolidinyl; or
their pharmaceutically acceptable salt or enantiomer or diastereoisomer.

2. The compound according to claim 1, in which R means methyl;
R1and R2each independently of one another denote hydrogen, methyl or CF3;
R3means hydrogen; and
R4means phenyl or phenyl substituted by one or more Deputy selected from the group consisting of fluorine, chlorine, methyl, isopropyl, propoxyethyl, CF3, CN, methoxy, deformedarse, methanesulfonyl, sulfamoyl, dimethylamino, N-formylmethionine, carboxyphenoxy, oxo-dihydropyridines, pyrazolyl, 3,5-dimethylpyrazole, imidazole, triazole, oxazole, N-acetylpiperidine, morpholinylmethyl and 2-oxo-pyrrolidinyl; or
R4is selected from the group consisting of benzofuranyl, dihydrobenzofuranyl, oxo-tetrahydrofuranyl, benzodioxolyl, dihydroergotoxine, dioxotetrahydrofuran-1H-benzo[e]diazepine and oxo-chromanol, and optionally substituted one or more times by Deputy selected from chlorine, methyl and methoxy; or R4is selected from the group consisting of dimethylaminomethyl, methysulfonylmethane, phenoxymethyl, vinylbenzyl, ethenylbenzene or vinylpyridine, and optionally substituted one or more times by fluorine, or
R4means pyridinyl which is optionally substituted one or more times by the Deputy, is gathered from chlorine, methyl, 2-hydroxyethylamino, 2-methoxyethylamine and morpholinyl; or
R4is selected from the group consisting of imidazopyridine, benzotriazolyl, benzoimidazolyl, oxo-dihydrobenzofuranyl, indolyl, indazoles, naphthyridine, chinoline and benzoimidazolyl, and optionally substituted one or more times by Deputy selected from fluorine, chlorine, hydroxy, methyl, isopropyl, methoxy, and pyridinyl; or
R4is selected from the group consisting of pyrrolyl, triazolyl, thienyl and thiazolyl, and optionally substituted one or more times by the Deputy, is selected from methyl, phenyl, benzoyl or pyridinyl; or
R4is selected from the group consisting of tetrahydrofuranyl or pyrrolidinyl, which is optionally substituted one or more times by acetyl.

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

where R, R1, R2, R3and R4characterized according to claim 1.

4. Pharmaceutical composition having activity to bind to the H3 ligand containing compound of the formula (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, enantiomer or diastereoisomer in combination with at least one pharmaceutically acceptable excipient, diluent or carrier.

5. The use of the compounds of formula (I) according to any one of claims 1 to 3 optionally in combination with FA is matemticas acceptable carrier, for the preparation of a pharmaceutical composition having activity to bind to the H3 ligand.

6. The use according to claim 5, where the pharmaceutical composition is intended for the treatment of sleep disorders 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 caused by a side effect of the drug.

7. The use according to claim 5, where the pharmaceutical composition is intended for the treatment of cognitive disorders.

8. The use according to claim 5, where the pharmaceutical composition is intended for the treatment of Alzheimer's disease.

9. The use according to claim 5, where the pharmaceutical composition is intended for treating depression.

10. The use according to claim 5, where the pharmaceutical composition is intended for the treatment of dementia.



 

Same patents:

FIELD: medicine, pharmaceutics.

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

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

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

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

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

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

17 cl, 18 dwg, 81 ex

FIELD: chemistry.

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

EFFECT: high efficiency of using the compounds.

2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

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

,

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

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: chemistry.

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

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

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

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

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

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

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

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

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

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

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

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

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

wherein the cycle A represents a carbocyclic group or a heterocyclic group; R1 means (i) lower alkyl optionally substituted by halogen, (ii) lower alkenyl, (iii) lower alkynyl or (iv) a carbocyclic group; each of R3a, R3b, R3c and R3d independently means hydrogen, halogen, lower alkyl optionally substituted by halogen, lower alkenyl, carbocyclyl - lower alkoxy or a carbocyclic group, or R3a and R3b or R3c and R3d can form C3-C10 cycloalkane ring together with an adjoining carbon atoms and can form oxo; a pharmaceutically acceptable salt or solvate of said compound effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

EFFECT: preparing the pharmaceutically acceptable salt or solvate effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

18 cl, 139 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 ex

FIELD: chemistry.

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

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

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

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: present invention relates to compounds of formula I

,

wherein radicals and symbols assume values given in the claim, or pharmaceutically acceptable salts thereof. The disclosed compounds inhibit serine protease activity, especially activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, compounds of the present invention inhibit the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to a pharmaceutical composition containing said compounds for administering to a patient suffering from HCV infection.

EFFECT: invention also relates to a method of treating HCV infection in a patient and a method of inhibiting replication of hepatitis C virus by administering a pharmaceutical composition containing compounds of the present invention.

7 cl, 7 tbl, 158 ex

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