Derivatives of pyridopyrimidines, methods for their preparing and pharmaceutical composition based on thereof

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

 

The present invention relates to pyridopyrimidines and their derivatives. In particular, the present invention provides a 2,6-disubstituted 7-occupied[2,3-d]pyrimidines, the method of production thereof, pharmaceutical preparations containing them, and methods of their use.

Mitogen-activated protein kinases (map-kinases) are a family of Proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. Kinases are activated by a variety of signals, including food and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. One of the groups of map kinases is a group of kinases R, which includes various isoforms (for example, Rα, Rβ, Rγ and Rδ). Kinase R responsible for fosforiliruyusciye and activating transcription factors, as well as other kinases and are activated by physical and chemical stress, Pro-inflammatory cytokines and bacterial lipopolysaccharide.

Moreover, it is shown that the products phosphorylation R are intermediate in the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL-1)and cyclooxygenase-2. Each of these cytokines implicated in a number of diseases and illnesses. For example, TNF-α is a cytokine produced mainly by aktivirovannyj monocytes and macrophages. It is believed that excessive or unregulated production is the cause of the pathogenesis of rheumatoid arthritis. Recently it was shown that the inhibition of production of TNF has wide application in the treatment of inflammation, inflammatory intestinal diseases, multiple sclerosis and asthma.

TNF is also involved in viral infection, such as HIV, influenza virus and herpes virus, including type-1 herpes simplex virus (HSV-1), type-2 herpes simplex virus (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus 6 human herpes (HHV-6), virus-7 human herpes (HHV-7), virus-8 human herpes (HHV-8), false rabies and bovine rhinotracheitis, among other things.

Similarly IL-1 is produced by activated monocytes and macrophages and plays a role in many pathophysiological response reactions, including rheumatoid arthritis, fever, and decrease bone resorption.

In addition, the involvement of HR in the pathological process has the effect of stroke, Alzheimer's disease, osteoarthritis, lung damage, septic shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis (see, e.g., J. Exp. Opin. Ther. Patents, (2000) 10 (1)).

The suppression of these cytokines by inhibiting kinase R has a beneficial effect to regulate, mitigate and facilitate many of these boleznennostew.

Detected according to the international patent application WO 96/34867 that some 6-arrepiado[2,3-(1]pyrimidine-7-ones, -7-imine and-7-thiones are inhibitors mediated by protein-tyrosine kinase cell proliferation. Other 6-arrepiado[2,3-d]pyrimidines and naphthirydines also disclosed as tyrosine kinase inhibitors in international patent application WO 96/15128. 6-Alkyl-pyrido[2,3-d]pyrimidine-7-ones disclosed as inhibitors of cyclin-dependent kinases in the international patent application WO 98/33798. Some 4 aminopyrido-pyrimidines are disclosed as inhibitors digidrofolatreduktazy in the application for the European patent EP 0278686 A1.

One aspect of the present invention provides compounds represented by formula I and II (summary of the invention):

or their pharmaceutically acceptable salt,

where:

Z denotes N or CH;

W means NR2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6independently of one another denote hydrogen or alkyl), or C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R2means hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxyalkyl, geterofullereny, heteroalicyclic bonil or-R 21-R22where R21means alkylene or-C(=O)and R22means alkyl or alkoxyl;

R1means hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroalkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh, R12-SO2-heterocyclization (where R12means haloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl), -Y1-C(O)-Y2-R11(where Y1and Y2independently of each other either absent or are alkalinous group and R11means hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl) (heteroaryl) alkyl;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)NR34, S(O)2or S(O)2NR35; R32, R34and R35independently of one another denote hydrogen or alkyl and R33means hydrogen, alkyl, cyclea the keel, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R7means hydrogen or alkyl, and

R8and R9mean independently from each other hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - or di-alkylamino, killingray or aryl(alkyl) amino group), or R8and R9together form =CR82R83(where R82and R83means independently hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl).

Another aspect of the present invention provides pharmaceutical finished dosage form comprising a compound of formula I or II and a pharmaceutically acceptable carrier, diluent or filler for this.

Compounds of formulas I and II and their aforementioned salts are inhibitors of protein kinases and show significant activity against R in vivo. They also suddenly exhibit selective activity against kinase R compared with cyclin-dependent kinases and tyrosine kinases. Therefore, compounds of the present invention can be applied for the treatment of diseases, oposredstvovanii Pro-inflammatory t is takinami, as, for example, TNF and IL-1. Thus, according to another aspect of the present invention provides a method of treating oposredstvovanii R diseases or conditions according to which a therapeutically effective amount of a substance of the formula I or II is introduced to the patient in need of such treatment.

Another aspect of the present invention provides a method of obtaining the above-described compounds and intermediate compounds of the formula I' and II'used for this purpose.

where:

Z denotes N or CH;

W means S, S(O), S(O)2or;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl), or C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R10means alkyl, aryl, aralkyl, cycloalkyl or cycloalkenyl, or R10W together form a leaving group or a hydroxyl;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)N 34, S(O)2or S(O)2NR35; R32, R34and R35means independently hydrogen or alkyl, and R33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R7means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - and di-alkyl, the amino group, killingray or aryl(alkyl)amino group), or R8and R9together form =CR82R83(where R82and R83means independently hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl).

Unless specified otherwise, the following terms used in the specification and in the claims, have the following values:

"Acyl" means a radical-C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl, where the alkyl, cycloalkyl, cycloalkenyl and phenylalkyl are as defined here, or in addition, these that are in particular compounds listed in the attached tables or described in the examples. It is clear that these R dicale can be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Examples include, but are not limited to this, formyl, acetyl, cyclohexylcarbonyl, cyclohexylcarbonyl, benzoyl, benzylcarbamoyl and the like.

"Alluminare" means a radical-NR'r C(O)R, where R' denotes hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl, where the alkyl, cycloalkyl, cycloalkenyl and phenylalkyl are as defined here, or in addition, these that are in particular compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Examples include, but are not limited to this, formylamino, acetylamino, cyclohexylcarbodiimide, cyclohexyloxycarbonyloxy, benzoylamino, benicarbenicar, and the like.

"Alkoxy" means a radical-OR where R is alkyl, as defined here, or in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear, is that these radicals can also be combined into a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, a methoxy group, ethoxypropan, propoxylate, butoxypropan and the like.

"Alkyl" means a saturated monovalent hydrocarbon radical with a straight chain containing from 1 to 6 carbon atoms, or a saturated monovalent hydrocarbon radical branched chain containing from 3 to 6 carbon atoms, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like.

"Alkylene" means an unsaturated divalent hydrocarbon radical with a straight chain containing from one to six carbon atoms, or an unsaturated divalent hydrocarbon radical branched chain, containing from three to six carbon atoms, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, about waywayway only those radicals, which mainly used only in the first or second turn or simultaneously, for example, methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl-propylene, butylene, pentile and the like.

"Allylthiourea" means a radical-SR where R is alkyl, as defined above, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, methylthiourea, ethylthiourea, PropertyGroup, butylthiourea and the like.

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical or, alternatively, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, which optionally independently substituted by one or more substituents, preferably one, two or three substituents, preferably selected from the group consisting of alkyl, g is droxia, alkoxyl, haloalkyl, haloalkoxy, Y-C(O)-R (where Y is absent or is alkalinous group and R is hydrogen, alkyl, haloalkyl, haloalkoxy, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), heteroalkyl, heteroskedacity, peterealkiller, halogen, nitro, langroup, amino, monoalkylamines, dialkylamines, alkylsulfonyl, generalsearchonline.com, sulfamido, methylendioxy, Ethylenedioxy, heterocyclyl or geterotsiklicheskikh or, in addition, of the radicals included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, methoxyphenyl, 2-forfinal, 2,4-differenl, 1-naphthyl, 2-naphthyl and derivatives thereof.

"Alloctype" means a radical-OR where R is aryl as defined here, or in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only glad the Kala which mainly used only in the first or second turn or simultaneously, for example, fenoxaprop.

"Aryloxyalkyl" means the radical R-C(=O)-, where R is aryloxy group, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, phenoxycarbonyl.

"Cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon radical containing from three to seven carbon atoms in the ring, and, furthermore, the radicals within the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group that includes only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl and the like.

"Cycloalkenyl" means a radical-RaRbwhere Rais alkalinous group and Rbis cycloalkyl group, as defined here, or in addition, it is the radicals that are included in any specific the e connection listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group that includes only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, cyclohexylmethyl and the like.

"Substituted cycloalkyl" means cycloalkyl radical, as defined here, with one, two or three (preferably one) of the hydrogen atoms with the ring atoms independently substituted by langroup or-Y-C(O)R (where Y is absent or is alkalinous group and R is hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl, amino, monoalkylamines, dialkylamines or optionally substituted phenyl), or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group that includes only those radicals, which are primarily used only in the first or second turn or simultaneously.

"Dialkylamino" means a radical-NRR'where R and R' independently represent alkyl, hydroxyalkyl, cycloalkyl or cycloalkenyl group, as defined here, or in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in PR the measures. It is clear that these radicals can also be combined in a group that includes only those radicals, which are primarily used only in the first or second turn or simultaneously. Examples include, but are not limited to this, dimethylamino, methylethylamine-, di(1-methylethyl)amino, (methyl) (hydroxymethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino group and the like.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

"Haloalkyl" means alkyl substituted by one or more identical or different halogen atoms, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, -CH2Cl-CF3, -CH2CF3, -CH2CCl3and similar to them.

"Heteroalkyl" means an alkyl radical, as defined here, in which one, two or three hydrogen atoms replaced by Deputy, is independently selected from the group consisting of-ORa-, N(O)nRbRc(where n oznachaet or 1, if Rband Rcmean both independently from each other alkyl, cycloalkyl or cycloalkenyl, and 0 if not), and-S(O)nRd(where n denotes an integer from 0 to 2), having in mind that heteroalkyl radical attached via a carbon atom, where Rameans hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently of one another denote hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl, cycloalkenyl, alkylsulfonyl, aminosulfonyl, mono - or di-alkylaminocarbonyl, aminoalkyl, mono - or di-acylaminoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkyl-sulfonyl or alkoxycarbonyl; and when n is 0, Rdmeans hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl, and when n is 1 or 2, Rdmeans alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl, an amino group, allmenalp, monoalkylamines or dialkylamines or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Examples include the, but do not limit these, 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 and the like.

"Geterofullereny" means the group Ra-C(=O)-, where Rameans heteroalkyl group or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Typical examples include acetylsalicyloyl, aminomethylpropanol, 4 atomic charges-2,2-dimethylbutan-2-oil, 2-amino-4-methylpentan-2 oil and similar groups.

"Heterouncinata" means the group Ra-O-, where Rameans heteroalkyl group or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which is what's mostly used only in the first or second turn or simultaneously. Typical examples include IU-C(=O)-O-CH2-O and similar groups.

"Heteroalicyclic" means the group Ra-C(=O), where Rais getrealcursorpos or, alternatively, that the constituent groups in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Typical examples include 1-acetyl-Oxymetazoline (IU-C(=O)-O-CH2-O-C(=O)-) and similar groups.

"Heteroaryl" means a monovalent monocyclic or bicyclic radical with 5-12 ring atoms, having at least one aromatic ring containing one, two or three ring heteroatoms selected from nitrogen, oxygen or sulfur, the remaining ring atoms are carbon, provided that the joining point of the heteroaryl radical is an aromatic ring, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. heteroarenes the ring optionally substituted independently by one or more substituents, preferably one or two selected from alkyl, haloalkyl, heteroalkyl, hydroxyl, alkoxyl, halogen, nitro or langroup or, in addition, deputies, members of the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydro-benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, tetrahydroquinoline, ethanolic, benzimidazolyl, benzisoxazole or sensational, imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazoles and their derivatives.

"Heteroalkyl" means a radical-RaRbwhere Rais alkalinous group and Rbis a heteroaryl group, as defined here, or in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group is at, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, pyridine-3-ylmethyl, imidazolylalkyl, pyridinylmethyl, 3-(benzofuran-2-yl)propyl and the like.

"Heterooligomeric cycloalkyl" means cycloalkyl radical, as defined here, where one, two or three hydrogen atoms in cycloalkyl radical substituted heteroalkyl group, implying that heteroalkyl radical associated with cycloalkyl radical carbon-carbon bond, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Typical examples include, but are not limited to this, 1-hydroxymethylglutaryl, 2-hydroxyethylcellulose and the like.

"Heterothermy cycloalkyl" means cycloalkyl radical, as defined here, where one, two or three hydrogen atoms in cycloalkyl radical is substituted by the Deputy, is independently selected from the group consisting of hydroxyl, alkoxyl, amino, acylamino, monoalkylamines, dialkylamines, the carbonyl group (C=O), aminogroup, oxyimino =NOH), NR'r SO2Rd(where R' denotes hydrogen or alkyl and Rdmeans alkyl, cycloalkyl, hydroxyalkyl, amino, monoalkylamines or dialkylamines), -X-Y-C(O)R (where X is oxygen or NR', Y means alkylen or absent, R is hydrogen, alkyl, haloalkyl, alkoxyl, amino, monoalkylamines, dialkylamines or optionally substituted phenyl, and R means hydrogen or alkyl), or-S(O)nR (where n denotes an integer from 0 to 2), such that when n is 0, R is hydrogen, alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl or thienyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl, thienyl, amino, acylamino, monoalkylamines or dialkylamines or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Typical examples include, but are not limited to this, 2-, 3-or 4-hydroxycyclohexyl, 2-, 3-or 4-aminocyclohexanol, 2-, 3 - or 4-methanesulfonamido-cyclohexyl and the like, preferably 4-hydroxycyclohexyl, 2-amino-cyclohexyl or 4-methanesulfonyl is hexyl.

"Heterothermy cycloalkenyl" means the radical RaRb-where Rameans heterothermy cycloalkenyl radical and Rbmeans alkilinity radical, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously.

"Heterocyclic amino group" means a saturated monovalent cyclic group of 4 to 8 atoms in the ring in which one ring atom is nitrogen and the remaining atoms in the ring are carbon, or, in addition, those atoms that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Typical examples include piperidine and pyrrolidine.

"Heterocyclyl" means a saturated or unsaturated non-aromatic cyclic radical with 3-8 atoms in the ring, in which one or two ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)n(where n is the integer from 0 to 2), the remaining ring atoms are carbon, and one or two carbon atoms may optionally be replaced by a carbonyl group, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Heterocyclyl ring may be optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, halogen, nitro, langroup, lanakila, hydroxyl, alkoxyl, amino, monoalkylamines, dialkylamines, aralkyl, -(X)n-C(O)R (where X is oxygen or NR', n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxyl (when n is 0), alkoxyl, amino, monoalkylamines, dialkylamines 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 haloalkyl, and R' and R" denote independently hydrogen or alkyl), or-S(O)nR (where n denotes an integer from 0 to 2), such that when n is 0, R is hydrogen, alkyl, cycloalkyl or cycloalkenyl, and, when n denotes 1 or 2, means alkyl, cycloalkyl, cycloalkenyl, amino, acylamino, monoalkylamines, dialkylamines or heteroalkyl, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. More specifically, the term heterocyclyl includes, but is not limited to this, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinil, N-methylpyrrolidine-3-yl, 3-pyrrolidinyl, morpholinyl, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, 4-(1,1-dioxotetrahydrofuran-2H-dipiradol), pyrrolidyl, imidazolyl, N-methanesulfonamido-4-yl, and their derivatives, or in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously.

"Geterotsiklicheskikh" means a radical-RaRbwhere Rameans alkylenes group, and Rbmeans heterocyclyl group, as defined above, or, in addition, it is the radicals that are included in oncrete connection listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, tetrahydropyran-2-ylmethyl, 2 - or 3-piperidinylmethyl, 3-(4-methylpiperazin-1-yl)propyl and the like.

"(Heterocyclyl)(cycloalkyl)alkyl" means an alkyl radical in which two hydrogen atoms replaced by heterocyclyl group and cycloalkyl group, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously.

"(Heterocyclyl)(heteroaryl)alkyl" means an alkyl radical in which two hydrogen atoms replaced by heterocyclyl group and heteroaryl group, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or at the same time.

"Heterocyclisation" means spirolateral consisting of cycloalkyl rings and heterocyclic rings, where each ring contains 5 to 8 ring atoms and two rings have only one common carbon atom, implying that the accession heterocyclisation radical is carried out according cycloalkyl ring. Spirolateral is formed when two hydrogen atoms on the same carbon atom cycloalkyl radical substituted heterocyclyl group, as defined here, or in addition, those radicals that are specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, and may be optionally substituted by alkyl, hydroxyl, hydroxyalkyl or exography, or, in addition, radicals within the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Examples include, but are not limited to this, the example 1,4-dioxaspiro[4.5]Decan-8-yl, 1,3-diazaspiro[4.5]-decane-8-yl, 2,4-dione-1,3-diazaspiro[4.5]Decan-8-yl, 1,5-dioxaspiro[5.5]undecane-9-yl, (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5.5]undecane-9-yl and the like.

"Hydroxyalkyl" means an alkyl radical, as here defined, substituted by one or more, preferably one, two or three hydroxyl groups, provided that to the same carbon atom are not attached to more than one hydroxyl group, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously. Typical examples include, but are not limited to this, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethyl-ethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxy-propyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly, as referred to in the context, the term "hydroxyalkyl" is used to define a subset of heteroalkyl the s group.

"Leaving group" has the meaning usually ascribed to it in synthetic organic chemistry, i.e. it is an atom or group capable of being substituted by a nucleophile, it includes halogen (e.g. chlorine, bromine and iodine), alkane-sulfonyloxy, arenesulfonates, alkylcarboxylic (for example, acetoxy), arylcarboxamide, methyloxirane, tailorshop, triftormetilfullerenov, alloctype (for example, 2,4-dinitrophenoxy), a methoxy group, N,O-dimethylhydroxylamine and the like, preferably group specifically shown in the examples.

"Monoalkylamines" means the radical other, where R is alkyl, hydroxyalkyl, cycloalkyl or cycloalkenyl group, as defined above, or, in addition, it is the radicals that are included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously, for example, methylaminopropyl, (1-methylethyl)amino group, hydroxymethylamino, cyclohexylamino, cyclohexylethylamine, cyclohexylethylamine and the like.

"Optionally substituted phenyl" means a phenyl ring, the cat is itself optionally substituted independently by one or more substituents, preferably one or two substituents selected from the group consisting of alkyl, hydroxyl, alkoxygroup, haloalkyl, haloalkoxy, heteroalkyl, halogen, nitro, langroup, amino, methylenedioxy, Ethylenedioxy and acyl, or, in addition, of the radicals included in the specific compounds listed in the attached tables or described in the examples. It is clear that these radicals can also be combined in a group, covering only those radicals, which are primarily used only in the first or second turn or simultaneously.

"Pharmaceutically acceptable excipient" means an excipient that is suitable for the preparation of a pharmaceutical composition that is generally safe, non-toxic and not junk either biologically or for any other reason, and includes a filler, which is acceptable for veterinary use, as well as for pharmaceutical applications for people. The term "pharmaceutically acceptable excipient", as used in the specification and in the claims includes both one and more than one, of these fillers.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the source is connected to who I am. Such salts include: (1) acid additive salts formed with inorganic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with 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, econsultation, 1,2-ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluensulfonate, camphorsulfonate, 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 acid and the like; or (2) salt formed so that the acidic proton present in the original connection, or somedays is a metal ion, for example, an alkali metal ion, alkali earth metal ion, or an aluminum ion; or forms a coordination bond with an organic base, such as, for example, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

The terms "Pro-drug" and "prodrug" are used herein interchangeably and refer to any compound which releases an active parent compound according to formulas I or II in vivo when such prodrug is administered to a mammal. Prodrugs of the compounds of formula I or II are obtained when modifying one or more functional groups present in the compound of formula I or II, in such a way that the modification (s) may be cleaved in vivo to release the parent compound. Prodrugs include compounds of formulas I and II, where the hydroxyl, amino, sulfhydryl group, a carboxyl group or a carbonyl group in the compound of formula I or II is associated with any group that may be cleaved in vivo to regenerate the free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to these, esters (for example, derivatives of acetates, dialkylaminomethyl, formate, phosphate, sulphate and benzoate) and carbamates (for example, N,N-dimethylamino-carbonyl) for hydroxylysyl functional groups, ester group (for example, a complex of ethyl esters, esters of morpholinoethyl) carboxyl functional groups, N-ACI-derivatives (e.g. N-acetyl) bases of manniche, Schiff bases and enaminones functional amino groups, oximes, acetals, ketals and enologia esters for ketone and aldehyde functional groups in compounds of formula I or II and the like, see Bundegaard, H. "the Creation of prodrugs" p. 1-92, ed. Elesevier, New York-Oxford (1985).

"Protective group" refers to a group of atoms which when joined to a reactive group in a molecule masks, reduces or prevents its reactivity. Examples of protective groups can be found in the book T.W.Green and P.G.Futs "Protective groups in organic chemistry", (Wiley, 2nd ed. 1991) and Harrison and Harrison and others, Compendium of Synthetic Organic Methods, volume 1-8 (ed. John Wiley and Sons, 1971-1996). Typical aminosidine groups include formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl (CBZ), tert-butoxy-carbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), triphenylmethane and substituted triphenylmethane group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NVOC) and the like. Typical protective groups for hydroxyl groups include those where the hydroxyl group or allyawan, or alkylated,such as, for example, a simple benzyl or triphenylmethyl esters, as well as simple alkalemia esters, simple tetrahydropyranyloxy esters, simple trialkylsilyl esters and simple allyl ethers.

"Treating" or "treatment" of a disease includes: (1) preventing the disease, that is, prodding the clinical symptoms of the disease did not develop in a mammal that may be susceptible or predisposed to the disease, but had not experienced disease or who have not yet manifested symptoms of the disease; (2) suppression of the disease are mild or reducing the development of the disease or its clinical symptoms; or (3) facilitation of the disease, that is, promoting regression of the disease or its clinical symptoms.

"Therapeutically effective amount" means an amount of compound that, when introduced to a mammal for treating a disease, is sufficient for effective treatment of the disease. "Therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc. being treated mammal.

When the image of the structural formulas in the present description "N" is represented with only one or two links in relation to the rest of the structure or "On" is represented with only one link to the firm in relation to the rest of the structure, the person skilled in the art will understand that in the case of "N" is two or one atom "H", respectively, and in the case Of a one-atom "N" are present in the formula, but not shown a computer program used for drawing structures, for example, ISISDraw. Therefore, "N" represents-NH2", "N" represents-NH-and-O is "HE".

Although the most detailed description of the invention presented in the summary of the invention, the specific aspects described below.

One aspect of the present invention provides a compound of formula I:

where R1, R3, W, Z, X1and Ar1are as defined above in the brief description of the invention.

Preferably W means NR2more preferably NH.

Preferably Z means n

Preferably X1means Oh or CH2more preferably O.

Preferably Ar1means optionally substituted phenyl, optionally substituted furyl or optionally substituted thienyl. More preferably Ar1means optionally substituted phenyl, in particular 2-substituted, 4-substituted or 2,4-disubstituted. Even more preferably Ar1means monopolization phenyl (for example, 2-chlorophenyl, 2-forfinal or 4-forfinal), monoalkylphenol (for example, 2-meth is fenil), dialogization phenyl (for example, 2,4-differenl), dialkylphenol (for example, 2,4-dimetilfenil or 2,6-dimetilfenil), 2,4-disubstituted phenyl (e.g. 4-fluoro-2-were, 2-fluoro-4-were) or preferably also monopolization and monoalkylamines phenyl.

Preferably R1means aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh. More preferably R1means heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl or heterocyclic. Especially preferred example of heteroalkyl R1is hydroxyalkyl, 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 and 2-hydroxy-2-methylpropyl or 1,3-dimethyl-3-hydroxybutyl and, in addition, 3-hydroxy-1(R)-3-dimethylbutyl or 3-hydroxy-1(S)-3-dimethylbutyl or radicals of the specific examples listed in the attached tables or in the specific examples. Particularly preferred examples heterocyclyl radical R1include tetrahydro-2H-Piran-4-yl, 1-(methylsulphonyl)piperidine-4-yl and 1,1-dissidocerida-2H-thiopyran-4-yl or a radical of the specific examples, the PE chislennyh in the attached tables or specific examples. Specific examples of R1include 4-hydroxycyclohexyl, tetrahydro-2H-Piran-4-yl, 1-(methylsulphonyl)piperidine-4-yl, cyclopentyl, (S)-(2-hydroxy-1,2-dimethyl)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, 2-morpholino-2-(pyridin-4-yl)ethyl, 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-oxo propyl, (1-(piperidine-1-yl)cyclohexyl)methyl, 3-methoxypropyl, cyclobutyl, 1-(accoutability)piperidine-4-yl, 4-methoxy-cyclohexyl, 2-cyclohexylethyl, (2-methylthiazole-5-yl)methyl, imidazo[2,1-b]thiazo the-6-ylmethyl, hydrogen, 4-phenylbutyl, 2-(4-AMINOPHENYL)ethyl, pyridin-3-yl, tetrahydro-2H-thiopyran-4-yl, and (1-hydroxymethyl)butyl, or radicals of the specific examples listed in the attached tables or in the specific examples.

Preferably R3means alkyl, aryl, cycloalkyl or heteroalkyl, more preferably alkyl or cycloalkyl and even more preferably methyl or propyl or cyclopropyl.

Another aspect of the invention provides compounds of formula II

or their pharmaceutically acceptable salts, where:

Z denotes N or CH;

W means NR2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl), or C=O;

Ar1means aryl or heteroaryl;

R1means hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh, -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or mean alkylenes group, and R11means hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), (heterocyclyl) (cyclo alkyl)alkyl or (gets recycler)(heteroaryl)alkyl;

R2means hydrogen or alkyl;

R7means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - and di-alkylamino, killingray or aryl(alkyl)amino group),

where R1, R3, W, Z, X1and Ar1have the above values.

Preferably W means NR2more preferably NH.

Preferably Z means n

Preferably X1means Oh or CH2more preferably O.

Preferably Ar1means optionally substituted phenyl, optionally substituted furyl or optionally substituted thienyl. More preferably Ar1means optionally substituted phenyl, in particular 2-substituted, 4-substituted or 2,4-disubstituted. Even more preferably Ar1means monopolization phenyl (for example, 2-chlorophenyl, 2-forfinal or 4-forfinal), monoalkylphenol (for example, 2-were), dialogization phenyl (for example, 2,4-differenl), dialkylphenol (for example, 2,4-dimetilfenil or 2,6-dimetilfenil), 2,4-disubstituted phenyl (e.g. 4-fluoro-2-were, for-4-were) or preferably also monopolization and monoalkylamines phenyl.

