6-alcoxypyridopyrimidines and pharmaceutical compound possessing activity of map p38 kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.

EFFECT: compounds possess inhibiting activity.

13 cl, 1 tbl, 8 ex

 

The present invention relates to pyridopyrimidines and their derivatives. First of all, the present invention relates to 2,6-disubstituted 7-occupied[2,3-d]pyrimidines containing pharmaceutical compositions and methods of use thereof.

Mitogen-activated protein (MAP) kinase belongs to a family of Proline-dependent serine/trainingin that activate their substrates by dual phosphorylation. Kinases are activated by a variety of signals, including (alimentary) nutritional and osmotic stress, UV irradiation, growth factors, endotoxin and inflammatory cytokines. One group of MAP kinases includes a group of kinases R containing multiple isoforms (for example, Rα, Rβ, Rγ and Rδ). Kinase R responsible for the phosphorylation and activation of transcription factors, as well as other kinases and are activated by physical and chemical stress, under the action of proinflammatory cytokines and bacterial lipopolysaccharide.

It was found that the most important action of kinases is that the products phosphorylation kinase R mediate the formation of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2. Each of these cytokines included in the process of a number of pathological processes and conditions. For example, the cytokine TNF-α first and foremost is produced by aktivirovannyj monocytes and macrophages. Such excessive or uncontrolled its production plays a major causal role in the pathogenesis of rheumatoid arthritis. Recently it was found that the inhibition of production of TNF finds wide application in the treatment of inflammatory processes of intestinal inflammation, multiple sclerosis and asthma.

TNF also plays a role in viral infections such as HIV, influenza virus and herpes virus, including, among others, herpes simplex type-1 (PWG-1), herpes simplex type-2 (PWG-2), cytomegalovirus (CMV), varicella zoster virus (OIE), Epstein-Barr, herpes virus-6 person (HHV-6), herpes virus-7 person (HHV-7), herpes virus-8 person (HHV-8), the virus areski and virus infectious bovine rhinotracheitis.

Similarly, IL-2 is produced by activated monocytes and macrophages and plays a role in many pathophysiological response reactions, including rheumatoid arthritis, fever, and decreased bone resorption.

In addition, R participates in the processes of stroke, Alzheimer's disease, arthritis, lung injury, septic shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis (J. Exp. Opin. Ther. Patents, Vol.10(1) (2000)).

Inhibition of these cytokines through inhibition of the kinase R can be used to control, reduce or alleviate symptoms of many diseases is.

In the application WO 96/34867 describes some 6 arrepiado[2,3-d]pyrimidine-7-ones, -7-imine and-7-thiones as inhibitors of cell proliferation mediated protein/tyrosine kinase. In the application WO 96/15128 described other 6 arrepiado[2,3-d]pyrimidines and naphthirydines as tyrosine kinase inhibitors. In the application WO 98/33798 described 6 alkylpyridine[2,3-d]pyrimidine-7-ones as inhibitors of cyclin-dependent kinases. In EP 0278686 describes some 4-aminopiperidine as inhibitors digidrofolatreduktazy. In patents and applications US Pat. No.6316464, US Pat. No.6451804, US Pat. No.6506749, US Pat. No.6518276B2, US No.09/693364 (WO 01/29042) and US No.10/073845 (WO 02/64594) describes the connection-kinase inhibitors R.

One object of the present invention (I) pertains to compounds of the formula

and their pharmaceutically acceptable salts, hydrates or prodrugs,

where Z denotes N or CH;

X1means O, S, C(=O) or NR4(where R4means hydrogen or alkyl);

R1means alkyl, cycloalkyl, cycloalkenyl or-CH2alkenyl;

R2means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, halogenated, heteroalkyl, cianelli, alkylen-C(O)-R21(where R21means hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamines or dialkylamino), amino, monoalkylamines, dialkylamino, acyl or NR22-Y-R23(g the s Y represents-C(O), -C(O)O-, -C(O)NR24, S(O)2or S(O)2NR25; R22, R24and R25independently mean hydrogen or alkyl, and R23means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl);

R3means alkyl, halogenated, aryl, aralkyl, heteroaryl, heteroalkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh or heterocyclimamines-SO2-R12(where R12means halogenated, aryl, aralkyl, heteroaryl or heteroalkyl).

In more detail, the present invention relates to the following compounds:

(II) the compounds of formula I, as defined in paragraph(1), but with the exception of R1that instead of-CH2-alkenyl means albaniles, and R3additionally denotes hydrogen, or its pharmaceutically acceptable salt, hydrate or prodrug, or

(III) the compound (I) or (II)where Z denotes N, X1means Of, R1means alkyl, R2means H or alkyl, and R3means heteroalkyl or heterocyclyl;

(IV) compound (III), where heteroalkyl means alkoxyalkyl and heterocyclyl means a saturated non-aromatic cyclic radical containing at cycle 6 atoms and in which one cyclic atom is not carbon, and to slort or nitrogen, optionally substituted on the nitrogen atom of the group-alkyl-SO2or alkoxycarbonyl, or

(V) the compound (I) or (II)where X1means-O-, or

(VI) compounds (I), (II) or (V), where R1means alkyl or cycloalkyl, or

(VII) the compound (I), (II), (V) or (VI), where R3means cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh, or

(VIII) the compound (I), (II), (V) or (VI-VII), where R3means cycloalkyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl or heterocyclyl, or

(IX) the compound (I), (II), (V) or (VI-VIII), where R3means optionally substituted heterocyclyl, or

(X) compounds (I), (II), (V) or (VI-IX), where R3means hydroxyalkyl or alkoxyalkyl, or

(XI) the compound (I), (II), (V) or (VI-X), where R2means hydrogen, alkyl, aryl, cycloalkyl or heteroalkyl, or

(XII) the compound (I), (II), (V) or (VI-XI), where R2means alkyl or hydroxyalkyl, or

(XIII) the compound (I) or (II) of the formula (I")

where

R1means alkyl;

R2selected from the group comprising hydrogen, alkyl, aryl, cycloalkyl and heteroaryl, and

R3means heteroalkyl or heterocyclyl or their pharmaceutically acceptable salts or

(XIV) connected to the I (XIII), where R3choose from the range: (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl, 3-methoxy-1-(2-methoxyethyl)propyl, tetrahydro-2H-Piran-4-Il, 1-(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl and morpholinyl, or

(XV) to compound (XIV), where

R1means ethyl,

R2means methyl and

R3choose from the range: (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl, 3-methoxy-1-(2-methoxyethyl)propyl, tetrahydro-2H-Piran-4-Il, 1-(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl and morpholinyl, or (XVI) of the compound (XIII) of the formula

where X represents-O-, -C(=O)-, -N(R12a)- or-CH(R12b)-;

R12achoose from a range of: hydrogen, C1-4alkyl, -C(=O)R15-C(O)2R15and-S(O)2(C1-4alkyl);

R12bchoose from a number hydrogen, C1-4alkyl, -OR15, -C(=O)R15-C(O)2R15and-S(O)2(C1-4alkyl);

R14choose from a range: From1-4alkyl, oxo (=O)- OR15, -C(=O)Rsup> 15, -C(O)2R15and-S(O)2(C1-4alkyl), and R15in each case, independently selected from each other R15chosen from a number of hydrogen and C1-4alkyl;

q is 0 or 1, and

r is 0, 1 or 2, or

(XVII) to the compound (XVI), where X represents-N(R12a)-, a R12ameans-S(O)2(C1-4alkyl).

Another object of the present invention relates to a pharmaceutical composition comprising a compound of formula I and pharmaceutically acceptable carrier, diluent or excipient.

The compounds of formula I and their aforementioned salts are inhibitors of protein kinases and exhibit high activity against kinase R in vivo. These compounds also exhibit selectivity for kinase R compared with cyclin-dependent kinases and tyrosine kinases. Therefore, the compounds of the present invention can be used for the treatment of diseases mediated by proinflammatory cytokines, such as TNF and IL-1. Thus, another object of the present invention is a method of treatment mediated by kinase R diseases or conditions, which consists of introducing a therapeutically effective amount of the compounds of formula I to a patient in need of such treatment.

Unless otherwise stated, the following terms, used in this context are the trail of the existing values.

The term "acyl" means a radical -(C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl, and alkyl, cycloalkyl, cycloalkenyl and phenylalkyl defined in this context. Typical examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylcarbonyl, benzoyl, benzylcarbamoyl etc. or specific meaning of the term.

The term "acylamino" means a radical-NR'r C(O)R, where R' denotes hydrogen or alkyl, and R means hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl, and values of the groups alkyl, cycloalkyl, cycloalkenyl and phenylalkyl defined above. Typical examples include, without limitation, formylamino, acetylamino, cyclohexylcarbodiimide, cyclohexyldimethylamine, benzoylamine, benzylmorphine etc. or specific meaning of the term.

The term "alkenyl" means a linear monovalent, hydrocarbon radical containing from two to six carbon atoms, or branched, monovalent, hydrocarbon radical containing from three to six carbon atoms and containing at least one double bond, for example ethynyl, propenyl etc. or specific meaning of the term.

Thus, if the group-CH2-R means alkanniny glad the feces, defined above, and this group includes, without limitation, groups such as (-CH2-CH=CH2), (-CH2-CH=CH-CH3), etc. or specific meaning of the term.

The term "alkoxy" means a radical-OR where R is alkyl, as defined in this context, for example methoxy, ethoxy, propoxy, butoxy etc. or specific meaning of the term.

The term "alkyl" means a linear, saturated, monovalent, hydrocarbon radical containing from one to eight carbon atoms, or branched, saturated, monovalent, hydrocarbon radical containing from three to eight carbon atoms, for example methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl etc., or stated otherwise, the meaning of the term. Alkyl preferably denotes a linear alkyl group containing from one to six carbon atoms, or a branched alkyl group containing from three to six carbon atoms, more preferably a linear alkyl group containing from one to four carbon atoms or branched alkyl group containing three to four carbon atoms.

The term "alkylene" means a linear saturated divalent hydrocarbon radical containing from one to six carbon atoms, or branched, saturated, divalent, coal is Ogorodny radical, containing three to six carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropene, butylene, pentile etc. or specific meaning of the term.

The term "alkylthio" means a radical-SR where R is a higher alkyl, such as methylthio, ethylthio, propylthio, butylthio etc. or specific meaning of the term.

The term "aryl" means a monovalent, monocyclic or bicyclic, aromatic, hydrocarbon radical, which is optionally and independently substituted by one or more substituents, preferably one, two or three substituents, which are preferably chosen from the group comprising alkyl, hydroxy, alkoxy, halogenated, halogenoalkane, alkylthio, alkylsulfonyl, alkylsulfonyl, - SO2NR'r R" (where R' and R" independently denote hydrogen or alkyl), Y-C(O)-R (where Y is absent or means alkylenes group, and R means hydrogen, alkyl, halogenated, halogenoalkane, hydroxy, alkoxy, amino, monoalkylamines or dialkylamino), heteroalkyl, heteroalkyl, heteroalkyl, halogen, nitro, cyano, amino, monoalkylamines, dialkylamines, alkylsulfonyl, geteroarilsulfoksidu, sulfonamide, methylendioxy, Ethylenedioxy, heterocyclyl and/or geterotsiklicheskikh. In more detail, the term "aryl" includes, without limitation, f the Nile, chlorophenyl, methoxyphenyl, 2-forfinal, 2,4-differenl, 1-naphthyl, 2-naphthyl and derivatives thereof or specific meaning of the term.

The term "aryloxy" means a radical-OR where R means the above-defined aryl, for example, phenoxy, or specify a specific value of the term.

The term "aryloxyalkyl" means the radical R-C(O=)-, where R is aryloxy, such as phenoxycarbonyl, or specify a specific value of the term.

The term "cycloalkyl" means saturated, monovalent, cyclic, hydrocarbon radical containing from three to seven carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl etc. or specific meaning of the term.

The term "cycloalkenyl" means a radical-RaRbwhere Rameans alkylen, a Rbmeans cycloalkyl defined above, such as cyclohexylmethyl etc. or specific meaning of the term.

