Heteroarylamino-substituted bicyclic nitrogen-containing heterocycles as inhibitors of p38 protein kinase

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

 

The present invention relates to bicyclic nitrogen-containing the heterocycles. The object of the invention is some heterooligomerization dihydropyrimido[4,5-d]pyrimidinone derivatives containing pharmaceutical preparations and their uses as therapeutic agents and methods for their preparation.

Mitogenactivated protein kinases (MAP kinases) are a family of polynaphthalene serine/threonine kinases that activate their substrates by dual phosphorylation. Kinases are activated by different signals, including food and osmotic stress, UV radiation, growth factors, endotoxin and inflammatory cytokines. One group of MAP kinases is a group R kinases, which includes various isoforms (for example, Rα, Rβ and Rγ). Like other kinases, Rα kinase responsible for the phosphorylation and activation of transcription factors and they are activated by physical and chemical stress, inflammatory cytokines and bacterial lipopolysaccharide. Even more importantly, as has been shown, the products phosphorylation by R are mediated production of inflammatory cytokines, including TNF (a factor that causes necrosis of tumor tissue), IL-1 (interleukin-1) and cyclooxygenase-2. Each of these cytokines involves the I part in various painful conditions and terms. So, for example, TNF-α is a cytokine produced mainly activated monocytes and macrophages. Its excessive and unregulated education plays an important role in the pathogenesis of rheumatoid arthritis. Recently it was shown that the inhibition of production of TNF can be widely used for the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

TNF sacrament and to the effects of viral infections such as HIV, influenza virus, herpes virus, including but not limited to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (OIE), Epstein-Barr, herpes simplex virus type b (GWh-6) human herpes virus type 7 (GWh-7) human herpes virus type 8 (GWh-8) human infectious bulbar paralysis and rhinotracheitis.

Similarly IL-1 is produced by activated monocytes and macrophages and plays a role in many pathophysiological reactions, including rheumatoid arthritis, fever, and decrease bone resorption. Inhibition of these cytokines inhibitors R kinase effective at suppressing, reducing and alleviating many of these disease conditions. One of the objects of the present invention provides compounds corresponding to the formula

in to the second subscript the symbol n denotes an integer from 0 to 3;

R1denotes acyl, heteroalkyl, optionally substituted arylheteroacetic, heteroalkyl, heteroalkyl, geterofullereny, heterothermy cycloalkyl, heterothermy cycloalkenyl, heterothermy cycloalkylcarbonyl, heterothermy cycloalkylcarbonyl, heterooligomeric cycloalkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh, optionally substituted heterocyclisation(alkylene)-C(O)-R11or -(heteroalkyl)-C(O)-R11;

where R11denotes alkyl, haloalkyl, amino, monosubstituted amino, disubstituted an amino group, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, hydroxyl or alkoxy;

R2everyone, in each case independently denotes an alkyl, halo, heteroalkyl or vinyl;

R3denotes a hydrogen atom, alkyl, heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, cycloalkenyl, optionally substituted cycloalkenyl, haloalkyl, cianelli, heterothermy qi is loukil, heterothermy cycloalkenyl, heterooligomeric cycloalkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh(alkylene)-C(O)R31or -(heteroalkyl)-C(O)R31where

R31denotes alkyl, haloalkyl, hydroxyl, alkoxy, amino, monosubstituted amino, disubstituted an amino group, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroalkyl, and

R4denotes a hydrogen atom, alkyl or -(alkylene)-C(O)R31,

as well as their individual isomers, racemic and nerezisca mixture of isomers and their pharmaceutically acceptable salts.

The compounds of formula I and their aforementioned salts are inhibitors of protein kinases and in vivo exhibit unexpectedly high activity against R. Of interest is the fact that the compounds of formula I exhibit activity against tyrosinekinase RlckT-cells at a level below about 10 microns. Such compounds may be effective in the treatment of diseases mediated by anti-inflammatory cytokines, such as TNF and IL-1.

Among used in the present description concepts

"alkyl" means a linear saturated monovalent uglev the portly radical, containing from one to six carbon atoms, or branched saturated monovalent hydrocarbon radical containing from three to six carbon atoms, for example methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl;

"alkylene" means a linear saturated divalent hydrocarbon radical containing from one to six carbon atoms, or a branched saturated divalent hydrocarbon radical containing from three to six carbon atoms, for example methylene, ethylene, propylene,2-methylpropene, pentile;

"albaniles" means a linear or branched divalent hydrocarbon radical containing from two to ten carbon atoms and also containing at least one carbon-carbon double bond, such as-CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -CH2SN=SNSN2and the like;

"alkenyl" means a linear monovalent hydrocarbon moiety containing from two to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, containing at least one double bond, for example ethynyl, propenyl; "quinil" means a linear monovalent hydrocarbon moiety containing from two to six carbon atoms, or a branched monovalent hydrocarbon radical, containing the t three to six carbon atoms, including at least one triple bond, such as ethinyl, PROPYNYL;

the term "optionally substituted cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon radical containing from three to seven ring carbon atoms;

cycloalkyl may be optionally independently substituted one, two or three substituents selected from alkyl, optionally substituted phenyl or-C(O)R (where R denotes a hydrogen atom, alkyl, haloalkyl, amino, monosubstituted amino, disubstituted amino, hydroxy, alkoxygroup or optionally substituted phenyl); more specifically the concept of "cycloalkyl includes, for example, cyclopropyl, cyclohexyl, phenylcyclohexyl, 4-carboxylicacid, 2-carboxymethyloxime, 2-dimethylaminocarbonylmethyl;

"optionally substituted cycloalkenyl" means a radical-RaRbwhere Rameans alkylenes group, and Rbdenotes optionally substituted cycloalkyl group, as it is presented in the present description, such as cyclopropylmethyl, cyclohexylmethyl, 3-cyclohexyl-2-methylpropyl;

"acyl" means a group-C(O)R', where R' denotes hydrogen atom, alkyl, haloalkyl, heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or it is certainly substituted heteroalkyl;

"alkoxy", "aryloxy", "aralkylated" or "heteroaromatics" means a radical-OR where R means alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroalkyl as they are presented in the present description, for example methoxy, phenoxy, pyridine-2-ylmethylene, benzyloxy;

"halo" or "halogen atom" means a fluorine atom, chlorine, bromine or iodine, preferably fluorine or chlorine; "haloalkyl" means alkyl substituted by one or more identical or different halogen atoms, such as-CH2Cl-CF3, -CH2CF3, -CH2CCl3, and further includes those alkyl groups, such as perfluoroalkyl in which all hydrogen atoms are substituted by fluorine atoms;

"hydroxyalkyl" means an alkyl radical, as it is presented in the present description, substituted by one or more, preferably one, two or three, hydroxyl groups, provided that one and the same carbon atom carries no more than one hydroxyl group; typical examples are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl, 1-(GI is roximity)ethyl, 2-hydroxy-1,1-dimethylethyl, 2-(hydroxymethyl)propyl, 1,1-(dihydroxymethyl)ethyl, 1-methyl-2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxypropyl, 1-hydroxymethyl-2-methylpropyl, 1-hydroxymethyluracil, 1-hydroxymethylene, 1-hydroxymethyl-3-methylbutyl, 1,1-dimethyl-2-hydroxyethyl, 1-(hydroxymethyl)ethyl, 2,3-(dihydroxy)-1-methylpropyl, 2,3-(dihydroxy)-1,1-dimethylpropyl, 1-(hydroxymethyl)-2-hydroxypropyl 1-(hydroxymethyl)propyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl;

"monosubstituted amino group" means a radical other, where R denotes alkyl, heteroalkyl, haloalkyl or optionally substituted cycloalkyl, cycloalkenyl, aryl, Uralkaliy, arancelario, heteroaryl, heteroalkyl, heteroalkyl, heterocyclyl or heterocyclisation group, such as methylamino, ethylamino, phenylamino, benzylamino;

"disubstituted amino group" means a radical-NRR'where each R and R' independently of each other denotes alkyl, heteroalkyl, haloalkyl, cycloalkyl or optionally substituted cycloalkenyl, aryl, aralkyl, aralkyl, heteroaryl, heteroalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh, or R and R' together with the nitrogen atom to which they are linked, form a heterocyclic ring; typical examples VK is ucaut dimethylamino-, methylethylamine-, di(1-methylethyl)amino groups, piperazine-1-yl;

"optionally substituted aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical containing from 6 to 10 ring atoms, each of which is independently substituted by one or more substituents, preferably one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano groups, methylendioxy, Ethylenedioxy, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, haloalkoxy, optionally substituted, phenoxy, optionally substituted, heteroaromatic, -COR (where R is alkyl or optionally substituted phenyl), -(CR'R")n-COOR (where n denotes an integer from 0 to 5, each R' and R" independently denotes a hydrogen atom or alkyl, and R denotes a hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl) and -(CR'R")n-CONRaRb(where n denotes an integer from 0 to 5, each R' and R" independently denotes a hydrogen atom or alkyl and each of Raand Rbindependently of one another denotes hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl or Raand Rbtogether with the nitrogen atom which they are linked, form a heterocyclic ring); examples include phenyl, 1-naphthyl, 2-naphthyl and derivatives thereof;

"optionally substituted aralkyl" means a radical-RaRbwhere Rameans alkylenes group, and Rbdenotes optionally substituted aryl group, as it is presented in the present description, for example benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl;

"optionally substituted aralkyl" means a radical-RaRbwhere Rameans alkynylamino group, and Rbdenotes optionally substituted aryl group, as it is presented in the present description, such as 3-phenyl-2-propenyl;

"optionally substituted arylheteroacetic" means a radical-RaRbwhere Rameans heteroalkyl group, and Rbdenotes optionally substituted aryl group, as it is presented in the present description, for example 2-hydroxy-2-phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl;

"optionally substituted phenyl" means a phenyl ring which is optionally independently substituted by one or more substituents, preferably one or two substituents selected from alkyl, alkoxy, hydroxyl, haloalkyl, heteroalkyl, halo, nitro, cyano groups, methylendioxy,Ethylenedioxy, cycloalkyl, cycloalkenyl, -COR (where R of the mean alkyl or optionally substituted phenyl), -(CR'R")n-COOR (where n denotes an integer from 0 to 5, each R' and R" independently denotes a hydrogen atom or alkyl, a R denotes a hydrogen atom, alkyl, cycloalkyl or cycloalkenyl) and -(CR'R")n-CONRaRb(where n denotes an integer from 0 to 5, each R' and R" independently denotes a hydrogen atom or alkyl and each of Raand Rbindependently of one another denotes hydrogen atom, alkyl, cycloalkyl or cycloalkenyl or Raand Rbtogether with the nitrogen atom to which they are linked, form a heterocyclic ring);

"optionally substituted heteroaryl" means a monovalent monocyclic or bicyclic radical, containing from 5 to 12 ring atoms, which has at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O and S, with remaining ring atoms are C and it must be borne in mind that the joining point of the heteroaryl radical is usually located in the aromatic ring; a is a heteroaryl ring optionally independently substituted by one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano groups, optionally substituted cycloalkyl, optionally substituted cycloalkyl is a, -COR (where R is alkyl or optionally substituted phenyl), -(CR'R")n-COOR (where n denotes an integer from 0 to 5, each R' and R" independently denotes a hydrogen atom or alkyl, and R denotes a hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl), -NRaRb(where each of Raand Rbindependently of one another denotes hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl) and -(CR'R")n-CONRcRd(where n denotes an integer from 0 to 5, each R' and R" independently denotes a hydrogen atom or alkyl and each of Rcand Rdindependently of one another denotes hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl or Rcand Rdtogether with the nitrogen atom to which they are bound, form an optionally substituted heterocyclic ring); examples include, though not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrofuranyl, isobenzofuranyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, tetrahydroquinoline, ethanolic, benzamid who was Salil, benzisoxazole, benzothiazyl and their derivatives;

"optionally substituted heteroaryl" means a radical-RaRbwhere Rameans alkylenes group, and Rbdenotes a heteroaryl group, as it is presented in the present description, for example pyridine-3-ylmethyl, 3-(benzofuran-2-yl)propyl and the like;

"optionally substituted heteroaryl" means a radical-RaRbwhere Rameans alkynylamino group, and Rbdenotes optionally substituted heteroaryl group, as it is presented in the present description, for example 3-(pyridin-3-yl)propen-2-yl and the like;

"optionally substituted heterocyclyl" means a saturated or unsaturated non-aromatic cyclic radical containing from 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O or S(O)n(where n denotes an integer from 0 to 2), with the remaining ring atoms are C, where one or two atoms can, but not necessarily, to be replaced by a carbonyl group; this heterocyclic ring may be optionally independently substituted one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyanoalanine, hydroxyl, alkoxy, amino, monosubstituted amino, disubstituted amino groups, it is not necessary what about the substituted aralkyl, -(CR'R")n-COR (where n denotes an integer from 0 to 5, and R represents alkyl or optionally substituted phenyl), -(CR'R")n-COOR (where n denotes an integer from 0 to 5, R' and R" each independently represents a hydrogen atom or alkyl, and R denotes a hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl), -(CR'R")n-CONRaRb(where n denotes an integer from 0 to 5, R' and R" each independently represents a hydrogen atom or alkyl and each of Raand Rbindependently of one another denotes hydrogen atom, alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl or Raand Rbtogether with the nitrogen atom to which they are bound, form an optionally substituted heterocyclic ring) and-S(O)nRd[where n denotes an integer from 0 to 2, a Rddenotes a hydrogen atom (provided that n is 0), alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, amino, monosubstituted amino, disubstituted an amino group or hydroxyalkyl]; more specifically the concept of "heterocyclyl covers tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazine derivatives, N-methylpyrrolidine-3-yl, 3-pyrrolidino, 2-oxopyrrolidin-1-yl, morpholino, thiomorpholine, thiomorpholine-1-hydroxy is, thiomorpholine-1,1-dioxide, 1,1-dioxotetrahydrofuran-3-yl, pyrrolyl, imidazolyl, 2-Oxymetazoline and their substituted derivatives, such 1-(phenylmethyl)piperidine-4-DRS, 1-(aminocarbonylmethyl)piperidine-4-DRS, 1-(methylsulphonyl)piperidine-4-DRS, 1-(hydroxyethyl)piperidine-4-DRS, 1-(2,3-dihydroxypropyl)piperidine-4-DRS, 1-(2-cyanoethyl)piperidine-4-DRS, 1-(1-cyanomethyl)piperidine-4-DRS, 1-(aminocarbonylmethyl)piperidine-4-DRS, 1-(etoxycarbonyl)piperidine-4-DRS, 1-(2-triptorelin)piperidine-4-DRS, piperidine-4-DRS, 1 methylpiperidin-3-DRS and 1 methylpiperidin-4-DRS;

"optionally substituted geterotsiklicheskikh" means a radical-RaRbwhere Rameans alkylenes group, and Rbdenotes a heterocyclic group, as it is presented in the present description, for example tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-retil, 3-piperidinylmethyl, 1-(dimethylaminocarbonylmethyl)piperidine-4-ylmethyl, 1-(2-methoxycarbonylethyl)piperidine-4-ylmethyl, 1-(2-triptorelin)piperidinyl-4-ylmethyl, 1-(cyanomethyl)piperidine-4-ylmethyl, 1-(aminocarbonylmethyl)piperidinyl-4-ylmethyl, 1-(hydroxycarbonylmethyl)piperidinyl-4-ylmethyl, 2-(piperidine-1-yl)ethyl, 3-(piperidine-1-yl)propyl, 2-(morpholine-1-yl)ethyl, 3-(morpholine-1-yl)propyl, 2-(2-Oxymetazoline-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl and pyrrolidin-1-ileti;

"heteroalkyl" means an alkyl radical, as the n presented in the present description, with one, two or three substituents, independently selected from-ORa, -NRbRcand-S(O)nRd(where n denotes an integer from 0 to 2), in which Radenotes a hydrogen atom, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, alkoxycarbonyl, optionally substituted aryloxyalkyl, carboxamido or mono - or dialkylamino; Rbdenotes a hydrogen atom, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroalkyl; Rcdenotes a hydrogen atom, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh, optionally substituted aryl, optionally substituted aralkyl, Alki sulfonyl, alkylsulphonyl, alkoxycarbonyl, optionally substituted aryloxyalkyl, carboxamido or mono - or dialkylamino; Rddenotes a hydrogen atom (provided that n is 0), alkyl, haloalkyl, optionally substituted cycloalkyl, cycloalkenyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, amino, monosubstituted amino, disubstituted an amino group or hydroxyalkyl; when Raindicates only the hydrogen atom, the concept of "heteroalkyl" applies to a subgroup that is subject see further the concept of "hydroxyalkyl"; examples include 2-methoxyethyl, benzoyloxymethyl, thiophene-2-altimeter, 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-amino-2,2-dimethylpropyl, 3-dimethylaminopropyl, 3-methylcarbamoylmethyl, 3-amino-2-hydroxypropyl, 2-ethoxy-1-ethoxymethyl, 2-diethylaminoethyl, 2-methylthioethyl, 3-dimethylaminoethyl, 3-dimethylamino-2,2-dimethylpropyl and 2 hydroxyethyl;

"heteroalkyl" means a linear saturated divalent hydrocarbon radical containing from one to six carbon atoms, or branched saturated hydrocarbon radical containing from three to six the low carbon atoms, with one, two or three substituents, independently selected from-ORa, -NRbRcand-S(O)nRd(where n denotes an integer from 0 to 2), in which Ra, Rb, Rcand Rdhave the same meanings as specified in the present description for heteroalkyl radical; examples include, though not limited to, 2-hydroxyethane-1,1-diyl, 2-hydroxypropane-1,1-diyl etc.;

"heterothermy cycloalkyl" means cycloalkyl radical, which is optionally independently substituted by one, two or three substituents selected from hydroxyl, hydroxyimino- (=NOH), alkoxy, amino, monosubstituted amino, disubstituted amino, oxoprop (=O), -OC(O)Ra(where Radenotes a hydrogen atom, alkyl, haloalkyl, amino, monosubstituted amino, disubstituted an amino group, hydroxyl, alkoxy or optionally substituted phenyl), -ORb(where Rbdenotes hydroxyalkyl, haloalkyl, alkenyl or alkoxyalkyl), -SOnRc[where n denotes an integer from 0 to 2, a Rcdenotes a hydrogen atom (provided that n is 0), alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, amino, monosubstituted amino, disubstituted an amino group or hydroxyalkyl]- NS(O)2Rd(where Rddenotes alkyl, haloalkyl, neobyazatelnostyu cycloalkyl, optionally substituted cycloalkenyl, amino, monosubstituted amino, disubstituted an amino group or hydroxyalkyl); examples include, in particular, although their list is not limited to, 4-hydroxycyclohexyl, 2-aminocyclohexanol, (2 methoxyethoxy)cyclohexyl, 4-oxocyclohexyl, 4-(methanesulfonamido)cyclohexyl, allyloxycarbonyl etc.;

"heterooligomeric cycloalkyl" means cycloalkyl radical, which may be optionally substituted by one, two or three heteroalkyl groups as they are presented in the present description; examples include 1-hydroxymethylcytosine-1-yl, 2-hydroxymethylcytosine-2-yl;

"heterocyclisation" means spirolateral, including cycloalkyl ring and a heterocyclic ring, each of which contains from 5 to 8 ring atoms, both of the rings contain only one common carbon atom, and it must be borne in mind that heterocyclisation radical attached via cycloalkyl ring; spirolateral is formed when two hydrogen atoms on the same carbon atom cycloalkyl radical substituted heterocyclyl group, as it is presented in the present description, and may be optionally substituted by alkyl, hydroxyl, hydroxyalkyl or oxopropoxy; examples include 1,4-dioxaspiro[4,5]decane-8-and who, 1,3-diazaspiro[4,5]Decan-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;

the term "leaving group" is used in the meaning usually associated with it in the chemistry of organic synthesis, i.e. the value of an atom or group capable of substitution of the nucleophile and the covering group, halo (such as chlorine atom, bromine, iodine), alkanesulfonyl, arenesulfonyl, alkylcarboxylic (for example, acetoxy), arylcarboxylic, mesilate, tosyloxy, tripterocalyx, aryloxy (for example, 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamine etc.;

the term "isomerism" is applicable to compounds that meet the same chemical formula but have different properties or sequence of links between the atoms or the arrangement of atoms in space; isomers, which differ by the arrangement of atoms in space are called "stereoisomers"; stereoisomers that are not mirror copies of each other, called "diastereoisomers"and stereoisomers that are see-through mirrored copies of each other, are called "enantiomers" or sometimes optical isomers;

carbon atom associated with four different substituents, referred to as "chiral center";

the concept of "Chi is real isomer is applicable for connection with at least one chiral center; it has two enantiomers with opposite chirality, and it can exist either in the form of an individual enantiomer or as a mixture of enantiomers; mixture comprising equal number of individual enantiomeric forms with opposite chirality, is called a "racemic mixture"; connection, which has more than one chiral center, there are 2n-1enantiomeric pairs, where n denotes the number of chiral centers, the compounds with more than one chiral center may exist either in the form of an individual diastereoisomer or mixture of diastereoisomers, called "diastereomeric mix"; if there is one chiral center stereoisomer can be characterized by the absolute configuration (R or S) of such a chiral center; absolute configuration is referred to as the location in space of the substituents associated with the chiral centre; existing in mind deputies associated with the chiral center, placed in a particular order in accordance with Rule sequence Kahn, Ingold and Prelog [see Cahn and other Angew. Chem. Inter., edition 1966, 5, 385; errata on s; Cahn and other Angew. Chem., 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. (London) 1951, 612; Cahn and other Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116];

the concept of "geometric isomers" are applicable to the diastereomers, which owe their being what W braked rotation around double bonds; these configurations are distinguished by adding their names prefixes CIS - and TRANS -, or Z and E, which indicate that the groups are the same or the opposite side of the plane of the comparison, which can be called total for stereoisomers, such as double bonds in the molecule, or to indicate the position of the substituents in the rings relative to each other in accordance with Rule Kahn, Ingold and Prelog;

"pharmaceutically acceptable excipient" means an excipient that can be used in the preparation of pharmaceutical compositions, which in General are harmless, non-toxic and neither biological, nor with any other point of view is not undesirable, and includes excipients that are acceptable for veterinary use as well as for human use pharmaceutical purposes;

the term "pharmaceutically acceptable excipient"as used in this description and the claims includes both one and more than one filler;

"pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the target pharmaceutical activity of the parent compound; such salts include:

(1) acid additive salts obtained with the use of mineral acids such as hydrochloric acid, bromilow the portly acid, sulfuric acid, nitric acid, phosphoric acid, etc. or obtained using 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, camphorsulfonic acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, laurilsulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like, and

(2) salts formed when an acidic proton contained in the initial connection, or is replaced by a metal ion, for example an alkali metal ion, ion alkaline-earth metal or aluminum ion, or forms a coordination bond with the organic base is a cation, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like;

"prodrug" means any compound that, when such prodrug is administered in the body of a mammal subject, in vivo secrete active original medicinal substance corresponding to the formula (I);

prodrugs of compounds of formula (I) are prepared by modifying functional groups present in compounds of formula (I), so that the modifying group were capable of in vivo be chipped off with the release of the original connection; prodrugs include compounds of formula (I)in which a hydroxyl, amino or sulfhydryl group [compounds of formula (I)] associated with any group, which in vivo is capable of chipped off recovery, respectively, of the free hydroxyl, amino or sulfhydryl group; examples of prodrugs include, though not limited to, esters (in particular, acetate, formiate and benzoate derivatives), carbamates (in particular, N,N-dimethylaminoethyl) hydroxyl functional groups in the compounds of formula (I) and the like; the term "protective group" refers to a grouping of atoms that when it is associated with a reactive group in a molecule masks, reduces or suppresses this reactivity; examples of protective groups can be found in T.W. Greene and P.. Futs, Protective Groups in Organic Chemistry (Wiley, 2nd edition, 1991), and Harrison, Harrison and others, Compendium of Synthetic Organic Methods, volumes 1-8 (John Wiley and Sons. 1971-1996); typical aminosidine groups include formyl, acetyl, trifluoracetyl, benzyl, benzyloxycarbonyl (AFC), tert-butoxycarbonyl (SIDE), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), trailing and substituted trityloxy group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NWAC) and the like; typical hydroxylamine groups include those in which a hydroxyl group or allerban or alkylated such as benzyl residues and tretilova esters, as well as residues of aliphatic esters, tetrahydropyranyl esters, trialkylsilyl ethers and allyl esters;

"treatment" or "cure" of the disease includes:

(1) preventing the disease, i.e. preventing the development of clinical symptoms of a disease in a mammal that may be exposed to or to be predisposed to the disease but has not yet affected and do not show symptoms of the disease;

(2) inhibiting the disease, i.e. the delay or failure of development of the disease or its clinical symptoms, or

(3) the weakening of the disease, i.e. the event, causing regression of the disease or its clinical symptom is in;

"therapeutically effective amount" means that amount of the compound, which, when injected into the body of a mammal for treating a disease, is sufficient to effect such treatment for the disease; "therapeutically effective amount" generally varies depending on the connection, a painful condition in which the treatment, the severity of the disease treated, the age and relative health of the subject, route of administration into the body, the opinions of assisting the practitioner, and other factors.