Preferably R1means aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh. More preferably R1means heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl or heterocyclic. Specific examples of R1include 4-hydroxycyclohexyl, tetrahydro-2H-Piran-4-yl, 1-(methylsulphonyl)piperidine-4-yl, cyclopentyl, (S)-(2-hydroxy-1,2-dimethyl)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, 2-morpholino-2-(pyridin-4-yl)ethyl 3-furylmethyl, 1 oxido-tetrahydro-2H-thiopyran-4-yl, 1-phenylpropyl, 1,1-dissidocerida-2H-thiopyran-4-yl, phenethyl, 4-(2-hydroxyethyl)phenyl, 3-(4-methylpiperazin-1-yl)propyl, 4-hydroxybutyl, 3 morpholino propyl, 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, who Tyl, 5-methylpyridin-2-yl, propyl, methyl, cyclopropyl, (1-hydroxymethyl-3-methylthio)propyl, (1-hydroxymethyl)cyclopentyl, 1,1-dimethylpropyl, 3 ethoxy-3-oxo propyl, (1-(piperidine-1-yl)cyclohexyl)methyl, 3-methoxypropyl, cyclobutyl, 1-(oxo-ethoxymethyl)piperidine-4-yl, 4-methoxycyclohexyl, 2-cyclohexylethyl, (2-methyl-thiazol-5-yl)methyl, imidazo[2,1-b]thiazole-6-ylmethyl, hydrogen, 4-phenylbutyl, 2-(4-AMINOPHENYL)ethyl, pyridin-3-yl, tetrahydro-2H-thiopyran-4-yl, and (1-hydroxymethyl)-butyl.

Preferably R8and R9means independently hydrogen, alkylsulfonyl or -- C(O)-R81where R81means monoalkylamines.

Other preferred variants of implementation of the present invention further include the following:

(i) a compound of formula I or II

or their pharmaceutically acceptable salt,

where:

Z denotes N or CH;

W means NR2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6independently mean hydrogen or alkyl), or C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R2means hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxyalkyl, geterofullereny, heteroalicyclic or-R21-R22where R21means alkylene or-C(=O and R 22means alkyl or alkoxyl;

R1means hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroalkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh, R12-SO2-heterocyclization (where R12means haloalkyl, aryl, aralkyl, heteroaryl or heteroalkyl), -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or mean alkylenes group, and R11means hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl)(heteroaryl)alkyl;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)NR34, S(O)2or S(O)2NR35; R32, R34and R35means independently hydrogen or alkyl, and R33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - or dialkylamino, arylamino - or aryl(alkyl)amino group), or R8and R9together form =CR82R83(where R82and R83means independently hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl). Or their pharmaceutically acceptable salts.

(ii) Compound as defined in (i), formula I or II

or their pharmaceutically acceptable salt,

where:

Z denotes N or CH;

W means NR2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen);

X2means Of;

Ar1means aryl;

R2means hydrogen, alkyl, acyl;

R1means hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl, geterotsiklicheskikh, R12-SO2-heterocyclization the PU (where R 12means haloalkyl, aryl, aralkyl, heteroaryl), -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or mean alkylenes group, and R11means alkoxyl), (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl)(heteroaryl)alkyl;

R3means alkyl, cycloalkyl, aryl, amino, monoalkylamines, dialkylamino group; and

R8and R9means independently hydrogen, alkylsulfonyl, -C(O)-R81where R81means monoalkylamines, or their pharmaceutically acceptable salts.

(iii) the Compound as set forth in (i), where:

Z denotes N or CH;

W means NR2or;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl), or C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R2means hydrogen or alkyl;

R1means hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh, -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or mean alkylenes group, and R11means hydrogen, alkyl, haloalkyl, hydro the forces, alkoxyl, amino, monoalkylamines or dialkylamines), (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl)(heteroaryl)alkyl;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, C(O)NR34, S(O)2or S(O)2NR35; R32, R34and R35means independently hydrogen or alkyl; and R33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R7means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - or dialkylamino, arylamino - or aryl(alkyl)amino group), or R8and R9together form =CR82R83(where R82and R83means independently hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl).

iv) Compound, as set out in (ii), where Ar1means not aryl, and heteroaryl.

(v) a Compound as defined in (iii), formula I, where:

Z denotes N;

W means NR2;

X1means O, S, or CR5R6(where R5and R6means independently hydrogen);

X2means Of;

Ar1means aryl;

R2means hydrogen or alkyl;

R1means hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl, geterotsiklicheskikh, -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or mean alkylenes group, and R11means alkoxyl, (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl)(heteroaryl)alkyl;

R3means alkyl, cycloalkyl and aryl.

(vi) Compound, as is well established in any of the sections (i) to (v), formula I or formula II, preferably of formula I.

(vii) Connection, as clearly established in any of the sections (i) to (vi), where Z denotes n

(viii) Connection, as clearly established in any of the sections (i) to (vii), where W denotes NH.

(ix) Connection, as clearly established in any of the sections (i) to (viii), where Ar1means optionally substituted phenyl.

(x) Connection, as clearly established in any of the sections (i) to(ix), where X1means Oh or CH2.

(xi) Connection, as clearly established in any of the sections (i) to (x), where X1means Acting

(xii) Connection, as clearly established in any of the sections (i) to (x), where R1means aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh.

(xiii) Connection, as clearly established in any of the sections (i) to (xii), where R1means heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl or heterocyclic.

(xiv) Connection, as clearly established in any of the sections (i) to (xiii), where R1means heterocyclyl.

(xv) Connection, as clearly established in any of the sections (i) to (xiii), where R1means heteroalkyl.

(xvi) Connection, as clearly established in any of the sections (i) to (xv), where R1means hydroxyalkyl.

(xvii) Connection, as clearly established in any of the sections (i) to (xvi), where Ar1mean 2-substituted phenyl, 4-substituted phenyl or 2,4-disubstituted phenyl.

(xviii) Connection, as clearly established in any of the sections (i) to (xvii), where Ar1mean 2-chlorophenyl, 2-forfinal, 2-were, 4-fluoro-2-were or 2,4-differenl.

(xix) Connection, as clearly established in any of the sections (i) to (viii), where X2means Acting

(XX) Connection, as clearly established in any of the sections (i) to (xviii), where X2mean NR7.

(xxi) Connection, as clearly established in any of the sections (i) to (XX), where R3means methyl, ethyl, propyl, cyclopropyl, amino group, dimethylaminopropyl, methylisobutylcarbinol, propylamino, substituted with halogen phenyl, for example, forfinal, preferably methyl, propyl or cyclopropyl, most preferably methyl.

(xxii) Connection, as clearly established in any of the sections (i) to (xxi), of the formula II, where R8means hydrogen and R9means alkyl, alkylsulfonyl, or -- C(O)-R81(where R81means alkyl, alkoxyl, alloctype, amino, monoalkylamines or dialkylamines), preferably R9means hydrogen, alkylsulfonyl, -C(O)-R81where R81is monoalkylamines.

(xxiii) the Connection, as specified in (xxi), where Ar1means 2,4-differenl and R1means tetrahydro-2H-Piran-4-yl, ie, 6-(2,4-divergence)-8-methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-he.

(xxiv) the Connection, as specified in (xxi), where Ar1means 2,4-differenl and R1means tetrahydro-2H-Piran-4-yl, ie, 6-(2,4-divergence)-8-propyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-he.

(xxv) Soy is inania, as specified in (xxi), where Ar1means 2,4-differenl and R1means tetrahydro-2H-Piran-4-yl, ie, 6-(2,4-divergence)-8-cyclopropyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-he.

(xxvi) the Connection, as specified in (xxi), where Ar1means 2,4-differenl and R1means 1,3-dimethyl-3-hydroxybutyl, ie, 6-(2,4-divergence)-2-(3-hydroxy-1,3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-he.

(xxvii) the Connection, as specified in (xxvi), which is 6-(2,4-divergence)-2-(3-hydroxy-1(S),3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one.

(xxviii) the Connection, as specified in (xxvi), which is 6-(2,4-divergence)-2-(3-hydroxy-1(R),3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one.

(xxix) Connection, as is well established in (i) or (ii), formula I, where R2means acyl, alkoxycarbonyl, aryloxyalkyl, geterofullereny, heteroalicyclic or-R21-R22where R21means alkylene or-C(=O) and R22means alkyl or alkoxyl.

(xxx) Connection, as specified in (xxix), where R1means heteroalkyl or heterocyclyl.

(xxxi) the Connection, as specified in (xxx), where R1means heterocyclyl.

(xxxii) Connection, as clearly established in any of the sections from (xxix) to (xxxi), where X1means On, X2 means Of and R3means methyl.

(xxxiii) Connection, as clearly established in any of the sections from (xxx) to (xxxii), where R2means acyl.

(xxxiv) Connection, as clearly established in any of the sections from (xxix) to (xxxiii), where Ar1means 2,4-differenl, R1means tetrahydro-2H-Piran-4-yl and R2means acetyl.

(xxxv) a Compound of the formula I' or II"

where:

Z denotes N or CH;

W means S, S(O), S(O)2or;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl), or C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R10means alkyl, aryl, aralkyl, cycloalkyl or cycloalkenyl, or

R10W together form a leaving group or a hydroxyl;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)NR34, S(O)2or S(O)2NR35; R32, R34and R35means the independent what about hydrogen or alkyl and R 33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R7means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino, mono - and dialkylamino, arylamino - or aryl(alkyl)amino group), or R8and R9together form =CR82R83(where R82and R83means independently hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl).

(xxxvi) the Composition, including, if desired, pharmaceutically acceptable excipient and one or more compounds identified in sections (i) to (xxxiv), or their pharmaceutically acceptable salts.

(xxxvii) the Manner of deriving sulfide of the formula:

where:

Z denotes N or CH;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, CR5R6(where R5and R6means independently hydrogen or alkyl) or C=O;

X2means Of;

Ar1means aryl or heteroaryl;

R is alkyl or aryl;

R3means bodoro is, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, acyl, alkylene-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)NR34, S(O)2or S(O)2NR35; R32, R34and R35means independently hydrogen or alkyl, and R33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl);

the above method involves the following stages:

the interaction of the aldehyde of the formula:

with aryl derivative of the formula

,

where X3means-C(=O)-OR', and R' is alkyl, under conditions suitable to obtain a sulfide compound.

(xxxviii) the Method as set forth in (xxxvii), where Z, X1, Ar1or R3are as defined in any of the sections (i) to (xxxiv).

(xxxix) the Method as set forth in (xxxviii), where R3means hydrogen.

(xxxx) Method, as set forth in any section of (xxxvii) to (xxxix), further comprising receiving sulfonylurea compounds of the formula:

where R, Z, R3X1X2and Ar1are as well established in any of the sections from (xxxvii) to (xxxix), including processing mentioned sulfide compounds in oxidative conditions with the aim of obtaining mentioned sulfonylurea connection.

(xxxxi) Method, specified in (xxxx), which referred to the oxidizing conditions include the use of m-chlormadinone acid (MSRA), Oksana®, periodate or species peroxide rhenium.

(xxxxii) a Method of obtaining the compounds of formula I, as clearly established in any of the sections (i) to (xxxiv), which includes stages:

interaction of the compounds of formula IV:

where Z, R3X1X2and Ar1are as well established in any of the sections (i) to (xxxiv); and

L is a leaving group;

with the amine R1R2NH, where R1and R2have the same meanings as R1and R2in any of the sections (i) to (xxxiv), in the conditions of the reactions of nucleophilic substitution.

(xxxxiii) the Method according to (xxxxii), where L means RS(O)nwhere R is an alkyl or phenyl group and n is an integer from 0 to 2.

(xxxxiv) Compound as defined in any of the sections (i) to (xxxiv), whenever it is received in a manner specified in (xxxxii).

(xxxxv) Connection, as set forth in (xxxv), whenever it is received in a manner specified in any of sections from (xxxvii) to (xxxx).

(xxxxvi) Application connection, as the mouth is beleno in any of the sections (i) to (xxxiv) or (xxxxiv) for the preparation of a medicinal product for treating disorders, oposredstvovanii R specifically, when mentioned oposredstvovanii R infringement is arthritis, Crohn's disease, irritable bowel syndrome, respiratory distress syndrome of adults or chronic obstructive pulmonary disease, or so referred to oposredstvovanii R infringement is Alzheimer's disease.

(xxxxvii) a Method of treating indirectly R violations, namely, when mentioned oposredstvovanii R infringement is arthritis, Crohn's disease, irritable bowel syndrome, respiratory distress syndrome of adults or chronic obstructive pulmonary disease, or when referred to oposredstvovanii R infringement is Alzheimer's disease involving the introduction of a patient in need of such treatment an effective amount of a compound as defined in any of the sections (i) to (xxxiv) or (xxxxiv).

Compounds of the present invention may exist in resolutiony forms, as well as in solvated, including hydrated forms. Usually solvated forms, including hydrated equivalent nonsolvated forms and assume that they are covered by the scope of the present invention. In addition to the above compounds, the compounds of the present invention includes all tautomeric forms. In addition, this is completed with the invention also includes all pharmaceutically acceptable salts of these compounds together with proletarienne forms of the compounds and all stereoisomers, if they are in pure chiral form or in the form of a racemic mixture, or a mixture of different forms.

The compounds of formula I and II can also form pharmaceutically acceptable acid salt additive. All these forms are covered by the scope of the present invention.

Pharmaceutically acceptable acid additive salts of compounds of formulas I and II include salts derived from inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, Hydrobromic, idiscovered, phosphorous acids and the like, as well as salts derived from organic acids, such as aliphatic mono - and dicarboxylic acids, phenylsilane alkanovykh acids, hydroxyl-containing alkanovykh acids, arcangioli acids, aromatic acids, aliphatic or aromatic sulfonic acids, etc. Such salts thus include sulfate, persulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, secondary acid phosphate, monopotassium phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, kaprilat, isobutyrate, oxalate, malonate, salt of succinic acid, salt, cork acid, salt sabatinovka acid, fumarate, maleate, salt almond acid, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, Mal is at, tartrate, methanesulfonate and the like. Also discusses salts of amino acids, as, for example, arginate and the like and gluconate, galacturonic (see, for example, Berge S.M., and others, "Pharmaceutical salts", J. Of Pharmaceutical Science, 1977, 66, 1-19).

Acid additive salts of the basic compounds can be obtained by the reaction of compounds as free base with a sufficient amount of the desired acid for the preparation of salts accepted way. The compound in the form of free base can be regenerated in the usual way when interacting compounds in the form of a salt with a base. The form of the free bases differ from the corresponding forms in the form of salts to some extent, certain physical properties, such as solubility in polar solvents, but, on the other hand, the salts are equivalent to their respective free base for the purposes of the present invention.

According to another aspect of the invention provides intermediate compounds of the formula I' and II", suitable for producing compounds of formulas I and II.

where:

Z denotes N or CH;

W means S, S(O), S(O)2or;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl), Il is C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R10means alkyl, aryl, aralkyl, cycloalkyl or cycloalkenyl, or R10W together form a leaving group or a hydroxyl;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino-, monoalkylamines, dialkylamines or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)NR34, S(O)2or S(O)2NR35; R32, R34and R35means independently hydrogen or alkyl, and R33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R7means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - and dialkylamino, arylamino - or aryl(alkyl)amino group), or R8and R9together form =CR82R83(where R82and R83independent means who indicate hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl).

The compounds of formula I' and II", where W means that, can be obtained by hydrolysis of the preceding sulfones, such as, for example. If, 2e, IIIg, presented in the following schemes 1 to 4, in boiling aqueous acetic acid or aqueous hydroxide to obtain a hydroxyl-containing compounds (i.e. compounds I' and II", where R10W stands for a hydroxyl). The resulting hydroxyl-containing compound can be proaccelerin with R10-L, where L is a leaving group, to obtain compounds of the formula I' and II", where W stands for O and R10is as described. Alternatively, the sulfonic group in the previous sulfone can be directly substituted alcohol R10As described in the international patent application WO 96/33798, to obtain the compounds of formulas I and II, where W stands for O and R10is as described. The compounds of formula I' and II", where R10W form a leaving group, such as halogen, can be obtained by treatment of the precursor, where R10W stands for a hydroxyl, halogenation agent, such as phosphorus oxychloride or bromacil phosphorus. The compounds of formula I' and II", where R10W form a leaving group, such as, for example, acetoxy, tailorshop etc. can be obtained PR is processing a previous connection, where R10W is hydroxyl, allermuir or sulfonylureas means, respectively.

Compounds of the present invention can be obtained in a variety of ways. In one embodiment of the present invention is a method of obtaining compounds of formula I, where Z denotes N, is depicted in figure 1 below. Note that, although the scheme is often identifies specific patterns, the methods of the present invention is widely applicable to similar compounds of the formula I or II, if provided the right solution to protect or unprotect reactive functional groups by methods standard in the field of organic chemistry. For example, a hydroxyl group to prevent unwanted side reactions, it is sometimes necessary to turn into a simple or complex esters when carrying out chemical reactions at other sites of the molecule. The protective group of the hydroxyl then removed to obtain the free hydroxyl group. Similarly, the amino and carboxyl groups can be converted into the corresponding derivatives to protect them from unwanted side reactions. Typical protective groups and methods for their joining and splitting are described in detail in the previously included references T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, new York, 1999, and Harrison and Harrison and others, Compendium of Synhetic Organic Methods, volumes 1-8 (John Wiley and Sons, 1971-1996).

Treatment of compounds of formula Ia primary amine (R3-NH2) leads to the compound of formula Ib. This reaction is usually carried out in a solvent which is inert under the reaction conditions, preferably in a halogenated aliphatic hydrocarbon, in particular, in dichloromethane, optionally halogenated aromatic hydrocarbon, or a simple ester with open-chain or cyclic, such as, for example, tetrahydrofuran, formamide or lower alkanol. Usually the reaction is carried out at a temperature of from about -20°C to about 120°C.

The recovery of the compounds of formula Ib leads to an alcohol of formula Ic. This recovery is usually carried out by applying alumoweld lithium, in a way well known to specialists in this field (for example, in a solvent inert under the conditions of recovery, preferably it is a simple ether with open-chain or cyclic simple ether, in particular tetrahydrofuran, at a temperature of from about -20°With up to about 70°C, preferably at a temperature of from approximately 0°C to room temperature).

Oxidation of the alcohol of formula Ic leads to carboxaldehyde formula Id. The oxidation is usually carried out using manganese dioxide, although can also be applied to numerous other ways (see, for example, Advanced Organic Chemistry, 4th ed., March, John Wiley & Sons, new York (1992)). Depending on the applied oxidizing agent, the reaction is usually conducted in a solvent inert to the specific oxidation conditions, preferably in a halogenated aliphatic hydrocarbon, in particular, in dichloromethane, or optionally halogenated aromatic hydrocarbon. Accordingly, the oxidation is carried out at a temperature of from approximately 0°With up to about 60°C.

The reaction carboxaldehyde formula Id with a complex ether, Ar1-X1CH2-CO2R' (where R' represents an alkyl group and Ar1and X1are as set out above), in the presence of a base leads to the compound of formula Ie. Can be applied any, in General, dinucleophiles base, including carbonates, such as potassium carbonate, lithium carbonate and sodium carbonate; bicarbonates, such as potassium bicarbonate, lithium bicarbonate and sodium bicarbonate; amines, such as, for example, secondary and tertiary amines, and attached to the resin amines, such as, for example, 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine. Usually the reaction is carried out in a solvent, relatively polar but inert under the reaction conditions, preferably in amide, as, for example, dimethylformamide, N-substituted, pyrrolidino, in particular, 1-methyl-2-pyrrolidinone, at a temperature of about at° With up to 150°C.

Oxidation Ie oxidizing agent, for example, nagkalat, as, for example, 3-chlormadinone acid (i.e., MSRWA) or axonom® leads to sulfone (If), which can be converted into different target compounds. Typically, the oxidation Ie is carried out in a solvent inert under the conditions of oxidation. For example, when used MSRWA as oxidizing agent, the solvent is preferably halogenated aliphatic hydrocarbons, in particular chloroform. When the oxidant is used Oxon®, the solvent is preferably methanol, aqueous ethanol or aqueous tetrahydrofuran. The reaction temperature depends on the used solvent. In the case of an organic solvent, the reaction temperature is usually about -20°With up to about 50°C, preferably from approximately 0°C to room temperature. When the solvent used water, the reaction temperature is usually from approximately 0°With up to about 50°C, preferably from approximately 0°C to room temperature. Alternatively, the oxidation can be carried out in a catalytic conditions using reagents based on rhenium/peroxide, see ("Oxidation of sulfoxidov hydrogen peroxide catalyzed by methyltrioxorhenium(VII)", Lahti, David W.; Espenson, James H., Inorg. Chem. (2000) 39 (10), str-2167; "Oxo-it is plexi rhenium in the catalytic oxidation", Catal. Today (2000) 55 (4), page 317-363, and "a Simple and efficient method of obtaining the N-oxides of pyridine", Coperet, Christophe; Adolfsson, Hans; Khuong, Tinh-Alfredo V.; Yudin, Andrei K.; Sharpless, K. Barry, J. Org. Chem. (1998) 63 (5), str-1741).

The reaction of the compound If with the amine (R1-NH2) leads to compounds of the formula I' (i.e., compounds of formula I, where W stands for NH). Further alkylation of I' then leads to compounds of formula I, where W means NR2where R2means alkyl. The reaction can be carried out in the presence or absence of a solvent. Usually the reaction is carried out at a temperature of from approximately 0°With up to about 200°S, more preferably approximately at a temperature of from room temperature to about 150°C. Alternatively, in some cases, not to use sulfon If sulfide Ie or the corresponding sulfoxide may be subjected to reaction directly with the amine (R1-NH2) to obtain the compounds of formula I'.

Accordingly, the present invention provides a method for producing compounds of formula I by treating compounds of General formula Ie, If, or the corresponding sulfoxide Amin (R1-NH2) and, optionally, reaction of the resulting product with R2-L, where R2means alkyl and L is a leaving group.

The compounds of formula I, where R3means amino, monoalkylamines, dialkylamines or NR -Y3-R33can be obtained as shown in scheme 2, from the corresponding 2-alkylthio-8-amino-[2,3-d]pyridopyrimidines-7(8H)-it (IV, Z=N) or 7-alkylthio-1-amino-1,6-naphthiridine-2-it (IV, Z=CH), shown in scheme 2, by amination using O-diphenyl-fosforilirovaniya.

Scheme 2

Substitution sulfide (or the corresponding sulfoxide or sulfone) Amin R1NH2as previously described for compound Ie in figure 1, leads to compounds of formula I (compounds of formula I, where Z denotes CH, and R2means hydrogen). The interaction of the resulting product with R2-L, where R2means alkyl and L is a leaving group leads to compounds of formula I, where R2means alkyl.

The compounds of formula I, where Z denotes CH, can be obtained as shown in scheme 3.

4-Amino-3,6-dibromopyridine (Den Hertog and others, Rec. Trav. Chim. Pays-Bas,6485-100 (1945)) is treated with nutrientlimited and receive a 4-amino-3-bromo-6-methylthiopyridine (stage a, see Windscheif, P; Voegtle, F.; Synthesis, 87092 (1994). Methylthiopyridine are combined by the Heck reaction under the catalysis of PD (e.g., palladium acetate) in the presence of a base (such as potassium acetate or tributylamine) with complex vinyl ether 2A to obtain the compounds of formula 2b (see Dong,Y.; Busacca, S. J. Org. Chem.. 62. 6464-65 (1997)). The circuit loop in basic conditions leads to a 1.6-naphthyridine formula 2C. Alkylation 2C-haloalkyl (or any other alkylating agent R3-X, where X is a leaving group) leads to 1-alkilirovannami naphthyridine formula 2d. Oxidation of 2d and substitution sulfone Amin R1NH2as described previously for compound Ie in figure 1, leads to compounds of formula II (compound of formula I, where Z denotes CH, and R2means hydrogen). Reaction of the resulting product with R2-L, where R2means alkyl and L is a leaving group leads to compounds of formula I, where R2means alkyl. An alternative method presented in scheme 3A.

Such is the way of synthesis described in example 88.

The compounds of formula II can be obtained, as shown in figure 4.

The reaction carboxaldehyde formula Id (R3means hydrogen) with nitrile, Ar1-X1CH2CN (where Ar1and X1are as defined above), in the presence of a base under conditions similar to those described for the conversion Id Ie in figure 1, leads to the compound of formula IIIe. The compounds of formula IIIe can be consistently proaccelerin, proanimirovany or subjected to sulfonylamino using alquiler the operating means, golodnikov carboxylic acids, isocyanates, anhydrides and haloalkaliphilic to obtain the compounds of formula IIIf, where R8and R9are as described in the summary of the invention. Subsequent oxidation IIIf and substitution sulfone Amin R1NH2as described previously for compound Ie in figure 1, leads to compounds of formula III'. Further reaction of the resulting product with R2-L, where R2means alkyl and L is a leaving group, to obtain compounds of formula II, where R2means alkyl.

The person skilled in the art it is clear that we propose certain modifications to the above schemes, which are covered by the scope of the present invention. For example, some stages will include the application of protective groups for functional groups that are incompatible with certain reaction conditions.

Compounds of formulas I and II and pharmaceutically acceptable salts of basic compounds of formula I and II with acids can be used as medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered enterline, for example, orally in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, through the nose, for example, in view of the nasal aerosols, or through the rectum, for example, in the form of suppositories. However, they can also be injected parenterally, for example, in the form of injection solutions.

The compounds of formula I and II and their aforementioned pharmaceutically acceptable salts can be processed with pharmaceutically inert organic or inorganic carriers for preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and similar compounds can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like compounds; however, depending on the nature of the active ingredient is not normally required media in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, semi-solid or liquid polyols and the like substances.

The pharmaceutical preparations can also contain preservatives, soljubilizatory article shall militatry, wetting means, emulsifiers, sweeteners, colorants, gives taste substances, salts for modifying the osmotic pressure, buffers, masking means or antioxidants. They may also contain therapeutically valuable substances, other than the compounds of formula I and II and their aforementioned pharmaceutically acceptable salt.

Pharmaceutical preparations containing a compound of formula I or II or pharmaceutically acceptable salt of the compound of formula I or II with acid in combination with a compatible pharmaceutical carrier are also an object of the present invention, as a method of obtaining such drugs, which involves combining one or more of these compounds or salts and, if desired, one or more other therapeutically valuable substances in herbal form for injection together with a compatible pharmaceutical carrier.

As mentioned earlier, the compounds of formula I and II and their aforementioned pharmaceutically acceptable salts can be used according to the invention as therapeutically active substances, especially as anti-inflammatory drugs or to prevent transplant rejection after surgical transplantation. The dose can vary within wide limits and in each case is chosen to head the dependence on individual requirements. Usually, in the case of adults suitable daily dose should be from about 0.1 mg/kg to about 100 mg/kg, preferably from about 0.5 mg/kg to about 5 mg/kg Daily dose may be entered as a single dose or in separate doses and, in addition, the upper dose limit referred to above may be exceeded, if they consider that there is reading.

Finally, it is also an object of the invention is the use of compounds of formulas I and II and their aforementioned pharmaceutically acceptable salts for the preparation of drugs, especially for the treatment or prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, for the treatment of asthma, Central nervous system disorders or complications of diabetes, or to prevent transplant rejection after surgical transplantation.