The term "substituted cycloalkyl" means cycloalkyl radical defined above and containing one, two or three (preferably one) of the atom in the cycle in which the hydrogen atom is independently replaced by a cyano group or a-Y-C(O)R (where Y is absent or means alkylene, and R means hydrogen, alkyl, halogenated, hydroxy, alkoxy, amino, monoalkylamines, dialkylamino or optionally substituted phenyl), or stated otherwise C is Uchenie term.

The term "dialkylamino" means a radical-NRR'where R and R' independently denote alkyl, hydroxyalkyl, cycloalkyl or cycloalkenyl, as defined above. Typical examples include, without limitation, dimethylamino, methylethylamine, di(1-methylethyl)amino, (methyl)(hydroxymethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino, etc. or specific meaning of the term.

The term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

The term "halogenated" means alkyl substituted by one or more identical or different halogen atoms, such as-CH2Cl-CF3, -CH2CF3, -CH2CCl3, etc. or specific meaning of the term.

The term "heteroalkyl" means an alkyl radical, as defined above, in which one, two or three hydrogen atoms replaced by the Deputy, which is independently chosen from the group comprising-ORa, -N(O)mRbRc(where m is 0 or 1) and-S(O)nRd(where n is an integer from 0 to 2), and it is clear that heteroalkyl radical attached via a carbon atom, and Rameans hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently on the UGA mean hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl, cycloalkenyl, alkylsulfonyl, aminosulfonyl, mono - or dialkylaminoalkyl, aminoalkyl, mono - or dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkylated or alkoxycarbonyl, but provided that when m is 1, Rband Rcboth independently chosen from the group comprising alkyl, cycloalkyl and cycloalkenyl, and if n is 0, Rdmeans hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl, and if n is 1 or 2, Rdmeans alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl, amino, acylamino, monoalkylamines or dialkylamino. Heteroalkyl preferably means an alkyl, as defined above and substituted by the group-ORaand Rameans alkyl. Typical examples include, without limitation, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol etc. or specific meaning of the term.

The term "geterofullereny" means the group R a-C(=O)-, where Rameans heteroalkyl group. Typical examples include acetylsalicyloyl, aminomethylpropanol, 4 atomic charges-2,2-dimethylbutan-2-oil, 2-amino-4-methylpentan-2 oil, etc. or specific meaning of the term.

The term "heteroalkyl" means the group Ra-O-, where Rameans heteroalkyl group. Typical examples include (IU-C(=O)-O-CH2-O -, etc. or specific meaning of the term.

The term "heteroalicyclic" means the group Ra-C(=O), where Rameans heteroantiserum. Typical examples include 1-acetylcholinesterase (IU-C(=O)-O-CH2-O-C(=O) -), etc. or specific meaning of the term.

The term "heteroaryl" means a monovalent, monocyclic or bicyclic radical, containing from 5 to 12 atoms in the cycle, and at least one aromatic ring containing one, two or three heteroatoms in the cycle selected from N, O or S and the remaining atoms are carbon atoms, and obviously heteroaryl radical attached via the aromatic ring. Heteroaryl ring is optionally and independently substituted by one or more substituents, preferably one or two substituents selected from the series alkyl, halogenated, heteroalkyl, hydroxy, alkoxy, halogen, nitro or cyano. In more detail, the term shall heteroaryl includes, not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrofuranyl, isobenzofuranyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, tetrahydroquinoline, ethanolic, benzimidazolyl, benzisoxazole or sensational, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl etc. or specific meaning of the term.

The term "heteroalkyl" means a radical-RaRbwhere Rameans alkylen, a Rbmeans heteroaryl, as defined above, for example pyridine-3-ylmethyl, imidazolylalkyl, pyridinylmethyl, 3-(benzofuran-2-yl)propyl, etc. or specific meaning of the term.

The term "heterooligomeric cycloalkyl" means cycloalkyl radical, as defined above, with one, two or three hydrogen atoms in cycloalkyl radical is replaced by heteroalkyl group, it is obvious that heteroalkyl radical attached to cycloalkenes the radical through a carbon-carbon bond. Typical examples include, without limitation, 1-hydroxymethylglutaryl, 2-hydroxymethylcellulose etc. or specific meaning of the term.

The term "heterothermy cycloalkyl" means cycloalkyl R is dical, as defined above, with one, two or three hydrogen atoms in cycloalkyl radical is replaced by the Deputy, is independently selected from the group comprising hydroxy, alkoxy, amino, acylamino, monoalkylamines, dialkylamino, oxo (=O), imino, hydroxyimino (=NOH), NR'r SO2Rd(where R' denotes hydrogen or alkyl, and Rdmeans alkyl, cycloalkyl, hydroxyalkyl, amino, monoalkylamines or dialkylamino), -X-Y-C(O)R (where X is O or NR', Y means alkylen or absent, R is hydrogen, alkyl, halogenated, alkoxy, amino, monoalkylamines, dialkylamino or optionally substituted phenyl, R' is H or alkyl), or-S(O)nR (where n is an integer from 0 to 2), for example, if n is 0, R is hydrogen, alkyl, cycloalkyl, optionally substituted phenyl or thienyl, and if n is 1 or 2, R denotes alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl, thienyl, amino, acylamino, monoalkylamines or dialkylamino. Typical examples include, without limitation, 2-, 3 - or 4-hydroxycyclohexyl, 2-, 3 - or 4-aminocyclohexanol, 2-, 3 - or 4-methanesulfonylaminoethyl and the like, preferably 4-hydroxycyclohexyl, 3,5-dihydroxytoluene, 2-aminocyclohexanol or 4-methanesulfonylaminoethyl or specific meaning of the term.

The term "heterothermy cycloalkenyl" means the AET radical R aRb-where Rameans heterothermy cycloalkenyl radical, and Rbmeans alkilinity radical or specific meaning of the term.

The term "heterocyclimamines" means saturated, monovalent cyclic group containing 4 to 8 atoms in the cycle, and the cycle contains one N atom and the remaining atoms in the cycle are carbon atoms. Typical examples include piperidine and pyrrolidine or specific meaning of the term.

The term "heterocyclyl" means saturated or unsaturated, nonaromatic, cyclic radical containing from 3 to 8 atoms in the cycle, preferably 6 atoms in the cycle, one or two, preferably one atom in the cycle is a heteroatom selected from N, O or S(O)n(where n is an integer from 0 to 2), preferably N or O, and the remaining atoms in the cycle are carbon atoms and one or two carbon atom optionally replaced by a carbonyl group. Heterocyclyl ring is optionally and independently substituted one, two or three, preferably one Deputy, selected from the series alkyl, halogenated, heteroalkyl, halogen, nitro, cyano, cianelli, hydroxy, alkoxy, amino, monoalkylamines, dialkylamines, aralkyl, -(X)n-C(O)R (where X is O or NR', n is 0 or 1, R is hydrogen, alkyl, halogenated, hydrox is (if n = 0), alkoxy, amino, monoalkylamines, dialkylamino or optionally substituted phenyl, and R' denotes hydrogen or alkyl), -alkylene-C(O)Ra(where Rameans alkyl, or or NR'r R", and R means hydrogen, alkyl or halogenated, and R' and R" independently denote hydrogen or alkyl), or-S(O)nR (where n is an integer from 0 to 2), for example, if n is 0, R is hydrogen, alkyl, cycloalkyl or cycloalkenyl, and if n is 1 or 2, R denotes alkyl, cycloalkyl, cycloalkenyl, amino, acylamino, monoalkylamines, dialkylamines or heteroalkyl, preferably alkylsulfate or alkoxycarbonyl. More preferably, the term "heterocyclyl" includes, without limitation peressini, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, 2-oxopiperidine, piperazine derivatives, N-methylpyrrolidine-3-yl, 3-pyrrolidino, morpholino, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, 4-(1,1-dioxotetrahydrofuran-2H-dipiradol), pyrrolidyl, imidazolyl, N-methanesulfonamido-4-yl, and their derivatives, or specify a specific value of the term.

The term "geterotsiklicheskikh" means a radical-RaRbwhere Rameans alkylenes group, a Rbmeans heterocyclyl group, as defined above, for example tetrahydropyran-2-ylmethyl, 2 - or 3-piperidinylmethyl, 1,3-(4-methylpiperazin-1-yl)propyl and the like or specified concrete is th meaning of the term.

The term "hydroxyalkyl" means an alkyl radical, as defined above, substituted by one or more, preferably one, two or three hydroxy groups, provided that one and the same carbon atom contains no more than one hydroxy-group. Typical examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 1,5-dihydroxyphenyl-3-yl and 2-(hydroxymethyl-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydromethyl)-2-hydroxyethyl. In this regard, the term "hydroxyalkyl" used in this context to determine the family heteroalkyl groups or specific meaning of the term.

The term "leaving group" has the ordinary meaning known in the field of organic synthesis, i.e. means an atom or group which is substituted by a nucleophile and includes halogen (such as chlorine, bromine or iodine), alkanesulfonyl, arenesulfonyl, alkylcarboxylic (for example, acetoxy), arylcarboxylic, mesilate, tosyloxy, tripterocalyx, aryloxy (for example, 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamine etc. or specific value is their term.

The term "monoalkylamines" means the radical other, where R is alkyl, hydroxyalkyl, cycloalkyl or cycloalkenyl, as defined above, for example, methylamino, (1-methylethyl)amino, hydroxymethylamino, cyclohexylamino, cyclohexylethylamine, cyclohexylethylamine etc. or specific meaning of the term.

The term "optionally substituted phenyl" means a phenyl ring which is optionally and independently substituted by one or more substituents, preferably one or two substituents selected from the group comprising alkyl, hydroxy, alkoxy, halogenated, halogenoalkane, heteroalkyl, halogen, nitro, cyano, amino, methylenedioxy, Ethylenedioxy and acyl or specific meaning of the term.

The term "pharmaceutically acceptable excipient" means excipient, which is used to produce pharmaceutical compositions and which basically is a safe, non-toxic and has no negative effects in biological or otherwise. This excipient includes acceptable excipients for use in veterinary medicine and in the pharmaceutical industry. "Pharmaceutically acceptable excipient"used in this context and claims includes both one, more than one of such excipients.

The term "pharmaceutically acceptable salt" of the compound of oznachaet the salt, which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include : (1) acid additive salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova kislota etc., or (2) salts obtained when replacing the acid proton contained in the initial connection, metal ion, such as alkali metal ion, alkali earth metal ion or aluminum ion, or in the formation of coordination bonds with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like, the Term "prodrug"as used in this context, refers to any compound, which is released in vivo active source drug formula I, with the introduction of such prodrug to the mammal. Prodrugs of the compounds of formula I obtained by modification of one or more functional groups present in the compound of formula I, with a modified (modified) group (group) rassheplenia in vivo to release the parent compound. Prodrugs include compounds of formula I in which the group hydroxy, amino, sulfgidrilnami or carbonyl (consisting of the compounds of formula (I) associated with any group that is cleaved in vivo by the formation of free hydroxy, amino or sulfhydril respectively. Examples of prodrugs include, without limitation, esters (e.g. acetate derivatives, dialkylaminomethyl, formate, phosphate, sulphate and benzoate) and carbamates (for example, N,N-dimethylamino bonyl) hydroxyl functional groups, ester groups (ethyl esters, morpholinoethyl esters) carboxyl functional groups, N-ACI-derivatives (e.g. N-acetyl) N-grounds manniche, Schiff bases and enaminones amidofunctional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of formula I and the like, see Bundegaard, H. "Design of Prodrugs" cc 1-92, Elesevier, New York-Oxford (1985).

The term "protective group" refers to a group of atoms, which are attached to the reactive group and thus mask, reduce its reactivity or block it. Examples of protective groups described in the books T.W.Green and P.G.Futs, Protective Groups in Organic Chemistry, (Wiley, 2nded. 1991) and Harrison and Harrison and others, Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996). Typical examples of protective groups include formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), trityl and substituted triteleia group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NVOC), etc. are Typical examples of protective groups for the hydroxyl group include derivatives in which a hydroxyl group allerban or alkylated with education, for example, benzyl and trailovic ethers, and alilovic esters, tetrahydropyranyl ether is, trialkylsilyl ethers and allyl ethers.

The term "treatment" of a disease includes (1) preventing the disease, i.e. preventing the development of clinical symptoms of the disease in a mammal, which undergoes disease or predisposed to it, but the symptoms have not seen or do not occur; (2) suppression of the disease, that is, suspending or reducing the development of the disease or its clinical symptoms; (3) the decrease in the intensity of the disease, so there is regression of the disease or its clinical symptoms.