One of the objects of the present invention provides compounds corresponding to the formula

The main variant of the compounds of formula (I) R1denotes acyl, heteroalkyl, optionally substituted arylheteroacetic, heteroalkyl, heteroalkyl, geterofullereny, heterothermy cycloalkyl, heterothermy cycloalkenyl, heterothermy cycloalkylcarbonyl, heterothermy cycloalkylcarbonyl, heterooligomeric cycloalkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh, optionally substituted heterocyclisation, the group -(alkylene)-C(O)-R11or -(heteroalkyl)-C(O)-R11where R11denotes alkyl, haloalkyl, Hydra is xinnuo, alkoxy, amino, monosubstituted amino, disubstituted an amino group, optionally substituted cycloalkyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryl, optionally substituted Uralkaliy, optionally substituted heteroaryl or optionally substituted heteroalkyl group. In a preferred embodiment, R1denotes acyl, heteroalkyl, optionally substituted arylheteroacetic, heteroalkyl, heteroalkyl, geterofullereny, heterothermy cycloalkyl, heterothermy cycloalkenyl, heterothermy cycloalkylcarbonyl, heterothermy cycloalkylcarbonyl, heterooligomeric cycloalkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh(alkylene)-C(O)-R11or -(heteroalkyl)-C(O)-R11where R11denotes alkyl, haloalkyl, amino, monosubstituted amino, disubstituted an amino group, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, hydroxyl or alkoxy.

In the preferred case the above option and the preferred option R1denotes heteroalkyl, obazatelno substituted arylheteroacetic, heterothermy cycloalkyl, heterothermy cycloalkenyl, heterooligomeric cycloalkyl, heterocyclyl or geterotsiklicheskikh preferred heteroalkyl or heterothermy cycloalkyl. In the case when R1denotes heteroalkyl, preferred alkyl substituted by one or two substituents, independently selected from-ORaand-NRbRcwhere Radenotes a hydrogen atom, Rbdenotes a hydrogen atom or alkyl, and Rcdenotes a hydrogen atom, alkyl or alkylaryl. Specific groups of R1are 3-amino-2,2-dimethylpropyl, 3-dimethylaminopropyl, 3-methylcarbamoylmethyl and 3-amino-2-hydroxypropyl. In a preferred embodiment of heteroalkyl R1denotes hydroxyalkyl.

In a preferred embodiment of heteroalkyl, where R1denotes hydroxyalkyl (Radenotes a hydrogen atom), such a group is preferably 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl, 1-(hydroxymethyl)ethyl, 2-hydroxy-1,1-dimethylethyl, 2-(hydroxymethyl)propyl, 1,1-(dihydroxymethyl)ethyl, 1-methyl-2, 3-dihydroxypropyl 1-(hydroxymethyl)-2-hydroxypropyl, 1-hydroxymethyl-2-methylpropyl, 1-hydroxymethyluracil, 1-hydroxymethylene, 1-hydroxymethyl-3-methylbutyl, 1,1-dimethyl-2-hydroxyethyl, 1-(hydroxymethyl)ethyl, 2,3-(dihydroxy)-1-methylpropyl, 2,3-(dihydroxy)-1,1-dimethylpropyl, 1-(hydroxymethyl)-2-hydroxypropyl and 1-(hydroxymethyl)propyl. However, in other preferred embodiments, R1refers to a group containing tetrahedral carbon atom linked to the nitrogen atom, more preferably comprising lower alkyl groups associated with this carbon atom. The preferred hydroxyalkyl in R1are 1-hydroxy-2-methyl-2-propyl and 1-hydroxy-2-propyl.

In the version in which R1means "heterothermy cycloalkyl"preferred cycloalkyl group optionally independently substituted by one, two or three, preferably one, substituents selected from hydroxy, hydroxyimino- (=NOH), alkoxy-, amino-, monoalkylamines amino, dialkylamino amino, oxoprop (=O), -OC(O)Ra(where Radenotes a hydrogen atom, alkyl, amino, monoalkylammonium amino, dialkylamino the amino group), -ORb(where Rbdenotes hydroxyalkyl, alkenyl or alkoxyalkyl), -SOnRc[where n denotes an integer from 0 to 2, preferably 2, and Rcdenotes a hydrogen atom (when the service is provided n represents 0 or an alkyl] or-NS(O)2Rd(where Rddenotes alkyl, amino, monoalkylammonium amino - or dialkylamino the amino group). More preferred heterogametes cycloalkyl is a 4-hydroxycyclohexyl, 2-aminocyclohexanol, (2 methoxyethoxy)cyclohexyl, 4-oxocyclohexyl, 4-(methanesulfonamido)cyclohexyl, allyloxycarbonyl, 2-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-methylcarbamoylmethyl, 2,3-dihydroxyphenylglycol, 4-(hydroxyimino)cyclohexyl, 4-(methylsulfonylamino)cyclohexyl, 4-(dimethylaminomethylene)cyclohexyl, 4-formyloxyethyl, 4-(methoxycarbonyl)cyclohexyl, 4-(aminocarbonyl)cyclohexyl or 4-(N-methylcarbamate)cyclohexyl, and the most preferred 4-hydroxycyclohexyl (including CIS - and TRANS-4-hydroxycyclohexyl).

When R1means "optional substituted heterocyclyl", preferred heterocyclic ring optionally independently substituted by one, two or three, preferably one, substituents selected from alkyl, haloalkyl, heteroalkyl, preferably of hydroxyalkyl, cyanoalanine, aralkyl, preferably of phenylalkyl, -(CR'R")n-COR (where n denotes an integer from 0 to 5, and R denotes alkyl), -(CR'R")n-COOR (where n denotes an integer from 0 to 5, each R' " denotes hydrogen atom, and R denotes a hydrogen atom or alkyl), -(CR'R")n-CONRaRb(where n denotes an integer from 0 to 5, each R' and R" denotes a hydrogen atom, and each of Raand Rbindependently of one another denotes hydrogen atom or alkyl) and-S(O)nRd[where n denotes an integer from 0 to 2, preferably 2, a Rddenotes a hydrogen atom (provided that n represents 0 or an alkyl]. More specifically the concept of "heterocyclyl covers tetrahydropyranyl, piperidino, piperazine derivatives, N-methylpyrrolidine-3-yl, 3-pyrrolidino, 2-oxopyrrolidin-1-yl, morpholino, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, 1,1-dioxotetrahydrofuran-3-yl, pyrrolyl, imidazolyl and 2-Oxymetazoline are not substituted as specified above, and more preferred piperidine derivatives, such as N-methylpiperidin-3-yl, 1-(phenylmethyl)piperidine-4-Il, 1-(aminocarbonylmethyl)piperidine-4-yl, 1-(methylsulphonyl)piperidine-4-yl, 1-(hydroxyethyl)piperidine-4-yl, 1-(2,3-dihydroxypropyl)piperidine-4-yl, 1-(2-cyanoethyl)piperidine-4-yl, 1-(1-cyanomethyl)piperidine-4-yl, 1-(aminocarbonylmethyl)piperidine-4-yl, 1-(etoxycarbonyl)piperidine-4-yl, 1-(2-triptorelin)piperidine-4-yl, 1-(dimethylaminocarbonylmethyl)piperidine-4-yl, 1-(2-methoxycarbonylethyl)piperidine-4-yl and 1-(hydroxycarbonylmethyl)piperidine-4-yl.

When R1 means "optional substituted geterotsiklicheskikh", the preferred values of the heterocyclic group include those listed for "heterocyclyl" in determining the values of R1. The most preferred heterocyclisation are 1-(dimethylaminocarbonylmethyl)piperidine-4-ylmethyl, 1-(2-methoxycarbonylethyl)piperidine-4-ylmethyl, 1-(2-triptorelin)piperidinyl-4-ylmethyl, 1-(cyanomethyl)piperidine-4-ylmethyl, 1-(aminocarbonylmethyl)piperidinyl-4-ylmethyl, 1-(hydroxycarbonylmethyl)piperidinyl-4-ylmethyl, 2-(piperidine-1-yl)ethyl, 3-(piperidine-1-yl)propyl, 2-(morpholine-1-yl)ethyl, 3-(morpholine-1-yl)propyl, 2-(2-Oxymetazoline-1-yl)ethyl and 2-(2-oxopyrrolidin-1-yl)ethyl.

When R1means "heterooligomeric cycloalkyl", cycloalkenyl radical may be optionally substituted by one, two or three, preferably one, heteroalkyl, preferably hydroxyalkyl groups as they are presented in the present description.

Preferred examples of such groups are 1-hydroxymethylcytosine-1-yl and 2-hydroxymethylcytosine-2-yl.

When R1means "optional substituted heterocyclisation", its preferred examples are 1,4-dioxaspiro[4,5]Decan-8-yl, 1,3-diazaspiro[4,5]Decan-8-yl, 2,4-dione-1,3-diazaspiro[4,5]Decan-8-yl, 1,5-dioxaspiro[55]undecane-9-yl and (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5,5]undecane-9-yl.

As for the formula I, R2denotes alkyl, halo, heteroalkyl or vinyl and can be linked to the phenyl ring in place of any of the other five valences, which is otherwise occupied by a hydrogen atom. Subscript letter n indicates an integer from 0 to 3, indicating that the phenyl ring substituted by groups R2in the amount of from one to three. In those embodiments in which there are two or three groups of R2each of them can be independent from each other (other). In a preferred embodiment, compounds of the formula I and in the preferred embodiment, the above-mentioned values of R1n denotes 1 or 2, and each R2represents halo or alkyl, mainly methyl and the preferred group R2is halo. Under this option the preferred those cases where -(R2)ndenotes the 2-halo or 2,6-dihalo, more preferably 2-chloro or 2,6-dichloro, or when -(R2)nrefers to 2-methyl.

In the compounds of formula (I) R3denotes a hydrogen atom, alkyl, heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, cycloalkenyl, optionally substituted cycloalkenyl, haloalkyl, cianelli, heterothermy cloaker, heterothermy cycloalkenyl, heterooligomeric cycloalkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklicheskikh(alkylene)-C(O)R31or -(heteroalkyl)-C(O)R31where R31denotes alkyl, haloalkyl, hydroxyl, alkoxy, amino, monosubstituted amino, disubstituted an amino group, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroalkyl.

In a preferred embodiment, the values of R3choose from a hydrogen atom, alkyl, heteroalkyl, aryl, preferably phenyl, aralkyl, mainly phenylmethyl, cycloalkyl, haloalkyl, cyanoalanine, heterogametes of cycloalkyl, heterocyclyl and -(alkylene)-C(O)R31where R31denotes alkyl, hydroxyl, alkoxy-, amino-, monoalkylammonium amino - or dialkylamino the amino group.

In a more preferred embodiment, the values of R3choose from a hydrogen atom, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterocyclyl and heterogametes of cycloalkyl. More preferred R3denotes a hydrogen atom, alkyl, haloalkyl or heteroalkyl. In a particularly preferred embodiment, R3indicates water is natural atom. In another particularly preferred embodiment, R3denotes methyl. However, in another group of particularly preferred options R3denotes haloalkyl, mainly 2,2,2-triptorelin, or R3denotes heteroalkyl, and especially preferred heteroalkyl groups are 2-ethoxy-1-ethoxymethyl, 2-diethylaminoethyl, 2-methylthioethyl, 3-dimethylaminoethyl, 3-dimethylamino-2,2-dimethylpropyl and 2-hydroxyethyl.

In the compounds of formula (I) R4denotes a hydrogen atom, alkyl or-alkylene-C(O)R31. In a preferred embodiment, especially when having in mind the above-mentioned primary and preferred values of R1, R4denotes a hydrogen atom. When R4means-alkylen-C(O)R31a preferred variant of this radical is-CH2CONH2.

In addition to the above compounds scope of the present invention includes all pharmaceutically acceptable salts of these compounds together with proletarienne forms of these compounds and all isomers if they are in pure chiral form or in the form of a racemic mixture, or a mixture of different forms.

In addition, other preferred variants comprise combinations of the above-described preferred groups. In the same group as the main, preferred, and more predpochtitelnei R 1this radical R1is heteroalkyl, R2represents halo or methyl, R3denotes methyl, and n denotes 1 or 2.

In another group of values, in which R1means heterothermy cycloalkyl, R2represents halo or methyl, R3denotes methyl, and n denotes 1 or 2, R1refers mainly hydroxycyclohexyl, including CIS - and TRANS-hydroxycyclohexyl, in particular CIS - or TRANS-4-hydroxycyclohexyl.

In another set of values, in which R1means heterocyclyl or geterotsiklicheskikh, R2represents halo or methyl, R3denotes methyl or hydrogen atom, and n denotes 1 or 2, or R2represents halo or methyl, R3denotes heteroalkyl, and n denotes 1 or 2.

Especially preferred compounds are selected from a number of 7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, 3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, 7-[1-(2-hydroxyethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, 3-(2-chlorophenyl)-7-[(TRANS-4-methoxycyclohexyl)methylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and their pharmaceutically acceptable salts.

On the other is one object of the present invention provides methods of obtaining the above-described compounds.

According to one of the methods of the compounds of formula I can be obtained according to the method, including

(a) treatment of compounds of formula II

in which n, R2and R3have the meanings given for the compounds of the above formula I, provided that any existing interfering reactive group is optionally protected form, a, L denotes a leaving group,

the amine of formula III

in which R1and R4have the meanings given for the compounds of the above formula I, provided that any existing interfering reactive group is optionally protected form, and, when necessary, release any protected reactive group contained in the reaction product.

When necessary, such a connection can be transformed into its pharmaceutically acceptable salt.

According to another method, the compounds of formula I can be obtained according to the method, including

(a) treatment of compounds of formula IV

in which X represents halo, R denotes alkyl, and R2and R3have the meanings given for the compounds of the above formula I,

in the presence of a base to obtain the compound is of ormolu V

(b) treatment of compounds of formula V oxidant, and then an amine of formula R1R4-NH (in which R1and R4have the meanings given for the compounds of the above formula (I) obtaining the compounds of formula (I).

When necessary, the compound obtained can (but not necessarily) be transformed into its pharmaceutically acceptable salt.

Compounds of the present invention can be obtained in a variety of ways using methods that are well known to specialists in this field of technology. If we refer to the above methods, compounds of the present invention are the so, as further illustrated in scheme 1 or represented in the General scheme 4.

As a result of processing the compounds of formula Ia (where R is alkyl, aryl or aracelio group) primary amine (R3-NH2) get the compound of formula Ib. This reaction is conveniently carried out in a solvent in which the reaction conditions in an inert, preferably acyclic or simple cyclic ether (such as tetrahydrofuran), halogenated aliphatic hydrocarbon, in particular in dichloromethane, optionally halogenated aromatic hydrocarbon, formamide, lower alkanol Il the water. The reaction is expediently carried out at temperatures from about -20 to about 120°C.

In the recovery of the compounds of formula Ib have the alcohol of formula Ic. The recovery is usually carried out using lithium aluminum hydride according to the method, which is well known to experts in the art (for example, in a solvent which is inert under the conditions of recovery, preferably acyclic or cyclic simple ether, in particular tetrahydrofuran, at a temperature of from about -20 to about 70°C, preferably at a temperature of from about 0°C to about room temperature).

Oxidation of the alcohol of the formula Ic in the next stage provides the possibility of obtaining carboxaldehyde formula Id. The oxidation is typically carried out using manganese dioxide, although you can also use many other methods [see, for example, ADVANCED ORGANIC CHEMISTRY, ed. 4th, March, John Wiley & Sons, New York (1992)]. Depending on the oxidant reaction is conveniently carried out in a solvent which is inert under the existing conditions, oxidation, preferably in a halogenated aliphatic hydrocarbon, in particular in dichloromethane, or optionally halogenated aromatic hydrocarbon. The oxidation is expediently carried out at a temperature of from about 0 to about 60°S./p>

The reaction carboxaldehyde formula Id with a substituted aniline (R2)n-C6H5-nNH2get the compound of formula Ie. This reaction can be carried out in the presence of acids, such as aromatic sulfonic acid, preferably 4-toluensulfonate acid with azeotropic removal of water formed during the reaction. This reaction is conveniently carried out in a solvent in which the reaction conditions in an inert, preferably in an aromatic hydrocarbon, in particular toluene or xylene, or in an optionally halogenated aromatic hydrocarbon, and at a temperature of from about 70 to about 150°With, mainly at the boiling temperature of the solvent, to facilitate mentioned azeotropic removal of water.

The recovery of the compounds of formula Ie with obtaining the compounds of formula If can be performed using, for example, hydride reducing agents such as sodium borohydride, alumoweld lithium and triacetoxyborohydride sodium, in conditions that are well known to specialists in this field of technology. In a preferred embodiment, the compound of formula Ie is not clear, and the reaction mixture in which it is produced, concentrated, and the obtained concentrate was dissolved in the solvent, the recovery of inert, preferably acyclic or simple cycle is Eskom ether, in particular tetrahydrofuran or optionally halogenated aromatic hydrocarbon, or lower alkanol, and then treated with the above-mentioned reducing agents. Restoration of appropriate conduct at a temperature of from about -10 to about 100°C, preferably at about 0°C.

The cyclization of the compounds of formula If get bicyclic nitrogen-containing heterocycle of the formula Ig. The cyclization can be carried out by reaction of the compound If with carbonyliron agent such as phosgene or trichloromethylcarbonate (or equivalent amount of phosgene), expediently in the presence of a tertiary organic base, preferably three(lower)alkylamine, in particular triethylamine. More specifically, the cyclization is carried out in a solvent in which the reaction conditions in an inert, preferably acyclic or simple cyclic ether, in particular tetrahydrofuran, optionally halogenated aromatic hydrocarbon or halogenated aliphatic hydrocarbon. This reaction is conveniently carried out at a temperature of from about -20 to about 50°C, preferably from approximately -20 to 0°C.

Oxidation of compound Ig-nagkalat, such as 3-chloroperbenzoic acid or Oxone product®(monopersulfate triple potassium salt) in aqueous aprotic solvent, such as tetrahydrof the Russian Academy of Sciences, provides reception sulfone (Ih) (or, if necessary, its corresponding sulfoxide by controlling the oxidation conditions), which can be turned into a variety of target compounds. Typically, oxidation of compound Ig carried out in a solvent which under oxidizing inert, preferably in a halogenated aliphatic hydrocarbon, in particular in chloroform or dichloromethane, and at a temperature of from about -20 to about 50°C, preferably from approximately 0°C to about room temperature.

Finally, the process of joining Ih Amin (R1R4-NH) provides obtain the desired compounds of formula I. the Reaction can be carried out in the presence or in the absence of solvent. The solvents that can be used include polar aprotic solvents, including ethers, such as dimethoxyethane, dimethoxytrityl ether and tetrahydrofuran, and such polar aprotic solvents, such as dimethylformamide and N,N-dimethylpyrimidin. This reaction is conveniently carried out at temperatures from about 0 to about 200°S, more preferably from about room temperature to about 150°C.

Thus, the present invention proposes a method of obtaining compounds of formula I by treatment of compounds of General formula Ii with the amine (R1R4 -NH).

The compound (Ii) symbols R2, R3and R4and the subscript n have the meanings given above with reference to formula I. the Letter L denotes a leaving group, which may be a halogen atom, a lower alkanesulfonyl group (for example, methanesulfonyl, methanesulfonyl or trifloromethyl) or aromatic sulfonylurea or sulfonylurea group (for example, benzazolyl, benzosulfimide or 4-toluensulfonyl). Other acceptable leaving group the specialists in this field of technology are known, they can be found, for example, in ADVANCED ORGANIC CHEMISTRY, ed. 4th, March, John Wiley & Sons, New York (1992). Acceptable amines (R1-NH2) are those in which R1means any of the groups R1mentioned for formula I.

In another embodiment can be obtained bicyclic nitrogen-containing heterocycle, and R3can be entered at a later stage of the synthesis as shown in scheme 2.

Compound IIa, the source material in scheme 2, can be obtained by the reaction of substitution of commercially available compounds of formula Ia with obtaining compounds of formula Ib, as described above in scheme 1. Briefly, processing mercaptoethane appropriate amine provides the possibility of obtaining compounds of formula Ib (R3the seat is et N). For the stages shown in figure 1, may be followed by conversion of compound Ib (R3denotes H) in connection IIa.