The compounds of formula I or II pretend to be useful, but is not limited to this, for the treatment of any disorders or conditions in human or other mammal, which is exacerbated or called excessive or unregulated produced TNF or kinase R such a mammal. Accordingly, the present invention provides a method of treating indirectly cytokine disease is, which includes the introduction of effective, suppressing cytokine amounts of compounds of formula I or its pharmaceutically acceptable salt, or its tautomer.

The compounds of formula I and II want to be helpful, but is not limited to this, for the treatment of inflammation in a subject, and for use as antipyretics to treat fevers. Compounds according to the invention can be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and disease Steele and other arthritic condition. Such compounds may be useful for the treatment of lung disorders or inflammation of the lungs, including respiratory distress syndrome in adults, pulmonary sarcoidosis, asthma, silicosis, and chronic pneumonia. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, sepsis caused by gram-negative bacteria, malaria, meningitis, cachexia as a result of infection or malignant disease, cachexia as a result of the syndrome of acquired immunolo deficiency (AIDS), AIDS, ARC (complex related to AIDS), pneumonia, and herpes virus. The compounds are also useful for treatment of diseases associated with bone resorption is, for example, osteoporosis, endotoxic shock, toxic shock syndrome, disorders of reperfusion, autoimmune disease, including the reaction of the recipient to the graft and allograft rejection, cardiovascular disease including atherosclerosis, thrombosis, congestive heart failure, cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgia due to infection.

The compounds are also useful for the treatment of Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), conditions associated with the skin, such as psoriasis, eczema, burns, dermatitis, education keloid zone and the formation of scar tissue. In addition, the compounds according to the invention is useful in the treatment of gastrointestinal diseases, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds are also suitable for the treatment of ophthalmic diseases, such as retinitis, retinopathy, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds can also be applied in the treatment of angiogenesis including neoplasia, metastasis, ophthalmic diseases, as, for example, rejection of a corneal transplant, ocular revascularization is, retinal revascularization, including revascularization after 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 hemangiomas of infants, angiofibroma of the nasopharynx and avascular bone necrosis, diabetic nephropathy and cardiomyopathy, disorders of the reproductive system in women, such as endometriosis. The connection can also be used to prevent the production of cyclooxygenase-2.

In addition, they are suitable for the treatment of humans, these compounds are also useful in veterinary medicine for the treatment of domestic animals, exotic animals and farm animals, including mammals, rodents, and the like. Preferred animals include horses, dogs and cats.

Presents compounds can also be used for joint therapies, partially or completely, instead of other conventional anti-inflammatory drugs, such as together with steroids, inhibitors of cyclooxygenase-2, nonsteroidal anti-inflammatory drugs (NSAIDs), DMARDS, suppressing immune system means, an inhibitor of 5-lipoxygenase, antagonists LTB4and inhibitors hydrolases LTA4.

Used herein, the term "mediated R violation" refers to any or all violations and painful condition, which plays a role R or by self-regulation, or causing the release of another factor, such as, but not limited to, IL-1, IL-6 or IL-8. A painful condition in which, for example, IL-1 is the main component and the production or effect or it is secreted in response to R could therefore be considered as indirect R violation.

TNF-β structurally homologous to TNF-α (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis and TNF-αand TNF-β inhibited by compounds of the present invention and, thus, in the context of them together referred to as "TNF"unless specifically defined otherwise.

EXAMPLES

If the e specified otherwise, all temperatures, including the melting point (i.e., TPL), are given in degrees Celsius (°).

Example 1: get a 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) in 250 ml of dichloromethane at 0°C was slowly added a solution of methylamine in ethanol (33%, 35 ml, 281 mmol). After stirring for 30 minutes was added water (150 ml) and the phases were separated. The organic phase was dried by magnesium sulfate and filtered. The filtrate was evaporated in vacuum, 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

Alumoweld lithium (8,2 g, 215 mmol) was stirred in anhydrous tetrahydrofuran (300 ml) at 5°and treated dropwise with a solution of ethyl ester of 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid (46 g, 215 mmol) in anhydrous tetrahydrofuran (450 ml). The reaction mixture was stirred 15 minutes and was added cautiously dropwise water (18 ml). The reaction mixture was stirred 30 minutes and then was added dropwise an aqueous solution of sodium hydroxide (15%, 8,5 ml)and then water (25,5 ml). The resulting suspension was stirred 17 hours at room temperature and then filtered. The residue after filtration was washed with tetrahydrofuran (2x, 100 ml) and the combined filtrate and wash solution was evaporated under reduced pressure. The residue is suspended in ethyl acetate/hexane-1/2 (200 ml) and the solid was filtered and dried, was given 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) and 1 l of dichloromethane were combined with stirring and treated with manganese dioxide (87 g, 1 mol). The resulting suspension was stirred for 24 hours and then filtered through celite. The filter residue was washed with dichloromethane (100 ml) and the combined filtrate and wash solution was evaporated under reduced pressure, got to 15.8 g of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde in a solid white color.

Example 2: Obtain 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde

4 Cyclopropylamino-2-methylthiopyrimidin-5-carboxaldehyde was obtained as described in example 1 (stage a), from ethyl EPE is 4-chloro-2-methylthio-pyrimidine-5-carboxylic acid (Aldrich Chemical Co.) and cyclopropylamine (Aldrich Chemical Co.).

Example 3: Obtaining 4-[(4-forfinal)amino]-2-(methylthio)pyrimidine-5-carboxaldehyde

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

Example 4: obtain the methyl ester of 2-ftordesoxyglucose acid

To a solution of 2-terfenol (6,72 g, 60 mmol) in 50 ml of 1-methyl-2-pyrrolidinone was added methyl ether bromoxynil acid (6,24 ml, 65,92 mmole) and potassium carbonate (9,9 g, 72 mmole). The reaction mixture was stirred 12 hours at room temperature and then poured into water. The aqueous solution was extracted with ethyl acetate, washed with water and dried (saturated salt solution, sodium sulfate). Evaporation of the organic solvent led to 10.5 g of the corresponding acetate (spectral data were consistent with those for known from literature connections).

Example 5: Receiving methyl ether (phenylthio)acetic acid

To a solution of thiophenol (1,09 g of 9.9 mmole) in 25 ml of 1-methyl-2-pyrrolidinone was added methyl ether bromoxynil acid (1.1 ml, 12 mmol) and potassium carbonate (2.0 g, 14.5 mmol). The reaction mixture was stirred 12 hours at on the th temperature and then poured into water. The aqueous solution was extracted with ethyl acetate, washed with water and dried (saturated salt solution, sodium sulfate). Evaporation of organic solvents resulted in 1.2 g of the corresponding acetate (spectral data were consistent with those for known from literature connections).

Example 6: obtain the ethyl ester of 3-(2-forfinal)propanoic acid

Stage A:

To a solution of (2E)-3-(2-forfinal)prop-2-ene acid (10.0 g, a 9.9 mmole) in 100 ml of ethanol was added sulfuric acid (0.2 ml). The reaction mixture is boiled under reflux for 5 hours and then cooled to room temperature. The reaction solution is evaporated to 1/4 of the original volume and poured into water. Extraction of the mixture with ethyl acetate, and then dried (saturated salt solution, sodium sulfate) and evaporation led to a complex ether, which is used to stage B.

Stage B:

Ester (from step A) was dissolved in 50 ml ethanol was added a catalytic amount of palladium on coal. The reaction mixture was first made in hydrogenator Parra for 6 hours at room temperature. Filtering the reaction mixture through a layer of celite, subsequent evaporation of the solvent under reduced pressure resulted in a value of 9.8 g of forproperty (spectral data were consistent with those known for the CSOs from literature connections).

Example 7: Obtain 6-phenoxy-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]-pyrimidine-7(8H)-she (sulfon 1)

Stage a: Obtaining 6-phenoxy-8-methyl-2-(thiomethyl)pyrido[2,3-d]-pyrimidine-7(8H)-it

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (10 g, 54,6 mmole) and methyl ester phenoxyalkanoic acid (Aldrich, 11.4 g, 68,6 mmole) in 150 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (14 g, 101,4 mmole). The reaction mixture was heated to 120°and after 12 hours was added advanced phenoxyacetate (3, 6.0 g, 36,1 mmole) and potassium carbonate (6.0 g, 44 mmole). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and was added water (300 ml). The solution was stirred for 1 hour and filtered. The resulting solid was chromatographically (SiO2, ethyl acetate/hexane 50/50 to ethyl acetate 100%) and then was isolated by evaporation of the solvents, received 5 g of the sulfide (mass spectrum /MS/: M+1=300).

Stage B: Obtaining 6-phenoxy-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]-pyrimidine-7(8H)-she (sulfon 1)

Sulfide (5,07 g, 17.8 mmole) was dissolved in 100 ml of methylene chloride was added 3-chlormadinone acid (77%, 5.9 g, 24 mmole). The mixture was stirred at room temperature for 12 to 16 hours, filtered and then amywali aqueous solution of sodium sulfite (2, 75 ml), then saturated sodium bicarbonate solution (2, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and evaporated under reduced pressure. The resulting solid was chromatographically (SiO2, ethyl acetate/hexane 80/20) and then was isolated by evaporation of the solvents, were obtained 3.0 g of the sulfone (MS: M+1=332).

Example 8: Obtain 6-(2-pertenece)-8-methyl-2-(methylsulphonyl)pyrido-[2,3-d]pyrimidine-7(8H)-she (sulfon 2)

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

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26,2 mmole) and methyl ester 2-ftordesoxyglucose acid (5.9 g, 32 mmole) in 50 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (6.0 g, 43.5 mmole). The reaction mixture was heated to 120°and after 12 hours was added to phenoxyacetate (2.0 g, 10.8 mmole) and potassium carbonate (2.0 g, 15 mmol). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and was added water (700 ml). The solution was stirred for 45 minutes and filtered. The resulting solid was washed with water (2x 100 ml) and was added to ethyl acetate (100 ml), and stirred 1 hour. The solid was then isolated by filtration and dried, received 6,4 who sulfide (MS: M+1=318, tPL234-236°).

Stage B: Obtain 6-(2-pertenece)-8-methyl-2-(methylsulphonyl)pyrido-[2,3-d]pyrimidine-7(8H)-she (sulfon 2)

Sulfide (6.3 g, 20,5 mmole) was dissolved in 50 ml of methylene chloride was added 3-chlormadinone acid (77%, to 9.9 g, a 44.2 mmole). The mixture was stirred at room temperature for 12 to 16 hours, then washed with an aqueous solution of sodium sulfite (2, 75 ml), then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and was evaporated. The resulting solid residue was stirred with ethyl ether for 1 hour and filtered, received sulfon (MS: M+1=350, tPL158-162°).

Example 9: Obtain 6-(3-pertenece)-8-methyl-2-(methylsulphonyl)pyrido-[2,3-d]pyrimidine-7(8H)-she (sulfon 3)

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

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 26,2 mmole) and methyl ester 3-ftordesoxyglucose acid (0,61 g, 3.3 mmole) in 5 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (0.6 g, 4.3 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount of phenoxyacetate (0.3 g, 1.5 mmole) and potassium carbonate (04 g 2.9 mmole). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and water was added (100 ml). The reaction mixture was extracted with ethyl acetate (2x, 75 ml) and the resulting organic solution was washed with water (5 x 50 ml), then dried (saturated solution of salt, magnesium sulfate). Evaporation of the solution gave a solid residue that was recrystallized (ethyl acetate/hexane), was obtained 1.0 g of sulfide (MS: M+1=317).

Stage B: Obtain 6-(3-pertenece)-8-methyl-2-(methylsulphonyl)pyrido-[2,3-d]pyrimidine-7(8H)-she (sulfon 3)

Sulfide (1,02 g, 3.2 mmole) was dissolved in 25 ml of methylene chloride was added 3-chlormadinone acid (77%, 1.7 g, 9.6 mmole). The mixture was stirred at room temperature for 16 hours, diluted with methylene chloride (25 ml), then washed with an aqueous solution of sodium sulfite (3, 50 ml), then saturated aqueous sodium bicarbonate (3x 50 ml). The organic solution was then dried (saturated solution of salt, magnesium sulfate) and was evaporated, was obtained 0.64 g of the sulfone (MS: M+1=349).

Example 10: Obtain 6-(2,6-divergence)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 4)

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

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To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26,2 mmole) and methyl ester of 2,6-differentsialnoi acid (prepared as in example 4, using 2,6-diferena, 5.9 g, 32 mmole) in 50 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (6.0 g, 43.5 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount of phenoxyacetate (2, 2.0 g, 10.8 mmole) and potassium carbonate (2.0 g, 15 mmol). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and was added water (70 ml). The solution was stirred 30 minutes and filtered. The resulting solid was washed with water (2x), ethyl acetate and diethyl ether. The solid is then dried, was obtained 7.0 g of the sulfide (MS: M+1=336, tPL247-250,7°).

Stage B: Obtain 6-(2,6-divergence)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 4)

Sulfide (7.0 g, 20.8 mmole) was dissolved in 50 ml of methylene chloride was added 3-chlormadinone acid (77%, and 11.5 g, 51,5 mmole). The mixture was stirred at room temperature for 16 hours, filtered, then washed with an aqueous solution of sodium sulfite (2, 75 ml), then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and UPrev the Lee. The resulting solid residue was stirred in diethyl ether for 1 hour and filtered, was obtained 5.5 g of the sulfone (MS: M+1=368, tPL215,2-216,4°).

Example 11: Obtain 6-(2,4-divergence)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 5)

Stage A: Obtain 6-(2,4-divergence)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-it

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26,2 mmole) and methyl ester of 2,4-differentsialnoi acid (obtained as in example 4, using 2,4-diferena, 5,4 g, 29 mmol) in 50 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (6.0 g, 43.5 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount of phenoxyacetate (2.5 g, to 13.4 mmole) and potassium carbonate (2.5 g, 18 mmol). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and water was added (100 ml). The solution was stirred for 45 minutes and filtered. The resulting solid was washed with water (3x) and was added to ethyl acetate (75 ml), stirred for 1 hour. The solid was then isolated by filtration and dried, was received with 6.1 g of the sulfide (MS: M+1=336, tPL175,2-176,9°C).

Stage B: Obtain 6-(2,4-divergence)-8-methyl-2-(methylsulphonyl)-pyrido,3-d]pyrimidine-7(8H)-she (sulfon 5)

Sulfide (6.0 g, 20,5 mmole) was dissolved in 50 ml of methylene chloride was added 3-chlormadinone acid (77%, 9.3 g, 41.5 mmole). The mixture was stirred at room temperature for 16 hours, then washed with an aqueous solution of sodium sulfite (2, 75 ml), then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and was evaporated. The resulting solid residue was stirred in diethyl ether for 1 hour and filtered, received sulfon (MS: M+1=368, tPL177,2-178,5°).

Example 12: Obtain 6-(2-chlorophenoxy)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 6)

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

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (5.5 g, 30 mmol) and methyl ester 2-chlorophenoxyacetic acid (obtained as in example 4 using 2-chlorophenol, 7.0 g, 35 mmol) in 80 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (9.0 g, 65,2 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount of phenoxyacetate (2, 0.5 g, 2.5 mmole) and potassium carbonate (2, 2.0 g, 15 mmol). After 6 hours stirring at 120°With reactio the ing the mixture was cooled to room temperature and water was added (100 ml). The solution was stirred for 45 minutes and filtered. The resulting solid was filtered and washed with water (2x) and diethyl ether (2x). After drying the product in a vacuum Cabinet was obtained 9.0 g of sulfide (MS: M+1=334).

Stage B: Obtain 6-(2-chlorophenoxy)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 6)

Sulfide (8,9 g, to 26.7 mmole) was dissolved in 70 ml of methylene chloride was added 3-chlormadinone acid (77%, 13 g, 58 mmol). The mixture was stirred at room temperature for 16 hours, filtered, then washed with an aqueous solution of sodium sulfite (2, 75 ml), then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and was evaporated. The resulting solid residue was stirred with diethyl ether for 18 hours and filtered, was obtained 8.5 g of the sulfone (MS: M+1=366).

Example 13: Obtain 6-(4-chlorphenoxy)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 7)

Stage A: Obtain 6-(4-chlorphenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-it

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 3.0 mmole) and methyl ester 4-chlorophenoxyacetic acid (obtained as in example 4,using 4-chlorophenol, 0.66 g, 3.3 mmole) in 5 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (0.5 g, 3.6 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount of phenoxyacetate (0.3 g, 1.5 mmole) and potassium carbonate (0.4 g, 2.9 mmole). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and poured into water (100 ml). The reaction mixture was extracted with ethyl acetate (2x, 75 ml) and the resulting organic solution was washed with water (5 x 50 ml), then dried (saturated solution of salt, magnesium sulfate). Evaporation of the solution led to a solid substance, which was recrystallized (ethyl acetate/hexane), was obtained 0.55 g of the sulfide (MS: M+1=334).

Stage B: Obtain 6-(4-chlorphenoxy)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 7)

Sulfide (1.44 g, 4.3 mmole) was dissolved in 50 ml of methylene chloride was added 3-chlormadinone acid (77%, 2.2 g, 12.8 mmole). The mixture was stirred at room temperature for 16 hours, filtered, then washed with an aqueous solution of sodium sulfite (3, 75 ml), then saturated aqueous sodium bicarbonate (3x 50 ml). The organic solution was then dried (saturated solution of salt, magnesium sulfate) and was evaporated. The resulting solid residue was stirred with diethyl ether for 18 hours and filter the Ali, was obtained 0.7 g of the sulfone (MS: M+1=366).

Example 14: Getting 8-methyl-2-(methylthio)-6-(phenylthio)pyrido[2,3-d]pyrimidine-7(8H)-she (PBS 1)

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (549 mg, 3 mmole) and methyl ester (phenylthio)acetic acid (600 mg, 3.3 mmole) in 25 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (750 mg, 5.4 mmole). The reaction mixture was heated to 120°and after 12 hours it was cooled to room temperature, added water (50 ml). The aqueous mixture was extracted with ethyl acetate (75 ml), obtained organic solution was washed with water (2x, 50 ml) and dried (saturated salt solution, sodium sulfate). Evaporation of the solvent led to a solid substance, which was stirred with diethyl ether and hexane for 1 hour. Filtering of sediment caused to 0.67 g of the sulfide (MS: M+1=316).

Example 15: Obtain 6-[(4-forfinal)thio]-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-she (PBS 2)

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (0.55 g, 3 mmole) and methyl ester (4 forfinally)acetic acid (obtained as in example 5 using 4-portifino, 0.65 g, 3.3 mmole) in 25 ml of 1-methyl-2-pyrrolidinone added 1,3,4,6,7,8-hexahydro-2H-pyrimido(1,2-a)pyrimidine, associated with a polymer resin (Aldrich, 200 mg). Reaction the second mixture was heated to 120° C. After 12 hours, it was cooled to room temperature and added to water (50 ml). The aqueous mixture was extracted with ethyl acetate (75 ml), obtained organic solution was washed with water (2x, 50 ml) and dried (saturated salt solution, sodium sulfate). After evaporation of the solvent was obtained 0.95 g of the sulfide (MS: M+1=334).

Example 16: Obtain 6-(2-terbisil)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 8)

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

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26,2 mmole) and ethyl ester of 3-(2-forfinal)propanoic acid (5.7 g, 29 mmol) in 50 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (6.0 g, 43.5 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount of propanoate (1.5 g, 7.6 mmole) and potassium carbonate (3.0 g, 22 mmole). After 6 hours stirring at 120°C, the reaction mixture was cooled to room temperature and was added water (700 ml). The solution was stirred for 45 minutes and filtered. The resulting solid was washed with water (3x 50 ml) and was added to ethyl acetate (75 ml), stirred for 1 hour. The solid was then isolated by filtration and dried, received 7.5 g of sulfide (MS: M+1=316, t PL156-159°).

Stage B: Obtain 6-(2-terbisil)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 8)

Sulfide (7,4 g, 23.5 mmole) was dissolved in 50 ml of methylene chloride was added 3-chlormadinone acid (77%, and 11.5 g, 51 mmol). The mixture was stirred at room temperature for 16 hours, filtered and then washed with an aqueous solution of sodium sulfite (2, 75 ml), then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and was evaporated. The resulting solid residue was stirred in diethyl ether for 1 hour and filtered, received sulfon (MS: M+1=348, tPL153,8-154,4°C).

Example 17: Obtain 6-(4-terbisil)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 9)

Stage A: Obtain 6-(4-terbisil)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-it

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (4.8 g, 26,2 mmole) and ethyl ester of 3-(4-forfinal)propanoic acid (obtained as in example 6, 5.7 g, 29 mmol) in 50 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (6.0 g, 43.5 mmole). The reaction mixture was heated to 120°and after 12 hours was added an additional amount is propanoate (1.5 g, 7.6 mmole) and potassium carbonate (3.0 g, 22 mmole). After 6 hours stirring at 120°the reaction mixture was cooled to room temperature and water was added (100 ml). The solution was stirred for 45 minutes and filtered. The resulting solid was washed with water (2x) and then was isolated by filtration, dried, were obtained 6.5 g of sulfide (MS: M+1=316).

Stage B: Obtain 6-(4-terbisil)-8-methyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 9)

Sulfide (6.5 g, to 20.6 mmole) was dissolved in 50 ml of methylene chloride was added 3-chlormadinone acid (77%, to 10.1 g, 45 mmol). The mixture was stirred at room temperature for 16 hours, filtered and then washed with an aqueous solution of sodium sulfite (2, 75 ml), then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (saturated salt solution, sodium sulfate) and was evaporated. The resulting solid residue was stirred in diethyl ether for 1 hour and filtered, received 6.7 g of the sulfone (MS: M+1=348).

Example 18: Getting 8-cyclopropyl-6-(2-pertenece)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 10)

Stage A: Getting 8-cyclopropyl-6-(2-pertenece)-2-(methylthio)-pyrido[2,3-d]pyrimidine-7(8H)-it

Cyclopropyl ulfig received, using the procedure described in example 8 (stage A), from 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (example 2, 1,814 g, 8,67 mmole) and methyl ester of 2-pertenece-acetic acid (example 4, 1,756 g, at 9.53 mmole). The product is directly used in stage B.

Stage B: Getting 8-cyclopropyl-6-(2-pertenece)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 10)

Sulfide (3,02 g, 8.8 mmole) was dissolved in 50 ml of tetrahydrofuran, cooled to 0°and added dropwise Oxon (Aldrich, 10.8 g, to 17.6 mmole) in 50 ml of water, keeping the temperature constant. Upon completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Then added water (50 ml) and ethyl acetate (75 ml) and the reaction mixture was distributed between two phases. The organic layer was dried (saturated solution of salt, magnesium sulfate and after evaporation of the solvent was received and 2.26 g of the sulfone (MS: M+1=376).

Example 19: Obtain 6-(2-pertenece)-8-(4-forfinal)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 11)

Stage A: Obtain 6-(2-pertenece)-8-(4-forfinal)-2-(methylthio)-pyrido[2,3-d]pyrimidine-7(8H)-it

Florfenicol was obtained using the procedure described in example 8 (stage A), from 4-[(-forfinal)amino]-2-(methylthio)pyrimidine-5-carboxaldehyde (example 3, 1.22 g, 4.6 mmole) and methyl ester of 2-pertenece-acetic acid (example 4, 0,93 g, 5.7 mmole). The reaction product is directly used in stage B.

Stage B: Obtain 6-(2-pertenece)-8-(4-forfinal)-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-she (sulfon 11)

Sulfide (0.75 g, a 1.88 mmole) was dissolved in 20 ml of tetrahydrofuran, cooled to 0°and added dropwise Oxon (Aldrich, of 2.38 g, 3,88 mmole) in 20 ml of water, keeping the temperature constant. Upon completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Then added water (100 ml) and ethyl acetate (100 ml) and the reaction mixture was distributed between two phases. The organic layer was dried (saturated solution of salt, magnesium sulfate and after evaporation of the solvent was received of 0.77 g of the sulfone (MS: M+1=414, tPL82,3-91,5°).

Example 20: Obtaining 2-amino-6-(2-pertenece)-8-methylpurine[2,3-d] pyrimidine-7(8H)-it

A mixture of sulfone 2 (0,315 g, 0.9 mmole) and ammonia (0.5 M solution in 1,4-dioxane, 2 ml, 1 mmol) in 1 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 4 hours in nitrogen atmosphere. The reaction mixture was cooled, evaporated under reduced pressure and was purified by column chromatography (SiO2CH2Cl2/Meon - 99/1). After separation of the product by in the of pariwana solvents and drying was obtained 0.33 g of amine (MS: M+1=287, tPL240,8-242,6°).

Example 21: Obtain 6-(phenoxy)-8-methyl-2-(tetrahydro-2H-Piran-4-yl-amino)pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 1 (0.20 g, 0.6 mmole) and 4-aminotetrahydrofuran (provider Combi-Blocks, 0,183 g, is 1.81 mmole) in 0.2 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled, poured into water and was extracted with ethyl acetate (2x 50 ml). The organic solution was washed with water (5 x 50 ml) and dried (saturated solution of salt, magnesium sulfate). Evaporation of the solvent and addition of methanol followed by acidification (1 M HCl/Et2O, 1.5 EQ.) led to a hydrochloric salt, which was isolated as solids by filtration (0,166 g, MS: M+1=353).

Example 22: Obtain 6-(3-pertenece)-8-methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 3 (0.20 g, 0.57 mmole) and 4-aminotetrahydrofuran (provider Combi-Blocks, 0,173 g, 1,72 mmole) in 0.2 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled and was added methanol (0.2-0.5 ml). The product precipitated was isolated by filtration. Solid yellow color was transferred into a flask with methanol (5 ml). The dropwise addition of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) and subsequent stirring to use the e 15 hours led to a hydrochloric salt, which was allocated in the form of solids (0,129 g, MS: M+1=371).

Example 23: Obtain 6-(2,4-divergence)-8-methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 5 (0.20 g, 0.54 mmole) and 4-aminotetrahydrofuran (provider Combi-Blocks, 0,165 g, and 1.63 mmole) in 0.3 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled, poured into water and was extracted with ethyl acetate (2x 50 ml). The organic solution was washed with water (5x, 25 ml) and dried (saturated solution of salt, magnesium sulfate). Evaporation of the solvent and addition of methanol, and then hydrochloric acid in diethyl ether (1M, 1.5 EQ.) led to a hydrochloric salt, which was isolated as solids by filtration (0,180 g, MS: M+1=389).

Example 24: Obtain 6-(2-terbisil)-8-methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 8 (0.35 g, 1,01 mmole) and 4-aminotetrahydrofuran (provider Combi-Blocks, 0.35 g, 3,47 mmole) in 0.3 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled, poured into water and was extracted with ethyl acetate (2x 50 ml). The organic solution was washed with water (5x, 25 ml) and dried (saturated solution of salt, magnesium sulfate). Evaporation of the solvent and chromatography on a column (SiO2 CH2Cl2/Meon - 95/5) gave a product which was placed in a flask with methanol (5 ml). Was added dropwise hydrochloric acid in diethyl ether (1M, 1.5 EQ.), then stirred for 1 hour, received a hydrochloric salt, which was isolated as solids by filtration (0,299 g, MS: M+1=369, tPL198,4-201,6°).