"Therapeutically effective amount" means an amount of compound that when administered to a mammal for treatment, is sufficient to achieve therapeutic action. A therapeutically effective amount varies depending on the compound, the disease and its severity, and the age, body weight, etc. of a mammal in need of treatment.

The object of the present invention is a compound of formula I

where R1, R2Z and X1have the values specified above.

Z preferably denotes n

X1preferably means O, S, or C=O, more preferably O.

R1preferably denotes alkyl, more preferably R1means e is Il.

R2preferably means alkyl, aryl, cycloalkyl or heteroalkyl, more preferably methyl or hydroxyalkyl.

R3preferably means cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh.

R3more preferably means cycloalkyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl or heterocyclic. If R3means heteroalkyl, especially preferred examples include hydroxyalkyl and/or alkoxyalkyl, for example (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl and 3-methoxy-1-(2-methoxyethyl)propyl. First of all preferred examples of (R3means heterocyclyl) include tetrahydro-2H-Piran-4-yl, 1-(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl and morpholinyl. Another object of the present invention preferably includes the above-described compounds of formula (I) according to the present invention, in which R3choose from a range of: 4-hydroxycyclohexyl, tetrahydro-2H-Piran-4-yl, 1-(methylsulphonyl)piperidine-4-yl, cyclopentyl, (S)-(2-hydroxy-1,2-dim is Teal)propyl, 2.2-diatexites, 2,2-dimethoxymethyl, 3 hydroxypyridine-2-yl, (S)-(1-hydroxymethyl-2-methyl)propyl, 4-(2-(N,N-diethylamino)ethoxy)phenyl, benzyl, phenyl, butyl, dodecyl, 2-hydroxyethyl, 3-methylbutyl, 2-methylpropyl, (2-hydroxy-1,1-dimethyl)ethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, hexyl, pyridine-2-yl, 2-morpholinoethyl, 2-(piperidine-1-yl)ethyl cyclohexylmethyl, 1-(hydroxymethyl)butyl, 4-forfinal, cyclopropylmethyl, 2-methoxyethyl, 3-(N,N-dimethylamino)propyl, isopropyl, methyl, 3-furylmethyl, 1 oxalacetate-2H-thiopyran-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl, 1-phenylpropyl, phenethyl, 4-(2-hydroxyethyl)phenyl, 3-(4-methylpiperazin-1-yl)propyl, 4-hydroxybutyl, 3-morpholinopropan, 3-(2-pyrrolidino-1-yl)propyl, 2-acetamidophenyl, 2-(pyridin-2-yl)ethyl, pentyl, 2-(N,N-dimethylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, ethyl, 5-methylpyridin-2-yl, propyl, methyl, cyclopropyl, (1-hydroxymethyl-3-methylthio)propyl, (1-hydroxymethyl)cyclopentyl, 1,1-dimethylpropyl, 3 ethoxy-3-oxopropyl, 3-methoxypropyl, cyclobutyl, 1-(accoutability)piperidine-4-yl, 4-methoxycyclohexyl, 3,5-dihydroxytoluene, 2-cyclohexylethyl, (2-methylthiazole-5-yl)methyl, imidazo[2,1-b]thiazole-6-ylmethyl, 4-phenylbutyl, 2-(4-AMINOPHENYL)ethyl, pyridin-3-yl, tetrahydro-2H-thiopyran-4-yl, and (1-hydroxymethyl)butyl.

Another group of preferred compounds includes compounds of formula (I")

where R1means alkyl, more preferably ethyl; R2choose from a range of: hydrogen, alkyl, aryl, cycloalkyl and heteroaryl (more preferably methyl or hydroxyalkyl), and R3means heteroalkyl or heterocyclyl. Even more preferred compounds of formula (I), the values of which are defined above, where R1and R2choose from the group of substituents defined above, and R3choose from the range: (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl, 3-methoxy-1-(2-methoxyethyl)propyl, tetrahydro-2H-Piran-4-Il, 1-(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl and morpholinyl. The most preferred compounds, in which R1means ethyl, R2means methyl and R3mean (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl, 3-methoxy-1-(2-methoxyethyl)propyl, tetrahydro-2H-Piran-4-yl, 1-(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-Tician-4-yl and morpholinyl.

Another group of preferred compounds in which incorporates both the compounds of formula

where R1and R2have the meanings given above,

X represents-O-, -S(=O)-, -N(R12a)- or-CH(R12b)-;

R12achoose from a range of: hydrogen, C1-4alkyl, -C(=O)R15, -C(O)2R15and-S(O)2(C1-4alkyl);

R12bchoose from a range of: hydrogen, C1-4alkyl, -OR15, -C(=O)R15-C(O)2R15and-S(O)2(C1-4alkyl);

R14choose from a range: From1-4alkyl, oxo (=O)- OR15, -C(=O)R15, -C(O)2R15and-S(O)2(C1-4alkyl);

R15in each case, independently of one another selected from the series of: hydrogen, C1-4alkyl;

q is 0 or 1, r is 0, 1 or 2.

In this group of preferred compounds, the most preferred compounds, in which the

X represents-N(R12a- and

R12ameans-S(O)2(C1-4alkyl).

Compounds of the present invention can exist as in resolutional, and solvated forms, including hydrated forms. In the General case, the solvated forms, including hydrated forms, are equivalent nonsolvated forms and it is assumed that they are included in the scope of the present invention. Along with the compounds described above, compounds of the present invention includes all tautomeric forms. In addition, this image is the buy also includes all pharmaceutically acceptable salts of these compounds, including proletarienne form connections and all stereoisomers, in the form of optically pure compounds, mixtures of racemates or mixtures of other elements.

In addition, the compounds of formula I can form pharmaceutically acceptable acid salt additive. All these forms are included in the scope of the present invention.

Pharmaceutically acceptable acid additive salts of compounds of formula I include salts of inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, Hydrobromic, itestosterone, phosphoric acid, etc. and organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid, arcangioli acids, aromatic acids, aliphatic and aromatic sulfonic acid and the like Acid additive salts respectively include sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, nitrates, phosphates, hydrogen phosphates, dihydrophosphate, metaphosphates, pyrophosphates, chlorides, bromides, the iodides, acetates, propionate, caprylate, isobutyrate, oxalates, malonate, succinate, suberate, Sabatini, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalates, bansilalpet, toluensulfonate, phenylacetate, citrates, lactates, maleate, tartratami, methansulfonate etc. In the scope of what bretania also included are salts of amino acids, for example, arginate etc., gluconate and galacturonase (see, for example, Berge S.., and others, "Pharmaceutical Salts," J. of Pharmaceutical Science, 66, 1-19, (1977)).

Acid additive salts of the basic compounds can be obtained by the known methods in the interaction of the compounds in the form of free bases with a sufficient amount of the desired acid. Connections in the form of free bases can be obtained by the known methods in the interaction of the corresponding salt with a base, followed by separation of the free base. Connections in the form of free bases differ from their respective salt in certain physical properties, such as solubility in polar solvents, but otherwise the salts of the present invention is equivalent to the corresponding free base forms.

It should be assumed that along with the preferred variant of the invention, specified in the bid, other variants of the invention. In the present description are not described all possible equivalent options or other modifications of the present invention. It is assumed that the terms used in the description of the application, are used mainly to illustrate the invention and do not limit its scope, and possible options do not limit the nature and scope of the present invention.

In the description of techniques, methods and examples, the following abbreviations are used:

EtOH means ethanol;

Meon means methanol;

EDC means dichloroethane;

DHM means dichloromethane;

EtOAc means ethyl acetate;

THF means tetrahydrofuran;

tPLmeans melting point.

Compounds of the present invention receive a variety of ways. The first object of the present invention in schemes 1 and 4 and below is the method of obtaining compounds of formula I'where Z signifies N. a Method of obtaining compounds of formula I, where R2means an amino group, presented in figure 2. Methods for obtaining compounds of formula I, where Z denotes CH, presented on figures 3 and 3A.

It should be understood that, although the diagrams show the sequence of reactions for specific compounds, the methodology presented in this invention can be used to obtain other compounds similar to the compounds of formula I which is obtained using standard methods of protection of reactive groups and the removal of the protective groups known in the field of organic chemistry. For example, to prevent the passage of undesirable side reactions at the hydroxyl group is in the process of modification of various fragments of molecules, compounds with a hydroxyl group of pre-converted into simple or complex esters. After removal of the protective group again which are square-compound with a free hydroxyl group. Similarly, you can find the derivatives of the amino groups and carboxyl groups in order to avoid undesirable side reactions. Typical protective groups and methods for their introduction and removal are described in detail in the above monographs T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons, New York (1999), and Harrison and Harrison and others, Compendium of Synthetic Organic Methods, TT-8 (John Wiley and Sons, 1971-1996).

Scheme 1

The compound of formula Ia is treated with a primary amine (R2-NH2), you get a compound of formula Ib. The reaction is carried out in a solvent inert under the reaction conditions, preferably using halogenated aliphatic hydrocarbon series, especially DHM, optionally halogenated aromatic hydrocarbon, acyclic or cyclic ether, for example THF, formamide or low-molecular alkanol. The reaction is carried out at a temperature of from about -20°C to about 120°C.

The alcohol of formula Ic is obtained by reduction of compound of formula Ib. The reaction of recovery performed by standard methods known to the person skilled in the art, using sociallyengaged (for example, in an inert under the reaction conditions the recovery of the solvent, preferably in an acyclic or cyclic ether, most preferably using THF, re is the Ktsia conducted at a temperature of from about -20° With up to about 70°C, preferably at temperatures from approximately 0°C to about room temperature).

Carboxaldehyde formula Id is obtained by oxidation of the alcohol of formula Ic. The oxidation reaction is carried out by a standard method using manganese dioxide, however, you can use many other methods (e.g., as described in Advanced Organic Chemistry, 4thed., March, John Wiley & Sons, New York (1992)). Depending on the nature of the oxidizing agent the reaction is carried out in a solvent inert under certain conditions, oxidation, preferably using halogenated aliphatic hydrocarbons, primarily DHM or optionally halogenated aromatic hydrocarbons. The oxidation reaction is carried out at a temperature of approximately 0°With up to about 60°C.

In the interaction of carboxaldehyde formula Id with ether R1-X1CH2-CO2R' (where R' represents an alkyl group, and R1and X1have the values specified above), in the presence of a base to receive the connection formula Ie. You can use any relatively non-nucleophilic base, including carbonates, for example potassium carbonate, lithium carbonate and sodium carbonate; bicarbonates such as potassium bicarbonate, lithium bicarbonate and sodium bicarbonate; tert-piperonyl potassium, hexamethyldisilazane n is sodium, hexamethyldisilazane potassium, hexamethyldisilazane lithium, LDA, sodium hydride or amines, such as secondary and tertiary amines, and amino compounds resins, for example, 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine. The reaction is carried out in a relatively polar solvent, inert under the reaction conditions, preferably using amide, such as dimethylformamide, N-substituted, pyrrolidine, most preferably using 1-methyl-2-pyrrolidinone, at a temperature of from about 25°With up to approximately 150°C.

The oxidation of compounds of formula Ie oxidant, such as percolate, such as 3-chloroperbenzoic acid (MSRA) or reagent Oxone®get sulfon (If), which in turn various end connections. Oxidation of compounds of formula Ie is carried out in a solvent inert to specific reaction conditions of the oxidation. For example, when using as the oxidant MSRWA reaction is preferably carried out in a halogenated aliphatic hydrocarbon, most preferably in chloroform. If the oxidant used reagent Oxone®then the solvent is preferably used Meon, aqueous ethanol or aqueous THF solution. The reaction temperature depends on the used solvent. In the case of using an organic solvent reaction in the foundations of the om is carried out at a temperature of from about -20° With up to approximately 50°C, preferably at temperatures from approximately 0°C to about room temperature. If the solvent used water, the reaction is carried out generally at a temperature of approximately 0°50°C, preferably at temperatures from approximately 0°C to about room temperature. In another embodiment, the oxidation is carried out in the presence of a catalyst system rhenium/reagent peroxide-based (e.g., as described in "Oxidation of Sulfoxides by Hydrogen Peroxide, Catalyzed by Methyltrioxorhenium (VII)", Lahti, David W., James Espenson H, Inorg. Chem. 39(10), c. 2164-2167 (2000); "Rhenium oxo complexes in catalytic oxidations, Catal. Today 55(4), c. 317-363 (2000) and "A Simple and Efficient Method for the Preparation of Pyridine N-Oxides", Christophe Coperet, Hans Adolfsson, Khuong Tinh-Alfredo V., Yudin Andrei K., Sharpless, K. Barry, J. Org. Chem. 63(5), c. 1740-1741 (1998)).