In the cyclization of compounds IIa get bicyclic nitrogen-containing heterocycle of the formula IIb. This cyclization can be carried out by reaction of the compound IIa with phosgene or trichloromethylcarbonate (or the equivalent of phosgene), usually in the presence of a tertiary organic base, preferably three(lower)alkylamine, in particular triethylamine. More specifically, the cyclization is carried out in a solvent in which the reaction conditions in an inert, preferably acyclic or simple cyclic ether, in particular tetrahydrofuran, optionally halogenated aromatic hydrocarbon or halogenated aliphatic hydrocarbon. Usually the reaction is carried out at a temperature of from about -20 to about 50°C, preferably at a temperature of from about 0°C to about room temperature.

The introduction of the group R3to obtain the compound of formula IIc can be implemented in a variety of conditions. For example, compound IIb can be treated with a hydride of an alkali metal, in particular sodium hydride, followed by reaction with a compound of General formula R3-L in which R3has any of the values in accordance with the above in the present description for R 3except for hydrogen atom, aryl or heteroaryl, and L denotes a leaving group (e.g. halo, methansulfonate, triftormetilfosfinov etc). N-substitution is usually carried out in a solvent in which the reaction conditions in an inert, preferably formamide, in particular in N-methylpyrrolidinone or dimethylformamide, acyclic or simple cyclic ether or optionally halogenated aromatic hydrocarbon. This reaction is expediently carried out at a temperature of from about 50 to about 200°C, preferably at a temperature of from about 50 to about 150°C. alternatively, the alkylation can be carried out with an inorganic base such as potassium carbonate, in formamide a solvent such as N-methylpyrrolidone, at temperatures from about 0 to about 25°C.

An alternative and preferred method of introducing R3includes alkylation by pyrimidinedione nitrogen atom in the conditions of the Mitsonobu reaction. In this method, the alcohol of General formula R3-IT is combined with a compound of General formula IIb in the presence of, for example, triphenylphosphine and diethylazodicarboxylate or diphenylpiperazine and tert-utilization.bacteria [see Tetrahedron Lett., 40: 4497-4500 (1999)]. The alkylation is usually carried out in a solvent, in a reaction inert conditions, predpochtitel is but in acyclic or cyclic simple ether, at temperatures from about -20 to about 100°C, preferably at temperatures of from about 0 to about 30°C (or room temperature). As for other methods of alkylation, for the reaction under these conditions, the most appropriate primary and secondary alcohols.

After the introduction of R3to obtain the target compounds of formula I can be carried out under oxidation and substitution (for the introduction of R1R4-N-), as in General terms above in scheme 1.

However, in other variants, these compounds can be obtained by changing to the reverse procedure of alkylation stages and replacement, making changes to reverse the order-R3and-NR1R4shown in figure 3.

Therefore, the compound of formula IIa can be cyklinowanie obtaining compound IIb (as previously shown in scheme 2). Oxidation of compounds IIb to compounds IIIa provides the possibility of obtaining a template for the subsequent stages of substitution and alkylation. Thus, treatment of compounds IIIa using R1-NH2in the conditions described above, enables to obtain a connection IIIb, which can be alkilirovanii using connection R3-L (L has the meanings mentioned above) or R3HE is the Mitsunobu reaction conditions, as described previously, to obtain the target compounds of formula I.

Figure 4 presents an alternative method of preparing compounds of formula I.

Compound Ia, the source material in schemes 1 and 4, is technically available. Treatment of compounds of formula Ia with a suitable aminimum agent, or the nucleophile, as it is depicted in figure 1, obtain the connection formula Ib.

By treating the compounds of formula Ib substituted or unsubstituted phenylisocyanate get amide compound of the formula IVa. This reaction is carried out in an inert organic solvent, preferably in an aromatic hydrocarbon, such as toluene and xylene, at a temperature of from about 0 to about 150°C.

In the recovery of compounds of formula IVa get the alcohol of the formula IVb. This repair is carried out using lithium aluminum hydride according to the method, which is well known to experts in the art (in particular, in an inert organic solvent, such as acyclic or cyclic simple ether, in particular tetrahydrofuran, at a temperature of from about -60 to about 90°C, preferably from approximately -20°C to about room temperature).

Reaction of the alcohol of formula IVb with palodiruyut agent receives the connection of the formula IVc in which X denotes and what Ohm bromine, chlorine or iodine, preferably bromine. Despite the possibility of using a variety of methods haloiding [see, for example, ADVANCED ORGANIC CHEMISTRY, ed. 4th, March, John Wiley & Sons, New York (1992)], this reaction can be performed using tribromide phosphorus or pentachloride phosphorus, receiving respectively the connection of bromine or chlorine. This reaction is conveniently carried out in a solvent in which the reaction conditions in an inert, preferably acyclic or simple cyclic ether, in particular tetrahydrofuran, or a halogenated aliphatic hydrocarbon, at a temperature of from about 0 to about 60°C.

In the cyclization of compounds of formula IVc get bicyclic nitrogen-containing heterocycle of the formula IVd. The cyclization can be carried out in the presence of a base, preferably hexamethyldisilazane. The cyclization, as a rule, is carried out in a solvent environment, which under reaction conditions an inert, preferably polar organic solvent such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, at a temperature of from about 10 to about 200°C for from about 1 to about 50 hours In the preferred embodiment, the reaction mixture was incubated for from about 1 to about 10 hours at a temperature of from about 60 to about 150°C.

Finally, is the processing of the connection Id oxidant, such as N-chlorosuccinimide or chlorine water, and amine (R1R4-NH) through sulfoxide intermediate compound of the formula And get the target compounds of formula I. the Reaction of oxidation/substitution in situ is carried out in a solvent environment, which under reaction conditions an inert, preferably polar aprotic organic solvent such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide and tetrahydrofuran. This reaction is expediently carried out at a temperature of from about 0 to about 120°S, more preferably at room temperature.

Specialist in the art it is clear that the possibility of entry in the above scheme some modifications, which are included in the scope of the present invention. For example, some stages will include the protection and release of reactive functional groups that are incompatible with the data specific reaction conditions.

Another object of the present invention offers pharmaceutical compositions comprising the compounds of formula I.

The compounds of formula I and pharmaceutically acceptable salts of basic compounds of formula I with acids can be used as medicines, for example in the form of pharmaceutical preparations. Pharmaceuticals can enter the body enterline, nab the emer orally in pill form, the coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, intranasally, for example in the form of intranasal sprays, or rectally, for example in the form of suppositories. However, they can also enter parenterally, for example in the form of solutions for injection.

When the pharmaceutical preparation of the compounds of formula I and their pharmaceutically acceptable salts can be combined with pharmaceutically inert organic or inorganic carriers. As such carriers in the manufacture of tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch and its derivatives, talc, stearic acid and its salts, etc. are Acceptable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, solid fats, semi-solid and liquid polyols and the like, but in the case of soft gelatin capsules, depending on the nature of the active substance is usually no media required. Preparation of solutions and syrups acceptable carriers are, for example, water, polyols, sucrose, invert sugar, glucose, etc. are Acceptable for the manufacture of suppositories carriers are, for example, natural or hardened oils, waxes, solid fats, semi-liquid and liquid the polyols, etc.

Moreover, the pharmaceutical preparations can include preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for varying the osmotic pressure, buffers, masking additives and antioxidants. They may also include other therapeutically valuable substances, other than compounds of formula I and their aforementioned pharmaceutically acceptable salt.

Medicines that contain compounds of formula I or pharmaceutically acceptable salts of basic compounds of formula I with acids in combination with a pharmaceutically acceptable material carrier are also an object of the present invention. Another object of the invention is a method of preparation of such medicines, which includes making one or more of these compounds or their salt forms Galanova preparation for introduction into the body together with a compatible pharmaceutically acceptable carrier. Optionally, the composition of such drugs you can enter one or more other therapeutically valuable substances that can be added in the preparation of this medication.

As mentioned above, the compounds of formula I and their aforementioned pharmaceutically acceptable salts can be used with the availa able scientific C with the invention as therapeutically active substances, in particular as anti-inflammatory drugs, or for the prevention of graft rejection after surgery transplant. The dose can be varied within wide intervals and in each case it obviously has to fit individual needs. Usually, the daily dose when injected into the body of an adult person should be from about 0.1 to about 100 mg/kg, preferably from about 0.5 to about 5 mg/kg Daily dose can be administered in doses at one time or fractional doses. In addition, when there are indications above the upper limit may be exceeded.

Finally, the object of the invention is also the use of compounds of the formula I and their aforementioned pharmaceutically acceptable salts for the preparation of medicines, primarily for the treatment and prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for the treatment of asthma, disorders of the Central nervous system or diabetic complications, or to prevent transplant rejection after surgery transplant.

The compounds of formula I can be used, although their list is not limited to, for treating humans or other mammals any Russ is of hardware or painful conditions, which of these mammals are exacerbated or caused by excessive or unregulated produced TNF and/or IL-1, or R kinase. Thus, the present invention proposes a method of treatment cytokineproducing diseases, which includes the introduction in the body effective to inhibit the activity of cytokines amount of the compounds of formula I or pharmaceutically acceptable salts, or its tautomer.

More specifically, the compounds of formula I can be used to treat arthritis, Crohn's disease, irritable bowel syndrome, respiratory distress syndrome in adults, chronic pneumonia, osteoporosis or Alzheimer's disease. The compounds of formula I can be used, although their list is not limited to treatment of the subject of inflammation or as an antipyretic agent in the treatment of fever. Compounds of the present invention can be used to treat arthritis, including, though not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic condition. Such compounds can be used to treat lung diseases or lung inflammation, including respiratory distress syndrome of adults is small, pulmonary sarcoidosis, asthma, silicosis, and chronic pneumonia. The connection can also be used to treat viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, secondary cachexia as a result of infection or malignant disease, secondary cachexia to acquired immunodeficiency syndrome (AIDS), AIDS, redspeed (state pre-acquired immunodeficiency syndrome, ARC (AIDS related complex), pneumonia, and herpes virus. Connections can also be used for treatment of diseases associated with bone resorption, such as osteoporosis, as well as endotoxic shock, toxic shock syndrome, damage from repeated transfusions, autoimmune diseases, including graft versus host and allograft rejection, cardiovascular disease including atherosclerosis, thrombosis, congestive heart failure, and cardiac damage from repeated transfusions, renal damage from repeated transfusions, liver disease and nephritis, and myalgia as a result of the infection.

The proposed connection can also be used for treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), conditions associated with skin disease is mi, such as psoriasis, eczema, burns, dermatitis, keloid formation, and scar formation on the fabric. Compounds according to the invention can also be used to treat gastrointestinal disorders such as colitis, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. These compounds can be used, apparently, in the treatment of ophthalmic diseases such as retinitis, retinopathy, uveitis, photophobia eye and acute damage to the eye tissues. Compounds according to the invention can also be used to treat angiogenesis including neoplasia; metastasis; ophthalmological conditions such as corneal rejection of the implant, eye revascularization, renal revascularization, including revascularization as a result of injury or infection, diabetic retinopathy, retrolental fibroplasia and-neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but not malignant diseases, such as hemagioma, including infantile hemagioma, angiofibroma of the nasopharynx and avascular bone necrosis, diabetic nephropathy and cardiomyopathy, and diseases of the female reproductive system such as endometriosis. Compounds according to the invention can also be used to prevent producerof is of cyclooxygenase-2 and it is believed that the compounds of the present invention can be also used for the prevention and treatment of cancer, mainly colon cancer. Assume that the compounds of the present invention can be effective in the prevention and treatment of Alzheimer's disease.

In addition to the use of these compounds in the treatment of humans, they are also effective in veterinary medicine for the treatment of domestic animals, exotic animals, farm animals, including mammals, rodents, and the like, more preferably for the treatment of animals such as horses, dogs and cats.

The proposed connection can also be used in joint therapy (partially or completely instead of other conventional anti-inflammatory drugs), in particular together with steroids, inhibitors of cyclooxygenase-2, NSPs (non-steroidal anti-inflammatory drugs), DMARDS, immunosuppressive agents, inhibitors of 5-lipoxygenase, leukotriene antagonists In4and inhibitors of hydrolases leukotriene And4.

The concept of "disorder mediated by TNF used in the present description, refers to any or all of the disorders or painful conditions involving TNF, and either the TNF controls the process, either with TNF released other Monokini, such as, for example, IL-1, IL or IL-8, although their list is not limited. Therefore, a painful condition in which, for example, IL-1 is the main component and the production or activity increases and is secreted in response to TNF, should be treated as a disorder mediated by TNF.

The concept of "disorder mediated R"used in the present description, refers to any or all of the disorders or painful conditions involving R ever himself R controls the process, either through R released other factors, such as, for example, IL-1, IL-6 and IL-8, although their list is not limited. Therefore, a painful condition in which, for example, IL-1 is the main component and the production or activity is rapidly increasing and is secreted as a response to R should be considered as a disorder mediated R.

Because TNF-β is a close structural homologue of TNF-α (also known as cachectin) and since each induces similar biologic responses and binds to the same receptors of the cells, the synthesis of TNF-αand TNF-β inhibited by compounds of the present invention, and thus they relate, unless otherwise noted, the entire group "TNF".

EXAMPLES

The following examples are intended for illustrative purposes and needle limit the scope of the present invention.

In all cases, unless specified otherwise in the following examples, temperatures are in degrees Celsius (° (C)processes carried out at room temperature or ambient temperature (typically in the range of from about 18 to 25°C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (typically 4.5-30 mmHg) with a bath temperature of up to 60°; over the course of reactions was typically followed by TLC results, and duration of response shown for illustrative purposes only; melting points are not corrected; the products demonstrated satisfactory data1H-NMR and/or microanalysis; the yield of the products is shown only for illustrative purposes; it is also used following standard abbreviations: tPL(melting point): l (liter, liters), ml (milliliters), mmol (millimoles), g (grams)mg (milligrams), min (minutes) h (hours).

DEAD denotes diethylazodicarboxylate,

DYADS indicates diisopropylsalicylic,

DEM denotes 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

Example 1

This example illustrates obtaining 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, using as starting compound ethyl-4-chloro-2-methylthiopyrimidine-5-carboxylate.

1.1. Obtaining DIN-5-carboxylate ethyl-4-methylamino-2-methylthiopurine

A solution of 20 g (86 mmol) of ethyl-4-chloro-2-methylthiopyrimidine-5-carboxylate (company Aldrich Chemical Co., Milwaukee, PCs Wisconsin, USA) in 250 ml of dichloromethane was cooled to 0°and treated With slow addition of 35 ml (281 mmole) 33%solution of methylamine in ethanol. After stirring for 30 min was added 150 ml of water and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure obtaining in the form of a white solid substance of 19 g (yield 97%) of ethyl-4-methylamino-2-methylthiopyrimidine-5-carboxylate.

1.2. Getting 4-methylamino-2-methylthiopyrimidine-5-methanol

9 g (237 mmol) of lithium aluminum hydride was stirred in 300 ml of dry tetrahydrofuran and treated by the addition dropwise of a solution of 34 g (143 mmole) ethyl-4-methylamino-2-methylthiopyrimidine-5-carboxylate in 300 ml of dry tetrahydrofuran and left to stand for 15 minutes the Mixture was cooled on ice and carefully processed by adding dropwise 18 ml of water. Dropwise introduced thirty-six milliliters of 2 M sodium hydroxide solution, and then 48 ml of water. The resulting suspension was stirred for 17 h at room temperature, and then filtered. The residue on the filter dwai the s washed using each time with 100 ml of ethyl acetate and the combined filtrate and washing liquid evaporated under reduced pressure. The residue is suspended in 200 ml of dichloromethane/hexane (2:1 ratio) and the solid was isolated and dried to obtain a yellow solid of 23.5 g (yield 86%) 4-methylamino-2-methylthiopyrimidine-5-methanol.

1.3. Getting 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde

20 g (108 mmol) of 4-methylamino-2-methylthiopyrimidine-5-methanol and 1 l of dichloromethane were combined with stirring and treated 87 g (1 mol) of manganese dioxide. The resulting suspension was stirred for 24 h, and then filtered through an auxiliary filter substance. The filter residue was washed with 100 ml of dichloromethane and the combined filtrate and wash liquid evaporated under reduced pressure obtaining in the form of a white solid substance of 15.8 g (yield 80%) 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde.

1.4. Getting 5-(2,6-dichlorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine

A mixture of 6 g (32,8 mmole) 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde, 5.5 g (33,9 mmole) of 2,6-dichloraniline and 1 g (5.3 mmole) of 4-toluenesulfonic acid in 70 ml of toluene for 17 h and kept at the boiling temperature with azeotropic removal of water. The mixture was concentrated under reduced pressure to a residual volume of about 10 ml, and then was treated with 120 ml of ethanol. Arr is savusauna the suspension was heated to 75° With and treated for 15 min 6.2 g (160 mmol) of granules of sodium borohydride. The mixture was stirred for further 15 min and cooled to room temperature. Under reduced pressure, solvent was removed and the residue for 1 h and was stirred in a mixture of 200 ml of 2 M sodium hydroxide solution and 200 ml of ethyl acetate. The phases were separated, the organic phase was dried over magnesium sulfate and filtered. As the result of evaporation of the filtrate under reduced pressure and rapid chromatography of the residue using diethyl ether/hexane in the ratio of 3:7 for elution in the form of a white solid substance was obtained 5.2 g (yield 48%) of 5-(2,6-dichlorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine.

1.5. Obtaining 3-(2,6-dichlorophenyl)-7-methylthio-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Mix a solution of 12 ml of phosgene (20%solution in toluene, 23 mmole) in 100 ml of toluene, cooled on ice, treated by the addition dropwise of a solution of 5 g (15.2 mmole) of 5-(2,6-dichlorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 4 ml (29 mmole) of triethylamine in 80 ml of tetrahydrofuran. After stirring for 1 h the mixture was treated with 100 ml of a saturated aqueous solution of ammonium chloride and the phases were separated. The aqueous phase was extracted with 100 ml of tetrahydrofuran, and the combined organic solutions were dried over sulfate is m magnesium and filtered. The filtrate was concentrated under reduced pressure obtaining in the form of a white solid 4.8 g (yield 89%) of 3-(2,6-dichlorophenyl)-7-methylthio-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (PBS 1.1).

1.6. Obtaining 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

A solution of 5 g (a 14.1 mmole) of 3-(2,6-dichlorophenyl)-7-methylthio-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (compound 1.1) in 200 ml dichloromethane was cooled on ice and treated with 10 g (of 28.9 mmole) of 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 17 h, then was treated with 2 ml of dimethyl sulfoxide and left to stand for 10 minutes Then added 100 ml of saturated aqueous sodium bicarbonate solution and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. In the result, concentration of the filtrate under reduced pressure in the form of a white solid substance was obtained 5 g (yield 92%) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (sulfon 1.2).

Using the above mentioned stage 1.4 2-Chloroaniline instead of 2,6-dichloraniline received related compound, 3-(2-chlorophenyl)-7-methanesulfonyl-1-methyl-3,4-dihydropyrimidin-2(1H)-he (sulfon 1.3).

In a similar way with the use the of the above mentioned stage 1.4 o-toluidine instead of 2,6-dichloraniline received 7-methanesulfonyl-C-ortho-tolyl-1-methyl-3,4-dihydropyrimidin-2(1H)-he (sulfon 1.4).

Example 2

Connection 1-7

This example illustrates the process for the preparation of 3-(2-chlorophenyl)-7-(2-hydroxy-1,1-dimethylethylamine)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she, in the course of which the reaction of substitution of lead in the absence of solvent.

0,200 g (0.57 mmole) sulfone 1.3 United 0.11 ml (1.2 mmole) of 2-amino-2-methyl-1-propanol. The mixture was stirred at 100-110°C for 1 h and after this time it was cooled to room temperature. The residue was purified by column chromatography on silica gel using hexane/acetone in a ratio of 25:15. The column fractions containing product were combined and concentrated under vacuum to a residue in the form of oil, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried, highlighting 0,150 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(2-hydroxy-1,1-dimethylethylamine)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

With the replacement of 2-amino-2-methyl-1-propanol necessary Amin R1R4NH has received additional compounds according to the invention listed in table 1-3.

Example 3

Connection 1-13

This example shows how to obtain 3-(2-chlorophenyl)-7-((1S,2R)-2-hydroxy-1-hydroxymethylpropane)-1-ethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0.800 to g (of 2.27 mmole) sulfone 1.3 was combined with 3 ml of 2-methoxyethanol ether 0.480 g (4,56 mmole) D-allostreaming-((2R,3S)-2-amino-3-hydroxybutanal). The mixture was stirred at 100°C for one hour, after which the temperature was raised to 130°because the reaction was not completed. After 30 min the reaction was completed, the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel using dichloromethane/methanol/Isopropylamine in the ratio of 70:5:1. The column fractions containing product were combined and concentrated to a residue in the form of oil, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried, highlighting 0,448 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-((1S,2R)-2-hydroxy-1-hydroxymethylpropane)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Replacing D-allocreadiidae necessary Amin R1R4NH has received additional compounds according to the invention listed in tables 1-3.

Example 4

Connection 1-2

This example shows how to obtain 3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,200 g(0.57 mmole) sulfone 1.3 combined from 0.09 ml (1,13 mmole) of D,L-2-amino-1-propanol and kept at 100-110° C for 30 minutes Then the reaction mixture was cooled to room temperature and the mixture was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio 9:1. The column fractions containing product were combined and concentrated under vacuum to a residue in the form of oil, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried, highlighting 0,142 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 5

Connection 1-3

This example shows how to obtain 3-(2-chlorophenyl)-7-(2-hydroxypropylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,200 g (0.57 mmole) sulfone 1.3 combined from 0.09 ml (1,17 mmole) of 1-amino-2-propanol and kept at 100-110°C for 30 minutes Then the reaction mixture was cooled to room temperature and the mixture was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio 9:1. The column fractions containing product were combined and concentrated under vacuum to a residue in the form of oil, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (1,0 e the century) received salt, which was filtered and dried, highlighting 0,165 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(2-hydroxypropylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 6

Connection 3-28

This example shows how to obtain 3-(2-chlorophenyl)-7-(2,3-dihydroxy-1,1-dimethylpropylene)-1-methyl-3,4-dihydropyrimido[4,5-d] pyrimidine-2(1H)-it.

Obtain 3-amino-3-methylbutane-1,2-diol

In a solution of 20 ml (0.2 mol) of 3-methyl-2-butene-1-ol in 800 ml of water was introduced to 42.5 g (0.5 mole) of sodium bicarbonate. The solution was cooled to 5°and portions over 1 h was added 54 g (0,22 mole) of 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 12 h, then saturated with sodium chloride and was extracted with dichloromethane. The layers were separated, the organic layer was dried over potassium carbonate and concentrated under vacuum. The residue was purified Express chromatography, using as eluent hexane/ethyl acetate 2:1 ratio to produce in the form of oil 10,02 g (3,3-dimethyloxetane)methanol.