Example 25: Obtain 6-[(4-forfinal)thio]-2-[(4-hydroxycyclohexyl)-amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfide 2 (of 0.333 g, 1.0 mmol) and TRANS-4-aminocyclohexanol (0,345 g, 3.0 mmole) in 0.3 ml of 1-methyl-2-pyrrolidinone was heated at 120°C for 24 hours. The reaction mixture was cooled, poured into water and stirred for 2 hours. The resulting solid was filtered, washed with water (2x) and dried. The product was transferred into a flask with methanol (5 ml) and added dropwise hydrochloric acid in diethyl ether (1M, 1.5 EQ.). Organic solvents were evaporated under reduced pressure and was added diethyl ether/methanol. Was stirred for 2 hours, then filtered and dried, received hydrochloric salt, which was isolated in the form of solids (0,286 g, MS: M+1=401, tPL246,2-of 247.5°).

Example 26: Obtain 6-(4-pertenece)-2-[(4-hydroxycyclohexyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of 4-terfenol is sulfide (see example 8, step A, 0.4 g of 1.26 mmole) and TRANS-4-aminocyclohexanol (0.7 g, 6.0 mmol) in 0.5 ml of 1-methyl-2-pyrrolidinone was heated at 120°C for 24 hours. The reaction mixture was cooled, poured into water and was extracted with ethyl acetate (2x 50 ml). The organic solution was washed with water (5x, 25 ml) and dried (saturated solution of salt, magnesium sulfate). Evaporation of solvent and chromatography (SiO2CH2Cl2/MeOH - 95/5) gave a product which was transferred into a flask with methanol (5 ml). Was added dropwise hydrochloric acid in diethyl ether (1M, 1.5 EQ.), then was stirred for 1 hour, received a hydrochloric salt, which was isolated as solids by filtration (0,286 g, MS: M+1=385, tPL253,2-253,9°).

Example 27: Obtain 6-(2-terbisil)-2-[(4-hydroxycyclohexyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 8 (0,348 g, 1.0 mmol) and TRANS-4-aminocyclohexanol (0.35 g, 3.0 mmole) in 0.35 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 30 minutes. The reaction mixture was cooled and added with stirring methanol (0.2-0.5 ml). The product precipitated and was isolated by filtration. The solid was transferred into a flask with methanol (5 ml). Was added dropwise a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.), then stirred for 30 minutes, got chloris vodorodnoy salt, which was allocated in the form of solids (0,233 g, MS: M+1=383, tPLof 229.5-230,2°).

Example 28: Obtain 6-(2-pertenece)-2-[(4-methoxycyclohexyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it:

Stage A: Obtain 6-(2-pertenece)-2-[(4-hydroxycyclohexyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.20 g, 1.15 mmole) and TRANS-4-aminocyclohexanol (0,123 g, 1.15 mmole) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 120°C for 17 hours. The reaction mixture was cooled to room temperature, evaporated in vacuo and was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5). Containing the product fractions were combined and evaporated, was obtained 0.20 g of product. The product was used directly in stage B.

Stage B: Obtain 6-(2-pertenece)-2-[(4-methoxycyclohexyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

To a suspension of freshly prepared silver oxide (filtered/ dried from an aqueous mixture of silver nitrate, of 0.44 g, 2,70 mmole) and sodium hydroxide (0.21 g, 5,20 mmole) in 2 ml of tetrahydrofuran were added pyrimidine-7(8H)-he (stage A, 0.2 g of 0.52 mmole) and methyl iodide (0,065 ml, was 1.04 mmole). After stirring at 50°within three days was added silver oxide and methyl iodide (0,ml, 15.7 mmole); the temperature rose to the boiling point and the reaction continued for two weeks. After this period the mixture was cooled to room temperature, evaporated and purified via column chromatography (SiO2CH2Cl2/MeOH/NH4OH 90/9/1). The fractions containing the product were combined and evaporated under reduced pressure, obtained free amine. The latter was dissolved in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.0 EQ.). The selection of the solid precipitate by filtration, washing with diethyl ether and drying led to 0,030 g hydrochloric salt (MS: M+1=399, tPL135,0-145,0°C).

Example 29: Obtain 6-(2-pertenece)-8-methyl-2-{[1-(methylsulphonyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it:

Stage A: Getting benzyl ester 1-benzylpiperidine-4-ylcarbamate acid

To a cooled to 0°With the solution of 4-amino-1-benzylpiperidine (41,2 g, 216,5 mmole) and triethylamine (51,3 ml, 369 mmol) in 600 ml of tetrahydrofuran was added dropwise benzyl ether of Harborview acid (31 ml, 217 mmol) for 30-45 minutes at this speed, so that the reaction temperature remained between 5°and 10°C. Upon completion of addition, the reaction mixture was allowed to warm to room temperature is ture and stirred for 12 hours. The solvent and low-boiling substances were removed under reduced pressure. Then added water (500 ml) and ethyl acetate (1.2 l) and the reaction mixture was distributed between two phases. The organic layer was washed saturated aqueous sodium bicarbonate (2x 150 ml) and then dried (saturated solution of salt, magnesium sulfate). Evaporation of the solvent resulted in liquid yellowish-brown color, which was purified by column chromatography (SiO2, EtOAc/hexane - 30/70 to EtOAc - 100)were 27.8 g amine in the form of a solid white color (MS: M+=324, tPL79,1-79,6°C).

Stage B: obtain the benzyl ether piperidine-4-ylcarbamate acid

Benzylamine (27.8 g, 85,7 mmole) was dissolved in 400 ml of methylene chloride at room temperature and was added dropwise via addition funnel 1-chloro-ethylchloride (25.4 g, 178 mmol) in 50 ml of methylene chloride. Upon completion of addition, the reaction mixture was stirred at room temperature for 3 hours. The solvent and low-boiling substances were removed under reduced pressure and was added methanol (500 ml). The reaction mixture is boiled under reflux with stirring for 1 hour and then cooled to room temperature. After evaporation of the reaction solution was given to 26.3 g of the corresponding proizvedeniya as not quite white solid (MS: M+1=235, tPL190,7-192,2°).

Stage: Obtain benzyl ester 1-(methylsulphonyl)piperidine-4-ylcarbamate acid

Protected piperidine (10 g, and 42.7 mmole) and triethylamine (12 ml, 86,7 mmole) was dissolved in 500 ml of methylene chloride at room temperature. Was added dropwise via an addition funnel methansulfonate (4,3 ml of 55.5 mmole) in 20 ml of methylene chloride. Upon completion of addition, the reaction mixture was stirred at room temperature for 3 hours. The solvent and low-boiling substances were removed under reduced pressure. Were added ethyl acetate (500 ml) and aqueous hydrochloric acid (0.5 M, 350 ml). The reaction mixture was distributed between two phases and the aqueous layer was removed. The organic layer was again washed with an aqueous solution of hydrochloric acid (0.5 M, 2x, 100 ml) and then saturated aqueous sodium bicarbonate (3x 100 ml). The reaction solution was then dried (saturated solution of salt, magnesium sulfate) and was evaporated under reduced pressure, was obtained 9.2 grams of methansulfonate (tPLof 148.6-152,8°).

Stage G: Obtain 1-(methylsulphonyl)piperidine-4-amine

Methanesulfonic (9.2 grams, of 29.5 mmole) was dissolved in 200 ml of tetrahydrofuran at room temperature in a round bottom flask with a capacity of 500 ml in a nitrogen atmosphere. Then was added palladium on coal (10%, 2-3 g) the reaction vessel was purged with hydrogen (3). The balloon of hydrogen was attached to the reaction flask and the solution was stirred 15 hours (if needed, adding more catalyst and filled the balloon with hydrogen). To the reaction mixture were added methylene chloride (100 ml) and filtered through a layer of celite. Evaporation of the solvent in vacuo resulted in 4,63 g of the desired amine (MS: M+1=179, tPL65,3-65,7°).

Stage D: Obtain 6-(2-pertenece)-8-methyl-2-{[1-(methylsulphonyl)-piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.2 g, 0.57 mmole) and 1-(methylsulphonyl)piperidine-4-amine (example 29, stages a-D, 0,243 g of 1.36 mmole) of 0.45 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled and was added methanol (0.2-0.5 ml). The product precipitated and was isolated by filtration. The solid was transferred into a flask with methanol (5 ml). Was added dropwise a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) and stirred received hydrochloric salt, which was isolated in the form of solids (0,143 g, MS: M+1=448).

Example 30: Obtain 6-(2-pertenece)-8-(4-forfinal)-2-{[1-(methylsulphonyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 11 (0.2 g, and 0.46 mmole) and 1-(methylsulphonyl)piperidine-4-amine (example 29, stages a-D, 0,112 g of 0.62 mmole) in 0.2 ml of 1 is ethyl-2-pyrrolidinone was heated at 110° C for 1 hour. The reaction mixture was cooled and was added ethyl acetate (40 ml). The reaction mixture is transferred, dried (saturated solution of salt, magnesium sulfate) and was evaporated, received a technical product. Purification by chromatography (SiO2, preparative thin-layer chromatography /TLC, ethyl acetate/hexane - 80/20), followed by extraction and evaporation under reduced pressure led to the free amine. This product was dissolved in methylene chloride and was added a solution of hydrochloric acid in diethyl ether (1M, 0.4 ml), then stirred. Hydrochloric salt was isolated by filtration in the form of solids and dried (0,13 g, MS: M+1=528, tPL223,4-225°).

Example 31: Obtain 8-cyclopropyl-6-(2-pertenece)-2-{[1-(methylsulphonyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 10 (0,361 g, 0.97 mmole) and 1-(methylsulphonyl)piperidine-4-amine (example 29, stages a-D, 0,262 g of 1.47 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was heated at 110°C for 2 hours. The reaction mixture was cooled and was added ethyl acetate (40 ml) and water (40 ml). The reaction mixture was distributed between the two layers and the aqueous layer is discarded. The organic layer was then dried (saturated solution of salt, magnesium sulfate) and was evaporated, received a technical product. Purification of this product by chromatography (SiOsub> 2, preparative TLC, ethyl acetate/hexane - 80/20) followed by separation and evaporation under reduced pressure led to the free amine. This product was dissolved in methylene chloride and was added a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.), then was stirred. Hydrochloric salt was isolated as solids by filtration and dried (0.27 g, MS: M+1=474).

Example 32: Obtain 6-(2-chlorophenoxy)-8-methyl-2-{[1-(methylsulphonyl)-piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 6 (0.2 g, 0.55 mmole) and 1-(methylsulphonyl)piperidine-4-amine (example 29, stages a-D, of € 0.195 g, 1.09 mmole) in 0.2 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled and was added methanol (1 ml). The product precipitated and was isolated by filtration. The solid was placed in a flask with methanol (5 ml). Was added dropwise a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) and stirred received hydrochloric salt, which was isolated in the form of solids (0,145 g, MS: M+1=465).

Example 33: Obtain 6-(4-chlorphenoxy)-8-methyl-2-{[1-(methylsulphonyl)-piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 7 (0.17 g, and 0.46 mmole) and 1-(methylsulphonyl)piperidine-4-amine (example 29, stages a-D, 0,164 g of 0.92 mmole) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 80° C for 3 hours. The reaction mixture was cooled and was added methanol (1 ml). The product precipitated (3 days) and was isolated by filtration. The solid residue was placed in a flask with methanol (5 ml). The dropwise addition of a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) followed by stirring led to a hydrochloric salt (0.2 g, MS: M+1=465).

Example 34: Obtain 2-(cyclopropylamino)-6-(2-pertenece)-8-methyl-pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.35 g, 1.0 mmole) and cyclopropylamine (1 ml, 14 mmol) was heated at 60°C for 8 hours in nitrogen atmosphere. The reaction mixture was cooled, evaporated in vacuo and was purified by column chromatography (SiO2, hexane/ethyl acetate : 3/2). The product is suspended in methanol, was added a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) and the reaction mixture was stirred for 30 minutes. Was isolated solid by filtration and dried, received hydrochloric salt (MS: M+1=327, tPL178,2-179,6°C).

Example 35: Obtain 2-(cyclopentylamine)-6-(4-pertenece)-8-methyl-pyrido[2,3-d] pyrimidine-7(8H)-it

A mixture of 4-perteneciente (see example 8 was replaced with methyl ether 4-ftordesoxyglucose acid methyl ester 2-ftordesoxyglucose acid - stage a-B, 0.4 g of 1.26 mmole) and cyclo is entellina (Aldrich, 0,146 g, 1,71 mmole) in 0.3 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled and was added methanol (1 ml). The product precipitated and was isolated by filtration. The solid was transferred into a flask with methanol (5 ml). Was added dropwise a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) and then was stirred received hydrochloric salt (0,165 g, MS: M+1=355).

Example 36: Obtain 2-(cyclopentylamine)-6-(3-pertenece)-8-methyl-pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 3 (0.2 g, 0.57 mmole) and cyclopentylamine (Aldrich, 0,146 g, 1,71 mmole) in 0.3 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 4 hours. The reaction mixture was cooled and was added methanol (1 ml). The product precipitated and was isolated by filtration. The solid was transferred into a flask with methanol (5 ml). The dropwise addition of a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ.) followed by stirring led to a hydrochloric salt (0,105 g, MS: M+1=355).

Example 37: Obtain 2-(butylamino)-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole) and butylamine (0,017 g to 0.17 mmole) in 0.2 ml of 1-methyl-2-pyrrolidinone was heated at 65°C for 12 hours. The reaction mixture was cooled, was added methanol/water (0/10, 1 ml), the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated under reduced pressure, received Amin is 0.019 g, MS: M+1=343).

Example 38: Obtain 6-(2-pertenece)-2-[(2-hydroxyethyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 2-aminoethanol (0.015 g, 0.2 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the chloroform was removed in the process of evaporation. Was added methanol/water (90/10, 1 ml), the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated under reduced pressure, received Amin (0,027 g, MS: M+1=331).

Example 39: Obtain 6-(2-pertenece)-2-(isobutylamino)-8-methyl-pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), isobutylamine (0,013 g of 0.18 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the chloroform was removed in the process of evaporation. Was added methanol/water (90/10, 1 ml), the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated under reduced pressure, received Amin (0,038 g, MS: M+1=343).

Example 40: Obtain 6-(2-pertenece)-2-{[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole) and (2S)-2-amino-3-methylbutane-1-ol (0,044 g, 0.43 mmole) in 0.1 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled, was added methanol/water (90/10, 1 ml), the formed precipitate. The product was washed with water, dissolved in methylene chloride, filtered through the drying (magnesium sulfate) and was evaporated under reduced pressure, received Amin (0,047 g, MS: M+1=373).

Example 41: Obtain 2-[(2,3-dihydroxypropyl)amino]-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole) and 3-aminopropane-1,2-diol (0,016 g of 0.18 mmole) in 0.1 ml of 1-methyl-2-pyrrolidinone was heated at 65°C for 3 hours. The reaction mixture was cooled, was added methanol/water (90/10, 1 ml), but the sediment is not excluded. So I deleted all the solvents by evaporation under reduced pressure, water was added (1 ml) and ethyl acetate (1 ml) and the product was distributed in the organic layer. The aqueous layer was removed and ethyl acetate was dried (magnesium sulfate) and evaporated, got amine (0,034 g, MS: M+1=361).

Example 42: Obtain 6-(2-pertenece)-8-methyl-2-[(2-piperidine-1-retil)amino]pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 2-piperidine-1-ylethylamine (0,022 g to 0.17 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours the Reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, received Amin level (0.041 g, MS: M+1=398).

Example 43: Obtain 2-[(cyclohexylmethyl)amino]-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), cyclohexylethylamine is 0.019 g, to 0.17 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, got amine (0,045 g, MS: M+1=383).

Example 44: Obtain 2-[(cyclopropylmethyl)amino]-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), cyclopropanemethylamine (0.02 g to 0.28 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated under reduced pressure, obtained amine (0.03 g, MS: M+1=341).

Example 45: Obtain 6-(2-pertenece)-2-[(2-methoxyethyl]amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 2-methoxyethylamine (0.02 g, a 0.27 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated under reduced pressure, obtained amine (0.04 g, MS: M+1=345).

Example 46: Obtain 2-{[3-(dimethylamino)propyl]amino}-6-(2-fluoro-phenoxy)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), N,N-DIMETHYLPROPANE-1,3-diamine (0,018 g of 0.18 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, got amine (0,045 g, MS: M+1=372).

Example 47: Obtain 6-(2-pertenece)-8-methyl-2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 1-(3-aminopropyl)pyrrolidin-2-it (0,024 g to 0.17 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. Prod the CT was washed with water, was dissolved in methylene chloride and evaporated, got amine (0,033 g, MS: M+1=412).

Example 48: Obtaining N-(2-{[6-(2-pertenece)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]amino}ethyl)ndimethylacetamide

A mixture of sulfone 2 (0.05 g, 0,143 mmole), N-(2-amino-ethyl)ndimethylacetamide (0,024 g of 0.18 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, got amine (0.035 g, MS: M+1-373).

Example 49: Obtain 6-(2-pertenece)-8-methyl-2-[(2-pyridin-3-retil)amino]pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 2-pyridine-3-ylethylamine (0,021 g to 0.17 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, got amine (0,039, MS: M+1=392).

Example 50: obtaining the ethyl ester of N-[6-(2-pertenece)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]-β-alanine

The hydrochloric salt of ethyl ether β-alanine (0053 g, 0,34 mmole) in 3 ml of chloroform at room temperature was added melamine-phenol-carbonate polymer (Argonaut Technologies Inc.; Foster City, California, USA, 0.45 g). All was stirred 1 hour and then was added sulfon 2 (0.05 g, 0,143 mmole). The temperature of the reaction mixture was brought to 65°C and stirred for 24 hours. The mixture is then cooled and the polymer was removed by filtration. Evaporation of solvent and chromatography (SiO2CH2Cl2/MeOH - 95/5) and subsequent evaporation of the corresponding fractions led to Amin (0,027 g, MS: M+1=387).

Example 51: Obtain 6-(2-pertenece)-2-[(3-methoxypropyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 3-methoxypropylamine (0.015 g, to 0.17 mmole) in 1.5 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Technical reaction mixture was purified by column chromatography (Supelco /company Sigma Aldrich, St. Louis, Missouri, USA/gasket 3 ml, SiO2CH2Cl2/MeOH 95/5) and subsequent evaporation, got amine (0,027 g, MS: M+1=359).

Example 52: Obtain 6-(4-chlorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it:

Stage A: Obtain tert-butyl ether (1S)-2-hydroxy-1,2-dimethyl-propellerbuying KIS is the notes

To a cooled to 0°With a solution of methyl ester of N-(tert-butoxycarbonyl)-L-alanine (10.0 g, 49,3 mmole) in 70 ml of tetrahydrofuran under nitrogen atmosphere was added dropwise methylmagnesium (3.0 M in THF, 70 ml, 210 mmol) for 30-45 minutes. After completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent and low-boiling substances were removed under reduced pressure. Then added water (500 ml) and ethyl acetate (1.2 l) and the reaction mixture was distributed between two phases. The organic layer was dried (saturated solution of salt, magnesium sulfate) and the solvent evaporated, the received liquid, which was chromatographically (SiO2CH2Cl2/Meon 90/10)were 9.6 g of the protected amine in liquid form (MS: M+1=204).

Stage B: Obtain (3S)-3-amino-2-methylbutane-2-ol

To a cooled to 0°With the solution of the carbamate (9.6 g, 47,3 mmole) in 96 ml of methylene chloride was added dropwise in a nitrogen atmosphere triperoxonane acid (4 ml, 51,9 mmole). After completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. To the reaction mixture was added tert-butanol (2-3 ml) and removed under reduced pressure, the solvent/low-boiling impurities. Addition of toluene (3, 75 ml), pariwana and subsequent drying in a vacuum Cabinet led to technical Amin representing solid. This substance was placed in a flask and was then added with stirring methanol (10 ml) and hydrochloric acid (12M, 5-7 ml). After 30 minutes to precipitate hydrochloric amine salt, was washed with toluene (50 ml) and diethyl ether (2x 150 ml) and then dried under reduced pressure (MS: M+1=104, tPL128,1-to 130.1°). Note: this amine is hygroscopic and therefore, measures were taken to avoid prolonged contact with air/water at the selection.

Stage: Obtain 6-(4-chlorophenoxy)-2-{[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

The hydrochloric salt of (3S)-3-amino-2-methylbutane-2-ol (0,077 g, 0.55 mmole) in 3 ml of chloroform was added at room temperature, melamine-phenol-carbonate polymer (Argonaut Technologies Inc., 0.75 g). The mixture was left to mix for 1 hour and then was added sulfon 7 (0.1 g, of 0.28 mmole). The temperature of the reaction mixture was brought to 60°C and stirred for 24 hours. The mixture was then cooled and the polymer was removed by filtration. Evaporation of solvent and column chromatography (SiO2CH2Cl2) led to a technical product, which was chromatographically second time (SiO2CH2Cl2/hexane 1/1 gradient to CH2Cl2/MeOH 99/1). The selection of the appropriate fractions with p the following evaporation of the solvent under reduced pressure resulted in Amin (0,032 g, MS: M+1=389).

Example 53: Obtain 6-(2,4-divergence)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

The hydrochloric salt of (3S)-3-amino-2-methylbutane-2-ol (0.24 g, or 1.77 mmole) in 3 ml of acetonitrile at room temperature was added trimethylsilylacetamide (Aldrich, 0.7 ml, 5.2 mmole). All boiled under reflux for 30 minutes, cooled to room temperature and then was added sulfon 5 (0,367 g, 1.0 mmol). The reaction mixture is boiled under reflux for 2 hours and cooled to room temperature. Was added methanol (2 ml) and an aqueous solution of sodium hydroxide (2 N., 1-3 ml) and the mixture is boiled under reflux for 30 minutes. The reaction mixture was evaporated and were added ethyl acetate (25 ml). Drying of the organic solution (a saturated solution of salt, 3) followed by evaporation under reduced pressure and chromatography (SiO2, preparative TLC on vinyl, ethyl acetate/hexane 75/25) led to the technical product. The product was dissolved in methylene chloride (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, excess). The solid was isolated by filtration, was dried, was obtained 0.16 g of hydrochloric salt (MS: M+1=391, tPLthe 104.3-107,5°).

Example 54: Obtain 6-(2-terbisil)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-metylene what about[2,3-d]pyrimidine-7(8H)-it

The hydrochloric salt of (3S)-3-amino-2-methylbutane-2-ol (0.31 g, 2.21 mmole) in 3 ml of acetonitrile at room temperature was added N,N-diisopropylethylamine (0.7 ml, 4 mmole). All boiled under reflux for 30 minutes, cooled to room temperature and then was added sulfon 8 (0.4 g, 1.15 mmole). The reaction mixture is boiled under reflux for 2 hours and cooled to room temperature. Were added ethyl acetate (25 ml) and the solution was dried (saturated salt solution 3, magnesium sulfate). Evaporation under reduced pressure and chromatography (SiO2, preparative TLC on vinyl, ethyl acetate/hexane - 75/25) led to the technical product. The latter was dissolved in methylene chloride (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, excess). The solid was isolated by filtration and dried, was obtained 0.25 g of hydrochloric salt (MS: M+1=371, tPL162,9-170,5°C).

Example 55: Obtain 6-(2-pertenece)-8-methyl-2-[(1-oxalacetate-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it:

Stage A: Getting oxime tetrahydro-4H-thiopyran-4-it:

The suspension mixture tetrahydrothiopyran-4-it (5 g, 43 mmole), three-hydrate sodium acetate (29,26 g, 215 mmol what th) and hydroxylamine hydrochloride (14.9 g, 215 mmol) in 200 ml of ethanol was boiled under reflux for 6 hours. The reaction mixture was cooled and under reduced pressure, the solvent was removed/low-boiling impurities. The residue was diluted with cooled to the temperature of ice water (400 ml) and was extracted with ethyl acetate (3x 150 ml). The organic solution was dried (saturated solution of salt, magnesium sulfate) and was evaporated, was obtained 5.6 g of the oxime of tianna in a solid white color (MS: M+=131).

Stage B: Obtain 4-aminotetrahydrofuran:

To a solution of lithium aluminum hydride (1M, 76 ml, 76 mmol) in tetrahydrofuran at room temperature was added dropwise in a nitrogen atmosphere the reaction of Tanana (2 g, 15 mmol) in 30 ml of tetrahydrofuran. After the addition the mixture was stirred while boiling under reflux for 7 hours and then at room temperature for 12 hours. To the suspension slowly (dropwise) was added water (2.9 ml), then aqueous solution of sodium hydroxide (15%, to 2.9 ml). Then another was added water (8.7 ml) and the reaction mixture was stirred 30 minutes, filtered through a layer of celite and washed with ethyl acetate (200 ml). The filtrate was dried (saturated solution of salt, magnesium sulfate) and was evaporated under reduced pressure, was received of 1.62 g of 4-aminotetrahydrofuran (MS: M+1=118).

Stage: Obtain 6-(2-pertenece)-8-methyl-2-(tetrahydro-2H-thiopyran-4-yl) - Rev. Ino)pyrido[2,3-d]pyrimidine-7(8H)-it:

A mixture of sulfone 2 (1.0 g, 2.9 mmole) and 4-aminotetrahydrofuran (0,67 g, 5.8 mmole) in 1 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 1 hour. The reaction mixture was cooled, was added ethyl acetate (100 ml) and the organic solution washed with water (3, 75 ml) and then dried (saturated solution of salt, magnesium sulfate). Evaporation of the solvent under reduced pressure and column chromatography (SiO2, ethyl acetate/hexane - 40/60) led to 0.84 g of sulfide in the form of a solid white color that was used on stage,

Stage G: Obtain 6-(2-pertenece)-8-methyl-2-[(1-oxalacetate-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it:

Sulfide (0.84 g, 2.2 mmole) was dissolved in 80 ml dichloromethane and cooled to 5°With, while added in three receptions for 30 minutes 3-chlormadinone acid (77%, 0.5 g, 2.2 mmole). The reaction was complete within 30 minutes and the mixture was washed with an aqueous solution of sodium sulfite (10%, 100 ml), then with cold saturated aqueous sodium bicarbonate.

The solution was dried (saturated salt solution, sodium sulfate) and evaporated under reduced pressure. The product was purified by column chromatography (SiO2CH2Cl2/MeOH 95/5), received sulfoxide Amin. This product (0.4 g) was dissolved in ethyl acetate/d is chlormethine (1/1, 1 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.2 ml, 1.2 EQ.). Formed white suspension, all stirred 15 minutes. The solid was filtered and washed with diethyl ether, received 385 mg hydrochloric salt (MS: M+1=403, tPLto 188.8-189,7°).