The compound of formula If is treated with amine (R3-NH2), thus obtain the compounds of formula I'. The reaction is carried out in the presence or in the absence of a solvent at a temperature of from about 0°C to about 200°S, most preferably from about room temperature to about 150°C. In some cases, the compounds of formula I' preferably receive the reaction of the amine (R3-NH2directly with the sulfide of formula Ie or the corresponding sulfoxide, and not by the reaction with sulfona If.

Thus, the present invention proposes a method of producing compounds of the formula I by a sequence of reactions involving the interaction of connection to the basic formula Ie, If, or the corresponding sulfoxide with an amine (R3-NH2and optional reaction of the resulting product with the compound of the formula R2-L, where R2means alkyl, a L is a leaving group.

Scheme 2

The compounds of formula I, where R2means amino, monoalkylamines, dialkylamines or NR22-Y-R23get the sequence of reactions represented in scheme 2, when the aminating the corresponding 2-alkylthio-8-amino[2,3-d]pyridopyrimidines-7(8H)-it (IV, Z denotes N or 7 alkylthio-1-amino-1,6-naphthiridine-2-it (IV, Z denotes CH) in the presence of ortho-diphenylethylenediamine (method, for example, described in the article E.W. Colvin, G.W. Kirby, A.C. Wilson, Tetrahedron Lett. 23, 3835 (1982) and Klottzer W., Stadlwieser J., Raneburger J. Org. Synth. 64 c. 96-103 (1986)). Then in the resulting amino introduce substituents in various ways. Mono - and dialkylamino derivatives receive sequential reductive alkylation of amines using substituted aldehydes. In another embodiment, the amine acelerou halogenation, halogenfree or halogenecarbonate acids. Amines also sulfonylureas using the sulfanilamide. As a result, when replacing sulfide (or the corresponding sulfoxide or sulfone) Amin R3-NH2as described previously, the compounds of formula Ie (scheme 1)are the compounds of formula I (compounds of formula I, where Z denotes CH, a, R2means NA).

Scheme 3

Ethyl ester of 2,4-dichloropyridine-5-carboxylic acid is treated with the amine R2-NH2while getting an ester of formula 3g. The reaction is carried out in a solvent inert under the reaction conditions, preferably in acetonitrile or not halogenated aromatic hydrocarbon, acyclic or cyclic ether, such as THF, formamide or low molecular weight alkanol. The reaction is carried out at a temperature of from about -20°C to about 120°C.

When restoring the compounds of formula 3g receive the corresponding alcohol. The reduction is carried out with the use of sociallyengaged by standard methods known to the person skilled in the art (for example, in a solvent, inert under the reaction conditions recovery, preferably in an acyclic or cyclic ether, most preferably in THF. The reaction is carried out at a temperature of from about -20°With up to about 70°C, preferably at temperatures from approximately 0°to arr is siteline room temperature).

The oxidation of the resulting alcohol get carboxaldehyde formula 3h. The oxidation reaction is carried out by a standard method using manganese dioxide, however, you can use many other methods (e.g., as described in Advanced Organic Chemistry, 4thed., March, John Wiley & Sons, New York (1992)). Depending on the nature of the oxidant, the reaction is carried out in a solvent inert under certain conditions, oxidation, preferably use a halogenated aliphatic hydrocarbon, especially DHM or optionally halogenated aromatic hydrocarbon. Accordingly, the oxidation reaction is carried out at a temperature of approximately 0°With up to about 60°C.

In the interaction of carboxaldehyde formula 3h with ether R1-X1CH2-CO2R' (where R' represents an alkyl group, and R1and X1have the values specified above) in the presence of a base, to obtain the compound of formula 3i. You can use any relatively non-nucleophilic base, including carbonates, for example potassium carbonate, lithium carbonate and sodium carbonate; bicarbonates such as potassium bicarbonate, lithium bicarbonate and sodium bicarbonate; tert-piperonyl potassium, hexamethyldisilazane sodium, hexamethyldisilazane potassium, hexamethyldisilazane lithium, LDA, sodium hydride or amines, for example secondary and t is lichnye amines, and resins containing amino groups, for example, 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine. Accordingly, the reaction is carried out in a relatively polar solvent, inert under the reaction conditions, preferably using amides, such as dimethylformamide, N-substituted, pyrrolidine, most preferably using 1-methyl-2-pyrrolidinone, at a temperature of from about 25°With up to approximately 150°C.

When replacing chloride by Amin R3-NH2as described previously (scheme 1), for the compounds of formula Ie (preferably at a temperature of from 150 to 160° (C)obtain the compounds of formula I (compounds of formula I, where Z denotes CH).

Scheme 3A

4-Amino-3,6-dibromopyridine (obtained as described in article Den Hertog and others, Rec. Trav. Chim. Pays-Bas, 64. 85-100 (1945)) is treated with mertiolate sodium, you get a 4-amino-3-bromo-6-methylthiopyridine (for example, see Windscheif P, F. Voegtle, Synthesis. 87092 (1994), stage a). The compound of formula 3b is obtained by attaching methylthiopyridine by the condensation reaction of Hake to the vinyl ether of the formula in the presence of palladium catalyst (e.g. palladium acetate) and base (such as potassium acetate or tributylamine) (for example, as described in Y. Dong, Busacca S.A., J. Org. Chem., 62, 6464-65 (1997)). When cyclization in an alkaline environment receive 1,6-naphthyridin formula 3C. When alquiler the processes in the compounds of formula 3 haloalkyl (or any other alkylating agent of formula R 3-X, where X represents a leaving group) receive 1-alkyl derivatives of naphthyridine formula 3d. After oxidation of the compounds of formula 3d and replacement sulfone on Amin R3-NH2as described previously, the compounds of formula Ie (scheme 1) obtain the compounds of formula I (compounds of formula I, where Z denotes CH). Another sequence of reactions presented in scheme 3A.

Scheme 4

The compounds of formula (4d) interact with teleconsultation in an appropriate solvent, such as toluene, in the presence of tert-butoxide potassium, thus receive the compounds of formula (4h). Connection (4h) is transformed into the corresponding sulfonylmethane (4i) in collaboration with the oxidizer or percolate, such as chloroperbenzoic acid, in a solvent such as DHM. Compound (4i) is transformed into the compounds of formula (I") in collaboration with the desired amine R3-NH2in a solvent such as EDC.

Specialist in the art it is evident that there may be some modifications of the above described circuits without going beyond the scope of the present invention. For example, in some stages, you can use protective groups for functional groups that exhibit reactivity in a particular reaction conditions.

Such methods are also included in this volume is the first invention.

The compounds of formula I and pharmaceutically acceptable salts of basic compounds of formula I and acid can be used as medicines, for example, in the form of pharmaceutical preparations. Pharmaceuticals administered enteral way, for example, orally in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, nazalnam way, for example, in the form of nasal sprays, or rectal means, for example, in the form of suppositories. However, these medicines can be entered parenteral way, for example, in the form of injection solutions.

The compounds of formula I and their aforementioned pharmaceutically acceptable salts can be processed in a mixture with pharmaceutically inert, organic or inorganic carriers to obtain pharmaceuticals. As such carriers to obtain tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like are Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; however, depending on the nature of the active ingredient in the case of soft desire is inovah capsules usually carriers are not required. As suitable carriers for obtaining solutions and syrups are used, for example, water, polyols, saccharose, invert sugar, glucose, etc. as suitable carriers for suppositories using, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like

The pharmaceutical preparations can also contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffer substances, masking agents or antioxidants. They may also contain therapeutically valuable substances, which differ from the compounds of formula I and their pharmaceutically acceptable salts, of the above.

The aim of the present invention are also medicinal product containing a compound of formula I or pharmaceutically acceptable salt of the compound of formula I and the acid in the mixture with a compatible pharmaceutical carrier, and a method of obtaining such medicines, which includes processing one or more of such compounds or salts, and optionally in a mixture with one or more therapeutically valuable compounds in a mixture with a compatible pharmaceutical carrier in herbal medicinal form.

As indicated above, the compounds of formula I and their specified in the above pharmaceutically acceptable salts can be used according to the invention as therapeutically active substances, primarily as anti-inflammatory agents, or for the prevention of rejection of grafts after transplantation of the organ. The amount of dosages vary over a wide range depending on the specific circumstances in each particular case. Mainly with the introduction of adult patients standard daily dose of from approximately 0.1 mg/kg to about 100 mg/kg, preferably from about 0.5 mg/kg to about 5 mg/kg the Daily dose administered as a single dose or divided doses and, in addition, the upper limit can be exceeded in the case of specific indications.

Finally, the task of the invention was the use of compounds of the formula I and their aforementioned pharmaceutically acceptable salts to obtain drugs primarily for the treatment or prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological or cardiovascular disorders, for the treatment of asthma, CNS disorders or complications of the diabetes or to prevent rejection of grafts after surgical transplant.

The compounds of formula I can be used, without limitation, for the treatment of any disorders or diseases in human or other mammal, which is a complication of the disease or illness you the Vano excessive or unregulated production of TNF or kinase R. In this regard, the present invention features a method of treating diseases mediated by cytokines, including the introduction of an effective amount of the compounds of formula I sufficient to suppress the production of cytokines, or its pharmaceutically acceptable salt or tautomer.

The compounds of formula I can be applied, without limitation, for the treatment of inflammation in a subject and used as a febrifuge in the treatment of fever. Compounds of the present invention can be used for treatment, without limitation, the following diseases: rheumatoid arthritis, spondyloarthropathy (e.g., ankylosing spondylitis), gouty arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis and other arthritic condition. Such compounds can be used for the treatment of lung disease or pneumonia, including respiratory distress syndrome adults, sarcoidosis of the lungs, asthma, silicosis, and chronic pneumonia. Connections can also be used to treat viral and bacterial infections, including sepsis, septic shock, gram-negative sepsis, malaria, meningitis, secondary General atrophy caused by infection or neoplastic disease, secondary atrophy caused by syndrome priobretennogo the immunodeficiency syndrome (AIDS), AIDS, AIDS-associated complex (ARC), pneumonia and herpes virus. Connections can also be used for treatment of diseases associated with bone resorption, such as osteoporosis, endotoxic shock, toxic shock syndrome, damage during reperfusion, autoimmune disease, including the reaction of transplant rejection and allograft in the host body, cardiovascular disease including atherosclerosis, thrombosis, congestive heart failure, and damage after cardiac reperfusion damage after renal reperfusion, liver disease and nephritis, and myalgia caused by infection.

Compounds of the present invention can also be used for the treatment of Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus, skin diseases such as psoriasis, eczema, burns, dermatitis, keloid formation stitches and scarring. In addition, the compounds of the present invention can be used for the treatment of diseases of the gastrointestinal tract, such as colitis, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Connections can also be used for treatment of ophthalmic diseases such as retinitis, retinopathy, uveitis, ocular disease IsTrue damage eye tissue. Compounds can also be used to treat angiogenesis including neoplasia, manastireanu, ophthalmological conditions such as rejection in the transplantation of corneal tissue, revascularization in the eye tissues, revascularization in the kidneys, including revascularization after tissue injury or infection, diabetic retinopathy, retrolental fibroplasia and-neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant conditions, such as hemangioma, including child hemangioma, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nefropatia and cardiomyopathy, as well as diseases of the reproductive system in women, such as endometriosis. Compounds can also be used to prevent the production of cyclooxygenase-2.

Compounds of the present invention is preferably used for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, psoriasis, respiratory distress syndrome in adults, asthma or chronic obstructive pulmonary disease or Alzheimer's disease or cancer.

In addition, the use of these compounds for treatment of humans, they can use the SQL in veterinary medicine for the treatment of domestic animals, exotic animals and farm animals, including mammals, rodents, etc. To the most preferred animals include horses, dogs and cats.