A solution of 10 g (98 mmol) of (3,3-dimethyloxetane)methanol in 735 ml of dichloromethane was combined with a solution of 50 ml (169,4 mmole) of isopropoxide titanium in 100 ml dichloromethane and a solution of 40.6 ml (235 mmol) aminodiphenylamine in 100 ml dichloromethane and the reaction mixture was stirred at room temperature for 48 hours was Added 10%to the feet of the solution of sodium hydroxide in brine and the suspension was stirred for another 12 h, was filtered and washed with 0.2 M hydrochloric acid. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using as eluent hexane/ethyl acetate in the ratio of 4:1, receipt of 5.1 g of 3-(benzylamino)-3-methylbutane-1,2-diol.

to 5.1 g (17.9 mmole) 3-(benzylamino)-3-methylbutane-1,2-diol and 1.2 g of palladium hydroxide in 25 ml of methanol was shaken in a hydrogen atmosphere in a Parr apparatus under a pressure of 49 psi for 18 hours, the Suspension was filtered and the filtrate concentrated under vacuum. The residue is suspended in hexane, stirred for 2 min and the hexane layer decantation. The residue was concentrated under vacuum obtaining of 1.74 g of 3-amino-3-methyl-1,2-butanediol.

Obtaining 3-(2-chlorophenyl)-7-(2,3-dihydroxy-1,1-dimethylpropylene)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

700 mg (1.7 mmole) sulfone 1.3 was combined with 500 mg (2.1 mmole) 3-amino-3-methyl-1,2-butanediol and 2 ml of 2-methoxyethanol ether. The mixture was stirred at 100°C for 6 h, after which it was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 99:1. The column fractions containing product were combined and concentrated the Ali under vacuum, getting the balance in the form of oil specified in the title compound, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried, allocating 256 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(2,3-dihydroxy-1,1-dimethylpropylene)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 7

Connection 3-43

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-hydroxymethylcellulose)amino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

500 mg (1.2 mmole) sulfone 1.3 combined with 602 mg (4.6 mmole) of 1-amino-1-cyclohexanemethanol [obtained as described in J. Med. Chem., 1966, 9(6) 911-920] and 1 ml of 1-methyl-2-pyrrolidinone. The mixture was stirred at 120°C for 3 h, after which it was cooled to room temperature. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 98:2. The column fractions containing product were combined and concentrated under vacuum to a solid residue, which was ground into powder with water, was filtered, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried, highlighting 328 mg Sol cleaners containing hydrochloride is 3-(2-chlorophenyl)-7-[(1-hydroxymethylcellulose)amino]-1-methyl-3,4-dihydropyrimido[4,5-a]pyrimidine-2(1H)-it.

Example 8

Connection 3-45

This example shows how to obtain 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Obtaining 1,4-dioxaspiro[4.5]Dec-8-ylamine

The mixture 50,3 g (322,1 mmole) of 1,4-dioxaspiro[4.5]decane-8-she and 89.5 g (100,3 mmole) of hydroxylaminopurine in 450 ml water portions were injected 102,4 (966,2 mmole) of sodium carbonate. The reaction mixture was stirred for 40 min at room temperature, and then was extracted with ethyl acetate.

The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum obtaining of 68.2 g of crude 1,4-dioxaspiro[4.5]decane-8-noxema.

In a solution of 68 g (400 mmol) of 1,4-dioxaspiro[4.5]decane-8-noxema in 200 ml of ethanol in the form of a suspension in 52 ml of ethanol were introduced Raney Nickel. The resulting mixture was shaken in a hydrogen atmosphere under a pressure of 50 psi for 18 hours, the Reaction mixture was filtered and concentrated under vacuum obtaining of 57.5 g of 1,4-dioxaspiro[4.5]Dec-8-ylamine.

Obtaining 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

3.6 g (10 mmol) of sulfone 1.3 combined with 6.4 g (41 mmol) of 1,4-dioxaspiro[4.5]Dec-8-ylamine in 20 ml of 1-methyl-2-pyrrolidinone and kept at 100°C for 5 hours Then reaction the second mixture was cooled to room temperature and was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water and brine, dried with sodium sulfate, concentrated under vacuum and purified by column chromatography on silica gel using as eluent 0.5% ammonium hydroxide in ethyl acetate. The column fractions containing product were combined and concentrated under reduced pressure obtaining in the form of not quite white solid of 1.3 g of 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 9

Connection 3-47

This example shows how to obtain 3-(2-chlorophenyl)-7-(3-hydroxymethyl-3-methyl-1,5-dioxaspiro[5.5]undec-9 ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A mixture of 0.30 g (0,70 mmole) of 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 8), 0.17 g (of 0.91 mmole) of the monohydrate of p-toluenesulfonic acid and 0.84 g (7.0 mmole) of 1,1,1-Tris(hydroxymethyl)ethane in 40 ml of toluene was boiled under reflux and stirred overnight. The reaction mixture was cooled to room temperature, then was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under below the NYM pressure and was purified rapid chromatography on silica gel using as eluent 50-60% acetone in hexane. The column fractions containing product were combined and concentrated to produce in the form of a white foam 0.32g specified in the title compounds. By adding 1 M hydrochloric acid in diethyl ether was obtained salt, which was filtered, highlighting 160 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(3-hydroxymethyl-3-methyl-1,5-dioxaspiro[5.5]undec-9 ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 10

Connection 3-46

This example shows how to obtain 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A solution of 6.0 g (14 mmol) of 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 8) in 60 ml of 80%acetic acid was kept at 65°With during the night. Next, the reaction mixture was cooled to room temperature and was diluted with water, ethyl acetate and brine. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium bicarbonate and brine, dried and concentrated under reduced pressure. The residue was dissolved in chloroform and purified rapid chromatography on silica gel using as eluent of 4% methanol/dichloromethane to produce in the form of a white foam 2.2 g pointed to by the th in the title compounds. Some of the listed in the title compounds (0,30 g to 0.78 mmole) was dissolved in ethyl acetate, then was treated with 1 M hydrochloric acid in diethyl ether to obtain 150 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it is in the form of a white precipitate, which was filtered, washed with ethyl acetate and concentrated under reduced pressure.

Example 11

Connection 3-50

This example shows how to obtain 3-(2-chlorophenyl)-7-(4-hydroxymitragynine)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A mixture of 0.31 g (0,80 mmole) of 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 10) and 0.22 g (3.2 mmole) of hydroxylaminopurine in 5 ml of pyridine was kept at 65°C for 90 minutes Then the reaction mixture was cooled to room temperature, diluted with water and ethyl acetate and the phases were separated. The organic phase was filtered, dried under reduced pressure and suspended in methanol. By adding 1 M hydrochloric acid in diethyl ether was received cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(4-hydroxymitragynine)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it is in the form of a yellow foam, which was concentrated under reduced pressure.

When is EP 12

Connection 3-54

This example illustrates the receipt of 8-[6-(2-chlorophenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-1,3-diazaspiro[4.5]decane-2,4-dione.

A mixture of 0.33 g (0,86 mmole) of 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 10), 0,084 g (1.3 mmole) of potassium cyanide and 0.25 g (2.6 mmole) of ammonium carbonate in 25 ml of water/ethanol in a ratio of 1:1 was stirred at 65°With during the night. The reaction mixture was diluted with 40 ml of water and left to boil for 15 min, and then cooled to room temperature and poured into 100 ml ice water. The mixture was filtered and the residue suspended in methanol. By adding 1 M hydrochloric acid in diethyl ether was getting salt in a liquid medium, which was concentrated in a stream of nitrogen, highlighting in the form of a yellow powder (39 mg cleaners containing hydrochloride salt of 8-[6-(2-chlorophenyl)-8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2-ylamino]-1,3-diazaspiro[4.5]decane-2,4-dione.

Example 13

Connection 3-42

This example shows how to obtain 7-(TRANS-4-allyloxycarbonyl)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

2.6 g (of 7.48 mmole) sulfone 1.3 combined with 1.63 g (14.2 mmole) of TRANS-4-aminocyclohexanol in 10 ml of 1-methyl-2-is irreligion and stirred at 120° C for 4 h, and then poured into ice water, extracted with ethyl acetate, dried over magnesium sulfate and evaporated under vacuum. The residue was purified rapid chromatography on silica gel using as eluent 2-4% methanol/dichloromethane, receiving in the form of oil substance 1-methyl-2-pyrrolidinone basis. This substance is in the form of oil was again dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and evaporated under vacuum obtaining in the form of not quite white foam 2,80 g (7,21 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Part (0,274 g, 0,706 mmole) of 7-(TRANS-4-hydroxycyclohexyl)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 0,119 g (of 1.06 mmole) of tert-butoxide potassium in 5 ml of tetrahydrofuran. To this solution was added 0,061 ml (0,706 mmole) of allylbromide, and then kept at 50°C overnight, then cooled to room temperature and was purified rapid chromatography on silica gel using as eluent 10-25% acetone/hexanol. The column fractions containing product were combined and concentrated under vacuum. The concentrate was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), again evaporated to dryness, then washed with diethyl ether, filtered and dried to obtain 0.12 g cleaners containing hydrochloride salt of 7-(TRANS-4-allyloxycarbonyl)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 14

Connection 3-38 and 3-39

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-methoxycyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and 3-(2-chlorophenyl)-7-[(TRANS-4-methoxycyclohexyl)methylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,300 g (0,773 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 13) was combined with 0,174 g (of 1.55 mmole) of tert-butoxide potassium in 5 ml of terriitory. To this solution was added 0,053 ml (0,851 mmole) under the conditions, and then stirred at room temperature for 3 days. Additionally added 0,053 ml (0,851 mmole) under the conditions and 0,174 g (of 1.55 mmole) of tert-butoxide potassium, and then, after 4 h, additional 0,350 g (3,12 mmole) of tert-butoxide potassium. The reaction mixture was stirred at 60°C overnight, then cooled to room temperature and was purified rapid chromatography on silica gel using as eluent 25-35% acetone/hexanol, receiving a mixture of two products. Allocated to each individual column fractions and concentrated under vacuum. Each of the separate concentrate was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), again evaporated to dryness, washed with diethyl shall FYROM, was filtered and dried to obtain 0,049 g 3-(2-chlorophenyl)-7-(TRANS-4-methoxycyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and 0.217 g of 3-(2-chlorophenyl)-7-[(TRANS-4-methoxycyclohexyl)methylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 15

Connection 3-40

This example shows how to obtain 3-(2-chlorophenyl)-7-[TRANS-4-(2-methoxyethoxy)cyclohexylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,300 g (0,773 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 13) was combined with 0,174 g (of 1.55 mmole) of tert-butoxide potassium in 2 ml of tetrahydrofuran. To this solution was added 0.15 ml (1,55 mmole) 2-pomatoleios ether, then stirred at room temperature for 3 days. Additionally added 0,174 g (of 1.55 mmole) of tert-butoxide potassium and the temperature is gradually raised to 80°C. the Reaction residue was again dissolved in 2 ml N,N-dimethylformamide, was added additionally 0,348 g (3,10 mmole) of tert-butoxide potassium and the reaction mixture was stirred at 80°With during the night. Added 0,031 g (0,773 mmole) of sodium hydride (60%in oil) and the reaction mixture was stirred for one day at 100°and the next day at 140°S, and then cooled to room so the temperature.

The reaction mixture was poured into ice water, extracted with ethyl acetate, dried over magnesium sulfate and evaporated under vacuum. The residue was purified rapid chromatography on silica gel using as eluent 25-50% acetone/hexanol. The column fractions containing product were combined and concentrated under vacuum, and the concentrate was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), again evaporated to dryness, washed with diethyl ether, filtered and dried to obtain 0,040 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[TRANS-4-(2-methoxyethoxy)cyclohexylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 16

Connection 3-41

This example shows how to obtain 3-(2-chlorophenyl)-7-[(TRANS-4-methylcarbonate)cyclohexylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,200 g (0,516 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 13) was dissolved in 2 ml dichloromethane and combined with 0,074 ml of 1.03 mmole) of acetylchloride. The reaction mixture was stirred at room temperature overnight, then was purified rapid chromatography on silica gel using as eluent 1-5% methanol/dichloromethane. The column fractions containing product on heinali and concentrated under vacuum. The concentrate was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), again evaporated to dryness, washed with diethyl ether, filtered and dried to obtain 0,200 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(TRANS-4-methylcarbonate)cyclohexylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 17

Connection 3-44

This example shows how to obtain 3-(2-chlorophenyl)-7-[TRANS-4-(2,3-dihydroxypropane)cyclohexylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0.40 g (0,935 mmole) of free base, 7-(TRANS-4-allyloxycarbonyl)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 13) was dissolved in 4.9 ml of tert-butanol are added and this solution was added a solution of 2.91 in g 4.9 ml of AD-mix β (company Aldrich Chemicals), followed by exposure at 100°within 2 days and then at 80°C for 3 days. The reaction mixture was poured into saturated brine, extracted with ethyl acetate, dried with magnesium sulfate and evaporated under vacuum. The crude residue was purified rapid chromatography on silica gel using as eluent 3-5% methanol/dichloromethane. The column fractions containing product were combined and concentrated under vacuum. The concentrate was dissolved in methanol, was treated with 1.0 M hydrochloric is th acid in Et 2O (1.0 EQ.), again evaporated to dryness, then washed with diethyl ether, filtered and dried to obtain 0,019 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[TRANS-4-(2,3-dihydroxypropane)cyclohexylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 18

Connection 3-59

This example shows how to obtain 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

605 mg (1,71 mmole) sulfone 1.3 combined from 1.61 g (a 14.1 mmole) of TRANS-1,4-diaminocyclohexane and 5 ml of 1-methyl-2-pyrrolidone. The reaction mixture was stirred at 85°C for 4 h After cooling, the reaction mixture was diluted with 50 ml ethyl acetate. The organic layer was sequentially washed with water and brine, dried and concentrated under vacuum obtaining in the form of a pale yellow foam 654 mg (yield 99%) of the product in free base form. This free base was dissolved in ethyl acetate and treated with 1 m solution of HCl/Et2O obtaining in the form of a white powder cleaners containing hydrochloride salt of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 19

Connection 3-57

This example shows how to obtain 7-(TRANS-4-methylsulfonylmethane)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

img src="https://img.russianpatents.com/823/8231978-s.jpg" height="57" width="170" >

In a solution of 88 mg (0,227 mmole) of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 18) in 8 ml of dichloromethane were introduced and 0.40 ml (0,29 mmole) of triethylamine and 60 mg (0,34 mmole) methanesulfonamido anhydride. The reaction mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated under vacuum and purified by chromatography using as eluent 5% methanol/dichloromethane, receiving in the form of a white powder (86 mg (yield 81%) of the product in free base form. This free base was dissolved in ethyl acetate and treated with 1 m solution of HCl/Et2O obtaining in the form of a white powder cleaners containing hydrochloride salt of 7-(TRANS-4-methylsulfonylmethane)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 20

Connection 358 for

This example illustrates obtaining 7-[TRANS-4-(N,N-dimethylsulphamoyl)cyclohexylamino]-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

To a solution of 171 mg (0,442 mmole) of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 18) in 15 ml of dichloromethane were introduced to 0.11 ml (0.79, which mmole) of triethylamine and a solution of 0.31 g (of 0.21 mmole) dimethylsulphamoyl the IDA in 5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 19 h and then concentrated under vacuum. In the purification by chromatography using as eluent 5% methanol/dichloromethane in the form of a white powder was obtained 143 mg (yield 65%) of the product in free base form. This free base was dissolved in ethyl acetate and treated with HCl/Et2O obtaining in the form of a white powder cleaners containing hydrochloride salt of 7-[TRANS-4-(N,N-dimethylsulphamoyl)cyclohexylamino]-3-(2-chlorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 21

Connection 3-9

This example shows how to obtain 7-(TRANS-4-hydroxycyclohexyl)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

300 mg (of 0.903 mmole) sulfone 1.4 combined with 312 mg (2,71 mmole) of TRANS-4-aminocyclohexanol, stirred at 120°and its progress was monitored by TLC (5% methanol/dichloromethane). When the reaction was completed, the mixture was concentrated under vacuum and purified by chromatography using 5-10% methanol/dichloromethane, getting 263 mg (0,716 mmole, yield 79%) specified in the title compound, which was dissolved in ethyl acetate and treated with 1 EQ. HCl/Et2O, precipitating HCl salt of 7-(TRANS-4-hydroxycyclohexyl)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

The use of the 22

Connection 3-23

This example shows how to obtain 7-((R,R)-2,3-dihydroxy-1-methylpropylamine)-3-ortho-tolyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

455 mg (1,37 mmole) sulfone 1.4 and 180 mg (1,71 mmole) of (R,R)-3-amino-1,2-butanediol in 1 ml of 1,2-dimethoxyethane kept at 100°C for 2 h in an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with dichloromethane/methanol in the ratio 9:1 and purified by chromatography on silica gel using as eluents dichloromethane/methanol in the ratio of 96:4 and dichloromethane/methanol in the ratio 9:1 to produce in the form of a colourless oil, 175 mg specified in the title compound, which was dissolved in ethyl acetate and treated with 1 EQ. 1.0 M hydrochloric acid in diethyl ether. The precipitate was collected by filtration under vacuum, washed with ethyl acetate and dried under vacuum obtaining in the form of a white solid 190 mg of 7-((R,R)-2,3-dihydroxy-1-methylpropylamine)-3-ortho-tolyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 23

Connection 3-33

This example shows how to obtain 7-(2,3-dihydroxy-1,1-dimethylpropylene)-3-ortho-tolyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

400 mg (1.2 mmole) sulfone 1.4 combined with 305 mg (2.1 mmole) 3-amino-3-methyl-1,2-Boo is angiola and 1 ml of 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 100°C for 4 h and after this time it was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 99:1. The column fractions containing product were combined and concentrated under vacuum obtaining in the form of oil specified in the title compound, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 71 mg cleaners containing hydrochloride salt of 7-(2,3-dihydroxy-1,1-dimethylpropylene)-3-ortho-tolyl-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 24

Connection 2-9

This example shows how to obtain 7-(1-benzylpiperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

1 g (3 mmole) sulfone 1.4 combined with 687 mg (3.6 mmole) of 4-amino-1-benzylpiperidine and 1 ml of 2-methoxyethanol ether. The mixture was stirred at 120°C for 4 h and after this time it was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 97:3. is racchi column, containing the product were combined and concentrated under vacuum obtaining in the form of oil product, which was again dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 198 mg cleaners containing hydrochloride salt of 7-(1-benzylpiperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 25

Connection 2-8

This example shows how to obtain 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

In a three-neck flask under nitrogen atmosphere was downloaded 3.0 g of 10%palladium on coal and with a syringe under nitrogen atmosphere was introduced 3.0 g (6,78 mmole) of 7-(1-benzylpiperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received set forth in example 24) in 60 ml of methanol. Further, one portion was added 2.1 g (34 mmole) of ammonium formate. The mixture was boiled under reflux for 30 min to complete the reaction. The catalyst was filtered through brownmillerite and washed with methanol. The filtrate was concentrated under reduced pressure obtaining in the form of a white solid 1,937 g (yield 81%) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 26

Connection 2-14

Dennisprager illustrates obtaining (R)-7-[1-(2,3-dihydroxypropyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0.2 g (0,586 mmole) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (obtained by described in example 25), 0,264 g (0,92 mmole) piperidine-L-isopropylideneglycerol-γ-tosilata and 0.12 g (1.1 mmole) of potassium carbonate in 5 ml of N,N-dimethylformamide was kept at 100°C for 17 h, the Reaction mixture was diluted with 75 ml of water, was extracted with toluene/ethyl acetate in a ratio of 1:1 and the layers were separated. The organic layer was washed with water and brine, dried, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel using as eluent ethyl acetate/methanol/Isopropylamine in the ratio 95:5:0.2 to. Next column fractions containing the product (of) 0.157 g of 0.34 mmole), was dissolved in 10 ml isopropanol, 1 ml of water and 0.2 ml of concentrated hydrochloric acid and boiled under reflux for 1 h to complete the hydrolysis. The mixture was concentrated under reduced pressure, the residue was dissolved in methanol and the solution was again concentrated. The residue was purified by chromatography on silica gel using as eluent dichloromethane/methanol/Isopropylamine in the ratio 18:2:0,5, receiving 90 mg of product which was dissolved in 1.5 ml of ethyl acetate and 1.5 ml of methanol. By adding 1 M hydrochloric acid in diethyl EPE is e received 113 mg (yield of 72.5%) cleaners containing hydrochloride salt of (R)-7-[1-(2,3-dihydroxypropyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 27

Connection 2-13

This example illustrates obtaining 7-[1-(2-hydroxyethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A mixture of 0.1 g (0,284 mmole) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (obtained by described in example 25), 0,024 ml (0,34 mmole) of 2-bromoethanol and 0,047 ml (0,34 mmole) of triethylamine in 10 ml of toluene and 1.5 ml DMPM kept at 100°C for 17 hours Under reduced pressure, the solvent evaporated and the residue was purified by chromatography on silica gel using as eluent ethyl acetate/methanol/Isopropylamine in the ratio of 40:10:2, receiving 70 mg (yield 52%) of 7-[1-(2-hydroxyethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 28

Connection 2-15

This example illustrates obtaining 7-[1-(2-cyanoethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

The mixture 0,184 g (0,52 mmole) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (obtained by described in example 25), 1.5 ml of Acrylonitrile, 0.5 ml of triethylamine, 0.5 ml of 1-methyl-2-pyrrolidinone and 5 ml of tetrahydrofuran, kept at 75°C for 1.5 h to complete the reaction. The reaction to shift the ü concentrated under reduced pressure and was purified by chromatography on silica gel using as eluent 10% methanol in ethyl acetate, receiving of) 0.157 g (75%yield) of product. To 75 mg of the product dissolved in ethyl acetate, was added 1 M hydrochloric acid, the mixture was stirred at room temperature for 1 h and the residue was filtered in a nitrogen atmosphere to obtain cleaners containing hydrochloride salt of 7-[1-(2-cyanoethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 29

Connection 2-16

This example illustrates obtaining 7-[1-(2-cyanoethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

52 mg (1,28 mmole) of 7-[(1-ethoxycarbonylpyrimidine-4-yl)amino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 5 ml of dichloromethane with 0,88 ml (6,18 mmole) of attributively and boiled under reflux overnight, then the reaction is extinguished 1 ml of methanol and the mixture is evaporated under vacuum. The dry residue was re-dissolved in methanol, to the solution was added to 1.28 ml of 0.5 M sodium methoxide/methanol, after which the mixture is again evaporated under vacuum and purified rapid chromatography on silica gel using as eluent 10-40% methanol/dichloromethane with 1% ammonium hydroxide. The column fractions containing 7-piperidine-4-ylamino-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he, were combined and concentrated under vacuum.