Example 56: Obtain 2-[(1,1-dissidocerida-2H-thiopyran-4-yl)amino]-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfoxide (of 0.47 g, 1.2 mmole) and 3-chlormadinone acid (0.26 g, 1.2 mmole) in 50 ml dichloromethane was stirred at room temperature for 2 hours in nitrogen atmosphere. The reaction was then stopped by mixing with an aqueous solution of sodium sulfite (10%, 100 ml), then washed with cold saturated aqueous sodium bicarbonate (100 ml). The organic solution was dried (saturated solution of salt, sodium sulphate), evaporated under reduced pressure and was purified by column chromatography (SiO2CH2Cl2/MeOH - 97/3), was obtained 0.45 g of the sulfone. Sulfon was dissolved in methanol/dichloromethane (5/95, 1 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.3 ml). Formed suspension, which was stirred for 30 minutes. The solid was filtered and washed with diethyl ether, received 413 mg hydrochloric salt (MS: M+1=419, tPL186,2-230,7°C, the sample is partially what about the melted within these limits).

Example 57: Obtain 6-(2,4-divergence)-8-methyl-2-[(1-oxalacetate-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it:

Stage A: Obtain 6-(2,4-divergence)-8-methyl-2-(tetrahydro-2H-thiopyran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it:

A mixture of sulfone 5 (1,14 g, 3.1 mmole) and 4-aminotetrahydrofuran (0.73 g, 6.2 mmole) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 70°C for 15 minutes. The reaction mixture was cooled, was added ethyl acetate (100 ml). The organic solution is then washed with water (3, 75 ml) and dried (saturated solution of salt, magnesium sulfate). After evaporation of the solvent and column chromatography (SiO2CH2Cl2/ethyl acetate : 90/10) was obtained 0.9 g of sulfide (tPL230,7-232,8°S, MS: (M+H)=405), who used to stage B.

Stage B: Obtain 6-(2,4-divergence)-8-methyl-2-[(1-oxalacetate-2H-thiopyran-4-yl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it:

Sulfide (0.9 g, 2.2 mmole) was dissolved in 80 ml dichloromethane and cooled to 5°Since, while there was added 3-chlormadinone acid (77%, 0.5 g, 2.2 mmole) in three receptions for 30 minutes. The reaction was completed in 20 minutes and to the mixture was added an aqueous solution of sodium sulfite (10%, 100 ml)and then cold saturated aq is th solution of sodium bicarbonate. The solution was dried (saturated solution of salt, magnesium sulfate) and was evaporated under reduced pressure. The product was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5), received sulfoxide derived amine. This product (0.35 g, 0.8 mmole) was dissolved in 1 ml dichloromethane was added a solution of hydrochloric acid in diethyl ether (1M, 1.0 ml). Formed suspension, all stirred 15 minutes. After dilution of the solid in diethyl ether (10 ml), filtration and washing with diethyl ether received 344 mg hydrochloric salt (MS: M+1=421, tPL201,8 thousand cub.-202,5°).

Example 58: Obtain 2-[(1,1-dissidocerida-2H-thiopyran-4-yl)amino]-6-(2,4-divergence)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfoxide (0.6 g, 1.4 mmole) and 3-chlormadinone acid (0,48 g, 1.5 mmole) in 50 ml dichloromethane was stirred at room temperature for 12 hours under nitrogen atmosphere. The reaction was then stopped by addition of an aqueous solution of sodium sulfite (10%, 100 ml), then washed with cold saturated aqueous sodium bicarbonate (100 ml). The organic solution was dried (saturated solution of salt, sodium sulphate), evaporated under reduced pressure and was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5), received 0,41 g sulfone. The latter was dissolved in methanol/chlormethine (5/95, 1 ml), was added a solution of hydrochloric acid in diethyl ether (1M, 1.1 ml) and the solution was stirred for 15 minutes. Was evaporated under reduced pressure, then was added diethyl ether (10 ml) and stirred received solid. After filtering the precipitate and washing with diethyl ether received 382 mg hydrochloric salt (MS: M+1=437, tPL251,7-254,9°).

Example 59: Obtain 6-(2,6-divergence)-2-{[1-(hydroxymethyl)butyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 4 (of 0.38 g, 1 mmol) and 2-aminoindan-1-ol (0.35 g, 3.4 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 1 hour and then cooled to room temperature. Was added methanol/water (9/1, 1-2 ml) and the suspension was stirred for 30 minutes. Filtration and thorough washing of the precipitate with diethyl ether, then with water, and then drying led to the free amine. The latter was dissolved in methanol (1-2 ml), was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 30 minutes. After evaporation of the organic impurities, and then adding diethyl ether/methanol (1-2 ml) were obtained precipitate. Singled out this solid by filtration and dried, obtained 0.28 g of hydrochloric salt (MS: M+1=391, tPL176,7-177,7°).

Example 60: Obtain 6-(2,6-divergence)-2-[(2-hydroxy-1,1-DIMET later)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 4 (of 0.38 g, 1 mmol) and 2-amino-2-methylpropan-1-ol (0.35 g, 3.4 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 1 hour and then cooled to room temperature. Was added methanol/water (9/1, 1-2 ml) and the suspension was stirred for 30 minutes. Filtration and thorough washing of the precipitate with diethyl ether, then with water, and then drying led to the free amine. The latter was dissolved in methanol (1-2 ml), was added a solution of hydrochloric acid in diethyl ether (1M) and the reaction mixture was stirred for 30 minutes. Evaporation of the organic impurities, and then the addition of diethyl ether/methanol (1-2 ml) led to the precipitate. This solid was isolated by filtration and dried, received 0,212 g hydrochloric salt (MS: M+1=377, tPL212,8-213,5°).

Example 61: Obtain 6-(2-pertenece)-2-{[1-(hydroxymethyl)-cyclopentyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0,353 g, 1 mmol), (1-aminocyclopent)methanol (0,154 g of 1.42 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 1 hour. The reaction mixture was cooled, then added water (50 ml) and ethyl acetate (50 ml) and the reaction mixture was distributed between two phases. The organic layer was dried (saturated solution of salt, magnesium sulfate), the solvent evaporated and the Uchali residue, which was purified by column chromatography (SiO2CH2Cl2/Meon - 90/10). Fractions after column were combined and concentrated under reduced pressure, obtained free amine. Last suspended in methanol (1-2 ml), was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 30 minutes. Evaporated organic impurities, and then was added diethyl ether/methanol (1-2 ml)were obtained precipitate. Singled out this solid by filtration and dried, received 0,279 g hydrochloric salt (MS: M+1=385, tPL198,6-to 200.3°).

Example 62: Obtain 6-(2-pertenece)-2-{[1-(hydroxymethyl)-3-(methylthio)propyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (1.04 g, to 2.94 mmole), 2-amino-4-(methylthio)butane-1-ol (1.0 g, 9.7 mmole) in 1.0 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 1 hour. The reaction mixture was cooled and was added methanol/water (9/1, 5-7 ml), but not precipitate was formed. Therefore, all solvents were removed by evaporation under reduced pressure, water was added (25 ml) and ethyl acetate (25 ml). The reaction mixture was distributed between the two layers and the aqueous layer was removed. The solution in ethyl acetate was dried (saturated solution of salt, magnesium sulfate) and was evaporated under reduced pressure. Technical reaction mixture was purified with what omashu column chromatography (SiO 2CH2Cl2/Meon - 95/5) and fractions after column were combined and concentrated under reduced pressure, was obtained 0.8 g of the free amine. This product (0.2 g) suspended in methanol (1-3 ml), was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 30 minutes. Evaporated organic impurities, and then was added diethyl ether/methanol (1-2 ml)were obtained precipitate. After separation of this solid by filtration and drying were received 0.125 g hydrochloric salt (MS: M+1=405, tPLto 130.6-132,2°).

Example 63: Obtain 2-(benzylamino)-6-(4-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of 6-(4-pertenece)-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-it (see example 8 obtained by replacing methyl ester 2-pertenece-acetic acid methyl ester 4-ftordesoxyglucose acid - stages a and B, 0.35 g, 1.0 mmol) and benzylamine (0.33 ml, 3 mmole) in 5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Filtration and thorough washing of the precipitate with methanol and then drying led to the free amine. The latter was dissolved in ethyl acetate (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.5 EQ). The solid was isolated by filtration and dried, received MX 0.317 g hydrochloric salt (MS: M+1=377, tPLof 203.2-204°C).

Example 64: Obtain 2-(benzylamino)-6-(4-terbisil)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 9 (0.36 g, of 1.03 mmole) and benzylamine (0.35 ml, 3 mmole) in 0.3 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 1 hour and then cooled to room temperature. Was added diethyl ether (2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed residue in diethyl ether, then dried, received a free amine. The latter was dissolved in methanol (1-2 ml) was added a solution (1M, excess hydrochloric acid in diethyl ether. Was evaporated under reduced pressure, then was stirred with diethyl ether/methanol (1-3 ml)were obtained precipitate. This solid was isolated by filtration and dried, received 0,193 g hydrochloric salt (MS: M+1=375).

Example 65: Obtain 6-(2-pertenece)-8-methyl-2-[(1-phenylpropyl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.1 g, 0,286 mmole), α-ethylbenzylamine (0,088 ml, 0,573 mmole) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 120°C for 12 hours. The reaction mixture was cooled and purified by column chromatography (SiO2, hexane/acetone - 80/20). Faction in the Le column were combined and concentrated under reduced pressure, received a free amine. This product was dissolved in methanol (1-3 ml), was added a solution of hydrochloric acid in diethyl ether (1M, 1 EQ.) and the reaction mixture was stirred for 30 minutes. The solid was isolated by filtration, washed with diethyl ether and dried, received 0,084 g hydrochloric salt (MS: M+1=405, tPL109,4-111,3°).

Example 66: Obtain 6-(2-pertenece)-8-methyl-2-[(pyridine-2-ylmethyl)-amino]pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), pyridine-2-ylmethylamino (0,154 g of 1.42 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, got amine (0.035 g, MS: M+1=378).

Example 67: Obtain 6-(2-pertenece)-2-[(3-furylmethyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 3-pyrimethamine (0,023 g to 0.23 mmole) in 0.2 ml of chloroform was heated at 65°C for 12 hours. The reaction mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride and evaporated, got amine (0,042 g, MS: �+1=367).

Example 68: Getting 8-methyl-6-phenoxy-2-[(2-phenylethyl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 1 (0.33 g, 1 mmol) and phenethylamine (0,380 ml, 3 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed the precipitate with methanol, then dried, received a free amine. Last suspended in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 2 ml). Was isolated solid by filtration and dried, was given to 0.127 g hydrochloric salt (MS: M+1=373, tPL211,8-213°C).

Example 69: Obtain 6-(2-chlorophenoxy)-8-methyl-2-[(2-phenylethyl)amino]-pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 6 (0,365 g, 1 mmol) and phenethylamine (0.4 ml, 3.3 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 1 hour and then cooled to room temperature. Was added diethyl ether (2-3 ml), but the sediment is not excluded. Therefore, the solvents were removed by evaporation under reduced pressure, water was added (5 ml) and ethyl acetate (5 ml). The reaction mixture was distributed between the two layers and the aqueous layer was removed. The solution in ethyl acetate was dried (saturated solution of salt, magnesium sulfate)and was evaporated to obtain a residue. To the residue was added diethyl ether (2-3 ml) and the formed precipitate. Was filtered, washed with additional diethyl ether and dried, received a free amine. This solid is suspended in methanol (1-3 ml), was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 30 minutes. Was filtered off, washed with diethyl ether and dried, received 0,321 g hydrochloric salt (MS: M+1=407, tPL210-211°).

Example 70: obtaining the ethyl ester of 4-{[6-(2,4-divergence)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]amino}piperidine-1-carboxylic acid

A mixture of sulfone 5 (1.0 g, of 2.72 mmole) and ethyl ester of 4-amino-1-piperidine-carboxylic acid (0,93 ml, 5,44 mmole) in 5 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 17 hours and then cooled to room temperature. Was added water (200 ml) and the suspension was stirred over night. After filtration and thorough washing of the precipitate with methanol, and then drying was obtained the free amine. Part of this product (0,100 g, 0,216 mmole) was dissolved in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1 EQ.). The solid was isolated by filtration, then washed with diethyl ether and dried, received MX 0.317 g hydrochloric salt (MS: M+1=462, tPL197,0-204,0° C).

Example 71: Getting 8-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}-6-phenoxypyridine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 1 (0.33 g, 1 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (0.51 ml, 3 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed the precipitate with methanol, then dried, received a free amine. Last suspended in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 2 ml). The solid was isolated by filtration and dried, received 0,183 g hydrochloric salt (MS: M+1=409, tPL180,2-of 182.2°).

Example 72: Obtain 6-(2-chlorophenoxy)-8-methyl-2-{[3-(4-methylpiperazin-1-yl)propyl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 6 (of 0.38 g, 1 mmol) and 1-(3-aminopropyl)-4-methylpiperazine ones (0.46 ml, 2.9 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was stirred at 80°C for 1 hour and then cooled to room temperature. Was added diethyl ether (2 ml) and the suspension was stirred for 2 hours. Was filtered and thoroughly washed residue in diethyl ether, then dried, received a free amine. Last suspended in methanol (1-2 ml), was added a solution Sol is Oh acid in diethyl ether (1M, the excess) and the reaction mixture was stirred for 30 minutes. Evaporation of the organic impurities, and then the addition of diethyl ether/methanol (1-2 ml) led to the precipitate. This solid was isolated by filtration and dried, received 0,44 g hydrochloric salt (MS: M+1=443, tPL233,9-235,5°).

Example 73: Getting 2-aniline-6-(4-terbisil)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 9 (0.4 g, 1.15 mmole) and aniline (0.4 ml, 4.3 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed the precipitate with methanol, then dried, received a free amine. Last suspended in methanol (1-2 ml), was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 30 minutes. The solid was isolated by filtration, washed with diethyl ether and dried, received 0.167 g hydrochloric salt (MS: M+1=361, tPL243,1-246,3°).

Example 74: Obtain 6-(4-pertenece)-2-[(4-forfinal)amino]-8-methyl-pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of 6-(4-pertenece)-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-it (see example 8, replacing methyl ester 2-ftordesoxyglucose is islote methyl ether 4-ftordesoxyglucose acid stage a and B, 0.35 g, 1.0 mmol) and 4-foronline (0,284 ml, 3 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Filtration and thorough washing of the precipitate with methanol and then drying resulted in technical product, which was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5). Fractions after column were combined and concentrated under reduced pressure, obtained free amine. Last suspended in ethyl acetate (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.2 EQ.). The solid was isolated by filtration and dried, received 0,101 g hydrochloric salt (MS: M+1=381, tPL242,3-242,6°C).

Example 75: Obtain 6-(2,6-dichlorophenoxy)-2-[(4-forfinal)amino]-8-methylpurine [2,3-d]pyrimidine-7(8H)-it

A mixture of 6-(2,6-dichlorophenoxy)-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]-pyrimidine-7(8H)-it (see example 12, phase a-B (replacing methyl ester 2-ftordesoxyglucose acid methyl ester, 2,6-dichlorophenoxyacetic acid) 0.35 g, 1 mmol) and 4-foronline (0,284 ml, 3 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then was cooled to the room temperature. Was added methanol (2 ml) and the suspension was stirred for 3 minutes. Filtration and thorough washing of the precipitate with methanol and then drying resulted in technical product, which was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5). Fractions after column were combined and concentrated under reduced pressure, obtained free amine. Last suspended in ethyl acetate (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.2 EQ.). The solid was isolated by filtration and dried, received 0,131 g hydrochloric salt (MS: M+1=430, tPL248,2-249,1°).

Example 76: Obtain 6-(4-terbisil)-2-[(4-forfinal)amino]-8-methyl-pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 9 (0.36 g, 1 mmol) and 4-foronline (0.8 ml, 7.2 mmole) in 0.4 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Filtration and thorough washing of the precipitate with methanol and then drying resulted in the technical product. This product is suspended in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 1 hour. The solid was isolated by filtration, washed with diethyl ether and dried, received 0,207 g hydrochloric salt (MS: M+1=379, tPL246-250°)./p>

Example 77: Getting 2-{[4-(2-hydroxyethyl)phenyl]amino}-8-methyl-6-phenoxypyridine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 1 (0,331 g, 1 mmol) and 2-(4-AMINOPHENYL)ethanol (0,411 g, 3 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed the precipitate with methanol, then dried, received a free amine. Last suspended in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.5 ml), the reaction mixture was stirred for 30 minutes. The solid was isolated by filtration and dried, was given to 0.127 g hydrochloric salt (MS: M+1=389).

Example 78: Obtain 6-(6-chlorophenoxy)-2-({4-[2-(diethylamino)ethoxy]phenyl}amino)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 6 (0.4 g, 1.1 mmole) and 4-(2-diethylaminoethoxy)aniline (0.8 g, 3.8 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol/water (9/1, 1-2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed the precipitate with water, then dried and received a technical product, which was purified by column chromatography (SiO2CH2Cl2/MOH - 95/5). The appropriate fractions after column were combined and concentrated under reduced pressure, obtained free amine. Last suspended in methanol (1-2 ml), was added a solution of hydrochloric acid in diethyl ether (1M, excess) and the reaction mixture was stirred for 30 minutes. After evaporation of organic impurities, the subsequent addition of diethyl ether/methanol (1-2 ml) were obtained precipitate. This solid was isolated by filtration and dried, was obtained 0.16 g of hydrochloric salt (MS: M+1=494, tPL255,5-261,4°).

Example 79: Obtain 2-({4-[2-(diethylamino)ethoxy]phenyl}amino)-6-(4-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of 6-(4-pertenece)-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-it (see example 8 - stage a-B, 0.35 g, 1 mmol) and 4-(2-diethylaminoethoxy)-aniline (0.625 g, 3 mmole) in 0.5 ml of 1-methyl-2-pyrrolidinone was stirred at 110°C for 12 hours and then cooled to room temperature. Was added methanol (2 ml) and the suspension was stirred for 30 minutes. Was filtered and thoroughly washed the precipitate with methanol, then dried, received a free amine. Last suspended in ethyl acetate (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1.2 EQ.) and the reaction mixture was stirred for 30 minutes. The solid was isolated by filtration and dried; p who were given of 0.085 g of hydrochloric salt (MS: M+1=478, tPL245,2-246,1°).

Example 80: Obtain 6-(2-pertenece)-2-[(3-hydroxypyridine-2-yl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,143 mmole), 2-aminopyridine-3-ol (0,047 g, 0.43 mmole) in 0.1 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 3 hours. The reaction mixture was cooled, was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with water, dissolved in methylene chloride, filtered through a dewatering agent (magnesium sulfate) and was evaporated, got amine (0,040 g, MS: M+1=380).

Example 81: Obtain 6-(2-pertenece)-8-methyl-2-[(5-methylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidine-7(8H)-it

The hydrochloric salt of 5-methylpyridin-2-amine (0.025 g, to 0.17 mmole) in 2 ml of chloroform at room temperature was added monohydrate, barium hydroxide (0.16 g, 0,86 mmole). All was stirred for 1 hour, filtered and evaporated under reduced pressure. To the residue was added sulfon 2 (0.05 g, 0,143 mmole) in 1 ml of chloroform, the temperature of the reaction mixture was brought to 65°C and stirred for 24 hours. The mixture was cooled and the solvents were removed by evaporation. Was added methanol/water (90/10, 1 ml) and the formed precipitate. The product was washed with methanol/water, was dissolved in methylene chloride and evaporated, got amine (0,034 g, M+1=378).

When the EP 82: Obtain 2-(benzylthio)-6-(4-pertenece)pyrido[2,3-d]-pyrimidine-7-amine:

Stage A: Receive (4 fervency)acetonitrile:

Iodoacetonitrile (2,14 ml, 29 mmol) was added to a suspension of 4-terfenol (3.0 g, 27 mmol) and potassium carbonate (4,85 g, 35 mmol) in 10 ml of dimethylformamide. The reaction mixture was heated at 60°C for 15 hours, then the mixture was cooled, diluted with water and extracted with ethyl acetate-hexane (1:1, 150 ml, 3x). The organic solutions were combined and washed with water (200 ml, 2x), dried (saturated solution of salt, magnesium sulfate). The solvent was removed under reduced pressure, was obtained 4.1 g of product.

Stage B: Obtain 2-(benzylthio)-6-(4-pertenece)pyrido[2,3-d]pyrimidine-7-amine:

A mixture of nitrile (obtained in stage a, and 1.83 g, 12 mmol), aminopyrimidine-aldehyde (2,48 g, 10 mmol) and potassium carbonate (7.0 g, 50 mmol) in 30 ml of dimethylformamide was heated on an oil bath at 120°C for 4 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate (125 ml, 3x). The organic solutions were combined and washed with water (120 ml, 3x), dried (saturated solution of salt, magnesium sulfate) and filtered through a short column filled with silica. The solvent was removed under reduced pressure and the technical product was purified by column chromatography (SiO2, MeOH/CH2Cl2, 80/20 - 95/5), 1,3 received the product (MS: M+1=379, tPL186,2-192,2°).

The substitution of menzilcioglu (or the corresponding sulfoxide or sulfone) Amin R1NH2as previously described , leads to compounds of formula II, where R8and R9both signify hydrogen. Further alkylation, acylation, sulfonylamine, reductive amination, etc. led to compounds of formula II, where R8and R9are as described in the summary of the invention.

Example 83: Obtain 6-(2,4-divergence)-2-(benzylthio)pyrido[2,3-d]-pyrimidine-7(8H)-it

Stage A: Obtain 4-amino-2-benzoylthiophene-5-carboxaldehyde

To a 1 M solution of lithium aluminum hydride /LAH/ (185 ml, 185 mmol) in diethyl ether was added dropwise a solution of ester 4-amino-2-benzoylthiophene-5-carboxylic acid (46 g, 159 mmol) in 500 ml of anhydrous tetrahydrofuran over a period of 1.5 hours at 0°C. the Reaction mixture was slowly heated to ambient temperature and then was cooled to 0°With, before the slow reaction was stopped by addition of 7 ml of water, 7 ml of 2 M solution of sodium hydroxide, then 14 ml water. The resulting suspension was filtered and the filter cake was washed with ethyl acetate 2×300 ml of the Collected fractions were concentrated, was received of 45.7 g of 4-amino-2-benzoylthiophene-5-methanol in the form of a solid which substances white.

The suspension obtained above 4-amino-2-benzoylthiophene-5-methanol (45,7 g) in 800 ml of methylene chloride was treated with powder activated manganese dioxide (87 g). The reaction mixture was stirred 18 hours, then filtered through a layer of celite. The filter cake was repeatedly washed with a solution of hot methylene chloride and methanol. The combined fractions were concentrated and received 25 g of 4-amino-2-benzoylthiophene-5-carboxaldehyde in a solid white color.

Stage B: Obtain 6-(2,4-divergence)-2-(benzylthio)pyrido[2,3-d]-pyrimidine-7(8H)-it:

To a mixture of 4-amino-2-benzoylthiophene-5-carboxaldehyde (19.5 g, 80 mmol) and methyl ester of 2,4-differentsialnoi acid (25.6 g, 119 mmol) in N-organic (NMP) (50 ml) were added potassium carbonate (16.5 g, 119 mmol). The mixture was heated at 80-90°C for two days and cooled to room temperature. The mixture was added to a cooled to the temperature of ice water (1000 g) and stirred for 1 hour. The solid was filtered, washed with water and diethyl ether and dried, obtained 27 g of the sulfide (MS: M+1=398, tPL240-244°C).

Example 84: Obtain 1-tert-butyl-3-[6-(2,4-divergence)-2-(tetrahydro-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7-yl]urea

Stage A: Obtain 1-tert-butyl-3-[6-(2,4-divergence)-2-methylsulfanyl-pyrido[2,3-d]pyrimidine-7-yl]urea:

To a solution of amine IIIe (obtained are similar to those described in example 82) (0.32 g, 1.0 mmol) in 5 ml of 1-methyl-2-pyrrolidinone at room temperature was added sodium hydride (60%, 0.04 g, 1.0 mmol). The mixture was stirred at room temperature for 1 hour. Was added dropwise over three minutes tert-utilizationa (0.01 g, of 0.11 ml, 1.0 mmol). The solution is dark brown then stirred for another two hours and was poured into 50 ml of 1M HCl, extracted with ethyl acetate (2x 50 ml). The combined solution in ethyl acetate was washed with water (3, 75 ml) and dried (saturated solution of salt, magnesium sulfate). Evaporation of the solvent and purification of the product by column chromatography on silica gel with elution with 10% ethyl acetate in dichloromethane led to 0,164 g of the desired sulfide.

Stage B: Obtain 1-tert-butyl-3-[6-(2,4-divergence)-2-methanesulfonamido[2,3-d]pyrimidine-7-yl]urea:

To a solution of sulfide (0,164 g, 0.4 mmole) in dichloromethane (50 ml) was added meta-chlormadinone acid (77% max, 0,19 g to 0.88 mmole) in 5°C. the Mixture was then stirred at room temperature for 15 hours and poured into 10%aqueous solution of sodium bisulfite. The organic solution is then washed with 10%aqueous sodium bicarbonate solution and dried (saturated solution of salt, magnesium sulfate). After evaporation of the solvent which was alocale 0,176 g sulfone (MS: M+1=452).

Stage: Obtain 1-tert-butyl-3-[6-(2,4-divergence)-2-(tetrahydro-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7-yl]urea:

A solution of sulfone (0.17 g, 0.4 mmole) and 4-aminotetrahydrofuran (0.24 g, 2.3 mmole) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for three hours. The reaction mixture was cooled, poured into water and was extracted with ethyl acetate (2x 50 ml). The organic solution was washed with water (5 x 50 ml) and dried (saturated solution of salt, magnesium sulfate). The solvent evaporated under reduced pressure and was purified by column chromatography (SiO2CH2Cl2/ethyl acetate 50/50), received 0,123 g of the desired product (MS: M+1=473, tPL195-201°C).

Example 85: Obtaining N-[6-(2,4-divergence)-2-(tetrahydropyran-4-yl-amino)pyrido[2,3-d]pyrimidine-7-yl]methanesulfonamide

Stage a: Obtaining N-[6-(2,4-divergence)-2-methylsulfonylamino[2,3-d]pyrimidine-7-yl]methanesulfonamide

To a suspension of amine IIIe (obtained by the method similar to that described in example 82) (0.32 g, 1.0 mmol) in 10 ml of dichloromethane at 5°With added dropwise trimethylaluminium reagent (2 M in toluene, 0.5 ml, 1.0 mmol). The dark solution was stirred for 30 minutes at ambient temperature. Added anhydride of methansulfonate (0,174 g, 1.0 mmol) and the solution boiled with inverse x is Hladilnika. Over the course of the reaction was monitored by TLC for completion of the reaction required the addition of additional quantities of the anhydride of methansulfonate. Just was added 3.6 per equivalent of anhydride and after 5 hours boiling under reflux, the reaction mixture was poured into 1M aqueous hydrochloric acid (50 ml) and was extracted with ethyl acetate (2x 50 ml). The solution was dried (saturated solution of salt, magnesium sulfate and after evaporation of the substance was purified by column chromatography (SiO2CH2Cl2/MeOH - 97/3), received 0,164 g sulphonamide-sulfide (MS: M+1=399).