Compounds of the present invention can also be used for combination therapies, partially or completely replacing them with other known anti-inflammatory agents, such as together with steroids, inhibitors of cyclooxygenase-2, non-steroidal anti-inflammatory drugs, DMARDS, immunosuppressants, and inhibitors of 5-lipoxygenase, antagoniste LTB4and inhibitors hydrolases LTA4.

The term "mediated TNF violation"used in this context, refers to any and all violations or pathological States in which TNF exerts a function in the control of the release of TNF or mediated TNF release another monokine, for example, without limitation, IL-1, IL-6 or IL-8. Consequently, mediated TNF violation means, for example, is a disease in which IL-1 is a major component and the production or effect of which is amplified or results in its secretion in response to TNF.

The term "indirect R violation""used in this context, refers to any and all violations or pathological is practical conditions, in which R shows the function when controlling the release of R or indirect R release another monokine, for example, without limitation, IL-1, IL-6 or IL-8. Therefore, indirect R violation means, for example, is a disease in which IL-1 is a major component and the production or effect of which is amplified or results in its secretion in response to R.

Because TNF-β is the closest structural homologue of TNF-α (also known as cachectin), both factors induce similar biological response and bind to the same cellular receptor, the synthesis of both TNF-α and TNF-β inhibited by compounds of the present invention and, in this context, both factors under the General title of "TNF"unless otherwise indicated.

Examples

Unless otherwise stated, all values of the temperature, including the melting temperature (tPL) are indicated in degrees centigrade (°).

The drug 1

4-Methylamino-2-methylthiopyrimidine-5-carboxaldehyde

Stage A: obtaining the ethyl ester of 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid

To a solution of ethyl ester of 4-chloro-2-methylthiopyrimidine-5-carboxylic acid (Aldrich, 20 g, 86 mmol) is 250 ml DHM at a temperature of 0° With was slowly added a solution of methylamine in EtOH (33%, 35 ml, 281 mmol). After stirring for 30 min was added water (150 ml), then the phases were separated, the organic phase was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure, obtained 19 g of ethyl ester of 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid in the form of a solid white color.

Stage B: obtain 4-methylamino-2-methylthiopyrimidine-5-methanol

Sociallyengaged (8,2 g, 215 mmol) was stirred in anhydrous THF (300 ml) at a temperature of 5°With, then was added dropwise a solution of ethyl ester of 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid (46 g, 215 mmol) in anhydrous THF (450 ml). The reaction mixture was stirred for 15 min, then gently was added dropwise water (18 ml). The reaction mixture was stirred for 30 min, then was added dropwise an aqueous solution of sodium hydroxide (15%, to 8.5 ml) followed by addition of water (25,5 ml). The resulting suspension was stirred for 17 h at room temperature and was filtered. The filter residue washed with THF (2 times 100 ml), then the combined filtrate and extracts were evaporated under reduced pressure. The residue is suspended in a mixture of EtOAc/hexane (1:2, 200 ml), the solid was separated by filtration and dried, while the floor is Ali to 32.7 g of 4-methylamino-2-methylthiopyrimidine-5-methanol in the form of a solid yellow color.

Stage: obtain 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde

4-Methylamino-2-methylthiopyrimidine-5-methanol (20 g, 108 mmol) was dissolved under stirring in a 1 l DHM, then was added manganese dioxide (87 g, 1 mol). The resulting suspension was stirred for 24 h, then filtered through a layer of celite. The filter residue was washed DHM (100 ml), the combined filtrate and extracts were evaporated under reduced pressure, it was given to 15.8 g of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde in a solid white color.

The product 2

4-(Cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde

4 Cyclopropylamino-2-methylthiopyrimidin-5-carboxaldehyde was obtained from ethyl ether 4-chloro-2-methylthiopyrimidine-5-carboxylic acid (Aldrich Chemical Co.) and cyclopropylamine (Aldrich Chemical Co.) the sequence of reactions as described in example 1 (stage a).

Drug 3

4-[(4-Forfinal)amino]-2-(methylthio)pyrimidine-5-carboxaldehyde

4-[(4-Forfinal)amino]-2-(methylthio)pyrimidine-5-carbaldehyde was obtained from ethyl ether 4-chloro-2-methylthiopyrimidine-5-carboxylic acid (Aldrich Chemical Co.) and 4-foronline (Aldrich Chemical Co.) the sequence of reactions as described in example 1 (stage a).

The product 4

4-(Ethyl) - Rev. Mino)-2-(methylthio)pyrimidine-5-carboxaldehyde

Stage A: obtaining the ethyl ester of 4-ethylamino-2-methylthiopyrimidin-5-carboxylic acid

To a solution of 25 g (107 mmol) of ethyl ether 4-chloro-2-methylthio-5-pyrimidinecarbonitrile acid in 250 ml of THF was added 47 ml (337 mmol) of triethylamine and 43 ml of 70% solution of ethylamine (668 mmol). The mixture was stirred at room temperature for 4 h and evaporated to dryness. The residue was dissolved in a mixture of EtOAc/water, washed twice with a 10% solution of NaHCO3, dried (MgSO4) and was evaporated to dryness, to receive specified in the title compound in the form of solids. The yield of product amounted to 24.1,

Stage B: obtain 4-ethylamino-2-methylthiopyrimidine-5-methanol

A solution of ethyl ester of 4-ethylamino-2-methylthiopyrimidine acid (24,1 g, 100 mmol) in THF (250 ml) was cooled to a temperature of 0°in an ice bath, then for 1 h cautiously in small portions was added sociallyengaged (4.3 g, 113 mmol). After 1 h was slowly added water (4.3 ml), then was added a solution of NaOH (4.3 ml, 15%) and another portion of water (13 ml), then the mixture was stirred for 1 h, the resulting suspension was filtered, the filter residue washed twice with 100 ml of THF, the filtrate was evaporated under reduced pressure, the residue was stirred in 150 ml of Et2O, filter and dry. The product yield was 19.1,

Stage: obtain 4-ethylamino-2-methylthiopyrimidin-5-carboxaldehyde

To a solution of 4-ethylamino-2-methylthiopyrimidine-5-methanol (19,1 g, 96 mmol) in 1000 ml DHM added 87 g of manganese dioxide. The resulting suspension was stirred for 20 h and filtered through a layer of celite. The residue was washed DHM (2 times 100 ml), the combined filtrate and extracts were evaporated under reduced pressure, the thus obtained product in the form of solids. The product yield was 12.8,

The drug 5

4-Amino-2-methylthiopyrimidin-5-carbaldehyde

Stage A: obtaining potassium salt of 3,3-diethoxy-2-formylpyridine (P-5A))

To a mixture of 3,3-diethoxypropane (283,80 g of 1.98 mol) and methyl ester of formic acid (148,80 g, 2,48 mol) in anhydrous THF (1.1 l) at a temperature of 10°under stirring was added for 45 min 1.0 M solution of potassium tert-butylate in THF (2.2-liter and 2.2 mol), the temperature of the mixture was maintained in the range from 10 to 15°C. the resulting suspension was stirred for 2 h at room temperature, then was added hexane (400 ml) and was stirred for 20 minutes the Suspension was filtered, the filter cake was washed with hexane/THF (1:1) and dried overnight in a vacuum oven at temperature is round 60° With received 302,5 g (73,0%) of compound P-5A in the form of a powder pale yellow-brown color. The structure of the obtained compounds were confirmed1H-NMR (CD3OD.

Stage B: obtain 4-amino-2-sulfanilamide-5-carbaldehyde (P-5B))

A suspension of thiourea (92,8 g, 1,22 mol) in EtOH (90 ml) was boiled under reflux with vigorous stirring, then within 10 min five portions was added to a suspension of the potassium salt of 3,3-diethoxy-2-formylpyridine (P-5A) (222,20 g of 1.06 mol) in 25% solution of sodium methylate in Meon (85.5 ml of 0.37 mol) and EtOH (285 ml) by boiling under reflux (in another embodiment, added to the homogeneous solution obtained by heating to a temperature of 50°With the above suspension). To facilitate mixing of the injected an additional portion of EtOH (150 ml). After boiling under reflux for a further one hour, the viscous suspension was acquired bright yellow color. Then the mixture was cooled and evaporated almost to dryness on a rotary evaporator. The residue was dissolved in water (940 ml). The crude product is precipitated with addition of 30% acetic acid (280 ml) and was separated by filtration over a glass filter of medium porosity. The filter cake was washed with water (800 ml). The product was purified by rubbing in hot water (1 l) for 30 minutes After cooling, the OS is atok was separated by filtration, dried overnight in a vacuum drying Cabinet at 60°With received 118,9 g (72.3%) of product as a solid bright yellow (with further optimization of this technique, it was found that the stage of grinding can be excluded). According to GHWR the purity of the product was 98,67%. The structure of the obtained compound (P-5B) confirmed1H-NMR (DMSO-d6).

Stage: obtain 4-amino-2-methylthiopyrimidin-5-carbaldehyde

To a solution of 4-amino-2-sulfanilamide-5-carbaldehyde (P-5B) (100,00 g, 644,4 mmole) and potassium carbonate (325 mesh, 178,10 g of 1.29 mol) in acetone (1.5 l) was added dropwise itmean (128,10 g, 902,2 mmole) for 20 min at moderate cooling. Then the mixture was stirred at room temperature for 2 days. According to TLC, the reaction mixture contained the product (P-5B)obtained in stage B. Then added another portion of iodomethane (8 ml) and the mixture was stirred over night. According to TLC, the reaction mixture still contained the product (P-5B)obtained in stage B. Then added portion of iodomethane (8 ml) and the mixture was stirred for 24 h According to GHUR mixture contained 95.9% of the S-alkylated product and 3.7% of the compound (P-5B). The reaction mixture was dried in a rotary evaporator almost dry. To the residue was added water (1 l), the product was separated by filtration and p is washed with water (200 ml). The product was dried in a vacuum oven overnight at a temperature of 60°C. the Yield amounted to 103,37 g (94,8%). According to GHUR product contained 95,8% drug 5 and 4.2% of the compound (P-5B).

The drug 6

4-Amino-2-n-butylthiophene-5-carbaldehyde

4-Amino-2-(n-butylthio)pyrimidine-5-carbaldehyde was obtained by the procedure described to obtain the drug 5 (stages a-b), but instead of iodomethane (Aldrich Chemical Co.) at the stage used In iodobutane (Aldrich Chemical Co.).

Example 1

6 Ethoxy-2-[3-methoxy-1-(2-methoxyethyl)propylamino]-8,8A-dihydro-an-pyrido[2.3-d]pyrimidine-7-he

Stage A: 2-butylsulfonyl-6-ethoxy-8,8A-dihydro-an-pyrido[2,3-d]pyrimidine-7-he

4-Amino-2-butylsulfonyl-4,5-dihydropyrimidin-5-carbaldehyde (3 g, 14.2 mmole, obtained in the preparative synthesis) and ethyl ether detoxicates acid (2,34 g, 2.4 ml, 17,75 mmole) was stirred in 80 ml of toluene in a nitrogen atmosphere at a temperature of 0-5°C. and Then slowly added tert-butyl potassium (1.75 g, 15.6 mmole). The mixture was stirred at room temperature and then at a temperature of 65°C for 48 hours and Then added an additional portion of toluene (20 ml) and ethyl ether detoxicates acid (2.4 ml), the resulting mixture was stirred at a temperature of 65°C for 2 days. The reaction is ionic mixture was concentrated in vacuo and triturated with EtOAc, when this was removed unreacted original aldehyde. To remove impurities, the remainder of the solids triturated with chloroform, it was received 3,66 g 2-butylsulfonyl-6-ethoxy-8,8A-dihydro-an-pyrido[2,3-d]pyrimidine-7-she (1A), according to MS/IHVR and NMR purity of the product was 80%.

Stage B: 2-(butane-1-sulfonyl)-6-ethoxy-8H-pyrido[2,3-d]pyrimidine-7-he

A solution of the compound (1A) (3 g, 10.7 mmole) suspended in 40 ml DHM, cooled to a temperature of 0-5°in an ice bath and slowly added meta-chloroperbenzoic acid (5.5 g, and 32.3 mmole). The resulting mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue is triturated with EtOAc, the product was purified by chromatography on a column (eluent: CH2Cl2/Meon/acetone, 96:2:2), was obtained 1 g of 2-(butane-1-sulfonyl)-6-ethoxy-8H-pyrido[2,3-d]pyrimidine-7-it (3B).