0.035 g (0,099 mole of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in 1 ml N,N-dimethylformamide was combined with that of 0.014 ml (0,199 mmole) of bromoacetonitrile and stirred at 40° With during the night, then was purified rapid chromatography on silica gel using as eluent 3-10% (ammonium hydroxide/methanol in the ratio 1:9)/dichloromethane. The column fractions containing product were combined and concentrated under vacuum. The product was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), again evaporated to dryness, then washed with diethyl ether, filtered and dried to obtain 0,007 g cleaners containing hydrochloride salt of 7-[1-(2-cyanomethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 30

Connection 2-20

This example illustrates obtaining 7-[1-(2-methoxycarbonylethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

The mixture is 0.19 g (0.54 mmole) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(lH)-it (obtained by described in example 25), 1.0 ml of methyl acrylate, 0.5 ml of triethylamine, 0.5 ml of 1-methyl-2-pyrrolidinone and 5 ml of tetrahydrofuran, kept at 75°C for 17 h, the Reaction mixture was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using as eluent 5% methanol in dichloromethane, getting 132 mg (yield 56%) of product. To a solution of the product in ethyl acetate was added 1 M hydrochloric acid what are you in diethyl ether and the suspension was stirred at room temperature for 1 h The mixture is evaporated under reduced pressure to obtain cleaners containing hydrochloride salt of 7-[1-(2-methoxycarbonylethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 31

Connection 2-18

This example illustrates obtaining 7-[(1-carbamoylmethyl-4-yl)carbamoylmethyl]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,030 g (0,080 mmole) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (obtained by described in example 25) was dissolved in 1 ml N,N-dimethylformamide from 0.022 g (0,161 mmole) of bromoacetamide and stirred at 50°With during the night. Before returning the reaction mixture to 50°for exposure during the second night was added another portion (0,022 g) bromoacetamide. The reaction mixture was purified rapid chromatography on silica gel using as eluent 6-20% (ammonium hydroxide/methanol in the ratio 1:9)/dichloromethane. The column fractions containing product were combined and concentrated under vacuum. The final product was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), again evaporated to dryness, then washed with diethyl ether, filtered and dried to obtain 0.001 g cleaners containing hydrochloride salt of 7-[(1-carbamoylmethyl-4-yl)carbamoylmethyl]-1-m is Tyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 32

Connection 2-12

This example shows how to obtain 7-(1-methanesulfonamido-4-yl)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,200 g (0,567 mmole) of 7-(piperidine-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (obtained by described in example 25) was dissolved in 5 ml of pyridine and the solution was cooled to 0°then add 0,046 ml (0,596 mmole) of methanesulfonamide. The reaction mixture was stirred at 0°C for 2 h, then was rapidly cooled with a mixture of ice water and was extracted with ethyl acetate. The organic extracts were washed with water and saturated aqueous sodium bicarbonate, then again washed with water and evaporated under vacuum. The residue was purified by column chromatography on silica gel using as eluent methanol/dichloromethane in the ratio of 1:15. The column fractions containing product were combined and concentrated under vacuum and the final product was again dissolved in minimum amount of ethyl acetate and methanol. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried to obtain 0.124 g cleaners containing hydrochloride salt of 7-(1-methanesulfonamido-4-yl)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 33

Link is 2-17

This example shows how to obtain 3-(2-chlorophenyl)-7-(1-cyanoethylidene-4-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,030 g (0,080 mmole) of 3-(2-chlorophenyl)-7-(piperidine-4-ylamino)-1-methyl-3,4-dihydropyrimido [4,5-d]pyrimidine-2(1H)-she (obtained analogously to example 29) was dissolved in 1 ml N,N-dimethylformamide with to 0.011 ml (0,161 mmole) of bromoacetonitrile and stirred at 50°With during the night. Before returning the reaction mixture to 50°for exposure during the second night was added another portion (0,011 ml) bromoacetonitrile. The reaction mixture was purified rapid chromatography on silica gel using as eluent 1-20% (ammonium hydroxide/methanol in the ratio 1:9)/dichloromethane. The column fractions containing product were combined and concentrated under vacuum, the product was dissolved in methanol, was treated with 1.0 M hydrochloric acid in Et2O (1.0 EQ.), re-evaporated to dryness, then washed with diethyl ether, filtered and dried to obtain 0.002 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(1-cyanoethylidene-4-ylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 34

4-Amino-2-benzoylthiophene-5-carboxaldehyde

34.1. Getting 4-amino-5-carbamaxepine-2-thiol

272 g (4,0 mole) of ethoxide sodium (firm Lancastr) was stirred in 1 l of ethanol and treated 304 g (4,0 mole) thiourea (firm Avocado). Added 676 g (4,0 mole) of atlatonementaustin (firm Avocado) and the mixture is boiled under reflux for 8 hours After cooling to room temperature, and aging overnight, the reaction mixture was sequentially treated with 2 l of water and 400 ml of acetic acid. The reaction mixture is boiled under reflux for 30 minutes, cooled to room temperature and the suspension was filtered. The solid is washed with three 500 ml portions of water, two 500-ml portions of acetone and 500 ml of diethyl ether. The product was dried to produce in the form of a cream solid 473,3 g (yield 60%) of 4-amino-5-carbamaxepine-2-thiol with a melting point >250°C.

34.2. Getting 4-amino-2-benzoylthiophene-5-carboxylate

Mixed suspension 473 g (2,377 mole) 4-amino-5-carbamaxepine-2-thiol in 3.5 l of ethanol was treated 180,4 g (1,307 mole) of potassium carbonate and 447,1 g (2,615 mole) of benzylbromide. The mixture was boiled under reflux for 2 h, then it was allowed to cool to room temperature and kept overnight. The suspension was filtered and the solid is washed with two 500 ml portions of ethanol, 2 liters of water and two 500-ml portions of water. The product was dried under vacuum over phosphorus pentoxide at 50°obtaining in the form of a cream solid 416 g (Ihad 61%) of ethyl-4-amino-2-benzoylthiophene-5-carboxylate with a melting point of 117-118° C.

34.3. Getting 4-amino-2-benzoylthiophene-5-methanol

The solution 462,4 g (1,6 mole) ethyl-4-amino-2-benzoylthiophene-5-carboxylate in a 2.3 liter dried over molecular sieve of tetrahydrofuran in a nitrogen atmosphere with ice cooling slowly with stirring introduced in 1.6 l (of 1.6 mol) of 1 M solution of lithium aluminum hydride in tetrahydrofuran. The first solution was added in such a rate as to maintain a temperature of 18 to 20°C. Upon completion of addition the mixture was heated to 60°and carefully processed within 1.5 h of 60.8 ml of water. Within 30 minutes was added of 60.8 ml of 15%aqueous sodium hydroxide, and then within 30 minutes was introduced 182,5 ml of water. The suspension was stirred at 60°during the night, then in a still hot state filtered through the auxiliary filter substance Hyflo and the solid is washed with two 1 liter portions of tetrahydrofuran. As the result of evaporation of the filtrate to dryness in a not-quite-white solid substance was obtained 392,5 g (yield 99%) of 4-amino-2-benzoylthiophene-5-methanol, which was used in the next stage without additional purification.

34.4. Getting 4-amino-2-benzoylthiophene-5-carboxaldehyde

Suspension 392,5 g (1,59 mole) 4-amino-2-benzoylthiophene-5-methanol of 7.75 liters of dichloromethane in a nitrogen atmosphere was treated with 1,382 kg (15,9 mole) of activated dioxide is organza (firm Acros). The reaction mixture was stirred at room temperature overnight, then filtered through an auxiliary filter substance Hyflo. The solid is washed with three 1 liter portions of dichloromethane and the combined filtrates evaporated to produce in the form of a pale yellow solid 340,5 g (yield 88%) of 4-amino-2-benzoylthiophene-5-carboxaldehyde with a melting point 136-139°C.

Example 35

3-(2-Chlorophenyl)-7-benzylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he

35.1. Getting 5-(2-chlorophenyl)aminomethyl-4-amino-2-benzyltoluene

A mixture of 5 g (20.4 mmole) of 4-amino-2-benzoylthiophene-5-carboxaldehyde, 2.25 ml (21,4 mmole) of 2-Chloroaniline and 0.1 g (0.5 mmole) of the monohydrate of 4-toluensulfonate acid in 60 ml of toluene was heated with azeotropic removal of water for 3 hours the Mixture was cooled to 0°and the precipitate was collected by filtration under vacuum, washed with hexane and dried in the air. Then this solid substance was dissolved in 100 ml of tetrahydrofuran and the resulting solution was cooled to 0°C. in Small portions over 45 minutes was added 0,735 g (18,8 mmole) of lithium aluminum hydride. After the addition was completed, the mixture was stirred for further 15 min and gently sequentially processed 0.8 ml of water, 0.8 ml of 15%aqueous Hydra is xida sodium and then 2.4 ml of water. The mixture was stirred for 30 minutes, filtered through brownmillerite and the filtrate was concentrated under vacuum. The solid was stirred with diethyl ether, filtered and air-dried to obtain a white solid of 6.1 g of 5-(2-chlorophenyl)aminomethyl-4-amino-2-benzyltoluene.

35.2. Obtaining 3-(2-chlorophenyl)-7-benzylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In the mixed, cooled down to -10°With a solution of 4.3 g (12,1 mmole) 5-(2-chlorophenyl)aminomethyl-4-amino-2-benzyltoluene in 100 ml of tetrahydrofuran was added 3.1 ml (22,2 mmole) of triethylamine. Then this solution was treated by the addition dropwise of a solution x 6.15 ml of phosgene (20%solution in toluene; 11.8 mmole). After stirring for 30 min was added addition of 1.0 ml of triethylamine (7.1 mmole), and then 2.0 ml of phosgene (20%solution in toluene; 3.8 mmole). The reaction mixture was heated to room temperature, and treated with 0.5 ml of water and was stirred for 30 minutes Then the reaction mixture was filtered, the mother liquor was concentrated and stirred with dichloromethane. Then the product was collected by filtration under vacuum and dried under vacuum obtaining in the form of a white solid 3,83 g 3-(2-chlorophenyl)-7-benzylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (PBS 8.1).

Example 36

3-(2-Chlorophenyl)-7-gasoline sulphonyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he

A suspension of 1 g (2,61 mmole) sulfide 8.1 in 10 ml of dichloromethane was cooled on ice and treated 1.29 g (5,23 mmole) 70%3-chloroperbenzoic acid. The mixture was stirred at room temperature for 2 h, then was treated with 25 ml of 10%aqueous sodium thiosulfate and left to mix for 30 minutes the Resulting reaction mixture was diluted with 100 ml dichloromethane and the phases were separated. The organic phase is washed with 10%aqueous potassium carbonate, then brine, then dried over magnesium sulfate and filtered. Concentration of the filtrate under reduced pressure in the form of a white solid substance was obtained 0.73 g of 3-(2-chlorophenyl)-7-benzylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Using the example 35 ortho-toluidine instead of 2-Chloroaniline received related compound, 7-benzylmethyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he (sulfon 9.2).

Example 37

Connection 3-26

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

37.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

500 mg (1,31 mmole) sulfide 8.1 dissolved the 2 ml of tetrahydrofuran and combined with a 0.23 ml (1,96 mmole) 1-(2-hydroxyethyl)pyrrolidine, 514 mg (1,96 mmole) of triphenylphosphine and 0.31 ml (1,96 mmole) DEAD. The reaction mixture was stirred at room temperature for 3 h, then was added an additional amount of 1-(2-hydroxyethyl)pyrrolidine, triphenylphosphine and DEAD (optional for a 1.96 mmole each). The mixture was stirred at room temperature overnight and subjected to polyoxide chromatography on silica gel using as eluent a 2.5-10% methanol/dichloromethane, receiving >1 g of a mixture product, 7-benzylthio-3-(2-chlorophenyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and the remnants of the original materials.

37.2. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Oxidation of 7-benzylthio-3-(2-chlorophenyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was carried out with the use of 0.94 g (to 3.92 mmole) 3-chloroperoxybenzoic acid in dichloromethane with stirring at room temperature for 1 h the Reaction was suppressed 1 ml of saturated aqueous sodium sulfite and extracted with dichloromethane. The combined extracts were dried and concentrated under vacuum to obtain 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she, which was used without purification.

37.3. Obtaining 3-(2-chlorine is phenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Crude 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 6 ml of diglyme (dimethyl ether of diethylene glycol) with 165 mg (1.44 mmole) of TRANS-4-aminocyclohexanol and stirred at 120°C for 3 hours the Mixture was purified by chromatography on silica gel using as eluent 3-30% methanol/dichloromethane, receiving 45 mg (0,096 mmole) specified in the title compound. The purified product was dissolved in ethyl acetate and treated with 1 EQ. HCl/Et2O deposition cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-pyrrolidin-1-retil)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 38

Connection 3-27

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

38.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

500 mg (1,31 mmole) sulfide 8.1 was dissolved in 2 ml of tetrahydrofuran from 0.26 ml (1,96 mmole) of N,N-diethylethanolamine, 514 mg (1,96 mmole) of triphenylphosphine and 0.31 ml (1,96 mmole) DEAD and stirred at room temperature for 3 h, then was added an additional amount diethylethanolamine, triphenylphosphine and DEAD (additional is but a 1.96 mmole each). The mixture was stirred at room temperature overnight and subjected to polyoxide chromatography on silica gel using as eluent 1-3,5% methanol/dichloromethane, receiving >1 g of a mixture of 7-benzylthio-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and the remnants of the original materials.

38.2. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Oxidation of 7-benzylthio-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was performed using 0,339 g (a 1.96 mmole) 3-chloroperoxybenzoic acid in dichloromethane with stirring at room temperature for 1 h the Reaction was suppressed with 5 ml of 10%aqueous sodium sulfite, and the mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted with dichloromethane. The combined extracts were dried with magnesium sulfate and concentrated under vacuum to obtain 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she, which was used without purification.

38.3. Obtaining 3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Crude 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 2 ml of diglyme with 150 mg (1,31 mmole) of TRANS-4-aminocyclohexanol and stirred at 120° C for 4 h the Mixture was purified by chromatography on silica gel using as eluent 5-35% methanol/dichloromethane, receiving 52 mg (0,110 mmole) specified in the title compounds. The purified product was dissolved in ethyl acetate and treated with 1 EQ. HCl/Et2O deposition cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 39

Connection 3-30

This example shows how to obtain 3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

39.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Sulfide 8.1 in 5 ml of tetrahydrofuran was combined with that of 0.39 ml (to 3.92 mmole) of N,N-dimethylethanolamine, 1.04 g (to 3.92 mmole) of triphenylphosphine and 0.62 ml (to 3.92 mmole) DEAD and stirred at room temperature for 1 h the Mixture was subjected to polyoxide chromatography on silica gel using as eluent 1-3% methanol/dichloromethane, receiving >1 g of a mixture of 7-benzylthio-3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H it and the remaining triphenylphosphine.

39.2. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

The oxidation of sulfide was performed using 1.35 g (7,84 mmole) 3-chloroperoxybenzoic acid in dichloromethane with stirring at room temperature for 1 h the Reaction was suppressed 1 ml of saturated aqueous sodium sulfite and the mixture was extracted with dichloromethane. The organic extracts were washed with saturated aqueous sodium bicarbonate, dried with magnesium sulfate and concentrated under vacuum to obtain 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she, which was used without purification.

39.3. Obtaining 3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Crude 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 2 ml of diglyme with 331 mg (2,87 mmole) of TRANS-4-aminocyclohexanol and stirred at 120°C for 4 h the Mixture was purified by chromatography on silica gel using as eluent 10-30% methanol/dichloromethane, receiving 180 mg (0,405 mmole) specified in the title compounds. The purified product was dissolved in ethyl acetate and treated with 1 EQ. HCl/Et2O deposition cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he is.

Example 40

Connection 3-22

This example illustrates the obtaining (S)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

40.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In the suspension 850 mg (2,22 mmole) sulfide 8.1 in 10 ml of tetrahydrofuran was added 411 mg (2,22 mmole) of tert-butyl-4-hydroxy-1-piperidinecarboxylate and 878 mg (3.3 mmole) of diphenyl-2-pyridylamine. After 5 min was added 768 mg (3.33 mmole) of di-tert-utilization.bacteria and the reaction mixture was stirred at room temperature from Friday evening until Monday morning. The reaction mixture was injected directly into the column for rapid chromatography on silica, using as eluents hexane/ethyl acetate in ratios from 3:1 to 2:1 hexane/ethyl acetate in a ratio of 1:1, to obtain 930 mg of 7-benzylthio-3-(2-chlorophenyl)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

40.2. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To a solution of 920 mg (of 1.62 mmole) 7-benzylthio-3-(2-chlorophenyl)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in 16 ml of dichloromethane, cooled to 0°With added 403 mg (1,64 mmole) 3-harpers what Noynoy acid. After one hour exposure at room temperature was added 5 ml of 10%aqueous sodium thiosulfate. After 10 minutes the dichloromethane layer was separated and washed with 10%potassium carbonate and brine, dried over magnesium sulfate and concentrated under vacuum obtaining in the form of a white foam 650 mg of 3-(2-chlorophenyl)-7-benzylmethyl-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

40.3. Obtain (S)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In a suspension of 650 mg (1,136 mmole) 7-benzylmethyl-3-(2-chlorophenyl)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she in 0.5 ml of 1,2-dimethoxyethane was administered 250 mg (3.33 mmole) of (S)-(+)-2-amino-1-propanol. The reaction mixture was stirred at 100°in an argon atmosphere for 2 hours, the Reaction mixture was injected directly into the column for rapid chromatography on silica using as eluent dichloromethane/methanol in the ratio of 92:8 90:10, to obtain 300 mg of (S)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, which was again dissolved in 5 ml dichloromethane and 5 ml triperoxonane acid. After 5 h the solvent was removed under vacuum and added 5 ml of ethyl acetate and 5 ml of 10%aqueous sodium bicarbonate. The organic layer OTDELA and, washed with brine, dried over magnesium sulfate and concentrated under vacuum obtaining in the form of a white foam 130 mg specified in the title compound, which was dissolved in ethyl acetate and treated with 1 EQ. hydrochloric acid in the form of a 1.0 M solution in diethyl ether. The precipitate was collected, washed with diethyl ether and dried under vacuum to obtain 115 ml cleaners containing hydrochloride salt of (S)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-(piperidine-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 41

Connection 3-21

This example illustrates the receive (R)-3-(2-chlorophenyl)-7-[(2-hydroxy-1-methylethyl)amino]-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

41.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

A mixture of 600 mg (2.4 mmole) of sulfide 8.1, 619 mg (2.4 mmole) of diphenyl-2-pyridylamine and 232 mg (0.6 mmole) of 1,3-diethoxy-2-propanol under nitrogen atmosphere was dissolved in tetrahydrofuran. In this solution in one portion was added 542 mg (2.4 mmole) of di-tert-utilization.bacteria and the resulting mixture was stirred at room temperature for one day. Added 1 M hydrochloric acid in diethyl ether and after stirring the mixture for 1 h, evaporated the excess solvent. The residue was dissolved in diethyl ether and n the washed aqueous hydrochloric acid. The organic layer was dried over sodium sulfate, concentrated and the residue was purified by column chromatography on silica gel using as eluent 30%ethyl acetate in hexane. The column fractions containing product were combined and concentrated under vacuum to obtain 566 mg of 7-benzylthio-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

41.2. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Suspension 566 mg (1.1 mmole) of 7-benzylthio-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it is in 5 ml of dichloromethane was cooled in an ice bath was added 3-chloroperbenzoic acid. The reaction mixture was stirred for 1 h, concentrated under vacuum and the residue was purified by column chromatography on silica gel using dichloromethane/methanol in the ratio of 98:2. The column fractions containing product were combined and concentrated under vacuum to obtain 425 mg of 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

41.3. Obtaining (R)-3-(2-chlorophenyl)-7-[(2-hydroxy-1-methylethyl)amino]-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

25 mg (0.8 mmole) of 7-benzylmethyl-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it 1 ml of (R)-2-amino-1-propanol was kept at 140° C for 18 h, after which time the mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel using dichloromethane/methanol in the ratio of 98:2. The column fractions containing product were combined and concentrated under vacuum obtaining in the form of oil substances, which was re-dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried, highlighting 156 mg cleaners containing hydrochloride salt of (R)-3-(2-chlorophenyl)-7-(2-hydroxy-1-methylethylamine)-1-(2-ethoxy-1-ethoxymethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 42

Connection 3-60

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

42.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To 0,563 g (1,47 mmole) sulfide 8.1 in 3 ml of dry N,N-dimethylformamide at 0°With added 0.1 g (2.5 mmole) of 60%sodium hydride. After stirring the mixture at room temperature for 30 min was added 1 ml of 2,2,2-triftoratsetata and the mixture was stirred over night. In the reaction mixture were added ethyl acetate and the solution was washed with brine, dried over sodium sulfate, was filtered and evaporated. The obtained residue in the form of butter rubbed in hexano emitting 0.65 g of crude 7-benzylthio-3-(2-chlorophenyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she used directly in the next stage without purification.

42.2. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To 0,67 mg 7 benzylthio-3-(2-chlorophenyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in 7 ml of tetrahydrofuran at 0°C was added a solution of 2.27 g of Oxone product®in 7 ml of water. Next, the mixture was stirred at room temperature for one hour. Added additional 0.8 g of Oxone product® in 2 ml of water and the mixture was stirred for a further 1 h the Mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated to produce in the form of a white solid substance 0.65 g of crude 7-benzylmethyl-3-(2-chlorophenyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she used directly in the next stage without purification.

42.3. Obtaining 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

300 mg (0,604 mmole) 7-benzylmethyl-3-(2-chlorophenyl)-1-(2,2,2-trif oratel)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, 208 mg (3 EQ.) TRANS-4-aminocyclohexanol and 0.3 ml of 1-methyl-2-pyrrolidinone was kept with stirring at 110°C for 20 min, after which time the mixture was cooled to room temperature. The residue was purified using preparative thin-layer chromatography, using ethyl acetate as eluent, to obtain the as not quite white powder (155 mg of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2,2,2-triptorelin)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 43

Connection 3-32

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

43.1. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(ethoxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

2.0 g (5,22 mmole) sulfide 8.1 in 10 ml of N,N-dimethylformamide was combined with 230 mg (of 5.75 mmole) of sodium hydride and the reaction mixture was stirred for 20 min, then added to 1.16 ml (10,45 mmole) of ethylbromoacetate. After 3 h the reaction extinguished with water and was extracted with ethyl acetate.