Stage B: N-[6-(2,4-Divergence)-2-(tetrahydropyran-4-yl-amino)pyrido[2,3-d]pyrimidine-7-yl]methanesulfonic

To a solution of the sulphonamide-sulfide (0,164 g, 0.4 mmole) in 20 ml of dichloromethane was added meta-chlormadinone acid (0.2 g, 0.9 mmole). The reaction mixture was stirred at room temperature for 15 hours and washed with 10%aqueous solution of sodium bisulfite, dried (saturated solution of salt and magnesium sulfate). (Note: do not rinse with sodium bicarbonate, sulfon-sensitive basis). The solvent is evaporated under reduced pressure and the obtained sulphonamide-sulfon (0.4 mmole) and 4-aminotetrahydrofuran (0.5 g) in 1.0 ml of 1-methyl-2-pyrrolidinone was heated at 100°C for 12 hours after which the solvent is evaporated in the juice vacuum and the substance was purified by column chromatography (SiO 2CH2Cl2/Meon - 97/3), received 90 mg of the desired product (MS: M+1=452, tPL199-204°).

Example 86: Obtain 6-(2,4-divergence)-2-{[(1S)-2-fluoro-1,2-dimethyl-propyl]amino}-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

To the compound obtained in example 53 (free base, 0.28 g)in methylene chloride (5 ml) was added at -78°With diethylaminoacetate (DAST) (Aldrich, of 0.14 ml). The reaction mixture was slowly heated to room temperature. It was distributed between methylene chloride and water. The organic layer was separated and washed with saturated aqueous sodium carbonate, dried and concentrated, received a technical product. After carrying out preparative TLC (silica gel, 45% ethyl acetate/hexane) was obtained pure product (0.16 g). The product was converted into the hydrochloric salt in the processing of 1M HCl in diethyl ether was received RO3310297-001 (MS:M+1=393, tPL196-197,2°C).

Example 87: Obtain 6-(2,4-divergence)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-isopropylpyridine[2,3-d]pyrimidine-7(8H)-it

Stage A: Obtain 6-(2,4-divergence)-8-isopropyl-2-phenylmethane-sulfonyl-8H-pyrido[2,3-d]pyrimidine-7-it

The above sulfide (2.2 g, 5.5 mmole), potassium carbonate (0.84 g, 6.1 mmole) and 2-iodopropane (of 0.58 ml, 5.8 mmole) in anhydrous dimethylformamide (5 ml) premesis is whether at room temperature over night. Water treatment led to technical sulfide. The latter was dissolved in tetrahydrofuran (50 ml) and treated with axonom™ (8 g) in water (50 ml) at 0-5°C. the mixture is Then slowly heated to room temperature and stirred for another 5 hours. Water treatment led to technical sulfone.

Stage B: Obtain 6-(2,4-divergence)-2-{[(1S)-2-hydroxy-1,2-dimethylpropyl]amino}-8-isopropylpyridine[2,3-d]pyrimidine-7(8H)-it

Obtained above sulfon (0,93 g of 2.05 mmole), hydrochloric salt of (3S)-3-amino-2-methylbutane-2-ol (0.54 g, 4 mmole) and triethylamine (1 ml) in isopropyl alcohol (10 ml) was boiled under reflux for 10 hours. Water treatment resulted in the technical product. After column chromatography (silica gel, 35%-45% ethyl acetate/hexane) was obtained pure product (0,386 g). The product was converted to its hydrochloric salt in the processing of 1M HCl in diethyl ether) and recrystallized from isopropyl alcohol, received R3310294-001 (0,29 g) (MS: M+1=419, tPL200-202°).

Example 88: Obtain 6-(2,4-divergence)-8 methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyridine-7(8H)-it

Stage A: obtaining the ethyl ester of 6-chloro-4-methylaminophenol acid

Ethyl ester of 4,6-dichloro-3-nicotinic acid (individual samples, 7,37 g of 33.5 mmole)was stirred with aqueous methylamine (40%, of 14.5 ml) in acetonitrile (50 ml) at 0-5°and then at room temperature for 6 hours. The mixture was concentrated and was added ethyl acetate. The organic layer was washed with saturated salt solution (2x), dried and evaporated, was obtained the desired product (7,12 g; tPL61,4-63,1°).

Stage B: Obtain 6-chloro-4-methylaminomethyl-3-carboxaldehyde

To the resulting higher ether complex (7,1 g, a 33.2 mmole) in tetrahydrofuran (100 ml) was slowly added to alumoweld lithium (1.0 M in THF, 70 ml) at -78°C and stirred 3 hours. The temperature was slowly raised to -10°and the results of TLC indicated that the ester whole spent. Was added methanol/ethyl acetate (5 ml each) to decompose excess lithium aluminum hydride and the mixture was heated to room temperature. Was added water (50 ml) and ethyl acetate (500 ml) and filtered through a layer of celite. The filtrate was separated and dried. Technical product was then purified by column chromatography (silica gel, 40-75% EtOAc/hexane and then 5% MeOH/CH2Cl2), received a 3.3 g of a solid (MS: M+1=173,1, tPL168, 8mm-169,6°).

The resulting alcohol (3.2 g) was stirred with manganese dioxide (16.2 g) in methylene chloride (800 ml) at room temperature for two hours. The mixture was filtered through a layer of celite and washed with ethyl acetate. The filtrate was concentrated, received the aldehyde (2.8 g, tPL77,2-80,8°).

Stage: Obtain 7-chloro-3-(2,4-divergence)-1-methyl-1H-[1,6]naphthiridine-2-it

The aldehyde obtained above (1.8 g)was heated with methyl ether of 2,4-differentsialnoi acid (4.1 g) and potassium carbonate (4.1 g) in N-organic (20 ml) at 70°within two days. Were added ethyl acetate (200 ml) and washed with saturated salt solution (3x), dried and concentrated, received a technical product. Rubbed with hexane received of 3.07 g of solid white (MS: M+1=323, tPL168-170,5°C).

Stage G: Obtain 6-(2,4-divergence)-8 methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyridine-7(8H)-it

The above product (of 2.06 g, 6.4 mmole) was heated with 4-amino-tetrahydropyran (3.4 g, a 33.6 mmole) at 150-160°within three days. The mixture was cooled to room temperature and was stirred with ethyl acetate (200 ml) and saturated salt solution (50 ml). The organic layer was separated, dried and concentrated. The technical product was purified by column chromatography (40-60% EtOAc/hexane), received of 1.65 g of solid substance. The latter was dissolved in methylene chloride/methanol (5 ml each) and treated with 4.5 ml of 1 M HCl in diethyl ether. The solvent was removed and the resulting solid paracrystal obyvali of isopropyl alcohol, was obtained 1.3 g of white crystals (MS: M+1=388,2, tPL237,5-239°C).

Example 89: Getting 8-amino-6-(2,4-divergence)-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it

Stage A: Getting 8-amino-2-benzylmethyl-6-(2,4-divergence)-8H-pyrido[2,3-d]pyrimidine-7-it

To a solution of sulfide (see example 83 to receive) (2.67 g, 6,72 mmole) in dimethylformamide (120 ml) at 0°was added under stirring once 60% NaH (375 mg, 1.4 EQ.). The resulting mixture was stirred at 0°C for 30 minutes. Then he added one reception diphenylphosphinyl-O-hydroxylamine (Tet. Let., volume 23, No. 37, 3835-3836, 1982) (2,34 g, 1.5 EQ.). After about one minute, the mixture became thick and trudnoperevarivaema. Analysis by TLC showed that all of the original sulfide consumed. To the reaction mixture were added ethyl acetate (650 ml) and water (250 ml), distributed and shared layers. An ethyl acetate layer was further washed with water (4×200 ml) and then finally washed with a saturated solution of salt (1×200 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated. Kept at the vacuum pump high vacuum and got hydridable in the form of powder dark brown (2,683 g (M+N)+=413, tPL179,3-182,3°C).

Stage B: Getting 8-amino--(2,4-divergence)-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it

To the sulfide (820 mg, 1.99 mmole) and 4-aminotetrahydrofuran (500 mg, 2.5 EQ.) was added N-organic (0.8 ml) and the resulting mixture was heated with stirring at 150°C for 24 hours. According to TLC source hydridable was spent. Were added ethyl acetate (175 ml) and water (50 ml), was distributed and then the layers were separated. The aqueous layer was further extracted with ethyl acetate (100 ml) and the combined an ethyl acetate layers were washed with water (2×200 ml). Finally, the organic layer was washed with saturated salt solution (1×150 ml) and then an ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated, received 882 technical product. Purification using preparative TLC with elution with 6% methanol in dichloromethane led to the free amine in the form of a powder dark brown (44 mg). The free amine was dissolved in dichloromethane (15 ml) and then was added 1 M HCl in diethyl ether (0.17 ml, 1.5 EQ.) under stirring. Was stirred for 5 minutes and then the solvent was removed under reduced pressure at 50°C. Dried in high vacuum at 56°within 24 hours, was obtained the desired product (43 mg, (M+N)+=390) in the form of a powder, yellowish-brown.

Example 90: Obtain 6-(2,4-divergence)-8-isopropylamino-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-on the Sabbath.

Stage A: Getting 2-benzylmethyl-6-(2,4-divergence)-8-isopropylamino-8H-pyrido[2,3-d]pyrimidine-7-it:

To hydroidolina (300 mg, 0.73 mmole) in methanol (70 ml) and acetic acid (16 ml) was added acetone (0.16 ml), and then Lamborgini sodium (55 mg, 1.2 EQ.). The resulting mixture was stirred at room temperature for 24 hours. The next day the reaction mixture was poured into saturated sodium bicarbonate solution (100 ml) and then extracted with ethyl acetate (2×100 ml). Extracts in ethyl acetate was washed with saturated salt solution (1×150 ml) and then dried over magnesium sulfate, filtered and concentrated, received 323 mg of the technical product. Purification using preparative TLC with elution 30% ethyl acetate in hexano led to the desired compound (64 mg, (M+N)+=455).

Stage B: Getting 2-benzylsuccinic-6-(2,4-divergence)-8-isopropylamino-8H-pyrido[2,3-d]pyrimidine-7-it:

To N-isopropylimidazole (64 mg, 0,141 mmole) in tetrahydrofuran(10 ml) at 0°under stirring was added dropwise a solution of oxone (130 mg, 1.5 EQ.) in water (10 ml). Upon completion of addition, the resulting mixture was stirred overnight at a temperature of from 0°C to room temperature. The next day, according to TLC, the reaction was end is on. Were added ethyl acetate (75 ml) and water (25 ml) and then distributed and shared layers. It was further washed with water (2×25 ml) and saturated salt solution (1×75 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated and dried using a pump, the received N-isopropylidenedioxy (74 mg, (M+N)+=471).

Stage: Obtain 6-(2,4-divergence)-8-isopropylamino-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it:

Sulfoxide (74 mg, of) 0.157 mmole), 4-aminotetrahydrofuran (80 mg, 5 EQ.) and N-organic (0.1 ml) were mixed and heated at 80°With stirring for 30 minutes. According to TLC, the reaction was completed, it was cooled to room temperature. Were added ethyl acetate (35 ml) and water (25 ml) and then distributed and shared layers. The organic layer is then washed with water (2×25 ml) and saturated salt solution (1×25 ml). Then an ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. Dried using a pump at high vacuum, received 75 mg of a technical product. Purification using preparative thin layer chromatography with elution with 75% ethyl acetate in hexano led to the desired compound in the form of free amine (39 mg). The free amine was dissolved in dichloromethane (5 ml) and with stirring was added 1 M HCl diethyl ether (0,14 ml, 1.2 EQ.). The resulting mixture was stirred for 5 minutes. Then the solvent was removed under reduced pressure at 50°C. Dried in high vacuum at 56°within 24 hours, received specified in the title compound in the form of not quite white powder (39 mg, (M+H)+=432).

Example 91: Obtain 6-(2,4-divergence)-8-[N-methyl-N-3-methylbutyl)-amino]-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it

Stage A: Getting 2-benzylmethyl-6-(2,4-divergence)-8-N-isobutylamino-8H-pyrido[2,3-d]pyrimidine-7-it

To a mixture of hydroidolina (1 g, 2,52 mmole) in methanol (200 ml) and acetic acid were added Isobutyraldehyde (0.3 ml, 1.3 EQ.), then Lamborgini sodium (159 mg, 1 EQ.). The resulting mixture was stirred at room temperature for 3.5 hours. Then were added ethyl acetate (500 ml) and washed with saturated sodium bicarbonate solution (5×200 ml) to slightly alkaline reaction. At the end was washed with saturated salt solution (1×150 ml) and the organic layer was dried over magnesium sulfate, filtered, concentrated and dried using a pump, I got a technical product (1,083 g) as a solid, yellowish-brown. Purification using flash chromatography on silica gel with elution with 15% ethyl acetate in hexano led to the desired product in the form of panabrator the solid (487 mg, (M+H)+=469, tPL132,1-133,9°).

Stage B: Getting 2-benzylmethyl-6-(2,4-divergence)-8-(N-isobutyl-N-methylamino)-8H-pyrido[2,3-d]pyrimidine-7-it

To N-isobutylthiazole (100 mg, 0,213 mmole) in methanol (10.5 ml) at 0°With added acetic acid (3 ml), then 37% aqueous formaldehyde (25 μl, 1.6 EQ.) and then Lamborgini sodium (20 mg, 1.4 EQ). The resulting mixture was stirred at a temperature of from 0°to room during the night. On the next day by TLC were detected only traces of the original substance. The reaction mixture was poured into saturated sodium bicarbonate solution (150 ml) and then extracted with ethyl acetate (3×75 ml). United an ethyl acetate layers were washed with saturated salt solution (1×50 ml) and then dried over magnesium sulfate, filtered and concentrated. Technical product was purified using preparative thin-layer chromatography, elwira 20% ethyl acetate in hexano, was obtained the desired compound in the form of a solid foamy substance (96 mg, (M+H)+=483).

Stage: Getting 2-benzylsuccinic-6-(2,4-divergence)-8-(N-isobutyl-N-methylamino)-8H-pyrido[2,3-d]pyrimidine-7-it

To the sulfide (96 mg, 0,199 mmole) in tetrahydrofuran (10 ml) at 0°under stirring was added dropwise a solution of the Sona (185 mg, 1.5 EQ.) in water (10 ml). Upon completion of addition, the resulting mixture was stirred at a temperature of from 0°to room during the night. According to TLC, the reaction was terminated the next day. Were added ethyl acetate (75 ml) and washed with water (4×30 ml), and finally washed with a saturated solution of salt (1×30 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated, was obtained the desired compound in the form of a solid foamy substance white (95 mg, (M+N)+=499).

Stage G: Obtain 6-(2,4-divergence)-8-[N-methyl-N-3-methylbutyl)-amino]-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it:

N-Isobutyl, N-methylhydroperoxide (95 mg, 0,191 mmole), 4-amino-tetrahydropyran (97 mg, 5 EQ.) and N-organic (0.1 ml) were mixed and heated at 80°With stirring for 30 minutes. According to TLC the entire source sulfoxide was spent. Was cooled to room temperature and was added ethyl acetate (35 ml) and water (25 ml). Distributed and layers were separated and then washed with water (2×25 ml)and then with saturated salt solution (1×25 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated and dried using a pump. Purification using preparative thin layer chromatography with elution with 40% ethyl acetate in hexano Pref is present the desired product as the free amine (82 mg).

The free amine (82 mg) was dissolved in dichloromethane (5 ml) and then was added 1M HCl in diethyl ether (0.2 ml, 1.2 EQ.). The resulting mixture was stirred for 5 minutes and then the solvent was removed under reduced pressure at 50°C. Dried in high vacuum at 56°within 24 hours, received specified in the title compound (60 mg, (M+N)+=460) not quite white powder.

Example 92: Obtain 6-(2,4-divergence)-8-N,N-dimethylamino-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it:

Stage A: Getting 2-benzylmethyl-6-(2,4-divergence)-8-N,N-dimethylamino-8H-pyrido[2,3-d]pyrimidine-7-it:

Hydridable (1.5 g, 3.64 mmole) was dissolved in methanol (200 ml) and acetic acid (60 ml) and then was added 37% aqueous formaldehyde (0.5 ml, 4 equiv.) then were added Lamborghini sodium (458 mg, 2 EQ.). The resulting mixture was stirred at room temperature overnight. The next day there was still a certain amount of initial sulfide, so I added an additional 37% aqueous formaldehyde (0.5 ml, 4 EQ.) and the reaction mixture was stirred at room temperature for another day. On the second day according to TLC, the reaction was completed. Were added ethyl acetate (300 ml) and saturated sodium bicarbonate solution (150 ml) and distributed. Then divided slaii washed yet saturated sodium bicarbonate solution (3× 150 ml) to slightly alkaline reaction. Finally, washed with saturated salt solution (1×150 ml) and the organic layer was dried over magnesium sulfate, filtered, concentrated and dried using a pump, I got a technical product (1,93 g). After purification using flash chromatography on silica gel with elution with 15% ethyl acetate in hexano was obtained the desired product as a foamy solid substances not quite white (740 mg, (M+H)+=441, tPL63,0-66,0°).

Stage B: Getting 2-benzylsuccinic-6-(2,4-divergence)-8-N,N-dimethylamino-8H-pyrido[2,3-d]pyrimidine-7-it:

To the sulfide (725 mg, 1.65 mmole) in tetrahydrofuran (30 ml) at 0°With added dropwise with stirring a solution of oxone (1.01 g, 1 EQ.) in water (20 ml). Upon completion of addition, the resulting mixture was stirred at a temperature of from 0°to room within 6 hours. Then were added ethyl acetate (100 ml) and washed with water (3×50 ml), then saturated salt solution (1×50 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated and dried using a pump, got the desired compound in the form of a foamy solid white (727 mg, (M+N)+=457, tPL80,5-89,9°).

Stage: Obtain 6-(2,4-divergence)-8-N,N-dimethylamino-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]Piri is one-7-it:

Sulfoxide (308 mg, 0,675 mmole), 4-aminotetrahydrofuran (205 mg, 3 EQ.) and N-organic (0.3 ml) were mixed and heated at 80°With stirring for 30 minutes. According to TLC, the reaction was completed. Were added ethyl acetate (35 ml) and water (25 ml), distributed and shared layers. The organic layer was washed with water (2×25 ml)and then with saturated salt solution (1×25 ml). Dried an ethyl acetate layer over magnesium sulfate, filtered, concentrated and dried using a pump, I got a technical product (571 mg). Purification using preparative thin layer chromatography with elution with 70% ethyl acetate in hexano led to the product as the free amine (185 mg). The free amine was dissolved in dichloromethane (20 ml) and then was added 1M HCl in diethyl ether (1.2 EQ., 0.5 ml). The resulting mixture was stirred for 5 minutes and then the solvent was removed under reduced pressure at 50°C. Dried in high vacuum at 56°within 24 hours, received specified in the title compound in the form of not quite white powder (195 mg, (M+H)+=418, tPL126,4-131,0°C).

Example 93: Obtain 6-(2,4-dipertanyakan)-2-(2-hydroxy-1,1-dimethylethylamine)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-it:

Stage A: Getting benzyl ester (2,4-differenl)carbamino acid

Placed 2,4-diptiranjan (5,06 ml of 49.6 mmole) in a solution of 10% sodium hydroxide (76 ml). Cooled in a bath of ice and was added benzyl ether of Harborview acid (a 7.85 ml, 55 mmol). After stirring for 2 hours the product was filtered, stirred with hexane, and dried. The output of 9.4,

Stage B: Obtain methyl ester [benzyloxycarbonyl-(2,4-differenl)amino]acetic acid

Protected benzyloxycarbonyl (CBZ) derivative aniline (7,89 g, 30 mmol) was dissolved in 1-methyl-2-pyrrolidinone (NMP) and cooled in a bath with ice to 0°C. To this solution was added sodium hydride (1.3 g 60%dispersion in oil, or 32.5 mmole), all was stirred for 30 minutes. To this solution was added methyl ether bromoxynil acid (3.0 ml, 31 mmol), the resulting solution was allowed to warm to room temperature and stirred for 12 hours. Was added to water and extracted with ethyl acetate, washed 5 times with water, dried (magnesium sulfate) and was evaporated to dryness. The product was purified by column chromatography (80:20 hexane: ethyl acetate), was obtained the desired product. The output of 8.2,

Stage: Obtain benzyl ester (2,4-differenl)(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)carbamino acid

To a solution of aldehyde (1,69 g, 10 IMO is her) in 1-methyl-2-pyrrolidinone and protected benzyloxycarbonyl derivative aniline (3.5 g, 10.5 mmol) were added potassium carbonate (2.0 g, 14.5 mmole) and heated at 120°C for 12 hours. The reaction mixture was cooled to room temperature and added to water. Were extracted with ethyl acetate and washed 5 times with water, dried (magnesium sulfate) and was evaporated to dryness. The product was purified by column chromatography (75:25 ethyl acetate: hexane). The output of 1.9 g (M+N)+469.

Stage G: Getting benzyl ester (2,4-differenl)(8-methyl-2-methylsulphonyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)carbamino acid

To a solution of sulfide (8.5 g, 18 mmol) in methylene chloride (100 ml) was added meta-chlormadinone acid (9.0 g ˜75%, 39 mmol) and stirred at room temperature for 12 hours. The reaction solution washed with 10%solution of sodium sulfite, then three times 10%sodium bicarbonate solution, dried (magnesium sulfate) and was evaporated to dryness. Technical product was stirred with diethyl ether (100 ml) for 1 hour, filtered and dried. The output of 7.9,

Stage D: Getting benzyl ester (2,4-differenl)-[2-(2-hydroxy-1,1-dimethylethylamine)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl]carbamino acid

Sulfon (0.5 g, 1 mmol) was mixed with 2-amino-2-methyl-1-propanol (0.5 g, 5.5 mmole) and 0.5 ml of 1-methyl-2-pyrrolidinone, this races the thief was heated at 80° C for 1 hour. Was cooled to room temperature, was added methanol (2 ml) and water (4 ml), stirred for one hour, filtered, received the product in the form of solids. The output 450 mg, (M+N)+510.

Stage E: Obtain 6-(2,4-dipertanyakan)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-it

Replaced by benzyloxycarbonyl (CBZ) amine (450 mg, 0.8 mmole) was dissolved in ethanol (20 ml), to the solution was added 5% palladium on coal (50 mg) and was first made at atmospheric pressure. After 12 hours, filtered through celite, evaporated to dryness. The resulting substance suspended in methyl alcohol and acidified with hydrochloric acid (1.0 M/Et2O, 1 EQ.), was stirred for 20 minutes, evaporated under reduced pressure, stirred with a mixture of diethyl ether/methanol for 2 hours, filtered, received hydrochloric salt. The output 140 mg TPL216-217,9°C. MS: (M+H)+376.

Example 94: Obtain 6-[(2,4-differenl)methylamino]-8-methyl-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it:

Stage A: Obtaining methyl ester [(2,4-differenl)methylamino]-acetic acid

To a mixture of 2,4-debtor-N-methylaniline (Avacado Research Chemical, Heysham, UK) (1,43 g, 10 mmol) in 1-methyl-2-pyrrolidinone and potassium carbonate was added methyl EF the R bromoxynil acid (0,945 ml, 10 mmol) and stirred at room temperature for 24 hours. The reaction mixture was added to water and extracted with ethyl acetate (3×50 ml), the organic extracts were washed with water (6x), dried (magnesium sulfate) and was evaporated, the obtained product in the form of oil. The output of 2.0,

Stage B: Obtain 6-[(2,4-differenl)methylamino]-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidine-7-it

A mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (915 mg, 5 mmol) and the aniline derivative (1.1 g, 5.1 mmole)and potassium carbonate (1.5 g, 10.8 mmole) in 10 ml of 1-methyl-2-pyrrolidinone was heated at 120°C. After 12 hours the reaction mixture was cooled to room temperature and was added 100 ml of water. The resulting mixture was extracted with ethyl acetate (3x 100 ml) and the organic layer was washed with water (6x), dried (magnesium sulfate) and was evaporated under reduced pressure. The obtained residue was mixed with diethyl ether (50 ml) for 1 hour, filtered and received the product in the form of solids. The output of 1.07, MS: (M+N)+349.

Stage: Obtain 6-[(2,4-differenl)methylamino]-8-methyl-2-methylsulphonyl-8H-pyrido[2,3-d]pyrimidine-7-it

Sulfide (1.0 g, 2.8 mmole) was dissolved in 25 ml of dichloromethane, and to this solution was added 3-chlormadinone acid (77%, 1.4 g, 6.2 mmole). This solution is eremetical at room temperature for 6 hours, then washed with an aqueous solution of sodium sulfite (2x, 10 ml) and saturated sodium bicarbonate solution (3x 10 ml). The organic solution was dried (magnesium sulfate) and was evaporated, received a solid residue. This residue was stirred with diethyl ether (25 ml), filtered and dried, received sulfon in the form of solids. Yield 870 mg MS: (M+N)+381.

Stage G: Obtain 6-[(2,4-differenl)methylamino]-8-methyl-2-(tetrahydropyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidine-7-it

A mixture of sulfone (0.4 g, 1.05 mmole), 4-aminotetrahydrofuran (0.35 g, 3,47 mmole) and 0.3 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 1 hour. Was cooled to room temperature, was added 1.0 ml of methanol and 2.0 ml of water, stirred at room temperature for 1 hour and filtered, washed with water and dried, received the product in the form of solids. The product is suspended in methanol and acidified with hydrochloric acid (1,0 M/Et2O, 1 EQ.), was stirred for one hour. The organic solvent is evaporated, the residue was stirred with a mixture of methyl alcohol/ diethyl ether for one hour, filtered, received the product in the form of a hydrochloric salt. Output 0,358, TPL197-198,5°C. MS: (M+N)+402.