Stage: 6 ethoxy-2-[3-methoxy-1-(2-methoxyethyl)propylamino]-8,8A-dihydro-an-pyrido[2,3-d]pyrimidine-7-he

A solution of compound 3B (50 mg, 0.16 mmole) and 3-methoxy-1-(2-methoxyethyl)Propylamine (140 mg, 0.96 mmole) in 1 ml of EDC was heated at a temperature of 85°C for 72 h, the Reaction mixture was directly separated by chromatography on a column Supelco™ (silica gel, 2 g/12 ml, eluent: gradient from CH2Cl2until CH2Cl2/Meon/acetone, 94:3:3). Product vaidyasala chromatography, when this received 24 mg 6 ethoxy-2-[3-methoxy-1-(2-methoxyethyl)propylamino]-8,8A-dihydro-an-pyrido[2,3-d]pyrimidine-7-it (example 1), according to MS/IHVR the purity of the product was 86%. MS: 337 (M+1).

Example 2

6-Methoxy-8-methyl-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-he

Stage And

4-Methylamino-2-methylthio-5-pyrimidinecarboxylic (2 g, up 10.9 mmole), methyl ether methoxybutanol acid (1.6 ml, and 16.4 mmole), potassium carbonate (2.26 and g, and 16.4 mmole) and NMP (40 ml) was stirred at a temperature of 120°C for 66 hours, the Reaction mixture was cooled to room temperature, then poured into water (300 ml), the product was extracted with EtOAc (3 x 100 ml). The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified Express chromatography (eluent: gradient of 20-50% acetone/hexane), was obtained 502 mg of the compound (2A).

Stage B

A mixture of compound (2A) (450 mg, 1,90 mmole), 72% mCPBA (1,36 g, 5,69 mmole) and methylene chloride (100 ml) was stirred at room temperature for 3 hours To the reaction mixture were added an aqueous solution of sodium bisulfite (10%, 100 ml) and stirred at room temperature for 1 h, the product was extracted with EtOAc (200 ml). The organic layer was washed the feast upon the authorized aqueous solution of sodium bicarbonate, water and saline, dried over magnesium sulfate and concentrated in vacuum. The residue was purified Express chromatography (eluent: gradient 0-3% Meon/DHM), received 235 mg of the above compound (2B).

Stage

A mixture of compound (2B) (50 mg, 0,186 mmole), 4-aminotetrahydrofuran (38 mg, 0,371 mmole) and NMP (1 ml) was stirred at a temperature of 80°C for 66 hours, the Reaction mixture was cooled to room temperature, the product was purified Express chromatography (eluent: gradient of 1-5% Meon/DHM), received 47 mg of the compound (4A). The free base was dissolved in Meon, were treated with 1 EQ. 1 N. HCl in Et2O, the mixture was concentrated in vacuo, to receive the above compound (example 2) in the form of hydrochloride (44 mg).

Example 3

6 Ethoxy-8-methyl-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-he

Stage And

4-Methylamino-2-methylthio-5-pyrimidinecarboxylic (3 g, and 16.4 mmole), ethyl ester detoxicates acid (3.3 ml of 24.6 mmole), potassium carbonate (3.4 g, of 24.6 mmole) and NMP (50 ml) was stirred at a temperature of 120°C for 18 h Then the reaction mixture was stirred at a temperature of 80°C for 66 h, added an additional portion of ethyl ether detoxicates acid and potassium carbonate in the amount indicated above, and the mixture was naked evali at a temperature of 120° C for 18 h, the Reaction mixture was poured into water (300 ml) and stirred at room temperature for 1 h the Precipitate was separated by filtration, washed with water and hexane, then dried in vacuum, to receive 2.14 g of the compound (3A).

Stage B

A mixture of compound (3A) (2 g, of 7.96 mmole), 72% mCPBA (5.7 g, 23.9 mmole) and methylene chloride (100 ml) was stirred at room temperature for 1 h Aqueous solution of sodium bisulfite (10%, 100 ml) was added to the reaction mixture and stirred at room temperature for 15 min, the product was extracted with EtOAc (200 ml). The organic layer was washed saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated in vacuum were obtained 1.45 g of the compound (3B).

Stage

A mixture of compound (3B) (100 mg, 0,353 mmole), ethyl ester of 4-amino-1-piperidinecarboxylic acid (0,12 ml, 0,706 mmole) and NMP (3 ml) was stirred at a temperature of 120°C for 18 hours the Reaction mixture was cooled to room temperature and distributed between water and EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuum. The residue was dissolved in Meon and DHM, were treated with 1 N. HCl in Et2O (0.35 ml) and concentrated in vacuum. The obtained solid was washed on the ethyl ether and dried in vacuum, it was obtained 56 mg of the product (example 3) as hydrochloride.

Example 4

6 Ethoxy-8-methyl-2-(piperidine-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-

Stage A: obtain 6-(2,6-divergence)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-it

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (preparation 1) (4.8 g, 26,2 mmole) and methyl ester of 2,6-differentsialnoi acid (obtained according to the method described for obtaining preparation 4, using 2,6-differenoe, 5.9 g, 32 mmole) in 50 ml of 1-methyl-2-pyrrolidinone was added potassium carbonate (6.0 g, 43.5 mmole). The reaction mixture was heated at a temperature of 120°C for 12 h, then was added phenoxyacetate (2 times 2.0 g, 10.8 mmole) and potassium carbonate (2.0 g, 15 mmol). The mixture was stirred for b h at a temperature of 120°C, then cooled to room temperature and added water (70 ml). The solution was stirred for 30 min and filtered. The obtained solid substance was washed with water (2 times), EtOAc and ether. Then the solid was dried, it was obtained 7.0 g of the above sulfide (MS: 336 (M+1), tPL247-250,7°).

Stage B: obtain 6-(2,6-divergence)-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-it

Compound 4A (7.0 g, 20.8 mmole) was dissolved in 50 ml chloris is on methylene, then added 3-chloroperbenzoic acid (77%, and 11.5 g, 51,5 mmole). The mixture was stirred at room temperature for 16 h, filtered, the residue was washed with an aqueous solution of sodium sulfite (2 x 75 ml) and saturated aqueous sodium bicarbonate (3 x 75 ml). Then, the resulting organic solution was washed with saline and dried over dry Na2SO4that was evaporated. The obtained solid was stirred in ether for 1 h and was separated by filtration, it was obtained 5.5 g of the above sulfone 4B (MS: 368 (M+1), tPL215,2-216,4°).

Stage: obtaining the ethyl ester of 4-{[6-(2,6-divergence)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]amino}piperidine-1-carboxylic acid

A mixture of compound 4B (1.0 g, 2.7 mmole) and ethyl ester of 4-amino-1-piperidinecarboxylic acid (0,93 ml, 5.4 mmole) in 5 ml of 1-methyl-2-pyrrolidinone was stirred at a temperature of 100°C for 1 h, then cooled to room temperature. The resulting suspension was added to 20 ml of distilled water, yellow precipitate was separated by filtration under vacuum, then dried in vacuum, to receive 1.28 g of compound 4C. Approximately 80 mg of the obtained compound was dissolved in Meon (1-2 ml), the solution was treated with 1 M solution of hydrochloric acid in ether, then the organic solvent issue is rivali, added ether (1-2 ml), the product in the form of a solid substance was separated by filtration and dried, when it received 66 mg of compound 4C in the form of hydrochloride (tPL197-204°).

Stage D: 6 ethoxy-8-methyl-2-{[(1-methanesulfonyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)he

A mixture of ethyl ester of 4-{[6-(2,6-divergence)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]amino}piperidine-1-carboxylic acid, obtained in stage (1.2 g, 2,52 mmole), and potassium hydroxide (2.83 g, of 50.4 mmole) in 20 ml of EtOH was heated under reflux for 48 h, then the reaction mixture was evaporated in vacuum. The residue was transferred into 100 ml of water and before acidification adding dropwise conc. HCl was cooled in an ice bath. Then the acidic aqueous solution was treated DHM (2 times). The aqueous solution was cooled in an ice bath and was once again podslushivaet by adding sodium hydroxide. Then from alkaline solution, the product was extracted with DHM (2 times). The organic extracts obtained from the alkaline aqueous solution, combined, dried over magnesium sulfate, concentrated and dried in vacuum, when it received 92 mg of the crude product.

In another embodiment, the connection specified in the header of example 4 was obtained from a mixture of the free base (example 3, obtained as described above, 358 mg, 0,954 mmole), potassium hydroxide (1.07 g, 19,1 mmole) and EtOH (10 ml) by boiling with education is the principal refrigerator for 5 days. Then the reaction mixture was concentrated in vacuum. The residue was dissolved in water and acidified by adding 2 N. HCl, and then the product was extracted with DHM. The aqueous layer was podslushivaet the addition of saturated aqueous sodium bicarbonate solution and the product was extracted again DHM (2 times 100 ml). The organic extracts obtained from the alkaline solution, dried over magnesium sulfate and concentrated in vacuum, thus received 24 mg of the compound indicated in the heading of example 4. Part of the obtained compound (3 mg) was dissolved in Meon, were treated with 1 EQ. 1 N. HCl in Et2O and concentrated in vacuum to receive 4 mg of the compound indicated in the heading of example 4 in the form of hydrochloride.

Example 5

6 Ethoxy-8-methyl-2-{[(1-methanesulfonyl)piperidine-4-yl]amino)pyrido[2,3-d]pyrimidine-7(8H)-he

The crude piperidine (example 4, 0,92 g, 0,237 mmole) was transferred into a mixture of 5 ml DHM, sodium carbonate (0,050 g value (0.475) mmole) and methanesulfonamide (of 0.022 ml, 0,285 mmole), was stirred at room temperature for 17 hours Then added portion of methanesulfonanilide (0,040 ml) and sodium carbonate (50 mg), the reaction mixture was stirred at room temperature for 24 hours Then add the last portion of methanesulfonanilide (0,080 ml) and sodium carbonate (150 mg), the reaction mixture was stirred at room t is mperature within 48 h (this, there was complete consumption of the source piperidine). Then the organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuum to receive the oil. The product was purified by chromatography on a column (SiO2, eluent: gradient of CH2Cl2/Meon, from 0.5:99,5 to 3:97). The fractions containing the product were combined and concentrated under reduced pressure, to receive 25 mg of the desired product. The product was dissolved in EtOAc (1-2 ml), then treated with hydrochloric acid in ether (1m, 1 EQ.). After washing with ether, the solid was separated by filtration and dried in vacuum, to receive the product (19 mg, example 5) in the form of hydrochloride (tPL219,56-221,2°).

In another embodiment, the mixture of the compound (21 mg, 0,069 mmole, obtained as described in example 4), sodium carbonate (15 mg, was 0.138 mmole), methanesulfonamide (0.06 ml) and DHM (10 ml) was stirred at room temperature for 18 hours the Reaction mixture was poured into water (100 ml), the product was extracted with DHM (2 times 100 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuum. The residue was dissolved in Meon, were treated with 1 N. HCl in Et2O and concentrated in vacuum. The obtained solid is washed with Et2O and dried in vacuum, to receive 15 mg of the product (example 5) as hydrochloride.

Example 6

In the example described a method for the analysis of compounds by n the present invention in vitro by inhibition of the kinase R (MAP).

Inhibitory activity of the compounds of the present invention in relation to the kinase R MAP was evaluated in vitro by the reaction of transfer γphosphate group from γ-33P-ATPon myelinogenesis protein (MBP), catalyzed by the kinase R using a modified method described in the article Ahn and others, J.Biol.Chem., 266, 4220-4227 (1991).

Phosphorylated form of recombinant kinase R MAP expressed together with cells SEK-1 and MEKK in E. Coli (for example, as described in article Khokhlatchev, etc., J. Biol. Chem. 272:11057-11062 (1997)), and then purified metal-chelate chromatography on a Nickel column.