The combined organic extracts were washed with water, dried, filtered, concentrated under vacuum and the residue was purified by column chromatography on silica gel using as eluent 30% acetone/hexane. Fractions of the column, with ergasia product, were combined and concentrated under vacuum to obtain 1,438 g 7 benzylthio-3-(2-chlorophenyl)-1-(ethoxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

43.2. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(hydroxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

The mixture 1,435 g (3,36 mmole) 7-benzylthio-3-(2-chlorophenyl)-1-(ethoxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and 481 mg (11.5 mmole) of the monohydrate of lithium hydroxide in 10 ml of methanol and 30 ml of water was boiled under reflux for 48 hours the Reaction mixture was cooled to room temperature and was diluted with ethyl acetate/water. The pH value of the aqueous layer was brought to 4 and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated under vacuum to obtain 1.2 g of 7-benzylthio-3-(2-chlorophenyl)-1-(hydroxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

43.3. Getting 7 benzylthio-3-(2-chlorophenyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Through a solution of 500 mg (1,13 mmole) 7-benzylthio-3-(2-chlorophenyl)-1-(hydroxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and 885 mg (1,70 mmole) of hexaflurophosphate benzotriazol-1-yloxytris(pyrrolidino)phosphonium in 15 ml of N,N-dimethylformamide for two minutes was barbotirovany gas is brassy dimethylamine, then the mixture was stirred in a sealed tube for 2 h the Reaction mixture extinguished with water and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, dried, filtered, concentrated under vacuum and the residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 36:1. The column fractions containing product were combined and concentrated under vacuum to obtain 490 mg of 7-benzylthio-3-(2-chlorophenyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

43.4. Getting 7-benzylmethyl-3-(2-chlorophenyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To a solution of 490 mg (1,13 mmole) 7-benzylthio-3-(2-chlorophenyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in chloroform was administered 780 mg (to 4.52 mmole) of 3-chloroperbenzoic acid. The mixture was stirred for 2 h, then washed with 10%solution of sodium sulfite in water and aqueous sodium bicarbonate solution, dried, filtered and concentrated to obtain 550 mg of 7-benzylmethyl-3-(2-chlorophenyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

43.5. Obtaining 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihyd is pyrimido[4,5-d]pyrimidine-2(1H)-it

550 mg (1.1 mmole) of 7-benzylmethyl-3-(2-chlorophenyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she United with 253 mg (2.2 mmole) of TRANS-4-aminocyclohexanol. The mixture was stirred at 100-105°C for 3 h, after which it was cooled to room temperature. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio 9:1. The column fractions containing product were combined and concentrated under vacuum to a solid residue, which was ground into powder with methanol, was filtered, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 90 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(dimethylaminocarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 44

Connection 4-1

This example shows how to obtain 3-(2-chlorophenyl)-7-(2-hydroxy-1-hydroxymethyl-1-methylethylamine)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,500 g (1,21 mmole) sulfone 9.1 combined with 0,253 g (2,41 mmole) of 2-amino-2-methyl-1,3-propane diol. The mixture was stirred at 120-130°C for 2 h, after which it was cooled to the room for the Noah temperature. The residue was ground into powder in dichloromethane/methanol. The suspension was filtered to obtain the free amine specified in the title compound, which is then suspended in methanol. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt, which was dissolved in methanol. The solution was filtered and the filtrate was concentrated under vacuum to obtain hygroscopic solid, which was ground into powder in diethyl ether, was filtered and was dried with the receipt of € 0.195 g of 3-(2-chlorophenyl)-7-(2-hydroxy-1-hydroxymethyl-1-methylethylamine)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 45

Connection 4-6

This example shows how to obtain 3-(2-chlorophenyl)-7-((R,R)-2-hydroxy-1-hydroxymethylpropane)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

776 mg (1.9 mmole) sulfone 9.1 combined with 238 mg (2.3 mmole) of (R,R)-3-amino-1,2-butanediol and 5 ml of 2-methoxyethanol ether. The mixture was stirred at 120°C for 3 h, after which it was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 97:3. The column fractions containing product were combined and concentrated under vacuum obtaining in the form of oil substances to the e was re-dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 159 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-((R,R)-2-hydroxy-1-hydroxymethylpropane)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 46

Connection 4-8

This example shows how to obtain 3-(2-chlorophenyl)-7-[(4-hydroxycyclohexyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,500 g (1,21 mmole) sulfone 9.1 combined with a racemic mixture 0,70 g of 4-aminocyclohexanol [6.0 mmole, obtained by lyophilization of a 50%aqueous solution (ICN)] in 2 ml of N-methylpyrrolidinone. The mixture was stirred at 120°C for 1.5 h, after this time it was cooled to room temperature. The residue was purified by column chromatography on silica gel using as eluent 1-5% methanol/dichloromethane. The column fractions containing product were combined and concentrated under vacuum obtaining in the form of yellow granules specified in the title compound, which was re-dissolved in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried to obtain 0,258 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(4-hydroxycyclohexyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 47

With the unity 2-10

This example shows how to obtain 3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Getting 4-aminotetrahydrofuran

4,19 g (59,9 mmole) of hydroxylaminopurine at room temperature was dispersible in 13 ml of ethanol and the resulting suspension was washed with additional 15 ml of ethanol solution of 5 g (49,9 mmole) tetrahydrofuran-4-she's in 30 ml of pyridine. The reaction mixture was stirred at room temperature overnight, then evaporated under vacuum prior to the formation of thick syrup on the pyridine base, which was poured into saturated aqueous copper sulfate and extracted with ethyl acetate. The combined extracts were dried with sodium sulfate, evaporated under vacuum and suirable with ethyl acetate. The filtrate is evaporated under vacuum obtaining in the form of a greenish solid substance of 5.05 g (of 0.44 mmole) tetrahydropyran-4-noxema.

Part tetrahydropyran-4-noxema (2.8 g, a 24.3 mmole) was dissolved in 50 ml of tetrahydrofuran and cooled to 0°C, followed by slow addition of portions of 4.6 g (122 mmole) of lithium aluminum hydride. When the addition was completed, the reaction mixture with ice-bath was removed and stirred while boiling under reflux overnight, and then the reaction was suppressed by careful addition of water and 10%aqueous hydroxide n is sodium. The reaction mixture was stirred at room temperature for 1 h, after which the aluminum salts were filtered off and washed with dichloromethane. The filtrate is evaporated under vacuum obtaining in the form of a dark brown liquid of 1.74 g (0,17 mmole) 4-aminotetrahydrofuran.

Obtaining 3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

0,205 g (0,494 mmole) sulfone 9.1 in 5 ml of 1-methyl-2-pyrrolidinone combined with 0,100 g (0,988 mmole) 4-aminotetrahydrofuran. The reaction mixture was stirred at 100°C for 24 h and purified by column chromatography on silica gel using as eluent 3-7% methanol/dichloromethane. The column fractions containing product were combined and concentrated under vacuum obtaining in the form of a brown resin specified in the title compound, which was re-dissolved in methanol. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) received was 0.026 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 48

Connection 4-14

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-hydroxymethylglutaryl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

500 mg (1.2 mmole) sulfone 9.1 combined with 550 mg (4.8 mmole) of 1-amino-1-cyclopentanemethanol and 1 ml methyl-2-pyrrolidinone. The mixture was stirred at 120°C for 3 h, after which it was cooled to room temperature. Was added 3 ml of methanol and the suspension was stirred for 10 min, filtered and the residue was washed with methanol, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried emitting 260 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-hydroxymethylglutaryl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 49

Connection 4-16

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-hydroxymethylcellulose)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

500 mg (1.2 mmole) sulfone 9.1 combined with 623 mg (4.8 mmole) of 1-amino-1-cyclohexanemethanol [obtained as described in J.Med.Chem., 1966, 9(6) 911-920] and 1 ml of 1-methyl-2-pyrrolidinone. The mixture was stirred at 120°C for 3 h, after which it was cooled to room temperature. Was added 3 ml of methanol, the suspension was stirred for 10 min and filtered. The precipitate was thoroughly washed with methanol, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 328 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-hydroxamate the cyclohexyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 50

Connection 2-25

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-methylpiperidin-4-yl)methylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,512 g (1.2 mmole) sulfone 9.1 was combined with 2 ml of 1-methyl-4-(methylamino)piperidine (company Aldrich Chemicals) in 0.3 ml of 1-methyl-2-pyrrolidinone. The mixture was stirred at 100°C for 3 h, after which it was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel using as eluent 2 to 10% methanol in dichloromethane and finally 1% triethylamine/10% methanol in dichloromethane. The obtained solid particles suspended in 5 ml of methanol, through the suspension for 30 s was barbotirovany hydrogen chloride and evaporated solvents. Then the solids were stirred in ethyl acetate and was filtered to obtain 190 mg dichloride salt of 3-(2-chlorophenyl)-7-[(1-methylpiperidin-4-yl)methylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 51

Connection 4-18

This example shows how to obtain 3-(2-chlorophenyl)-7-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,81 g (1,95 mmole) sulfone 9.1 United is 0.45 g (3.9 mmole) of CIS-4-aminocyclohexanol (obtained as described in Aust.J.Chem., 1961, 14, 610) in 2.0 ml of 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 120°C for 24 h, after which the reaction mixture was cooled to room temperature and filtered. The filtrate is suspended in anhydrous methanol, the precipitate was collected and dried to obtain a white solid 0.400 g specified in the title compounds (with tPL263,7-264,6°). This white solid was dissolved in chloroform/methanol in a ratio of 10:1 was added 1 M hydrochloric acid in diethyl ether. The reaction mixture was stirred for 1 h, concentrated and dried under vacuum, and the residue was led from methanol/diethyl ether to obtain a white solid 0,285 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(CIS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 52

Connection 2-26

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-carbarnoyl-methylpiperidin-4-yl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

1.0 g (2,41 mmole) sulfone 9.1 was dissolved in 5 ml (29 mmol) of ethyl-4-amino-1-piperidinecarboxylate and stirred at 150°C. after 1 h the reaction suspension was cooled to room temperature, poured into 50 ml of methanol and filtered, collecting white solid. This solid was washed updat the additional 50 ml of methanol and dried under vacuum to obtain 0,569 g 3-(2-chlorophenyl)-7-(1-ethoxycarbonylpyrimidine-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

3-(2-Chlorophenyl)-7-(1-ethoxycarbonylpyrimidine-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 2 ml of dichloromethane from 0.94 ml (6,60 mmole) of attributively and kept at 60°C for 2 h, the reaction was suppressed by methanol and the mixture is evaporated under vacuum. The dry residue was again dissolved in minimum amount of methanol was treated with sodium methoxide (0.5 EQ., technical 0.5 M methanol solution) and re-evaporated. The residue was purified Express chromatography using as eluent 5-10% (ammonium hydroxide/methanol in the ratio 1:9)/dichloromethane. The column fractions containing product were combined and concentrated under vacuum to obtain 0,280 g (7,80 mmole) split piperidino intermediate product, 3-(2-chlorophenyl)-7-(piperidine-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,050 g (0,139 mmole) of 3-(2-chlorophenyl)-7-(piperidine-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 1 ml N,N-dimethylformamide with 0,029 g (0,209 mmole) of bromoacetamide and stirred at room temperature for 2.5 h, then the temperature was raised to 40°and was kept for one hour, then kept overnight at 80°C. the Reaction mixture was purified Express-chromatography using as eluent 5-40% methanol/dichloromethane+1% ammonium hydroxide. Faction Colo is key, containing the product were combined and concentrated under vacuum and the final product was re-dissolved in minimum volume of methanol. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried to obtain 0,007 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-carbamoylmethyl-4-yl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 53

Connection 2-27

This example shows how to obtain 3-(2-chlorophenyl)-7-[1-(2,2,2-triptorelin)piperidine-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Obtaining 1-(2,2,2-triptorelin)piperidine-4-ylamine

5 g (24,96 mmole) of tert-butyl methyl ether piperidine-4-ylcarbamate acid (technically available on the company ASTATECH), 7.03 is g (1 EQ.) 2,2,2-triftoratsetilatsetonom and 4.1 g (1.2 EQ.) potassium carbonate was dissolved in 80 ml of acetone and boiled under reflux with stirring for 17 hours Under reduced pressure at 40°solvent was removed and to the residue was added ethyl acetate and water. The layers were separated, and then allocated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to obtain on dark colored solid. In the purification by chromatography on silica gel using as eluent 15 ethyl acetate hexano as not quite white powder was obtained of 4.45 g of tert-butyl methyl ether [1-(2,2,2-triptorelin)piperidine-4-yl]carbamino acid with t PL99,2-99,8°C (M+N)+=283.

tert-Butyl ether [1-(2,2,2-triptorelin)piperidine-4-yl]carbamino acid was dissolved in 80 ml of dioxane and through the solution for 10 min was barbotirovany gaseous hydrogen chloride. The reaction vessel was tightly closed and the contents were stirred for 1.5 hours Under reduced pressure at 40°solvent was removed. The residue was dissolved in 42 ml of 0.5 M sodium methoxide in methanol was stirred for 3 h at room temperature and was filtered. The filtrate was concentrated, dissolved in ethyl acetate, filtered and concentrated to produce in the form of a dark oil 1.0 g of 1-(2,2,2-triptorelin)piperidine-4-ylamine, (M+N)+=183.

Obtaining 3-(2-chlorophenyl)-7-[1-(2,2,2-triptorelin)piperidine-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

200 mg (0,482 mmole) sulfone 9.1 and 263 mg (3 EQ.) 1-(2,2,2-triptorelin)piperidine-4-ylamine was combined with 0.3 ml of 1-methyl-2-pyrrolidinone and the reaction mixture with stirring and kept at 110°C for 2 h, after which it was cooled to room temperature. In the purification using preparative thin layer chromatography using as eluent 60% ethyl acetate in hexano as not quite white powder was obtained 12 mg of 3-(2-chlorophenyl)-7-[1-(2,2,2-triptorelin)piperidine-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(H)-she.

Example 54

Connection 4-17

This example shows how to obtain 3-(2-chlorophenyl)-7-[(4-hydroxycyclohexyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

400 mg (0.96 mmole) sulfone 9.1 combined with 470 mg (3.6 mmole) 4-aminomethylphenol and 0.4 ml of 1-methyl-2-pyrrolidinone. The mixture was stirred at 120°C for 3 h, after which it was cooled to room temperature. Was added 3 ml of methanol, the suspension was stirred for 10 min, the precipitate was filtered washed with methanol, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 198 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(4-hydroxycyclohexyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 55

Connection 2-21

This example shows how to obtain 3-(2-chlorophenyl)-7-[1-(2,2,2-triptorelin)piperidine-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Getting 4-aminomethyl-N-(2,2,2-triptorelin)piperidine

A mixture of 4 g (16,1 mmole) (4-benzyloxycarbonylamino)of piperidine, to 5.58 g (20 mmol) of 2,2,2-triftoratsetilatsetonom and 2.67 g (19 mmol) of potassium carbonate in 40 ml of acetone was heated under reflux for 17 hours the Mixture is evaporated and the processing is tivali with ethyl acetate and brine. The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. Solids crude product was purified by column chromatography on silica gel using as eluent 10-20% ethyl acetate in hexano to obtain 2.25 g of 4-benzoyloxymethyl-1-(2,2,2-triptorelin)piperidine, tPL93,8-95,1°C. 4-Benzoyloxymethyl-1-(2,2,2-triptorelin)piperidine was dissolved in 50 ml of ethanol and was first made in a period of 10 hours over 0.5 g of 10%palladium on coal. The mixture was filtered through a layer of brownmillerite and washed with methanol. The filtrate is evaporated to produce in the form of semi-solid substances of 1.17 g of 4-aminomethyl-1-(2,2,2-triptorelin)piperidine.

Obtaining 3-(2-chlorophenyl)-7-[1-(2,2,2-triptorelin)piperidine-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0,389 g (1 mmol) of sulfone 9.1 combined with 0.50 g (2.5 mmole) 4-aminomethyl-1-(2,2,2-triptorelin)piperidine (0.4 ml of 1-methyl-2-pyrrolidinone and kept at 100°C for 4 h the mixture was cooled to room temperature and treated with methanol, ethyl acetate and diethyl ether. The resulting solids were filtered and washed with ethyl acetate. 0,22 g of the obtained solids were dissolved in 5 ml of methanol and within one minute after the solution was barbotirovany hydrogen chloride. Remove the solvents and the residue was ground into powder with 2 ml of methanol and 0 ml of diethyl ether to obtain 210 mg dihydrochloride salt of 3-(2-chlorophenyl)-7-[1-(2,2,2-triptorelin)piperidine-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 56

Connection 2-22

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-cyanomethylene-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

2.24 g (5.4 mmole) sulfone 9.1 combined with 5.6 g (16.2 mmole) of N-tert-butoxycarbonyl-4-aminomethylpyridine and 9 ml of 1-methyl-2-pyrrolidine. The mixture was stirred at 100-110°C for 2 h, after which it was cooled to room temperature and was added ethyl acetate. The resulting white solid was filtered and washed with ethyl acetate to obtain 2.3 g of 3-(2-chlorophenyl)-7-[(1-tert-butoxycarbonylamino-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (MH+=473). Through 2.1 g protected amine, which is suspended in 22 ml of 1,4-dioxane was barbotirovany gaseous hydrogen chloride and the suspension was stirred for 1 h, concentrated under vacuum and dried to produce in the form of a white solid intermediate 3-(2-chlorophenyl)-7-[(piperidine-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

to 0.23 g (0,52 mmole) of 3-(2-chlorophenyl)-7-[(piperidine-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 8 ml of N,N-dimethylformamide. Added 0,175 g (1.6 mmole) of anhydrous sodium carbonate and 0.036 ml (0.57 mmole) of chloroacetonitrile. The mixture was stirred at room temperature for 17 h and RA is delali between ethyl acetate and water. The layers were separated the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under vacuum, and the residue was purified by chromatography on silica gel using as eluent 10% methanol/dichloromethane. Fractions containing the product were concentrated under vacuum and dissolved in 40 ml of 1,4-dioxane. After the solution was barbotirovany gaseous hydrogen chloride and the mixture was concentrated under vacuum. The resulting residue was ground into powder in diethyl ether and was dried to obtain 0,107 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-cyanomethylene-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 57

Connection 2-19

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-dimethylaminocarbonylmethyl-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0.3 g (0.67 mmole) of 3-(2-chlorophenyl)-7-[(piperidine-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 56) was dissolved in 7 ml of N,N-dimethylformamide. Added 0.26 g (2.4 mmole) of anhydrous sodium carbonate and 0,098 g (0,81 mmole) of 2-chloro-N,N-dimethylacetamide. The mixture was stirred at room temperature for 17 hours, the Reaction mixture was separated between ethyl acetate and water. The layers were separated the aqueous layer was extracted with ethyl acetate and 10 isopropanol/chloroform. The organic layers were washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate. Obtained after evaporation under vacuum, a white solid was dissolved in 50% methanol/1,2-dichloroethane. After the solution was barbotirovany gaseous hydrogen chloride and the solution evaporated under vacuum. The resulting residue was ground into powder in diethyl ether, was filtered and was dried with the receipt of 0.182 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-dimethylaminocarbonylmethyl-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 58

Connection 2-23

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-aminocarbonylmethyl-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0.3 g (0.67 mmole) of 3-(2-chlorophenyl)-7-[(piperidine-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 56) was dissolved in 7 ml of N,N-dimethylformamide. Added 0.26 g (2.4 mmole) of anhydrous sodium carbonate and 0,111 g (0,81 mmole) of 2-bromoacetamide. The mixture was stirred at room temperature for 17 hours, the Reaction mixture was separated between ethyl acetate and water. The layers were separated the aqueous layer was extracted with ethyl acetate and 10% isopropanol/chloroform. The combined organic layers were washed with a saturated solution of chloride n is sodium, and then was dried over anhydrous sodium sulfate. Obtained after evaporation under vacuum, a white solid is suspended in 1,4-dioxane. After the suspension was barbotirovany gaseous hydrogen chloride and the solution evaporated under vacuum. The resulting residue was ground into powder in diethyl ether, filtered and dried to obtain 0,185 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-aminocarbonylmethyl-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 59

Connection 2-24

This example shows how to obtain 3-(2-chlorophenyl)-7-[(1-hydroxycarbonylmethyl-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

0.3 g (0.67 mmole) of 3-(2-chlorophenyl)-7-[(piperidine-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(lH)-she received outlined in example 56) was dissolved in 7 ml of N,N-dimethylformamide. Added 0.26 g (2.4 mmole) of anhydrous sodium carbonate and 0.12 ml (0,81 mmole) of tert-butyl 2-bromoacetate. The mixture was stirred at room temperature for 17 hours, the Reaction mixture was separated between ethyl acetate and water. The layers were separated the aqueous layer was extracted with ethyl acetate and 10% isopropanol/chloroform. The combined organic layers were washed with a saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate. Received poliyarnaya under vacuum combined white solid particles suspended in 1,4-dioxane. After the suspension was barbotirovany gaseous hydrogen chloride, the solution was stirred for 10 h at room temperature and evaporated under vacuum. The resulting residue was ground into powder in diethyl ether, was filtered and was dried with the receipt of € 0.195 g cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[(1-hydroxycarbonylmethyl-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 60

Connection 3-29

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-methylthioethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

500 mg (1,21 mmole) sulfone 9.1 was dissolved in 2 ml of tetrahydrofuran with 0.16 ml (1,81 mmole) 1-(2-methylthio)ethanol, 474 mg (1,81 mmole) of triphenylphosphine and 0.28 ml (1,81 mmole) DEAD and stirred at room temperature for 2 days. By evaporation under vacuum was obtained the crude product, 3-(2-chlorophenyl)-7-benzylmethyl-1-(2-methylthioethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he, which was used without further purification.

Crude 3-(2-chlorophenyl)-7-benzylmethyl-1-(2-methylthioethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 2 ml of diglyme with 139 mg (1,21 mmole) of TRANS-4-aminocyclohexanol and stirred at 120°C for 4 h the Mixture was purified by chromatography on silica gel using as eluent 2,5-4,5% methane is a/dichloromethane, getting 226 mg (0,511 mmole) specified in the title compounds. The purified product was dissolved in ethyl acetate and treated with 1 EQ. HCl/Et2O deposition cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-methylthioethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 61

Connection 3-31

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(3-dimethylamino-2,2-dimethylpropyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

500 mg (1,21 mmole) sulfone 9.1 was dissolved in 2 ml of tetrahydrofuran from 0.28 ml (1,81 mmole) of 3-dimethylamino-2,2-dimethyl-1-propanol, 474 mg (1,81 mmole) of triphenylphosphine and 0.28 ml (1,81 mmole) DEAD and stirred at room temperature overnight. The mixture was subjected to polyoxide chromatography on silica gel using as eluent 3-15% methanol/dichloromethane, receiving >1 g of a mixture of 3-(2-chlorophenyl)-7-benzylmethyl-1-(3-dimethylamino-2,2-dimethylpropyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and the rest of triphenylphosphine.