Example 95: Obtain 6-(2,4-divergence)-8-ethyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it:

Stage A: Gender is an increase ethyl ester 4-ethylamino-2-methylthiopyrimidin-5-carboxylic acid

To a solution of 25 g (107 mmol) of ethyl ether 4-chloro-2-methylthio-5-pyrimidine-carboxylic acid in 250 ml of tetrahydrofuran was added 47 ml (337 mmol) and 43 ml of 70%solution of ethylamine (668 mmol). The mixture was stirred at room temperature for 4 hours. Was evaporated to dryness, the residue was dissolved in a mixture of ethyl acetate/water, twice washed with 10%sodium bicarbonate solution, dried (magnesium sulphate), evaporated to dryness, the obtained product in the form of solids. Output 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 tetrahydrofuran (250 ml) was cooled in a bath with ice to 0°C. To the resulting solution was carefully added in small portions during one hour of alumoweld lithium (4.3 g, 113 mmol), one hour after the addition was slowly added water (4.3 ml), then sodium hydroxide (4.3 ml, 15%), then an additional 13 ml of water, stirred for 1 hour. The resulting suspension was filtered, the filter residue washed twice with 100 ml of tetrahydrofuran. This solution was evaporated under reduced pressure. The residue was stirred with 150 ml of diethyl ether, was filtered, dried. The output of 19.1,

Stage: Obtain 4-ethylamino-2-methylthiopyrimidin-5-Carbo is zaldehyde

To a solution of 4-ethylamino-2-methylthiopyrimidine-5-methanol (19,1 g, 96 mmol) in 1000 ml of dichloromethane was added 87 g of manganese dioxide. The resulting suspension was stirred for 20 hours, filtered through celite. The residue was twice washed with 100 ml of dichloromethane, and the combined filtrate and washing solutions were evaporated under reduced pressure, the obtained product in the form of solids. The output of 12.8,

Stage G: Obtain 6-(2,4-divergence)-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-it

To a mixture of 4-ethylamino-2-methylthiopyrimidin-5-carboxaldehyde (5.0 g, 25.5 mmole) and phenoxyacetate (6.0 g, and 29.7 mmole) in 50 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (6.0 g, 43,4 mmole) and heated at 120°C. After 2 hours, was added 1.5 g of ester and heated an additional 2 hours. At this time, the reaction mixture was added 1.5 g of ester and 2.0 g of potassium carbonate, after an additional two hours, the reaction mixture was cooled to room temperature. The reaction mixture was added to water (300 ml) and stirred 2 hours. Was filtered and washed with diethyl ether, dried. The output of 8.7, TPL122-127,9°C. MS: (M+N)+350.

Stage D: Obtain 6-(2,4-divergence)-8-ethyl-2-(methylsulphonyl)-pyrido[2,3-d]pyrimidine-7(8H)-it

Sul the feed (8.7 g, 24,9 mmole) was dissolved in 100 ml dichloromethane was added 3-chlormadinone acid (77%, and 11.5 g, 50 mmol). The mixture was stirred at room temperature for 8 hours, then washed with a solution of sodium sulfite (2, 75 ml)and then saturated aqueous sodium bicarbonate (3, 75 ml). The organic solution was then dried (magnesium sulfate) and was evaporated. The resulting solid was stirred in diethyl ether for 1 hour and filtered, received sulfon in a solid white color. The output of 6.9, TPL128-129,1°C. MS: (M+H)+381.

Stage E: Obtain 6-(2,4-divergence)-8-ethyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone (6.0 g, 15.7 mmole) and 4-aminotetrahydrofuran (5.0 g, a 49.5 mmole) and 6.0 ml of 1-methyl-2-pyrrolidinone was heated at 80°C. After 1 hour, cooled to room temperature, was added 12 ml of methanol and 24 ml of water, stirred for 1 hour. The suspension was filtered, washed with water and dried. The solid residue suspended in methanol (60 ml) was added hydrochloric acid (1,0 M/Et2O, 1 EQ.), the mixture was stirred for 1 hour and evaporated. The solid residue was stirred with a mixture of methanol/diethyl ether for one hour, filtered, washed with diethyl ether and dried. The output of 5.9, TPL199,1-205,9°C. MS: (M+H)+403.

Example 96: Receive -(2,4-divergence)-8-ethyl-2-(3-hydroxyethylamino-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-it:

A mixture of sulfone (see getting in example 95) (0.50 g, 1,31 mmole) and TRANS-4-amino-3-hydroxymitragynine (0,23 g, 1.97 mmole) (see receipt in the following references: (a) Marquis, Robert W. and others, J. Med. Chem. (2001), 44 (5), 725-736. (b) Gribble, Andrew D., and others, the international application under the PCT (1998), p.74, (C) Mochalin V.B. have been, etc.. Journal of Organic Chemistry (1971), 7 (4), 825-8) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 100°C for 12 hours. The reaction mixture was cooled, was added ethyl acetate (15 ml) and the organic solution washed with water (3x 15 ml), saturated salt solution and then dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and column chromatography (methylene chloride/methanol 97/3) gave 120 mg of product (tPL174,9-176,3°S, MS: (M+N)+=419).

Example 97: Obtain 6-(2,4-divergence)-2-(3-hydroxy-1,3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-it:

Stage A: Getting oxime 4-hydroxy-4-methylpentan-2-it

A mixture of 4-hydroxy-4-methyl-2-pentanone (10.0 g, 85,7 mmole) and hydroxylamine hydrochloride (22,17 g, 343 mmole) in 90 ml of water was intensively stirred at room temperature. To this solution was slowly added within one hour of solid sodium bicarbonate (26,8 g, 343 mmole). After 3 hours the reaction mixture was extracted with ethyl acetate (3x 100 ml), dried (sulf is that magnesium) and evaporated under reduced pressure, received the product in the form of oil. The output of 11.2,

Stage B: Obtain 4-amino-2-methylpentan-2-ol

The oxime (11.2 g, 85 mmol) was dissolved in 150 ml of ethanol, to the solution was added a suspension of 20 ml of 50% Nickel catalyst Raney/ in the water and were all placed in hydrogenator Parra at a pressure of 3,515 kg/cm2. After 6 hours the reaction mixture was filtered through celite and evaporated, got amine in the form of oil. The output of 9.9,

Stage: Obtain 6-(2,4-divergence)-2-(3-hydroxy-1,3-dimethyl-butylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-it

A mixture of sulfone (1.0 g, 2.7 mmole), 4-amino-2-hydroxy-2-methylpentane (1.0 g, 8.5 mmole) and 1.0 ml of 1-methyl-2-pyrrolidinone was heated at 80°C for 2 hours. The reaction mixture was cooled and added to ice water, extracted with ethyl acetate (3, 75 ml), washed with water (6x, 75 ml), dried (magnesium sulfate) and was evaporated. The residue was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5)was obtained pure product. The residue is suspended in methanol and acidified with hydrochloric acid (Et2O/HCl, 1,0 M, 1 EQ.), was stirred for 30 minutes, then evaporated. The residue was stirred in methanol/diethyl ether for 1 hour, filtered and dried, received the product in a solid white color. The output 818 mg TPL158,9-161°S, MS: (M+H) +405.

Following the method described above and dividing amerosport on stage B before use on stage, you get:

6-(2,4-Divergence)-2-(3-hydroxy-1(S),3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-he

6-(2,4-divergence)-2-(3-hydroxy-1(R),3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-he.

Example 98: Obtain 6-(2,4-divergence)-8-methyl-2-(3-hydroxyethylamino-4-ylamino)pyrido[2,3-d|pyrimidine-7(8H)-it:

A mixture of sulfone 5 (0,70 g, 1.4 mmole) and TRANS-4-imino-3-hydroxytyramine-Piran (0.33 g, to 2.85 mmole) (see the following references for exercise: (a) Marquis, Robert W. and others, J. Med. Chem. (2001), 44 (5), 725-736. (b) Gribble, Andrew D., and others, the international application under the PCT (1998), page 74, (C) Mochalin V.B. have been, etc.. Journal of Organic Chemistry (1971), 7 (4), 825-8.) in 2 ml of 1-methyl-2-pyrrolidinone was heated at 100°C for 12 hours. The reaction mixture was cooled, was added ethyl acetate (20 ml). The organic solution is then washed with water (3x 30 ml) and dried (magnesium sulfate). Evaporation of the solvent and thin layer chromatography (methylene chloride/ethyl acetate 95/5) led to 0.25 g of the product. Was added hydrochloric acid (1,0 M/Et2O, 1.2 EQ.) and got salt which was filtered and dried, received 185 mg of the desired product (tPL226,4-227,7°S, MS: (M+H)+=405).

Example 99: Obtain 6-(2-torfin the XI)-2-[(5-hydroxypyrazol-3-yl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,142 mmole), 3-amino-5-hydroxypyrazol (0,017 g, 0,0172 mmole) in 1.0 ml of dimethylformamide was heated at 65°C for 42 hours and cooled. Evaporation of the solvent led to the residue, which was purified by means of liquid chromatography with the adsorption tube Supelco Supelclean™ LC-Si SPE, 6 ml /1 g - CH2Cl2up to 4% MeOH/CH2Cl2and MS/HPLC - (0,0013 g, MS: M+1=369).

Example 100: Obtain 6-(2-pertenece)-2-[(pyridine-2-ylmethyl)amino]-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

A mixture of sulfone 2 (0.05 g, 0,142 mmole), 4-(aminomethyl)pyridine (0,019 g, 0,0172 mmole) in 1 ml of dimethylformamide was heated at 65°C for 18 hours. The cooled reaction mixture was diluted with 2 ml water and 2 ml of ethyl acetate and distributed between two phases. The solution in ethyl acetate was filtered through a layer of 0.5 g of magnesium sulfate, evaporated and purified using liquid chromatography with adsorption tube Supelco Supelclean LC-Si SPE, 6 ml (1 g) (SN2Cl2up to 2% MeOH/CH2Cl2and MS/HPLC (0,0068 g, MS: M+1=378).

Example 101: Getting 2-{[(1,5-dimethyl-1H-pyrazole-4-yl)methyl]amino}-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

Hydrate hydrochloride (1,5-dimethyl-1H-pyrazole-4-yl)methylamine (0,031 g, 0,172 mmole) was treated 0,0172 ml 1M KOH/Meon and evaporated. Am the h was mixed with sulfona 2 (0.05 g, 0,142 mmole) in 1 ml of dimethylformamide at 65°C for 18 hours. The cooled reaction mixture was diluted with water and ethyl acetate, each in an amount of 2 ml, and distributed between two phases. The solution in ethyl acetate was filtered through a layer of 0.5 g of magnesium sulfate, evaporated and the resulting mixture was subjected to liquid chromatography with adsorption tube Supelco Supelclean LC-Si SPE, 6 ml (1 g) (CH2Cl2up to 2% of the Meon/CH2Cl2). (0.005 g, MS: M+1=395).

Example 102: Obtain 2-{[(1,3-dimethyl-1H-pyrazole-4-yl)methyl]amino}-6-(2-pertenece)-8-methylpurine[2,3-d]pyrimidine-7(8H)-it

(1,3-Dimethyl-1H-pyrazole-4-yl)methylamine of 1.8 1.5 N HCl2On (0.037 g, 0,172 mmole) was treated 0,0172 ml 1M KOH/Meon and evaporated. The free amine was mixed with sulfona 2 (0.05 g, 0,142 mmole) in 1 ml of dimethylformamide at 65°C for 18 hours. The cooled reaction mixture was diluted with water and ethyl acetate, each in an amount of 2 ml, and distributed between two phases. The solution in ethyl acetate was filtered through a layer of 0.5 g of magnesium sulfate and evaporated. The resulting mixture was chromatographically using liquid chromatography with adsorption tube Supelco Supelclean LC-Si SPE, 6 ml (1 g) (CH2Cl2up to 2% MeOH/CH2Cl2). (0,0266 g, MS: M+1=395).

Example 103: Obtain 6-(2-pertenece)-2-{[(3-methylisoxazol-5-yl)methyl]amino}-8-methylpurine[2,3-d-7(8H)-it

Hydrochloride (3-methylisoxazol-5-yl)methylamine (0,026 g, 0,172 mmole) was treated 0,0172 ml 1M KOH/Meon and evaporated. The free amine was mixed with sulfona 2 (0.05 g, 0,142 mmole) in 1 ml of dimethylformamide at 65°C for 18 hours. The cooled reaction mixture was diluted with water and ethyl acetate, each in an amount of 2 ml, and distributed between two phases. The solution in ethyl acetate was evaporated and the resulting mixture was chromatographically using liquid chromatography with adsorption tube Supelco Supelclean™ LC-Si SPE, 6 ml (1 g) (SN2Cl2up to 2% MeOH/CH2Cl2). (0,0094 g, MS: M+1=382).

Example 104: 2-{[1-(Hydroxymethyl)cyclohexyl]amino}-6-(2-methylbenzyl)-8-methylpurine[2,3-d]pyrimidine-7(8H)-he

A mixture of sulfone (obtained analogously to sulfone 8) (0.05 g, 0,146 mmole), (1-aminocyclohexane)methanol (0,038 g, 0,291 mmole) in 2 ml of chloroform was heated at 65°C for 18 hours. The cooled reaction mixture was evaporated, then added 1 ml of methanol. The resulting precipitate was collected and purified using liquid chromatography with adsorption tube Supelco Supelclean™ LC-Si SPE, 6 ml (1 g) (SN2Cl2up to 4% MeOH/CH2Cl2and MS/HPLC (0,0249 g, MS: M+1=393).

Example 105: 2-{[1-(Hydroxymethyl)cyclopentyl]amino}-6-(2-methylbenzyl)-8-methylpurine[2,3-d]pyrimidine-7(8H)-he

A mixture of sulfone (obtained analogously to sulfone 8) (0.05 g, 0,146 mmole), (1-aminocyclopent)methanol (0,033 g, 0,291 mmole) in 2 ml of chloroform was heated at 65°C for 18 hours. The cooled reaction mixture was evaporated, then added 1 ml of methanol. The resulting precipitate was collected and purified using liquid chromatography with adsorption tube Supelco Supelclean™ LC-Si SPE, 6 ml (1 g) (CH2Cl2up to 4% of the Meon/CH2Cl2and MS/HPLC (0,0155 g, MS: M+1=379).

Example 106: 6-Benzyl-2-{[1-(hydroxymethyl)cyclopentyl]amino}-8-methyl-pyrido[2,3-d]pyrimidine-7(8H)-he

A mixture of sulfone (obtained analogously to sulfone 8) (0.05 g, 0,152 mmole), (1-aminocyclopent)methanol (0,033 g, 0,291 mmole) in 1 ml of chloroform was heated at 65°C for 18 hours. Added another 0,020 g (1-aminocyclopent)of methanol and the mixture was heated at 65°C for 18 hours. The cooled reaction mixture was evaporated, then added 1 ml of methanol. The resulting precipitate was collected and purified using liquid chromatography with adsorption tube Supelco SupelcleanTMLC-Si SPE, 6 ml (1 g) (CH2Cl2up to 1% MeOH/CH2Cl2and MS/HPLC (0,0345 g, MS: M+1=379).

Example 107 N-[6-(2,4-Divergence)-8-methyl-7-oxo-4A,7,8,8A-tetrahydro-pyrido[2,3-d]pyrimidine-2-yl]-N-(tetrahydropyran-4-yl)ndimethylacetamide

a Mixture of 6-(2,4-divergence)-8-methyl-2-(tetrahydro-2H-Piran-4-ylamino)-pyrido[2,3-d]pyrimidine-7(8H)-it (example 23) (1.0 g, to 2.57 mmole), N,N-aminobutiramida-ethylamine (0,498 g of 0.67 ml, 3,86 mmole) in acetic anhydride (1.42 g, of 1.02 ml, 13.9 mmole) was heated at 123-127°C for 2 hours. Low-boiling impurities are evaporated at 60°received a thick residue, which was dissolved in 4 ml of acetone at 67-70°C. To the resulting solution was added 5 ml of hexane, maintaining the temperature 53-55°C. the mixture was allowed to cool to ambient temperature for 18 hours. The resulting solid was filtered and washed (3×3 ml) acetone: hexane 1:2. The washed solid is suspended in 5 ml of hexane and boiled under reflux for 45 minutes. After cooling to ambient temperature, the suspension was filtered and the solid is washed with hexane and dried in vacuum. (of 0.903 g, MS: M+1=431, tPL185,3-186,9°).

Example 108: obtaining the ethyl ester of 4-{[6-(2-pertenece)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]amino}piperidine-1-carboxylic acid

A mixture of sulfone 2 (1.0 g, 2.86 mmole) and ethyl ester of 4-amino-1-piperidine-carboxylic acid (0,98 ml, 5,73 mmole) in 5 ml of 1-methyl-2-pyrrolidinone was stirred at 120°C for 2 hours and then poured into water (200 ml), and stirred at room temperature for 1 hour. Filtration and subsequent drying led to the free amine. Part of this is product (0,050 g, 0,113 mmole) was dissolved in methanol (1-2 ml) was added a solution of hydrochloric acid in diethyl ether (1M, 1 EQ.). The solid was isolated by filtration after washing with diethyl ether and drying was received 0,038 g of the desired product in the form of a hydrochloric salt (tPL171,2-183,5°).

Example 109: Obtain 6-(2-pertenece)-8-methyl-2-{[(1-benzylmethyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it:

Stage A: Obtain 6-(2-pertenece)-8-methyl-2-(4-piperidylamine)pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of the free base of the ethyl ester of 4-{[6-(2-pertenece)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl]amino}piperidine-1-carboxylic acid (0,500 g of 1.13 mmole) and attributively (0,32 ml of 2.27 mmole) in 5 ml of dichloromethane was heated under reflux. After 4 hours was added an additional amount of attributively (0,32 ml of 2.27 mmole) and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with methanol and evaporated, the residue was dissolved in a methanol solution of sodium methylate (0.5 M, and 9.1 ml) and again evaporated. The resulting solid was washed with dichloromethane and dried in vacuum, obtained 540 mg of the desired aminopiperidine in the form of free base.

Stage B: Obtain 6-(2-pertenece)-8-methyl-2-{[(1-benzylmethyl)-PIP is ridin-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

A mixture of aminopiperidine (0.125 g, 0,338 mmole), sodium carbonate (0,072 g, 0,677 mmole) and benzosulfimide (0,052 ml, 0,406 mmole) in 4 ml of dichloromethane was stirred at room temperature for 4 days. The reaction mixture was purified by column chromatography (SiO2CH2Cl2/MeOH/NH4OH 95/4/1). Fractions after column were combined and concentrated under reduced pressure, obtained free amine. This free amine (0,040 g 0,078 mmole) was dissolved in ethyl acetate (1-2 ml) was added hydrochloric acid in diethyl ether (1M, 1 EQ.). By filtering allocated a solid, which was washed with diethyl ether and dried, was given to 0.032 g of the desired product in the form of a hydrochloric salt (tPL130,0-135,0°).

Example 110: Obtain 6-(2-ethoxy-4-pertenece)-8-methyl-2-{[(1-benzylmethyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it:

Stage A: Obtain 6-(2-ethoxy-4-pertenece)-8-methyl-2-(4-piperidylamine)pyrido[2,3-d]pyrimidine-7(8H)-it:

A mixture of ethyl ester of 4-{[6-(2,4-divergence)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-2-yl]amino}piperidine-1-carboxylic acid (example 70, 1.0 g, of 2.16 mmole) and potassium hydroxide (2,43 g, 43,2 mmole) in 20 ml of ethanol was boiled under reflux for 17 hours, after which was added 0.5 ml of water and boiling with reverse cold what linecom continued for another 20 hours, before the reaction mixture was evaporated under reduced pressure. The residue was dissolved in 100 ml of water and cooled in a bath of ice to acidification added dropwise concentrated hydrochloric acid. The acidic aqueous solution was extracted with dichloromethane (2x), before it was re-podlachian sodium hydroxide and was extracted again with dichloromethane (2x). The organic extracts after extraction of the alkaline aqueous solution was combined, dried with magnesium sulfate and dried in vacuo, got aminopiperidin (M+1=414,1).

Stage B: Obtain 6-(2-ethoxy-4-pertenece)-8-methyl-2-{[(1-benzylmethyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

Part of the derivative obtained above piperidine (0,150 g, 0,387 mmole) was dissolved in 2 ml of dichloromethane with sodium carbonate (0,082 g, 0,774 mmole) and α-toluenesulfonyl chloride (of 0.085 ml, 0,465 mmole) and stirred at room temperature for 17 hours. The reaction mixture was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5). Fractions after column were combined and concentrated under reduced pressure, obtained free amine. The free amine (0,076 g, 0,140 mmole) was dissolved in methanol (1-2 ml) was added hydrochloric acid in diethyl ether (1M, 1 EQ.) before evaporation under reduced pressure. The allocation of solids by the filter is, washing with diethyl ether and drying in vacuo resulted in 0,031 g of the desired product in the form of a hydrochloric salt (tPL134,6-187,3°C).

Example 111: Obtain 6-(2-methyl-4-pertenece)-8-methyl-2-{[(1-benzylmethyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

Stage A: Obtain 6-(2-methyl-4-pertenece)-8-methyl-2-(methylthio)-pyrido[2,3-d]pyrimidine-7(8H)-it

To a mixture of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde (receipt described in example 1) (7,3 g, 39.6 mmole) and methyl ester of 2-methyl-4-pertenece-acetic acid (obtained as in example 4, replacing 2-terfenol 2-methyl-4 tortenelem) (11.8 g, 59.4 mmole) in 80 ml of 1-methyl-2-pyrrolidinone were added potassium carbonate (11,0 g, 79,3 mmole). The reaction mixture was heated at 120°and 3 days later was added phenoxyacetate (15.0 g, to 75.7 mmole). After 18 hours stirring at 120°the reaction mixture was cooled to room temperature and was added water (1 l). The suspension was stirred for 2 hours and then was extracted with ethyl acetate (2x). The combined extracts were washed with water (3x) and saturated salt solution, dried by magnesium sulfate and evaporated in vacuum. Technical solid (10.1 g) was washed with diethyl ether and ethyl acetate, then dried under vacuum, was obtained 2.3 g of pure sulphide (MS: M+1=332).

Stage B: Obtain 6-(2-methyl-4-perfe is hydroxy)-8-methyl-2-(methylsulphonyl)pyrido[2,3-d]pyrimidine-7(8H)-it

Sulfide (2.3 g, 6.9 mmole) was dissolved in 100 ml of methylene chloride was added 3-chlormadinone acid (77%, 3.6 g of 20.6 mmole). The mixture was stirred 2 hours at room temperature, then poured into an aqueous solution of sodium sulfite (10%, 100 ml) and stirred 2 hours at room temperature before distribution. The organic layer was washed polysystem aqueous solution of sodium bicarbonate (3, 100 ml), dried with magnesium sulfate and evaporated. The resulting solid was stirred in diethyl ether for 1 hour and filtered, received sulfon.

Stage: Obtain 6-(2-methyl-4-pertenece)-8-methyl-2-(4-piperidyl-amino)pyrido[2,3-d]pyrimidine-7(8H)-it:

Ethyl ester derivative piperidinecarboxylic acid (derived from sulfone described in stage B, and ethyl ester of 4-amino-1-piperidinecarboxylic acid in the same manner as described in example 70) was isolated in the form of a hydrochloric salt (tPL184,0-210,3°). Boiled under reflux for 3 days of 1.03 g of the obtained ethylcarbamate (of 2.26 mmole) and potassium hydroxide (to 4.81 g of 85.7 mmole) in 60 ml of ethanol and evaporated in vacuum. The residue was dissolved in aqueous hydrochloric acid (2M) and extracted with dichloromethane (2x), then cooled in a bath of ice and re-podlachian solid hydroo ISU sodium. The resulting oily sludge decantation and washed with methanol and dichloromethane, dried with sodium carbonate and evaporated in vacuo, got 0,550 g of the desired derivative of piperidine.

Stage G: Obtain 6-(2-methyl-4-pertenece)-8-methyl-2-{[(1-benzylmethyl)piperidine-4-yl]amino}pyrido[2,3-d]pyrimidine-7(8H)-it

The mixture obtained above derived piperidine (0.125 g, 0,326 mmole), sodium carbonate (0,069 g, 0,652 mmole) and benzosulfimide (0,050 ml, 0,391 mmole) in 2 ml of dichloromethane was stirred at room temperature for 5 days and was purified by column chromatography (SiO2CH2Cl2/MeOH - 95/5). Fractions after column were combined and concentrated under reduced pressure, obtained free amine. This free amine (0,185 g, 0,353 mmole) was dissolved in ethyl acetate (1-2 ml) was added hydrochloric acid in diethyl ether (1M, 1 EQ.). The allocation of solids by filtration, washed with diethyl ether and drying in vacuo resulted in 0.156 g hydrochloric salt (tPL115,2-122,9°).

Example 112: Obtain 6-(2,4-divergence)-8-methyl-2-(N1-(methylsulphonyl)-1,3-diaminopentane)pyrido[2,3-d]pyrimidine-7(8H)-it

Stage A: Obtain 6-(2,4-divergence)-8-methyl-2-(N1(carbobenzoxy)-1,3-diaminopentane)pyrido[2,3-d]pyrimidine-7(8H)-it

Sulfon 5 (0,47 g, 6.4 mmole) was dissolved in anhydrous tetrahydrofuran, to which was added N'-(carbobenzoxy)-1,3-diaminopentane (Org. Prep. And Proceed. Int., 30(3), 339-348 (1998)), (1.52 g, 6.4 mmole) and stirred over night at 23°C in nitrogen atmosphere. Concentrated in vacuo and received a technical product in the form of oil, which was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated salt solution and dried (magnesium sulfate). Was filtered and concentrated, received crude oil, which was chromatographically on silica gel, elwira 2% methanol in dichloromethane, got 0,657 g of 6-(2,4-divergence)-8-methyl-2-(N1(carbobenzoxy)-1,3-diaminopentane)-pyrido[2,3-d]pyrimidine-7(8H)-she (MS: M+1=524).

Stage B: Obtain 6-(2,4-divergence)-8-methyl-2-(N1-(methylsulphonyl)-1,3-diaminopentane)pyrido[2,3-d]pyrimidine-7(8H)-it

To a solution of 6-(2,4-divergence)-8-methyl-2-(N1(carbobenzoxy)-1,3-diaminopentane)pyrido[2,3-d]pyrimidine-7(8H)-she (0.65 g, 1.2 mmole) in tetrahydrofuran was added 10% Pd-C (0,13 g) and stirred 4 hours at 23°C in an atmosphere of hydrogen. Was filtered and concentrated in vacuum. The residue was dissolved in 10 ml dichloromethane and cooled to -10°C, was added pyridine (5 ml, 62 mmole) and methanesulfonamide (0,070 ml, 0,86 mmole) and stirred. Concentri is ovale in vacuum and chromatographically on silica gel, elwira 1% solution of methanol in dichloromethane, got 0,121 g of 6-(2,4-divergence)-8-methyl-2-(N1-(methylsulphonyl)-1,3-diaminopentane)pyrido[2,3-d]pyrimidine-7(8H)-it, which was dissolved in anhydrous diethyl ether and was turned into a hydrochloric salt (MS: M+1=468, tPL178,6-181,2°).