Phosphorylated kinase R MAP was dissolved in the buffer solution for the determination of kinase activity (20 mm 3-(N-morpholino)propanesulfonate, pH of 7.2, 25 mm-getinvolved, 5 mm ethylene glycol-bis(beta-aminoacylase ether)-N,N,N',N'-tetraoxane acid, 1 mm orthovanadate sodium, 1 mm dithiotreitol, 40 mm magnesium chloride)was then added and a solution of the compound in DMSO or only DMSO (control), and the samples were incubated for 10 min at a temperature of 30°C. the phosphorylation Reaction catalyzed by the kinase, were initiated by addition of a mixture of substrates containing MBP andThen the reaction mixture was incubated for 20 min at a temperature of 30°C, the reaction was stopped by the addition of 0.75% fo what FORNEY acid. Then phosphorylated MBP was separated from unreactedby filtration through phosphocellulose membrane (Millipore, Bedfrod, MA), and radioactivity was measured by scintillation radioactivity counter (Packard, Meri den, CT).

The values of the IC50was defined as the concentration of the tested compound, corresponding to half of the maximum decrease in optical density at 450 nm.

Typical compounds of formula I
Connection # The structural formulatPLIC50(µm)Example
1-1˜and 7.71
1-2˜1,62
1-3>104
1-4to 219.5-221,2˜0,0585

Example 7

In the example described method of in vitro assays used to assess the inhibition of production of TNF-αinduced by lipopolysaccharide in the cell TNR.

p> The ability of the compounds of the present invention to inhibit the release of TNF-α was determined by the modified method, as described in article Blifeld et al. Transplantation, 51:498-503 (1991).

(a) Induction of the biosynthesis of TNF

Cells TNR-1 suspended in culture medium RPMI (Gibco-BRL, Gailthersburg, MD)containing 15% fetal calf serum, 0.02 mm 2-mercaptoethanol, at a concentration of 2.5×106cells/ml, and then cultured in 96-well plates (0.2 ml in each well). The compounds were dissolved in DMSO and diluted in culture medium to the final concentration of DMSO 5%. To each well was added 25 μl of a solution of tested compound or a solution of DMSO in the medium (control). Cells were incubated for 30 min at 37°C. the wells were added lipopolysaccharide LPS (Sigma, St.Louis, MO) at a final concentration of 0.5 μg/ml and cells were incubated for a further 2 hours At the end of the incubation period supernatant cells were collected and the number of contained TNF-α was determined by the method of ELISA analysis as described below.

(b) analysis Method ELISA

The number contained TNF-α people were determined using specific ELISA analysis using two antibodies to TNF-α (2TNF-H12 and 2TNF-H34), as described in article Reimund J.. and other GUT. Vol.39(5), 684-689 (1996).

In each well of a polystyrene 96-well tablet to relax is if 50 ál of antibody 2TNF-H12 and phosphate-saline buffer solution (FSB) (10 μg/ml) and incubated in a humid chamber at 4° With during the night. Then the tablets were washed FSB and blocked with 5% fat-free dried milk in FSB for 1 h at room temperature, then washed with 0.1% BSA (bovine serum albumin) in the FSB.

Standard samples of TNF was obtained from a concentrated solution of recombinant TNF-α person (firm R & D Systems, Minneapolis, MN). Then was prepared by serial dilution of standard samples with an initial concentration of 10 ng/ml on a semi-log scale (6 dilutions).

25 μl of the above supernatant cells or standard samples TNF or only medium (control) was mixed with 25 µl of biotinylated monoclonal antibodies 2TNF-H34 (2 μg/ml in the FSB, containing 0.1% BSA) and then was added to each well. Samples were incubated for 2 h at room temperature with gentle shaking and then washed 3 times with 0.1% BSA in the FSB. To each well was added 50 μl of a solution of streptavidin-peroxidase (Zymed, S. San Francisco, CA), containing 0,416 μg/ml streptavidin-peroxidase and 0.1% BSA in the FSB. Samples were incubated for another 1 h at room temperature and then washed 4 times with 0.1% BSA in the FSB. To each well was added 50 μl of a solution of ortho-phenylenediamine (1 mg/ml ortho-phenylenediamine and 0.03% hydrogen peroxide in 0.2 M citrate buffer solution at pH 4.5) and the samples were incubated in the dark for 30 min at room themes is the temperature value. The optical density of the samples and control were recorded at 450 nm and 650 nm, respectively. The level of TNF-α identified on schedule according to the optical density at 450 nm from the investigated concentrations.

The value of the IC50was defined as the concentration of the compounds in which there is a decrease in optical density at 450 nm at half maximum value.

Example 8

This example describes the method of analysis in vivo to determine the inhibition of LPS-induced production of TNF-α in mice (or rats).

The ability of the compounds of the present invention to inhibit the release of TNF-α in vivo was determined by a modified method as described in articles Zanetti and others, J.Immunol., 148:1890 (1992), Sekut, etc., J.Lab. Clin. Med., 124:813 (1994).

Female BALB/c mice weighing 18-21 g (Charles River, Hollister, CA) were acclimatized for 1 week. Each group of mice, including 8 species, is administered orally the compounds suspended or dissolved in water filler containing 0.9% sodium chloride, 0.5% sodium carboxymethyl cellulose, 0.4% Polysorbate 80, 0.9% of benzyl alcohol (solvent for CMC) or one filler (control group). After 30 min the mice were injected intraperitoneally 20 μg LPS (Sigma, St. Louis, MO). After 1.5 h, the mice were scored by inhalation of CO2and the blood was collected by puncture of the heart. Crowesville by centrifugation at 15600× g for 5 min, the serum was transferred into a clean test tubes were frozen at -20°and the samples were stored until analysis on the content of TNF-α by ELISA (Biosource Intrenational, Camarillo, CA) no recommendations of the manufacturer.

1. The compound of the formula I

or its pharmaceutically acceptable salt or hydrate

where Z denotes N;

X1means O or S,

R1means alkyl containing from one to six carbon atoms;

R2means hydrogen or alkyl containing from one to six carbon atoms; and

R3means alkyl containing from one to six carbon atoms, substituted by a group-ORawhere Rameans alkyl containing from one to six carbon atoms;

saturated non-aromatic cyclic radical containing from 3 to 8 atoms in the cycle, where one atom in the cycle is a heteroatom selected from N or O, and the remaining atoms in the cycle are carbon atoms and one or two carbon atoms optionally substituted on the nitrogen atom of the groups-C(O)(C1-C6alkoxy), or-SO2-C1-C6alkyl.

2. The compound according to claim 1, where Z denotes N, X1means Of, R1means alkyl, R2means H or alkyl, and R3means a saturated non-aromatic cyclic glad the feces, containing from 3 to 8 atoms in the cycle, where one atom in the cycle is a heteroatom selected from N or O, and the remaining atoms in the cycle are carbon atoms and one or two carbon atoms optionally substituted on the nitrogen atom of the groups-C(O)(C1-C6alkoxy), or-SO2-C1-C6alkyl.

3. The connection of claim 2, where R3means alkoxyalkyl or saturated, non-aromatic cyclic radical containing 6 atoms in the cycle, in which one atom does not mean carbon, a is oxygen or nitrogen, optionally substituted on the nitrogen atom of the groups-C(O)(C1-C6alkoxy), or-SO2-C1-C6alkyl.

4. The compound according to claim 1, where X1means-Oh.

5. The connection of claim 1, where R3means a saturated non-aromatic cyclic radical containing from 3 to 8 atoms in the cycle, where one atom in the cycle is a heteroatom selected from N or O, and the remaining atoms in the cycle are carbon atoms and one or two carbon atoms optionally substituted on the nitrogen atom of the groups-C(O)(C1-C6alkoxy), or-SO2-C1-C6alkyl.

6. The compound according to claim 1, where R2means alkyl containing from one to six carbon atoms.

7. The compound according to claim 1 of formula (I")

where R1means alkyl containing from one who go to six carbon atoms;

R2means hydrogen or alkyl containing from one to six carbon atoms; and

R3means a saturated non-aromatic cyclic radical containing from 3 to 8 atoms in the cycle, where one atom in the cycle is a heteroatom selected from N or O, and the remaining atoms in the cycle are carbon atoms and one or two carbon atoms optionally substituted on the nitrogen atom of the groups-C(O)(C1-C6alkoxy), or-SO2-C1-C6alkyl; or its pharmaceutically acceptable salt.

8. The connection according to claim 7, where R3choose from the range: (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl, 3-methoxy-1-(2-methoxyethyl)propyl, tetrahydro-2H-Piran-4-Il, 1-(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl and morpholinyl.

9. The connection of claim 8,

where R1means ethyl,

R2means methyl and

R3choose from a range of (1-hydroxy-2-methyl)prop-2-yl, 1-hydroxypentanal-2-yl, (S)-2-hydroxy-1,2-dimethylpropyl, (R)-2-hydroxy-1,2-dimethylpropyl, (S)-2-hydroxy-1-methylethyl, 1-hydroxymethylcytosine-1-yl, 2-hydroxy-2-methylpropyl, 3-methoxy-1-(2-methoxyethyl)propyl, tetrahydro-2H-Piran-4-yl, 1(methylsulphonyl)piperidine-4-yl, (1-carboxyethyl)piperidine-4-yl, 1,1-dissidocerida-2H-thiopyran-4-yl and morpholinyl.

10. The connection according to claim 7 of the formula

where X is-O-, -S(=O)-, -N(R12a)-;

R12achoose from a number hydrogen, -C(=O)R15and-S(O)2(C1-4alkyl);

R14choose from a number With1-4alkyl, -OR15, -C(=O)R15and

-S(O)2(C1-4alkyl); and R15in each case independently selected from a number of hydrogen and C1-4alkyl;

q is 0 or 1, and

r is 0, 1 or 2.

11. The connection of claim 10, or its isomer or pharmaceutically acceptable salt, where X is-N(R12a)-, a R12ameans-S(O)2(C1-4alkyl).

12. Compounds according to any one of claims 1 to 11, having inhibitory activity against the kinase p38 MAP.

13. Pharmaceutical composition having inhibitory activity against MAP kinase p38, including pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to any one of claims 1 to 11.



 

Same patents:

FIELD: CHEMISTRY.

SUBSTANCE: invention relates to novel method for preparation of compounds of formula IX or IXа, which implies reaction of compound of formula Va, in solvent, with compound of formula VII or formula VIIa, in the presence of palladium catalyst and phospho ligand, in the presence of amine base, resulting in compound of formula VIII or VIIIa. The method also implies reaction of compound of formula VIII or VIIIa, in solvent, with cyclopropylamine, not necessarily in the presence of catalyst. Also, invention relates to method for purification of compound of formula IX or IXa.

Va - R1 may be either С1-8alkyl, aryl or heteroaryl, not necessarily aryl- and/or С1-8alkyl-substituted; and

.

EFFECT: method for preparation of biologically useful compounds is described.

17 cl, 3 tbl, 77 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically suitable salt or solvate thereof, where dashed line stands for additional bond, а is a number from 0 to 2, b is a number from 0 to 2, n is 2, p is 2, r is 1, М1 stands for nitrogen, М2 stands for С(R3), X stands for either a bond or alkylene group with number of carbon atoms from 1 to 6, Y stands for -С(О)- group, Z stands for a bond, or alkylene group with number of carbon atoms from 1 to 6, or alkenylene group with number of carbon atoms from 1 to 6, or -С(O)-, -CH(CN)-, -SO2- or СН2С(O)NR4- group, R1 stands for groups, R2 stands for six-membered heteroaryl ring with one or two heteroatoms chosen independently of each other from either nitrogen atom or N-O group, other atoms of the cycle being carbon, five-membered heteroaryl ring with one, two, three or four heteroatoms chosen independently of each other from nitrogen, oxygen or sulphur, other atoms of the cycle being carbon, R32 stands for substituded quinoline group, R32 stands for substituted aryl group, heterocycloalkyl group, cycloalkyl group with number of carbon atoms from 3 to 6, alkyl group with number of carbon atoms from 1 to 6, group, where the said six-membered heteroaryl ring or the said five-membered heteroaryl ring may be R6-substituted, R12 independently of others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group or fluorine atom, provided in case R12 stands for hydroxyl or fluorine the rest of R12 cannot be bonded to a nitrogen-bonded carbon atom, or two R12 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjaicent carbon atoms of the ring, R13 independently of the others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group, alcoxy group with number of carbon atoms from 1 to 6, or fluorine atom, provided in case R13 stands for hydroxyl or fluorine the rest of R13 cannot be bonded to a nitrogen-bonded carbon atom, or two R13 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjacent carbon atoms of the ring. See description for meaning of the other structural elements. Invention relates also to pharmaceutical compositions, as well as to application of compounds of formula I.