3-(2-Chlorophenyl)-7-benzylmethyl-1-(3-dimethylamino-2,2-dimethylpropyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 3 ml of diglyme with 139 mg (1,21 mmole) of TRANS-4-aminocyclohexanol and stirred at 120°C for 4 h the Mixture was purified by chromatography on silica gel using a UV is as eluent 4-25% methanol/dichloromethane, receiving 52 mg (0,107 mmole) specified in the title compounds. The purified product was dissolved in ethyl acetate and treated with 1 EQ. HCl/Et2O deposition cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(3-dimethylamino-2,2-dimethylpropyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 62

Connection 3-36

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(1-methylpiperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A mixture of 1.0 g (2.4 mmole) sulfone 9.1, 1.9 grams (7.23 percent mmole) of diphenyl-2-pyridylamine and 0,555 g (4.8 mmole) of 4-hydroxy-1-methylpiperidine in nitrogen atmosphere was dissolved in anhydrous tetrahydrofuran. To this solution was added to 1.67 g (7.23 percent mmole) of di-tert-utilization.bacteria and the resulting mixture was stirred at room temperature for 2 h, and then concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio 9:1. The column fractions containing product were combined and concentrated under vacuum to obtain 354 mg of 7-benzylmethyl-3-(2-chlorophenyl)-1-(1-methylpiperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

354 mg (0,69 mmole) 7-benzylmethyl-3-(2-chlorophenyl)-1-(1-methylpiperidin-4-yl)-3,4-dihydropyrimido[4,5-d]PI is kidin-2(1H)-she United with 160 mg (1,38 mmole) of TRANS-4-aminocyclohexanol and 1 ml of 1-methyl-2-pyrrolidinone. The mixture was stirred at 110°C for 1 h, after which it was cooled to room temperature. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol/Diisopropylamine in the ratio of 9:1:0.5 in. The column fractions containing product were combined, concentrated under vacuum and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt which was filtered and dried emitting 135 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(1-methylpiperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 63

Connection 4-4

This example illustrates the receive (R,R)-7-(2,3-dihydroxy-1-methylpropylamine)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Receive (R,R)-3-aminobutane-1,2-diol

3 Aminobutane-1,2-diol was obtained similarly described in Tetrahedron: Asymmetry, 1995, 6(9), 2329-2342. Briefly, a solution of 10.0 g (42,2 mmole) of (2S,3S)-TRANS-3-methyloxiran-2-methyl-4-nitrobenzoate (firm Fluka) in 150 ml of dichloromethane in an argon atmosphere was combined with 25 ml (84,3 mmole) of isopropoxide titanium and was stirred for 10 min at room temperature. Added to 14.5 ml (84,4 mmole) aminodiphenylamine and the reaction mixture was stirred at room temperature in those who tell the night. Solution was added 10% sodium hydroxide in a saturated brine, and the suspension was stirred for 2 h the Mixture was filtered and was extracted with 0.2 M hydrochloric acid. The acid layers were extracted with dichloromethane and the extract was discarded. The acid layer was podslushivaet granulated sodium hydroxide to pH 9, and then was extracted with dichloromethane. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated under vacuum obtaining in the form of oil substance, which was purified in a column for the Express chromatography using as eluents of hexanol/ethyl acetate in ratios from 2:1 to 1:1 ethyl acetate/hexane in the ratio 2:1, obtaining 2.6 g (R,R)-3-(benzhydrylamine)butane-1,2-diol.

In degassed solution of 2.6 g (9,59 mmole) of (R,R)-3-(benzhydrylamine)butane-1,2-diol in 20 ml of methanol was injected 260 mg of palladium hydroxide on coal. Over the reactionary environment created depression and three times was introduced hydrogen, after which he entered a hydrogen pressure of 50 psi and hydrogenator was shaken at room temperature overnight. The reaction mixture was filtered and concentrated to produce in the form of oil 922 mg (R,R)-3-aminobutane-1,2-diol, which was washed with hexane and then dried under vacuum.

Receive (R,R)-7-(2,3-dihydroxy-1-methylpropylamine)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

622 the g (1,58 mmole) sulfone 9.2 combined with 250 mg (1.9 mmole) of (R,R)-3-aminobutane-1,2-diol in 1 ml of 1,2-dimethoxyethane and in an argon atmosphere maintained at 100° C for 2 h, the Reaction mixture was cooled to room temperature, diluted with dichloromethane/methanol in the ratio 9:1 and injected directly into the column with silica to Express chromatography using as eluent dichloromethane/methanol in the ratio of 96:4 and dichloromethane/methanol in the ratio 9:1, receiving in the form of a colorless oil 120 mg of the substance, which was dissolved in 10 ml of ethyl acetate and treated with 1 EQ. 1.0 M hydrochloric acid in diethyl ether. The precipitate was collected by filtration under vacuum, washed with ethyl acetate and dried under vacuum obtaining in the form of a white solid substance 118 mg (R,R)-7-(2,3-dihydroxy-1-methylpropylamine)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 64

3-(2-Chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he

64.1. Getting 5-(2-chlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine

A mixture of 9.5 g (56,1 mmole) of 4-amino-2-methylthiopyrimidin-5-carboxaldehyde, of 6.7 ml (63.7 mmole) of 2-Chloroaniline and 0,85 g (4.5 mmole) of the monohydrate of 4-toluenesulfonic acid in 350 ml of xylene kept at the boiling temperature with azeotropic removal of water for 6 hours the Mixture was cooled to 25°and the precipitate was collected by filtration under vacuum, washed with hexane and dried in the air. Then this solid venturesomely in 300 ml of tetrahydrofuran and the reaction mixture was cooled to 0° C. in Small portions over 45 minutes was added 2.3 g (to 60.6 mmole) of lithium aluminum hydride. After the addition was completed, the mixture was stirred for another 15 min and gently sequentially treated with 4.5 ml of water and 4.5 ml of 15%aqueous sodium hydroxide and then with 20 ml of water. The mixture was stirred for 30 minutes, filtered through brownmillerite and the filtrate was concentrated under vacuum. The solid was purified by column chromatography on silica gel using 25% acetone/hexanol. The column fractions containing product were concentrated under reduced pressure to a solid, which was recrystallized from ethyl acetate to obtain a white solid of 7.0 g of 5-(2-chlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine.

64.2. Obtaining 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In the mixed solution was cooled to 0°S, 7.0 g (24,9 mmole) 5-(2-chlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine in 200 ml of tetrahydrofuran was added 10 ml (71.7 mmole) of triethylamine. Then this solution was treated by the addition dropwise of a solution of 14.2 ml of phosgene (20%solution in toluene; to 27.2 mmole). After stirring for 2 h was added addition of 5.0 ml (35,9 mmole) of triethylamine, and then 6.5 ml of phosgene (20%solution in toluene, 12.5 mmole). After paramashiva the Oia for a further 2 h was added an additional 2 ml (14.3 mmole) of triethylamine, and then 3 ml of phosgene (20%solution in toluene, 5.8 mmole). The reaction mixture was stirred for one additional hour, and then heated to room temperature, poured in a heterogeneous solution of 75 ml of water and 150 ml ethyl acetate. Next, the mixture was filtered and the phases were separated. The aqueous phase and was twice re-extracted with 150 ml of ethyl acetate. United an ethyl acetate extracts were concentrated under reduced pressure. The residue was stirred with ethyl acetate. Then the product was collected by filtration under vacuum and dried under vacuum obtaining in the form of a white solid 3.2 g of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 65

Another method to obtain 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

65.1. Getting ethyl-4-amino-2-methylthiopyrimidine-5-carboxylate

The solution 1450 (6,23 mole) ethyl-4-chloro-2-methylthiopyrimidine-5-carboxylate (company Aldrich Chemical Co., Milwaukee, steveascension, USA) 2987 ml of tetrahydrofuran was cooled to 5-10°and was treated by slow addition 2407 ml of 37%aqueous solution of ammonium hydroxide in 2978 ml of triethylamine. After stirring for 16 h the reaction mixture was concentrated under vacuum to about 5 liters and filtered. The filter cake was washed with hexane and dried in a vacuum drying Cabinet is ri 60-65° C. the Filtrate is evaporated under reduced pressure obtaining in the form of a white solid 1314 g (yield 94%) of ethyl-4-amino-2-methylthiopyrimidine-5-carboxylate, tPLto 130.1-130,7°C.

65.2. Getting ethyl-4-{[(2-chlorophenyl)amino]carbylamine}-2-methylthiopyrimidine-5-carboxylate

In the suspension 1215 (5,7 mole) ethyl-4-amino-2-methylthiopyrimidine-5-carboxylate in 2600 ml of xylene, heated to 100-105°, 965,5 g (6,23 mole) 2-chlorophenylalanine was introduced in such a way as to maintain the temperature ˜100°C. the Temperature of the reaction mixture was raised to 120°and it was stirred for 14 hours, the Heating was stopped and started slow cooling to 110°C. When started crystallization, by slow addition 5256 ml ethyl acetate crystallization was completed. The mixture was cooled to 20°and filtered. The filter cake was washed with ethyl acetate, was placed in a vacuum drying oven and dried for 10-12 hours at a temperature of from 60 to 80°obtaining 1895 (output 90.7 percent) ethyl-4-{[(2-chlorophenyl)amino]carbylamine}-2-methylthiopyrimidine-5-carboxylate, tPL172,3-172,6°C.

65.3. Getting [(2-chlorophenyl)amino]-N-[5-(hydroxymethyl)-2-methylthiopyrimidin-4-yl]carboxamide

Stir in suspension 1000 g (2,73 mole) ethyl-4-{[(2-chlorophenyl)amino]carbylamine}-2-methylthio rimidine-5-carboxylate 4.7 l of anhydrous tetrahydrofuran at -25° C in nitrogen atmosphere for 3-hour period was introduced 2730 ml (3,19 mole) of 1 M solution of lithium aluminum hydride in tetrahydrofuran. The resulting yellow homogeneous solution was kept at -25°C for another 45 min, then it was allowed to warm up over the next 90 min to 0°C. Data HPLC analysis indicated the absence of starting ether complex. Then, the solution was rapidly cooled in an 8.0 litre mix 1.0 M solution of Rochelle salt and extracted with ethyl acetate. The combined extracts containing suspended insoluble yellow product was concentrated and filtered. The yellow solid was washed with hexane, and then dried under vacuum at 60°obtaining in the form of yellow crystals 617 g (yield of 69.3%) [(2-chlorophenyl)amino]-N-[5-(hydroxymethyl)-2-methylthiopyrimidin-4-yl]carboxamide, tPL182,5-182,9°C. This experiment was repeated using 1168 g of educt, having 717,8 g specified in the title compound.

65.4. Getting [(2-chlorophenyl)amino]-N-[5-(methyl bromide)-2-methylthiopyrimidin-4-yl]carboxamide

1363 [(2-chlorophenyl)amino]-N-[5-(hydroxymethyl)-2-methylthiopyrimidin-4-yl]carboxamide was mixed with 8 l of tetrahydrofuran in a nitrogen atmosphere began mechanical stirring. Then the mixture for 15 min was added 135 ml of tribromide phosphorus in 800 ml of tetr is hydrofuran. Stirring was continued for 4 h after which the reaction was stopped and the mixture was filtered. The filter cake was washed once with tetrahydrofuran and dried overnight in a vacuum oven at 55°obtaining 1360 g (71%yield) of [(2-chlorophenyl)amino]-N-[5-(methyl bromide)-2-methylthiopyrimidin-4-yl]carboxamide (M+1377).

65.5. Obtaining 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In the suspension 1360 g (3,62 mole) of [(2-chlorophenyl)amino]-N-[5-(methyl bromide)-2-methylthiopyrimidin-4-yl]carboxamide in 10 l of 1-methyl-2-pyrrolidinone was administered to 136 ml hexamethyldisilazane. The mixture was stirred at a temperature in the mass of 105-115°for 1.5 hours the mixture was cooled to 30°and treated With 20 l of water. Then the mixture was stirred at 5-8°C for 2 h and filtered. Product filtration was collected and washed successively with water and hexane. The product was placed in a drying Cabinet and under vacuum was kept at elevated temperature for 16 h to produce in the form of not quite white solids 780 g (yield 70,1%) of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (M+1308).

Using the above mentioned stage 65,2 ortho-trilinoleate instead of 2-chlorophenylalanine received related compound, 7-methylthio-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrim the DIN-2(1H)-he.

Example 66

3-(2-Chlorophenyl)-7-methylsulphonyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he

A suspension of 4.1 g (12.8 mmole) of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in 50 ml of chloroform was cooled in ice and treated with 70%3-chloroperbenzoic acid (9.8 g, of 39.8 mmole). The mixture was stirred at room temperature for 2 h, then was twice treated with 100 ml of 10%aqueous sodium thiosulfate and left to mix for 30 minutes the Reaction mixture was diluted with 400 ml of dichloromethane and the phases were separated. The organic phase is washed with saturated aqueous sodium bicarbonate, and then dried over magnesium sulfate and filtered. In the result, concentration of the filtrate under reduced pressure was obtained a solid which was stirred with ethyl acetate, and then filtered, highlighting in the form of a white solid 2.6 g of 3-(2-chlorophenyl)-7-methylsulphonyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (sulfon 11.1) (MH+=364).

Example 67

Connection 4-19

This example shows how to obtain 3-(2-chlorophenyl)-7-(4-hydroxymethylglycinate)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

350 mg (1.04 million mmole) sulfone 11.1 combined with 400 mg (3.3 mmole) of 4-aminocyclohexanol (CIS-/TRANS - sootnoshenie is 1:1) (obtained as described in Chem.Ber.; GE; 96; 1963; 2377-2386) with 0.3 ml of 1-methyl-2-pyrrolidinone. The mixture was stirred at 100° within 2 h after which it was cooled to room temperature. The reaction mixture was put into water and was extracted with ethyl acetate, washed with water, dried and concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent methanol/dichloromethane in the ratio 10:90. The column fractions containing product were concentrated to substances in the form of foam, which is suspended in methanol. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt, which was filtered to obtain cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(4-hydroxymethylglycinate)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 68

Connection 2-28

This example shows how to obtain 3-(2-chlorophenyl)-7-(1-ethoxycarbonylpyrimidine-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

1.3 g of (3.75 mmole) sulfone 11.1 was dissolved in 3.7 ml (21 mmol) of ethyl-4-amino-1-piperidinecarboxylate and heated to a temperature of 120°in which the original suspension were completely dissolved, and after 10 min again fell residue with formation of a suspension. This secondary suspension was kept at 150°C for 1 h, then cooled to room temperature and poured the water of obtaining a resinous mass. When this resinous mass was mixed with 50 ml of diethyl ether, a small amount of white solid, which was removed to the side. The remaining resinous mass was treated for 10-15 min with methanol to obtain white solids. The total combined weight of the white solid substance was 0,685 g (1.59 mmole), of which 30 mg had, as expected, the proportion of free base.

Example 69

Connection 4-25

This example shows how to obtain 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

196 mg (0,579 mmole) sulfone 11.1 and 0.36 g (3.2 mmole) of TRANS-1,4-diaminocyclohexane was dissolved in 5 ml of 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 80°C for 3 h, cooled, then added 30 ml of ethyl acetate and 30 ml of water. The organic layer was separated, and the aqueous layer was re-extracted with 30 ml dichloromethane. The combined organic layers were concentrated under vacuum, the crude liquid when standing precipitated white precipitate. These solids were filtered off and washed with ethyl acetate to obtain a white powder (28 mg (yield 13%) specified in the title compound with tPL>300°C. the Product was dissolved in ethyl acetate and treated with HCl/Et2O obtaining in the form of a white powder is and cleaners containing hydrochloride salt of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 70

Connection 4-26

This example shows how to obtain 3-(2-chlorophenyl)-7-[TRANS-4-(N,N-dimethylsulphamoyl)cyclohexylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

To a solution of 318 mg (0,632 mmole) of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (obtained is similar to that presented in example 87) in 20 ml of dichloromethane was added 0.10 ml (0.72 mmole) of trimethylamine and a solution of 0.12 g (from 0.84 mmole) of dimethylsulfoxide in 5 ml of dichloromethane. The reaction mixture is boiled under reflux for 18 h, cooled, then concentrated under vacuum. In the purification by chromatography using as eluent 5% methanol/dichloromethane as a white foam was obtained 271 mg (yield 70%) of 3-(2-chlorophenyl)-7-[TRANS-4-(N,N-dimethylsulphamoyl)cyclohexylamino]-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. (MN+=610, tPL106,5-110,0°).

250 mg (0,410 mmole) of 3-(2-chlorophenyl)-7-[TRANS-4-(N,N-dimethylsulphamoyl-amido)cyclohexylamino]-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in 10 ml of methanol and was treated with 10 ml of 10%aqueous hydrochloric acid. The reaction mixture was stirred at 50°and its progress was monitored via this TLC (5% methanol/harmatan). The reaction temperature for 3 h increased to 85°and the reaction mixture was concentrated under vacuum. The resulting suspension was filtered to obtain a white solid, which was washed with ethyl acetate to obtain 125 mg (yield 59%) cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-[TRANS-4-(N,N-dimethylsulphamoyl)cyclohexylamino]-3,4-dihydropyrimido[4,5-4]pyrimidine-2(1H)-it.

Example 71

Connection 4-24

This example shows how to obtain 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

4.6 g (13 mmol) of sulfone 11.1 combined with 4.2 g (27 mmol) of 1,4-dioxaspiro[4.5]Dec-8-ylamine (obtained by described in example 8) in 40 ml of 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 100°during the night, after this time it was cooled to room temperature, diluted with ethyl acetate and water and filtered to obtain not quite white solid. To a suspension of 0.12 g (0,29 mmole) of the product in methanol was added 1 M hydrochloric acid in diethyl ether and the resulting solution was concentrated under vacuum. The residue was dissolved in methanol/dichloromethane and purified rapid chromatography on silica gel using as eluent 2% methanol/dichloromethane, getting in free base form the net of the criminal code is mentioned in the title compound. A suspension of this product in methanol was added 1 M hydrochloric acid in diethyl ether. The resulting solution was concentrated in a stream of nitrogen, then pumped under reduced pressure to obtain a yellow solid 80 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 72

Connection 4-23

This example shows how to obtain 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A mixture of 0.17 g (0,41 mmole) of 3-(2-chlorophenyl)-7-(1,4-dioxaspiro[4.5]Dec-8-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it (obtained by described in example 71) with tetrahydrofuran/3 N. aqueous hydrochloric acid in a ratio of 1:1 was stirred at room temperature overnight. Next, the reaction mixture was diluted with ethyl acetate and treated with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol and purified rapid chromatography on silica gel using as eluent 2% ammonium hydroxide in 35% acetone/hexane. Fractions containing the product were combined and concentrated under bonigen the m pressure to a white solid, which is suspended in methanol. By adding 1 M hydrochloric acid in diethyl ether was obtained salt which was concentrated and pumped under reduced pressure obtaining in the form of a yellow foam 80 mg of pure cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 73

Compound 4-2

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

73.1. Getting

0.400 g (1,18 mmole) sulfone 11.1 combined with 0,272 g (a 2.36 mmole) of TRANS-4-aminocyclohexanol and 0.4 ml of 2-methoxyethanol ether. The reaction mixture was stirred at 100-105°C for 1 h, after which it was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel using dichloromethane/methanol in the ratio 9:1. Fractions containing the product were combined and concentrated under vacuum to matter in the form of oil, which was re-dissolved in ethyl acetate and methanol. With the addition of 1.0 M hydrochloric acid in Et2O (1.0 EQ.) got salt, which was dissolved in the solvents. The solution was concentrated under vacuum to a solid, which was ground into powder in diethyl ether, Hotfile revival and dried to obtain 0,220 g 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

73.2. Another option for obtaining

A solution of 700 g of the sulfide 10.1 in 3000 ml of 1-methyl-2-pyrrolidinone was combined with 350 g of N-chlorosuccinimide in 500 ml of 1-methyl-2-pyrrolidinone and 40 g of water and the mixture was stirred for 1.5 h at 25°C. To this solution was added to 865 g of TRANS-4-aminocyclohexanol. The mixture was stirred at 60°C for 12 to 26 h, cooled to 20-25°and processed 10500 ml of water. This mixture was cooled to 5-8°and was stirred for 2 hours, the Solid was collected by filtration, washed with water, hexane and were dried at 65°in a vacuum drying Cabinet with 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. Cleaners containing hydrochloride salt was obtained by impact on a free basis of an ethanol solution of hydrochloric acid/water.

Example 74

Connection 4-5

This example illustrates another variant obtain 7-(TRANS-4-hydroxycyclohexyl)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A solution of 2 g of the sulfide 10.2 in 4 ml of 1-methyl-2-pyrrolidinone combined with of 1.03 g of N-chlorosuccinimide in 4 ml of 1-methyl-2-pyrrolidinone and 0.125 g of water and the mixture was stirred for 1.5 h at 25°C. To this solution was added 2.65 g of TRANS-4-aminocyclohexanol. The mixture was stirred at 60°C for 48 h, cooled to 20-2° And was treated with 10 ml of water. This mixture was cooled to 5°and was stirred for 2 hours, the Solid was collected by filtration, washed with water, hexane and dried under vacuum. This solid was purified Express by column chromatography using as eluent dichloromethane/methanol in the ratio of from 95/5 to 90/10, getting 614 mg of 7-(TRANS-4-hydroxycyclohexyl)-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. The obtained solid substance was transformed into cleaners containing hydrochloride salt effects on the free basis of ethereal hydrochloric acid/water.