Example 113: Obtain 4-amino-2-methylthiopyrimidin-5-carbaldehyde

Obtaining potassium salt of 3,3-diethoxy-2-formylpyridine (II)

To a stirred solution of 3,3-diethoxypropionate (I, 283,80 g of 1.98 mol) and methylformate (148, 80 g, 2,48 mol) in anhydrous tetrahydrofuran (1.1 l) at 10°C was added 1.0 M solution of potassium tert-butylate in tetrahydrofuran (2.2-liter and 2.2 mol). The temperature was maintained in the range from 10°to 15°With all the time adding within 45 minutes. After adding the resulting suspension was stirred 2 hours at ambient temperature. Then was added hexane (400 ml) and stirring continued for another 20 minutes. The suspension was filtered and the Packed sediment was washed with hexane/tetrahydrofuran 1/1 and dried over night at 60°With vacuum dryer. The output of powder pale brown was 302,5 g (73,0%).1H-NMR-spectrum (CD3OD) was consistent with the desired structure II.

Getting 4-amino-2-sulfanilamide-5-carbaldehyde (III)

Suspension of timoc the guilt (of 92.8 g, 1,22 mol) in ethanol (90 ml) was boiled under reflux and intensively stirred. To this suspension was added a suspension of the potassium salt of 3,3-diethoxy-2-formylpyridine (II) (222,20 g of 1.06 mol) in 25% MeONa/MeOH (85.5 ml of 0.37 mole) and ethanol (285 ml) in five aliquot in 10 minutes, while boiling (alternative, the final slurry may be heated to 50°to obtain a homogeneous solution to add). Added additional portion of ethanol (150 ml) to facilitate stirring. After adding the thick suspension was acquired bright yellow color and boiled under reflux for another one hour. The mixture was then cooled and evaporated almost to dryness in a rotary evaporator. The residue was dissolved in water (940 ml). Technical product besieged from the solution by the addition of 30%acetic acid (280 ml) and was isolated by filtration, using a funnel with srednemotornoy porous glass plate. Agglomerated precipitate was washed with water (800 ml). Was purified by trituration in hot water (1 l) for 30 minutes, then cooled and filtered, was obtained after drying at 60°overnight in a vacuum drying Cabinet 118,9 g (72.3%) of product as a solid bright yellow (subsequent experiments receipt demonstrated that such rubbing is not necessary). According to the HPLC purity was 98,67% 1H-NMR spectrum (DMSO-d6) consistent with the desired structure III.

Getting 4-amino-2-methylthiopyrimidin-5-carbaldehyde (IV)

To a solution of 4-amino-2-sulfanilamide-5-carbaldehyde III (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 methyl iodide (128,10 g, 902,2 mmole) for 20 minutes at a low cooling. The mixture was stirred at room temperature over a weekend at the end of the week. Thin layer chromatography showed the presence of residual III, was added an additional aliquot of methyl iodide (8 ml) and stirring continued over night. TLC again showed some amount of residual III, added an additional portion of methyl iodide (8 ml) and stirring continued for another 24 hours. Analysis by HPLC showed the presence of 95.9% of the S-alkylated product and 3.7% of compound III. The reaction mixture was evaporated almost to dryness in a rotary evaporator. To the residue was added water (1 l) and the product was collected by filtration and washed with water (200 ml). The product was dried overnight in a vacuum drying Cabinet at 60°C. the Output was 103,37 g (94,8%). Analysis by HPLC indicated the presence of 95,8% IV and 4.2% III.

Example 114

This example illustrates in vitro analysis of map-kinase R suitable for evaluation of the compounds of the present invention.

Inhibitory AK is Yunosti compounds of the present invention with respect to map-kinase R in vitro was determined by measuring the transfer γ -phosphate from γ-33P-ATP using kinase p-38 to myelin basic protein (MBP), using a slight modification of the method described by Ahn and others in J. Biol. Chem. 266:4220-4227 (1991).

Phosphorylated form of recombinant map kinase R was subjected to a joint expression with kinase SEK-1 and MEKK in E. coli (see Khokhlatchev, etc., J. Biol. Chem. 272: 11057-11062 (1997)) and then carried out the purification using affinity chromatography using a Nickel column.

Phosphorylated map-kinase R was diluted in buffer for kinase (20 mm 3-(N-morpholine)propanesulfonate, pH of 7.2, 25 mm β-glycerophosphoric acid, 5 mm ethylene glycol-bis(β-aminoacylase ether)-N,N,N',N'-tetraoxane acid, 1 mm sodium salt orthovanadate acid, 1 mm dithiothreitol, 40 mm magnesium chloride). The investigated compound was dissolved in dimethyl sulfoxide (DMSO) or added only DMSO (control) and samples were incubated for 10 minutes at 30°C. the Reaction kinase initiated by addition of substrate in the form of a cocktail containing MBP and γ-33P-ATP. After incubation for an additional 20 minutes at 30°the reaction was completed by addition of 0.75%phosphoric acid. Phosphorylated MBP was then separated from the remaining γ-33P-ATP using phosphocellulose membrane (Millipore, Bedford, Minnesota, USA), and quantitatively evaluated using scintillation the th counter (Packard, Meriden, Connecticut, USA).

Example 115

This example results in vitro analysis to assess the inhibition induced by lipopolysaccharide (LPS) production of TNF-α in cells TNR.

The ability of compounds of this invention inhibit the release of TNF-α was determined using a minor modification of the methods described Blifeld and others in Transplantation, 51: 498-503 (1991).

(a) Induction of TNF biosynthesis:

Cells TNR-1 suspended in culture medium [RPMI(Gibco-BRL, Gailthersburg, MD, USA)containing 15% serum fetal cow, 0.02 mm 2-mercaptoethanol] concentration of 2.5×106cells/ml and then were placed in a 96-cell tablet (aliquots of 0.2 ml in each cell). The compounds were dissolved in DMSO and then diluted in culture medium to the final concentration of DMSO was 5%. Aliquot 25 ál sample solution or only medium with DMSO (control) was added to each cell. Cells were incubated for 30 minutes at 37°C. was Added to the cells lipopolysaccharide (Sigma, St. Louis, Missouri, USA) to a final concentration of 0.5 μg/ml and cells were incubated for another 2 hours. At the end of the incubation period, the culture supernatant was collected and the amount present of TNF-α were determined using enzyme immunosorbent assay (ELISA), as described below.

(b) ELISA analysis:

Quantities of the present human TNF-α were determined using ELISA analysis with specific capture using two antibodies against TNF-α (2TNF-H12 and 2TNF-H34), described Reimund, J.M., and others in the GUT. volume 39 (5), 684-689 (1996).

In each of the wells of polystyrene 96-cell tablet was placed 50 μl of antibody 2TNF-H12 in phosphate buffered saline (SFR) (10 μg/ml) and incubated in a humidified chamber at 4°With during the night. The tablets were washed SFR and then blocked with 5%solution of nonfat dry milk in SFR for 1 hour at room temperature, and washed with 0.1%solution of bovine serum albumin (BSA) in SFR.

Standards TNF was prepared from the original solution of human recombinant TNF-α (R&D Systems, Minneapolis, mn). The concentration of the standards in the analysis was initially 10 ng/ml, and then did six serial dilutions on semi-logarithmic law.

Aliquot 25 ál of the above culture supernatant fluids or standards TNF, or only medium (control) was mixed with an aliquot 25 ál of biotinylated monoclonal antibodies 2TNF-H34 (2 μg/ml in SFR containing 0.1% BSA) and added to each cell. Samples were incubated 2 hours at room temperature with gentle shaking and then washed 3 times with 0.1% BSA in SFR. Was added to each well 50 μl of a solution of peroxidase-streptavidin, Zymed, S. San Francisco, CA, USA)containing 0,416 μg/ml peroxidase-streptavidin, and 0.1% BSA in SFR. Samples were incubated 1 hour at room temperature and then washed 4 times with 0.1% BSA in SFR. In each cell was added 50 μl of a solution of O-phenylenediamine (1 mg/ml O-phenylenediamine and 0.03% hydrogen peroxide in 0.2 M citrate buffer pH 4.5) and the samples were incubated in the dark for 30 minutes at room temperature. The optical density of the sample and standard was determined at 450 nm and 650 nm, respectively. The content of TNF-α was determined by curve optical density at 450 nm against concentration.

Value IR50(the concentration that causes 50%inhibition) was determined as the concentration of the compounds corresponding to 50%of the resultant decrease in the absorption at 450 nm.

Example 116

The example illustrates in vivo evaluation of the inhibition induced by lipopolysaccharide production of TNF-α in mice (or rats).

The ability of compounds of this invention inhibit the release of TNF-αand, in vivo, was determined using a minor modification of the methods described Zanetti and others in J.Immunol., 148: 1890 (1992) and Sekut, etc. in J. Lab.Clin. Med., 124: 813 (1994).

Female mice of BALB/c mice weighing 18-21 g (Charles River, Hollister, CA, USA) were subjected to acclimatization during the week. Groups of 8 mice in each metered enter the oral or the compounds, suspended or dissolved in an aqueous medium containing 0.9% sodium chloride, 0.5% sodium carboxymethyl cellulose, 0.4% Polysorbate 80, 0.9% of benzyl alcohol (karboksimetilcelljulozy /CMC/ media)or media (control group). After 30 minutes, mice were intraperitoneally injected with 20 μg of lipopolysaccharide (Sigma, St. Louis, Missouri). After 1.5 hours, the mice were killed by inhalation of CO2and blood was collected by puncture of the heart. Blood was osvetleni by centrifugation at 15,600×g for 5 minutes and the serum was transferred into a clean test tube and frozen at -20°to analyze TNF-α using ELISA-assay (Biosource International, Camarillo, CA, USA)following the manufacturer's Protocol.

Typical compounds of the present invention are presented below in table 1 and table 2. Inhibiting activity of the compounds from tables 1 and 2 in relation kinase R characterized by the values IR50in the range of from about 0.1 to 5000 nm, for most compounds, these values range from 1 to 1000 nm and unexpectedly, these compounds are selective inhibitors of the kinase R compared with cyclin-dependent kinases and receptor. These IR50for specific compounds are presented in units, with a unit (micromolar), denoted in the tables "0,01", corresponds to 10 nm.

Physical data and activity

The compound of the formula I

where W denotes NH, X1means On, X2means O Z denotes N, Ar1means 2,4-differenl the R 1means-Y1-C(O)-Y2-R11where Y2no

Table 3
No.Y1R11R3IR50TPLMass spectrum
1C(CH3)2N(CH3)2CH30,0352(M+N)+=418
2C(CH3)2Och3CH30,0072150,9-153,1
3C(CH3)2NH2CH30,2562(M+H)+=390
4CH(CH3)N(CH3)2CH30,6672(M+H)+=404
5C(CH3)2CH2CH3CH30,0207182,0-183,3
6C(CH3)2Och3cyclopropyl0,0003159,0-161,0
7C(CH3)2 NHCH3cyclopropyl0,0708203,4-204,8
8C(CH3)2N(CH3)2cyclopropyl0,0036(M+H)+=442
9C(CH3)24-methylsulphonyl-piperazine-4-ylCH30,1076(M+H)+=537
10C(CH3)2morpholine-4-ylCH30,0042(M+N)+=460
11CH(CH3)N(CH3)2CH30,6281143,7-144,6

Pharmaceutical compositions.

The pharmaceutical composition introduced in different ways, are as shown below. As the "active ingredient" or "active compound" is used one or more compounds of formula I.

Composition for oral administration

Ingredient %weight/weight
The active ingredient20,0%
Lactose79,5%
Magnesium stearate0,5%

And gradienty mixed and placed in capsules, containing 100 mg each; one capsule approximately corresponds to the total single dose.

Composition for oral administration

Ingredient %weight/weight
The active ingredient20,0%
Magnesium stearate0,5%
Crosscarmelose sodium2,0%
Lactose76,5%
PVP (polyvinylpyrrolidine)1,0%

The components are mixed and granularit, using as solvent methanol. Then the composition is dried and formed into tablets (containing about 20 mg of active compound) using the equipment for manufacture of tablets.

Composition for oral administration

Ingredientnumber
The active ingredient1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methyl paraben0.15 g
Propyl paraben0.05 g
Granulated sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Wigum To (Varderbilt Co.)1.0 g
Flavoringa 0.035 ml
Dyes0.5 mg
Distilled waterto 100 ml

The ingredients are mixed to form a suspension for oral administration.

The composition for parenteral administration

Ingredient %weight/weight
The active ingredient0.25 g
Sodium chlorideto obtain isotonic
Water for injection100 ml

The active ingredient is dissolved in a portion of water for injection. Next, add with stirring a sufficient amount of sodium chloride to education isotonic. The solution was adjusted to the desired amount of injection water, filtered through an 0.2 micron membrane filter and packaged under sterile conditions.

Suppositories

Ingredient %weight/weight
The active ingredient1,0%
Polyethylene glycol 100074,5%
Polyethylene glycol 400024,5%

The ingredients are melted and mixed in a steam bath, pour into molds 2.5,

Composition

Ingredientgrams
Active connection0,2-2
Span 602
Tween 602
Mineral oil5
Vaseline10
Methyl paraben0,15
Propyl paraben0,05
BGA (bottled hydroxyanisol)0,01
Water100

All ingredients, except water, are combined and heated with stirring at 60°C. Then, with vigorous stirring, a sufficient amount of water at 60°to emulsify the ingredients, then add water to 100 mg.

Composition for nasal use

From a water suspension containing 0.025-0.5% of active compound, receive the nasal spray. Optional compositions contain inactive ingredients such as microcrystalline cellulose, carboxymethylcellulose sodium, dextose and the like. Can be added hydrochloric acid to maintain pH. Nasal composition may be injected through the pump for nasal administration in the amount of 50-100 µl on one action. Usual dose is 2-4 times every 4-12 hours.

1. Derived pyridopyrimidines Faure the uly I or II

or its pharmaceutically acceptable salt, where

Z denotes N or CH;

W means NR2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6mean hydrogen);

X2means Of;

Ar1means unsubstituted or substituted phenyl;

R2means hydrogen, alkyl or acyl;

R1means hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroalkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh, R12-SO2-heterocyclization (where R12means aryl or aralkyl), -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or are alkalinous group and R11means alkyl, alkoxyl, amino, monoalkylamines or dialkylamines), substituted piperazinil or morpholinyl;

R3means alkyl, cycloalkyl, aryl, amino, monoalkylamines or dialkylamines;

R8and R9mean independently from each other hydrogen, alkylsulfonyl, -C(O)-R81(where R81means mono - or dialkylamino the PU).

2. Derived pyridopyrimidines according to claim 1, where

Z denotes N or CH;

W means NR2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6mean hydrogen);

X2means Of;

Ar1means unsubstituted or substituted phenyl;

R2means hydrogen or alkyl;

R1means hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, cianelli, heterocyclyl, geterotsiklicheskikh, -Y1-C(O)-Y2-R11(where Y1and Y2independently either absent or are alkalinous group and R11means alkyl, alkoxyl, amino, monoalkylamines or dialkylamines), substituted piperazinil or morpholinyl;

R3means alkyl, cycloalkyl, aryl, amino, monoalkylamines or dialkylamines;

R8and R9mean independently from each other hydrogen, alkylsulfonyl, -C(O)-R81(where R81means mono - or dialkylamino).

3. Derived pyridopyrimidines according to claim 1 or 2, where Z denotes n

4. Derived pyridopyrimidines according to any one of claims 1 to 3, where W denotes NH.

5. Derived pyridopyrimidines according to any one of claims 1 to 4, where Ar1 means optionally substituted phenyl

6. Derived pyridopyrimidines according to any one of claims 1 to 5, where X1means Oh or CH2.

7. Derived pyridopyrimidines according to any one of claims 1 to 6, where X1means Acting

8. Derived pyridopyrimidines according to any one of claims 1 to 7, where R1means aryl, aralkyl, cycloalkyl, cycloalkenyl, heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh.

9. Derived pyridopyrimidines according to any one of claims 1 to 8, wherein R1means heterooligomeric cycloalkyl, heterothermy cycloalkyl, heteroalkyl or heterocyclic.

10. Derived pyridopyrimidines according to any one of claims 1 to 9, where R1means heterocyclyl.

11. Derived pyridopyrimidines according to any one of claims 1 to 9, where R1means heteroalkyl.

12. Derived pyridopyrimidines according to any one of claims 1 to 11, where Ar1mean 2-substituted phenyl, 4-substituted phenyl or 2,4-disubstituted phenyl.

13. Derived pyridopyrimidines according to any one of claims 1 to 12, where Ar1mean 2-chlorophenyl, 2-forfinal, 2-were, 2-fluoro-4-were or 2,4-differenl.

14. Derived pyridopyrimidines according to any one of claims 1-13 of formula I where X is O and R3means methyl, propyl or cyclopropyl, preferably methyl.

15. Derived pyridopyrimidines according to any one of p is.1-13 formula II, where R8means hydrogen and R9means alkylsulfonyl or -- C(O)-R81(where R81is monoalkylamines or dialkylamines).

16. Derived pyridopyrimidines at 14, where Ar1means 2,4-differenl and R1means tetrahydro-2H-Piran-4-yl, ie 6-(2,4-divergence)-8-methyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-he.

17. Derived pyridopyrimidines at 14, where Ar1means 2,4-differenl and R1means tetrahydro-2H-Piran-4-yl, ie 6-(2,4-divergence)-8-propyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-he.

18. Derived pyridopyrimidines at 14, where Ar1means 2,4-differenl and R1means tetrahydro-2H-Piran-4-yl, ie 6-(2,4-divergence)-8-cyclopropyl-2-(tetrahydro-2H-Piran-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H)-he.

19. Derived pyridopyrimidines at 14, where Ar1means 2,4-differenl and R1means 1,3-dimethyl-3-hydroxybutyl, ie 6-(2,4-divergence)-2-(3-hydroxy-1,3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-he.

20. Derived pyridopyrimidines according to claim 19, which is 6-(2,4-divergence)-2-(3-hydroxy-1(S),3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one.

21. Connection claim 20, which is 6-(2,4-divergence)-2-(3-hydroxy-1(R), 3-dimethylbutylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one.

22. proizvodnje of pyridopyrimidines according to claim 1 of formula I, where R2means acyl.

23. Derived pyridopyrimidines on p.22, where R1means heteroalkyl or heterocyclyl.

24. Derived pyridopyrimidines according to item 23, where R1means heterocyclyl.

25. Derived pyridopyrimidines on any of PP-24, where X1means On, X2means Of and R3means methyl.

26. Derived pyridopyrimidines on any of PP-25, where R2means acyl.

27. Derived pyridopyrimidines on any of PP-26, where Ar1means 2,4-differenl, R1means tetrahydro-2H-Piran-4-yl and R2means acetyl.

28. The compound of the formula I' or II"

where

Z denotes N or CH;

W means S, S(O), S(O)2;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl), or C=O;

X2means O or NR7;

Ar1means aryl or heteroaryl;

R10means alkyl or penalcol;

R3means hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, haloalkyl, heteroalkyl, cianelli, alkylen-C(O)-R31(where R31means hydrogen, alkyl, hydroxyl, alkoxyl, amino, monoalkylamines or dialkylamines), amino, mo is alkylamino-, dialkylamino or NR32-Y3-R33(where Y3means-C(O), -C(O)O-, -C(O)NR34, S(O)2or S(O)2NR35;

R32, R34and R35means independently hydrogen or alkyl, and R33means hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl or optionally substituted phenyl)or acyl;

R7means hydrogen or alkyl; and

R8and R9means independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkylsulfonyl,

arylsulfonyl, -C(O)-R81(where R81means alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heteroalkyl, alkoxy, alloctype, amino group, mono - and di-alkylamino, killingray or aryl(alkyl)amino group), or R8and R9together form =CR82R83(where R82and R83means independently hydrogen, alkyl, cycloalkyl, cycloalkenyl or optionally substituted phenyl).

29. Pharmaceutical composition having inhibitory activity against the kinase R38and include pharmaceutically acceptable filler, if desired, and one or more compounds according to any one of claims 1 to 27 or their pharmaceutically acceptable salts.

30. A method of obtaining a sulfide compound of the formula

where

Z denotes N or CH;

X1means Oh, NR4(where R4means hydrogen or alkyl), S, or CR5R6(where R5and R6means independently hydrogen or alkyl);

X2means Of;

Ar1means unsubstituted or substituted phenyl;

R means alkyl or penalcol;

R3means alkyl, cycloalkyl, aryl, amino, monoalkylamines or dialkylamines;

the interaction of the aldehyde of the formula

with an aryl compound of the formula

,

where X3means-C(=O)-OR', and R' represents an alkyl,

under conditions suitable to obtain a sulfide compound, obtaining sulfide compound, which optionally is treated in oxidizing conditions to receive sulfonating the compounds of formula

where R, Z, R3X1X2and Ar1defined above.

31. The method according to item 30, where Z, X1, Ar1or R3are as defined according to any one of claims 1 to 27.

32. The method according to item 30 where the above-mentioned oxidizing conditions include m-chlormadinone acid, Oxon®, periodic or peroxide rhenium.

33. The method of obtaining the compounds of formula I according to any one of p is.1-27, including the stage of interaction of the compounds of formula IV:

where Z, R3X1X2and Ar1are as defined in any one of claims 1 to 27, and L is a leaving group,

with the amine R1R2NH in which R1and R2have the same meanings as R1and R2according to any one of claims 1 to 27, in the conditions of a nucleophilic substitution.

34. The method according to p, where L means the group RS(O)n-where R is an alkyl or phenyl group and n is an integer from 0 to 2.

35. The compound according to any one of claims 1 to 27, obtained by the method according to p.

36. Connection p obtained by the method according to any of PP-33.

37. Derivatives pyridopyrimidines according to any one of claims 1 to 27 or 35 to obtain drugs for the treatment of indirect R violations.

38. Derivatives pyridopyrimidines on clause 37, where mentioned oposredstvovanii R infringement is arthritis, Crohn's disease, irritable bowel syndrome, respiratory distress syndrome in adults or chronic obstructive pulmonary disease, or referred to oposredstvovanii R infringement is Alzheimer's disease.

Priority from 12.02.2001 installed according to claims 1-38,

Priority from 30.11.2001 installed according to claims 1 to 38 (clarification points).



 

Same patents:

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to a heteroarylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone taken among of compounds order corresponding to the formula (I): wherein a subscript symbol n mans a whole number 1; R1 means (C1-C6)-alkyl (substituted with one or two substitutes taken among group involving hydroxy group, (C1-C6)-alkoxy group and others), piperidinyl-(C0-C4)-alkyl [wherein piperidinyl fragment is monosubstituted optionally with benzyl, carbamoyl, (C1-C4)-alkane sulfonyl, (C1-C6)-alkyl and so on], morpholinyl-(C0-C4)-alkyl, tetrahydropyranyl-(C0-C4)-alkyl, 2-oxoimidazolidinyl-(C0-C4)-alkyl, 2-oxopyrrolidinyl-(C0-C4)-alkyl or 1,1-dioxotetrahydrothienyl-(C0-C4)-alkyl, (C3-C6)-cycloalkyl (monosubstituted with monohydroxy group, (C1-C6)-alkoxy group and so on), 1,4-dioxaspiro[4,5]decane-8-yl, 2,4-dione-1,3-diazaspiro[4,5]decane-8-yl or (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5,5]undecane-9-yl; R2 means (C1-C4)-alkyl, halogen atom; R3 means hydrogen atom, (C1-C6)-alkyl (optionally substituted with one or two substitutes taken among group involving (C1-C4)-alkoxy group, pyrrolidinyl, di-(C1-C4-alkyl)-amino-group and so on), phenyl, benzyl or piperidinyl (N-substituted optionally with (C1-C4)-alkyl); R4 means hydrogen atom, and also its individual isomers, racemic and nonracemic mixtures of isomers, prodrugs and its pharmaceutically acceptable salts. Also, invention proposes a pharmaceutical composition possessing inhibitory activity with respect to activity of p38 MAP kinase. The composition comprises a heteroalkylamino-derivative of dihydropyrimido[4,5-d]pyrimidinone of the formula (I), isomer, racemic or nonracemic mixture of isomers or its pharmaceutically acceptable salt in mixture with at least one pharmaceutically acceptable vehicle. Invention provides representing a heteroalkylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone possessing inhibitory activity with respect to activity of p38 MAP kinase.

EFFECT: valuable biochemical properties of compounds and composition.

14 cl, 4 tbl, 90 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry, pharmacy.

SUBSTANCE: invention describes alkylamino-substituted bicyclic nitrogen-containing heterocycles of the general formula (I):

wherein n = 1; R1 means (C1-C6)-alkyl; R2 means halogen atom; R3 means (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, N-heterocyclyl-(C1-C6)-alkyl or (C1-C6-alkylene)-C(O)R31 wherein R31 means hydroxy- or (C1-C6)-alkoxy-group, and its pharmaceutically acceptable salts. New compounds are inhibitors of protein kinase p38 and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new derivatives of pyrrolopyrimidine of the formula (1) and their pharmaceutically acceptable salts possessing properties of selective inhibitor of specific cyclic guanosine 3',5'-monophosphate phosphodiesterase (specific cGMP PDE) (PDE V). In the formula (1) R1 represents hydrogen atom (H), (C1-C3)-alkyl substituted optionally with one or some fluorine atoms; R2 represents H, halogen atom, (C1-C6)-alkyl substituted optionally with hydroxyl group (-OH), (C1-C3)-alkoxy-group, (C3-C6)-cycloalkyl or one or some fluorine atoms, (C3-C6)-cycloalkyl; R3 represents (C1-C6)-alkyl substituted optionally with (C3-C6)-cycloalkyl or one or some fluorine atoms; R4 represents (C1-C6)-alkyl substituted optionally with one or some fluorine atoms; R5 represents -SO2NR6R, -NHSO2R8 or heterocyclyl such as tetrazolyl; each R6 and R7 represents independently H or (C1-C6)-alkyl substituted optionally with -CO2H or one or some fluorine atoms; or in common with nitrogen atom to which they are bound form monocylic ring, such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine wherein indicated group is replaced optionally with R9 wherein R9 represents (C1-C6)-alkyl substituted optionally with one or some halogen atoms, hydroxyl group (OH), (C1-C3)-alkoxy-group that is replaced optionally with one or some fluorine atoms, -NR11R12, -C=NR13(NR14R15) or tetrazolyl group, 6-membered nitrogen-containing heteroaryl group; each R11 and R12 represents independently H or (C1-C4)-alkyl; R13represents H; each R14 and R15 represents independently H. Also, invention relates to intermediate compounds, methods for preparing compounds and pharmaceutical compositions. Proposed compounds can be used in treatment of impotency, sexual dysfunction in females, stable, nonstable and variant (Prinzmental) stenocardia and other diseases also.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 250 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and drug.

17 cl, 6 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

EFFECT: improved preparing method, valuable properties of compounds and compositions.

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

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

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: the present innovation deals with treating affected amnestic functions in women after uterine and adnexal extirpation. For this purpose, after a 7-d-long introduction of estradiol as suppositories at curative dosage of 8-20 mcg/kg body weight patients should be additionally injected with galanthamine intramuscularly once daily for 7-10 d at the dosage 5 mg, moreover, decreasing the number of estradiol injections up to once/3 d. The innovation suggested provides high antiamnestic effect at decreased dosage of preparations due to their agonistic action.

EFFECT: higher efficiency of therapy.

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