EFFECT: preparation of novel biologically active substances and pharmaceutical compositions.

20 cl, 659 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method (variants) for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone and its (+)-enantiomer. The first variant of method for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone involves step (e) and another variant involves steps (b)-(e). Method for synthesis of (+)-enantiomer involves the following steps (a)-(f): (a) interaction of 2,6-diaminopyridine with malic and sulfuric acids to form 2-amino-7-hydroxy-1,8-naphthyridine hydrosulfate that (b) is treated with phthalyl reagent in a solvent medium to form phthalimidylnaphthyridine of the formula (2): that (c) is chlorinated to form chloride of the formula (3): that (d) is reduced to hydroxyindolinone of the formula (4): that (e) is treated with 5-methyl-2-oxohexyltriphenylphosphonium halide to yield racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone that (f) is separated and final (+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone is prepared. Invention provides improving method for synthesis of 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone from 2-(7-chloro-1,8-naphthyridine-2-yl)-3-hydroxyisoindolinone-1-one based on using 5-methyl-2-oxohexyltriphenylphosphonium halide.

EFFECT: improved methods of synthesis.

13 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): that are antagonists of CRF receptors and wherein Ar means optionally substituted phenyl or monocyclic 6-membered heteroaryl comprising one heteroatom chosen from nitrogen, oxygen or sulfur atoms; R1-R4 have values given in the invention claim, or to their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of indicated compounds and to pharmaceutical compositions containing these compounds that are useful for administration to a patient suffering from diseases that are relived in therapy using antagonists of CRF receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 tbl, 17 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one isethionate salt and to its crystalline forms. These substances show properties of selective inhibitor of cyclin-dependent kinase 4 (CDK4) and can be used in treatment, for example, of inflammatory and cellular proliferative diseases. Crystalline forms of salt show powdery roentgenogram in values 2θ about 8.7, 13.5 and 17.6 (form A); 5.1, 11.8, 12.1, 12.8, 13.1 and 14.7 (form B), and 8.4, 8.9 and 21.9 (form D). Also, invention relates to methods for preparing crystalline 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-one isethionate salt, to medicinal agent and its using for preparing a medicinal agent.

EFFECT: valuable medicinal and biochemical properties of compound.

23 cl, 5 tbl, 18 dwg, 12 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel compound - ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate of the formula: that possesses property of CCR-2 antagonist. Also, invention relates to a method for modulation of activity of chemokine receptors and a method for treatment, improvement, control and reducing risk of inflammatory and immunoregulatory disorder or disease, and to a method for improvement, control and reducing risk of rheumatic arthritis.

EFFECT: valuable medicinal properties of compound.

4 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, cycle A, cycles B, X, Y and Z have values given in the invention claims and in description of the claim, and to their pharmaceutically acceptable salts also. Proposed compound possess an antitumor activity and can be used in treatment of oncological diseases. Also, invention relates to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

23 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes imidazoquinoline derivatives of the formula (I): wherein X represents alkyl, -CHR3-; Z represents groups -S-. -SO-, or -SO2-; R1 is chosen from group comprising alkyl and unsubstituted phenyl; R2 is chosen from group comprising hydrogen atom, alkyl, alkyl-Y-alkyl; each R3 represents hydrogen atom; Y represents -O-; n = 0. Also, invention describes a tetraimidazoquinoline derivative, pharmaceutical compositions based on thereof and a method for stimulating biosynthesis of cytokine in animal body. Proposed compounds and compositions can induce biosynthesis of different cytokines and therefore they can be used in treatment of different diseases being among them viral and tumor diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

20 cl, 1 tbl, 20 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the amyloid-binding compound or its water-soluble non-toxic salt, where Y is presented by NR1R2; Z means S; R1 is chosen from group consisting of H, methyl, propyl, (CH2)nOR' (where n = 1, 2 or 3 and R' is presented by H or by lowest alkyl group), CF3, CH2-CH2X, CH2-CH2-CH2X (where X = F, Cl, Br or I); where R2 is chosen from group consisting of lowest alkyl group, (CH2)nOR' (where n = 1, 2 or 3 and R' is presented by H or by lowest alkyl group), CF3, CH2-CH2X, CH2-CH2-CH2X (where X = F, Cl, Br or I); R3 - R10 are chosen independently from group, consisting of H, F, CI, Br, I, lowest alkyl group, (CH2)nOR' (where n = 1, 2 or 3) or OR' , and R' means H lowest alkyl group); provided, the compound isn't related one of the following compounds: methyl-[4-(6- methyl -benzothiazole-2-il)phenyl]amin, dimethyl -[4-(6- methyl - benzothiazole-2-il)phenyl]amin, and where at least one of R1-R10 substitutors contains the radioactive marker, chosen from group, which consists of 11C, 123I, 125I or 127I, and the described compounds don't contain the nitrogen quaternary atoms. The invented compounds are used for detection of the amyloid deposit in patient and in differential diagnostics of brain affected by Alzhemer's disease and normal brain. .

EFFECT: thioflavin derivatives are obtained for in vivo visualization and identification of amyloid deposit in patient.

16 cl, 2 tbl, 9 dwg, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystallic hydrate of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one of example В1, to method for preparation thereof, to anhydrous crystalline forms of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one of examples D1, С1, Е1, as well as to pharmaceutical composition. Technical effect - easy commercial preparation of 3-(2-cyanophenyl)-5-(2-pyridyl-1-phenyl-1,2-dihydropyridine-2-one as a homogeneous crystalline form, which is an АМРА receptor antagonist and/or kainate receptor inhibitor.

EFFECT: facilitation of dyhydropyridine preparation.

26 cl, 9 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of thioxanthine of the formula (Ia): or (Ib): and their pharmaceutically acceptable salts, and to their using for preparing a drug and pharmaceutical composition based on thereof. Proposed compounds inhibit myeloperoxidase activity and can be used in treatment of diseases or states wherein inhibition of myeloperoxidase activity is useful, in particular, in neuroinflammatory diseases. In compounds of the general formula (Ia) or (Ib) X represents sulfur atom (S); Y represents oxygen atom (O); R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents (C1-C6)-alkyl substituted with saturated or partially unsaturated 3-7-membered ring comprising possibly one or two heteroatoms chosen independently from O, S and nitrogen atom (N) and wherein indicated ring is substituted possibly with one or more substitutes chosen from halogen atom, hydroxy, (C1-C6)-alkoxy and (C1-C6)-alkyl; R3 and R4 represent independently hydrogen atom or (C1-C6)-alkyl.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

9 cl, 4 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidone of the formula (I): wherein Q means =N, =C(R24)-; X-Y means -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 are chosen independently from group comprising hydrogen atom (H), halogen atom, halogen-(C1-C6)-alkyl, -CN, (C1-C6)-alkoxy group; R21, R22 and R23 are chosen independently of one another from group comprising H, halogen atom; R24 means H; R3 means -NHR6; R4 means H; R6 means -C(O)H, -C(O)-(C1-C3)-alkyl, -C(O)-halogen-(C1-C3)-alkyl, -C(O)O-(C1-C3)-alkyl, -C(O)-NH2, -SO2-(C1-C3)-alkyl, and also its individual isomers, racemic and nonracemic mixtures. Proposed compounds inhibit activity of monoamine oxidase B that allows its using in prophylaxis and treatment of disease mediated by monoamine oxidase B inhibitor, in particular, Alzheimer's disease and senile feeble-mindedness.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

15 cl, 4 sch, 31 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 2,3-dihydroisoindoles of the formula (I): or the formula (II): wherein X means -CH=; R1 means -(CH2)n-CO-NR5R6, -(CH2)n-NR5R6, -(CH2)n-COOR7, -(CH2)n-CN, -(CH2)n-isoindol-1,3-dionyl, -(CH2)p-OR; R2 means hydrogen atom (H), (C1-C6)-alkyl, -OH; R3 means H, (C1-C6)-alkyl; R4 means halogen atom, halogen-(C1-C6)-alkyl, (C1-C6)-alkoxy-, halogen -(C1-C6)-alkoxy group; R5 and R6 mean independently of one another H, (C1-C3)-alkyl; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; m = 1, 2 or 3; n = 0, 1 or 2; p = 1 or 2, and to their pharmaceutically acceptable salts. Proposed compounds possess inhibitory effect on activity of enzyme monoamine oxidase B that allows their using for production of drugs designated for prophylaxis and treatment of diseases mediated by enzyme monoamine oxidase B.

EFFECT: valuable medicinal and biochemical properties of compounds.

19 cl, 4 sch, 34 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes agent that possesses the nootropic activity and comprises dimephosphone as an active substance. Medicinal agent in form of an aqueous solution comprises additionally citric acid and lithium carbonate in the following ratio of components, wt.-%: dimephosphone, 15.0-30.0; lithium carbonate, 0.5-5.0; citric acid, 3.0-4.0, and deionized water, up to 100. Medicinal agent in form of syrup comprises the following composition, wt.-%: dimephosphone, 3.0-5.0; lithium carbonate, 1.0-1.2; citric acid, 4.0-5.0, and 64% sugar syrup, 89.0-92.0. Variants of the invention are syrup with the increased concentration of dimephosphone, and syrup comprising glycine additionally. Novel medicinal agents show physiological pH values elicited in the broad range of concentrations, stability of solutions in dilution, pleasant taste that simplified their using in pediatrics.

EFFECT: improved and valuable pharmaceutical properties of drug.

5 cl, 5 tbl, 1 dwg, 12 ex

FIELD: medicine.

SUBSTANCE: method involves administering non-prolonged action Carbamazepin at a dose of 30-50 mg in cases of children younger then 10, at a dose of 50-100 mg in cases of persons older than 50 before going to sleep. Glycin, angiotropic preparations selected from group: Vinpocetin, Pentoxifillin, Gingo Biloba and L-carnitine preparations are additionally given in therapeutic doses before noon. The total continuous treatment course is 3 months to 3 years long. Persons of marked mental insufficiency older than 8, additionally receive preparations of L-DOFA + Carbidopa at a dose of 30-60 mg of L-DOFA once a day in the morning.

EFFECT: preparation is applicable for long time (several years); no psychophysical addiction observed.

2 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), halogen atom and oxygen atom (O); R2 is chosen from consisting of H, halogen atom and N=N; R3 is chosen from group consisting of H and halogen atom; R4 is chosen from group consisting of H, halogen atom, amino and N=N; R5 is chosen from group consisting of H, halogen atom, methoxy, methyl and O; or R1 and R2, or R and R5 are joined and form unsaturated carbon ring; R6 is chosen from group consisting of H, (C1-C6)-alkyl, (C2-C6)-alkenyl, 3-phenyl-2-propin-1-yl, benzyl, benzyl substituted with halogen atom, phenyl or methoxy, CH2-cycloalkyl, CH2-2-furan, -(CH2)2SCH3 and -(CH2)2NHBOC; R7 is chosen from group consisting of H, (C1-C6)-alkyl and cycloalkyl; R8 is chosen from group consisting of benzyl and benzyl substituted with OCH2-phenyl; T represents group of the formula or wherein R9 and R10 represent H; or R9 represents H, and R10 are chosen from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, methyl-substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, cycloalkyl, phenyl substituted with (C1-C6)-alkyl, halogen atom, methoxy, -SCH3 or -N(CH3)2, 1-naphthyl and CH2-CH2-1,3-dioxolane; or R9 and R10 are chosen independently from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl, phenyl substituted at position 4 with halogen atom, methoxy, -SCH3 or -N(CH3)2 and 1-naphthyl, or its pharmaceutically acceptable salt, hydrate, or its prodrug as carbamate or ester. Also, invention relates to compounds of the formula (Ia) and the formula (Ib) given in the invention description, and to a method for decreasing levels of beta-amyloid, and to their using and to a method for prophylaxis or treatment of Alzheimer's disease, Down's syndrome. Invention provides preparing novel biologically active compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 17 tbl, 278 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

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