Example 75

Connection 4-15

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-formalininactivated)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

300 mg (0.8 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 73) and 2 ml of 96%formic acid was stirred at 60°C for 3 h, then concentrated under reduced pressure. The residue was ground into powder in diethyl ether, filtered and dried to obtain 250 mg of 3-(2-chlorophenyl)-7-(TRANS-4-formalininactivated)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 76

Connection 4-13

This example shows how to obtain 7-(TRANS-4-AC is tuloksellisuuden)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

400 mg (1,07 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 73), 0.3 ml (3.2 mmole) of acetic anhydride and 0.34 ml (4.3 mmole) of pyridine in 5 ml of dichloromethane was stirred at 25°C for 18 hours the Reaction mixture was filtered and the precipitate washed with dichloromethane, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried emitting 200 mg cleaners containing hydrochloride salt of 7-(TRANS-4-acetylcyclohexanone)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 77

Connection 4-20

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-methoxycarbonylmethylene)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A suspension of 200 mg (0.5 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 73) and 6.5 mg (0.05 mmole) of 4-dimethylaminopyridine in tetrahydrofuran was cooled in an ice bath. Added 0.6 ml (5,35 mmole) of diethylpyrocarbonate and the mixture was stirred for 18 hours, the Reaction mixture was filtered and the residue was purified by column chromatography on silica gel using as e is uent dichloromethane/methanol in the ratio 98:2, receiving 30 mg specified in the title compounds. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried emitting 34 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-methoxycarbonylmethylene)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 78

Connection 4-21

This example shows how to obtain 7-(TRANS-4-carbamoyloximes)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A suspension of 285 mg (0.77 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 73) in 3 ml dichloromethane was cooled in an ice bath was added and 0.09 ml (1,01 mmole) chlorosulfonylisocyanate. The reaction mixture was stirred at 25°C for 18 h, then was treated with 0.5 ml of water. A two-phase mixture was stirred for 8 h, filtered and the residue was purified by column chromatography on silica gel using dichloromethane/methanol in the ratio of 97:3, receiving 110 mg specified in the title compounds. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 94 mg cleaners containing hydrochloride salt of 7-(TRANS-4-carbamoyloximes)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-(1H)-it.

Example 79

Connection 4-22

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-methylenedioxyamphetamine)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

A suspension of 350 mg (0,94 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 73) in 3 ml of dichloromethane was treated with 1 ml (excess) of methyl isocyanate and 1 ml of triethylamine. The mixture was stirred in nitrogen atmosphere for one week. The reaction mixture was filtered and the precipitate washed with dichloromethane, dried and suspended in ethyl acetate. With the addition of 1.0 M hydrochloric acid in Et2O (2.0 EQ.) got salt which was filtered and dried to obtain 250 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-methylenedioxyamphetamine)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 80

Connection 4-3

This example shows how to obtain 7-(3-carboxymethylamino)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

1.0 g (2.97 mmole) sulfone 11.1 combined with of 0.87 ml (5,94 mmole) ethyl-3-aminobutyrate. The mixture was stirred at 110-115°C for 1 h, after which it was cooled to room temperature. The residue was purified by column chromatography on si is imagele using dichloromethane/methanol in the ratio of 10:1. The column fractions containing the obtained ester, 7-(3-carboxymethylamino)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he, were combined and concentrated under vacuum to obtain 1.10 g of a solid substance. 0,500 g (1,24 mmole) of ester was dissolved in methanol. By adding 0.05 g (1,24 mmole) of sodium hydroxide and 1 ml of water was obtained sodium salt. The solution was concentrated under vacuum to a solid, which was ground into powder in ethyl acetate for 1 h, was filtered and dried to obtain 0,41 g of 7-(3-carboxymethylamino)-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. (MN+=376, tPL170,0-185,5°).

Example 81

Connection 3-48

This example illustrates the obtaining of 1-benzyl-3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

81.1. Obtaining 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Suspension of 1.86 mg (5 mmol) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 73) was combined with that of 1.05 g (7 mmol) of tert-butyldimethylsilyloxy and 0.75 g (11 mmol) of imidazole in 35 ml of dimethylformamide. The reaction mixture was stirred at 50°C for 24 h, which was ladli to room temperature and introduced into the water, was stirred for 30 min, filtered and dried to obtain 1.88 g of 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, tPL289-294°C.

81.2. Obtain 1-benzyl-3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

In the suspension 486 mg (1 mmol) 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it 1-methyl-2-pyrrolidinone was administered to 44 mg (1.1 mmole) of sodium hydride (60%dispersion in oil) and stirred at room temperature for 25 minutes In the resulting solution was added to 0.12 ml (1 mmol) benzylbromide and at room temperature was stirred for 4 h, the Reaction mixture introduced in the water and was extracted with ethyl acetate. The layers were separated and the organic layer was washed with water, dried with magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography using as eluent acetone/hexane in the ratio of 25:75, receiving in the form of butter 1-benzyl-3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

81.3. Obtain 1-benzyl-3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he is.

1-Benzyl-3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in tetrahydrofuran and added to tetrabutylammonium (1.0 M/tetrahydrofuran, 1.0 EQ.). The reaction mixture was stirred at room temperature for 24 h, was introduced into ice water, extracted with ethyl acetate, dried with magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 90:10. The column fractions containing product were combined and concentrated under vacuum to obtain specified in the title compounds. This product is suspended in methanol and was added 1.0 M hydrochloric acid in Et2O (1.0 EQ.), was stirred for 30 min, and then evaporated to obtain the substance in the form of foam. This foam was stirred with methanol/diethyl ether, filtered and dried, receiving 130 mg cleaners containing hydrochloride salt of 1-benzyl-3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 82

Connection 3-55

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-cyanomethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

486 mg (1.0 mmole) of 3-(2-what lorgeril)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 81) suspended in 7 ml of 1-methyl-2-pyrrolidinone and 44 mg (1.1 mmole) of sodium hydride (60%dispersion in oil). The reaction mixture was stirred at room temperature for 25 minutes In the resulting solution was added 0,167 mg (1.0 mmole) of iodoacetonitrile and at room temperature was stirred for 4 h the Reaction mixture was put into water and was extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to obtain the substance in the form of oil. This substance is in the form of oil was purified by column chromatography on silica gel using as eluent acetone/hexane in the ratio of 25:75. The column fractions containing product were combined and evaporated under reduced pressure obtaining in the form of a white solid substance 510 mg of 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-1-cyanomethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. (M+N)+527, tPL100,2-148, 7mm°C.

510 mg (0.97 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyl-oxocyclohexyl)-1-cyanomethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in tetrahydrofuran was added 1.0 M of tetrabutylammonium in THF (1.0 EQ.). The reaction mixture was stirred at room temperature for 12 h, was added water, extracted with ethyl acetate, dried over magnesium sulfate and evaporated under reduced pressure obtaining in the form of oil specified in the title is soedineniya. This residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 90:10. The column fractions containing the product is evaporated under vacuum obtaining in the form of foam 249 mg of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-cyanomethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 33

Connection 3-49

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methoxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

972 mg (2 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyl-xillovebieber)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 81) suspended in 15 ml of 1-methyl-2-pyrrolidinone and the suspension was administered to 88 mg (2.2 mmole) of sodium hydride (60%dispersion in oil). The reaction mixture was stirred at room temperature for 30 min and added 0,190 ml (2 mmole) of methylpropanoate. The mixture was stirred for 6 hours the Reaction mixture was put into water and was extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent hexane/acetone in a ratio of 70:30. Fractions containing the product, the volume of Denali and evaporated under reduced pressure obtaining in the form of a white solid substance 425 mg of 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-1-methoxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. (M+H)+560, tPL165,7-167,4°C.

3-(2-Chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-1-methoxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in tetrahydrofuran, was added 1.0 M of tetrabutylammonium (1.0 EQ.) and stirred at room temperature for 12 hours, the Reaction mixture is introduced into ice water, extracted with ethyl acetate, dried with magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent dichloromethane/methanol in the ratio of 90:10. Fractions containing the product were combined and evaporated under reduced pressure obtaining in the form of foam specified in the title compounds. This product was dissolved in methanol and was added 1.0 M hydrochloric acid (1.0 EQ.), was stirred for 30 min and evaporated under reduced pressure. The residue was stirred with methanol/diethyl ether for 4 h, filtered and dried to obtain a white solid 294 mg of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methoxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 84

Connection 3-53

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-hydroxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

395 mg (from 0.88 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-methoxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 83) suspended in 5 ml of ethanol and the suspension was added to 0.85 ml 1,037 N. (0,88 mmole) of aqueous sodium hydroxide. The reaction mixture was stirred at room temperature for 72 h, then evaporated under reduced pressure obtaining in the form of foam specified in the title compounds. This residue was stirred in a mixture of methanol/diethyl ether for 2 h, filtered and dried to obtain a white solid of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-hydroxycarbonylmethyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 85

Connection 3-56

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-(2-hydroxyethyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

85.1. Obtain 1-(2-triisopropylsilyl)-3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In the suspension 486 mg (1.0 mmole) of 3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she received outlined in example 81) in 7 ml of 1-methyl-2-pyrrolidinone was administered to 44 mg (1,1 the mole) of sodium hydride (60%dispersion in oil) and stirred at room temperature for 25 minutes Added 328 mg (1.0 mmole) of triisopropylsilane and the reaction mixture at room temperature was stirred for 4 h the resulting solution was introduced into water and was extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated under reduced pressure obtaining in the form of oil intermediate product, is protected by silicom. The residue was purified by column chromatography on silica gel using as eluent acetone/hexane in the ratio of 25:75 and the fractions containing the product were combined and evaporated under reduced pressure obtaining in the form of oil 604 mg of 1-(2-triisopropylsilyl)-3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, (M+N)+688.

85.2. Obtain 1-(2-hydroxyethyl)-3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

604 mg (from 0.88 mmole) 1-(2-triisopropylsilyl)-3-(2-chlorophenyl)-7-(TRANS-4-tert-butyldimethylsilyloxy)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it was dissolved in tetrahydrofuran. In the reaction mixture was added 1.0 M of tetrabutylammonium in tetrahydrofuran and stirred at room temperature for 12 hours the resulting solution was introduced into water and was extracted with ethyl acetate, dried over sulfate is Agnes and evaporated under reduced pressure obtaining in the form of oil specified in the title compounds. This residue was purified by column chromatography on silica gel using dichloromethane/methanol in the ratio of 90:10 and the fractions containing the product were concentrated under vacuum, obtaining in the form of foam 145 mg of 1-(2-hydroxyethyl)-3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 86

Connection 3-52

This example shows how to obtain 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

86.1. Obtaining DIN-5-carboxylate ethyl-4-phenylamino-2-methylthiopurine

A mixture of 15 g (64.5 mmole) ethyl-4-chloro-2-methylthiopyrimidine-5-carboxylate and 12 ml (132 mmole) of aniline in 200 ml of acetonitrile at room temperature was stirred for 24 hours the mixture is evaporated and to the residue was added ethyl acetate and 2 M aqueous hydrochloric acid. The phases were separated and the organic phase is washed with aqueous hydrochloric acid, dried over sodium sulfate, filtered and evaporated. The obtained solid was purified by kneading the powder with diethyl ether/hexane in the ratio of 1:3, releasing in the form of a white solid substance of 14.2 g (yield 64%) of ethyl-4-phenylamino-2-methylthiopyrimidine-5-carboxylate, tPL88,2 to 88.7°C.

86.2. Getting 4-phenylamino-2-methylthiopyrimidine-5-methanol

RA the solution of 14.2 g (49 mmol) of ethyl-4-phenylamino-2-methylthiopyrimidine-5-carboxylate in 100 ml of tetrahydrofuran at 0° With dropwise added to 1.9 g of lithium aluminum hydride in 50 ml of tetrahydrofuran, after which the mixture was stirred at room temperature for 9 hours Then the mixture was cooled on ice and gently treated by the addition dropwise of 3.3 ml of water and 3.3 ml of 2 M aqueous sodium hydroxide, 4,4 ml of water and 500 ml of ethyl acetate. The resulting suspension was filtered through an auxiliary filter substance and the filtrate was concentrated. The product was filtered and washed with diethyl ether to produce in the form of slightly colored solids 7 g 4 phenylamino-2-methylthiopyrimidine-5-methanol, tPL142,2-143,2°C.

86.3. Getting 4-phenylamino-2-methylthiopyrimidin-5-carboxaldehyde

7 g (28,3 mmole) 4-phenylamino-2-methylthiopyrimidine-5-methanol was stirred in 130 ml of dichloromethane and treated with 25 g (289 mmol) of manganese dioxide. The suspension was stirred for 7 h, and then filtered and the filtrate evaporated. The residue was ground into powder with diethyl ether/hexane in the ratio 1:3 with selection in the form of a white solid substance of 6.4 g of 4-phenylamino-2-methylthiopyrimidin-5-carboxaldehyde, tPL105,6-106,2°C.

86.4. Getting 5-(2-chlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine

A mixture of 6.4 g (of 26.5 mmole) of 4-phenylamino-2-methylthiopyrimidin-5-carboxaldehyde, 3 the l 2-Chloroaniline and 300 mg of 4-toluenesulfonic acid in 150 ml of toluene for 2.5 h and kept at the boiling temperature with azeotropic removal of water. The mixture was cooled and filtered with the release 6.6 g of solid particles. This solid substance in 50 ml of tetrahydrofuran was added 20 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran. After stirring for 1.5 h the mixture was added 1.2 ml of water, 1.2 ml of 15%aqueous sodium hydroxide and 3.8 ml of water. The mixture was stirred for 15 min, filtered and washed with ethyl acetate. The filtrate was ground into powder with diethyl ether/hexane in the ratio of 1:1 with the selection in the form of a white solid of 6 g of 5-(2-chlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine, tPLRB 131.1-131, 5mm°C.

86.5. Obtaining 3-(2-chlorophenyl)-1-methyl-7-phenylthio-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To the cooled solution of 6 g of 5-(2-chlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine and 5.2 ml of triethylamine in 75 ml of tetrahydrofuran was added dropwise to 8.5 ml of phosgene (20%solution in toluene) in 35 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight. This mixture was further added 3 ml of phosgene (20%solution in toluene). After stirring for 15 min the mixture was treated with water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using as e is enta ethyl acetate/hexanol in the ratio of 10:45, receiving in the form of a white solid substance 2.1 g of 3-(2-chlorophenyl)-7-methylthio-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, tPL79,5-82,4°C.

86.6. Obtaining 3-(2-chlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To 2 g of 3-(2-chlorophenyl)-7-methylthio-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in 20 ml of tetrahydrofuran at 0°C was added a solution of 8.1 g of the product Oxone®in 24 ml of water. The mixture was stirred at room temperature for 5 h, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated to obtain 2 g of 3-(2-chlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, tPL185.8-186,3°C.

86.7. Obtaining 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

Suspension 0,212 g 3-(2-chlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she is 0.19 g of 1-amino-4-cyclohexanol in 0.3 ml of 1-methyl-2-pyrrolidinone kept at 100°C for 2 hours the Mixture was cooled, and treated with diethyl ether/hexane in the ratio 1:2 and filtered. The residue was purified using 10% methanol in dichloromethane, getting 149 mg specified in the title compound, which was dissolved in 10 ml of ethanol. Through RA the solution for 5 min was barbotirovany gaseous hydrogen chloride, the solution was concentrated and treated with methanol and diethyl ether. The obtained solids were filtered off and washed with diethyl ether emitting 100 mg cleaners containing hydrochloride salt of 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-1-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

Example 87

Connection 4-28

This example shows how to obtain 3-(2-chlorophenyl)-7-[TRANS-4-(methanesulfonamido)cyclohexylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it.

87.1. Obtain 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

To a solution of 3.0 g (8,87 mmole) sulfone 11.1 in 10 ml of 1-methyl-2-pyrrolidinone was added 60%sodium hydride (390 mg, 9,76 mmole, in mineral oil). The reaction mixture was stirred for 15 min at room temperature, and then added of 1.57 ml (8,87 mmole) of 2-(trimethylsilyl)ethoxymethylene. The reaction mixture was stirred at room temperature for 4 h Then the resulting solution was added of 5.06 g of TRANS-1,4-diaminocyclohexane, pre-dissolved in 15 ml of 1-methyl-2-pyrrolidinone. Next, the reaction mixture was stirred at 60°within 24 hours the Reaction mixture was poured into brine and the product was extracted with ethyl acetate. The combined organic extracts were washed on Ishenim sodium bicarbonate and water, was dried over magnesium sulfate and concentrated under vacuum to obtain the substance in the form of a light brown oil. In the purification by chromatography using as an eluent of 2% methanol/dichloromethane to 5% methanol/dichloromethane as a pale yellow foam was obtained 2.8 g of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she. (MH+=502).

87.2. Obtaining 3-(2-chlorophenyl)-7-[TRANS-4-(methanesulfonamido)cyclohexylamino]-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In a solution of 500 mg (1.04 million mmole) of 7-(TRANS-4-aminocyclohexane)-3-(2-chlorophenyl)-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it is in 5 ml of dichloromethane were introduced to 0.29 ml (0,207 mmole) of triethylamine and a solution of 0.2 g (1,14 mmole) methanesulfonamido anhydride in 5 ml of dichloromethane. The reaction mixture was stirred at room temperature for 24 h, diluted with ethyl acetate and washed with aqueous 10%sodium bicarbonate. The organic extracts were concentrated under vacuum and purified by chromatography using as an eluent of 2% methanol/dichloromethane to 3% methanol/dichloromethane, receiving in the form of a white foam 292 mg of 3-(2-chlorophenyl)-7-[TRANS-4-(methanesulfonamido)yclohexanol]-1-[2-(trimethylsilyl)ethoxy ethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she (MH +=581).

87.3. Obtaining 3-(2-chlorophenyl)-7-[TRANS-4-(methanesulfonamido)cyclohexylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it

In a solution of 290 mg (0.5 mmole) of 3-(2-chlorophenyl)-7-[TRANS-4-(methanesulfonamido)cyclohexylamino]-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she's in 5 ml of methanol was introduced in 4.0 ml of 10%aqueous hydrochloric acid. The reaction mixture was stirred at 40°C for 24 h and concentrated under vacuum. In the result of repeated rubbing of the substance in the form of a colourless oil with ethyl acetate in the form of a white solid substance was obtained 3-(2-chlorophenyl)-7-[TRANS-4-(methanesulfonamido)cyclohexylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-it, which was collected by filtration under vacuum.

Values IR50compounds 1-1 through 1-23 in tests with R in vitro was less than 10 microns.

Values IR50compounds 2-1 to 2-11, 2-13 for 2-24 and 2-28 in tests with R in vitro was less than 10 microns.

Values IR50compounds 3-1, 3-3, 3-5 through 3-10, 3-12, 3-14 through 3-23, 3-27 for 3-36, 3-38, 3-39 to 3-41 on 358 for and 3-60 in tests with R in vitro was less than 10 microns.

Values IR50connections 4-1 through 4-8 and 4-10 on 4-28 in tests with R in vitro was less than 10 microns.

Example 88

Test for inhibition R MAP kinase in vitro

This example illustrates the method of determining the in vitro activity R MAP kinase used to estimate the compounds of the present invention.

In order to evaluate the inhibitory activity of the compounds of the present invention in relation to the MAP kinase R was determined in vitro transfer γ-phosphate from γ-33P-ATP to myelin basic protein (exchange rate), catalyzed by the kinase R using with some modifications of the method described by Ahn and others, J.Biol.Chem. 266:4220-4227 (1991).

Phosphorylated form of recombinant MAP kinase R was coexpression with SEK-1 and MEKK in E. coli (see Khokhlatchev, etc., J.Biol.Chem. 272:11057-11062 (1997)) and then purified affinity chromatography using a Nickel column.

Phosphorylated MAP kinase R was diluted in kinase buffer [20 mm 3-(N-morpholino)propanesulfonic acid, pH of 7.2, 25 mm β-glycerophosphate, 5 mm ethylene glycol-bis-beta-aminoacylase ether N,N,N',N'-tetraoxo the Oh of the acid, 1 mm orthovanadate sodium, 1 mm dithiotreitol, 40 mm magnesium chloride]. The test compound dissolved in DMSO, or only DMSO (standard), was added and samples were incubated for 10 min at 30°C. Kinase reactions were initiated by addition of substrate cocktail containing exchange rate and γ≠33P-ATP. After incubation for a further 20 min at 30°the reaction was stopped by the addition of 0.75%phosphoric acid. Then phosphorylated exchange rate was separated from residual γ-33P-ATP using phosphocellulose membrane, Millipore, Bedford, iminnesota), and using a scintillation counter (Packard company, Meridian, standartised) conducted a quantitative definition.

Example 89

Test for inhibition of TNF in vitro

This example illustrates in vitro evaluation method of inhibiting the production of TNF-αinduced by LPS in the cells TNR.

The ability of the compounds of the present invention to inhibit the release of TNF-α determined by applying with minor modification of the methods described in Blifeld and other Transplantation, 51:498-503 (1991).

a) Induction of TNF biosynthesis

Cells TNR suspended in culture medium [RPMI, Gibco-BRL, Gaithersburg, stmaryrd)containing 15%fetal bovine serum, 0.02 mm 2-mercaptoethanol] at a concentration of 2.5×106cells/ml and then were placed in a 96-l the night tablet (0.2-ml aliquots to each well). Test compounds were dissolved in DMSO and then diluted in culture medium so that the final concentration of DMSO has reached 5%. To each well was added an aliquot twenty five microliter test solution or only medium with DMSO (reference). Cells were incubated at 37°C for 30 min In the wells was added LPS (firm Sigma, St. Louis, stricture) to a final concentration of 0.5 μg/ml and cells were incubated for another 2 hours To the end of the incubation period, the culture supernatant was collected and the amount present of TNF-α defined, with the following ELISA method.

b) ELISA method

The amount present of TNF-α man was determined by the specific binding according to the method ELISA using two antibodies to TNF-α (2TNF-H12 and 2TNF-H34), described by Reimund, J.M., and others, GUT, vol 39(5), 684-689 (1996).

In wells of polystyrene 96-well tablet barbirolli 50 ál antibody 2TNF-H12 in RBF (solution containing phosphate buffer) (10 μg/ml) and incubated at 4°overnight in humidified chamber. The tablet was washed RBF and then for 1 h at room temperature, blocked with 5%fat-free dried milk in RBF and washed with 0.1%BSA (bovine serum albumin) in RBF.

Standards TNF was prepared from standby solution of recombinant TNF-α person (firm R&D Systems, Minneapolis, STM nnesota). The initial concentration of the standards in the tests was 10 ng/ml, followed by 6 semi-log serial dilutions.

The aliquots of twenty μl of the above-mentioned culture supernatant fluids or TNF standards or only medium (standard) was mixed with 25-Microlitre an aliquot of the biotinylated monoclonal antibodies 2TNH-H34 (2 µg/ml RBF containing 0.1%BSA) and then was added to each well. Samples were incubated with careful shaking at room temperature for 2 h and then washed 3 times with 0.1%BSA in RBF. To each well was injected 50 μl of a solution of streptomycinresistant (firm Zymed, S. San Francisco, stilborne), containing 0,416 µg/ml streptomycinresistant and 0.1%BSA in RBF. The additional samples were incubated for 1 h at room temperature and then washed 4 times with 0.1%BSA in RBF. Each was introduced by fifty microlitres 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 for 30 min at room temperature in the dark. The optical density of the sample and the comparative cell was defined by respectively 450 and 650 nm. The levels of TNF-α was determined by curve optical density at 450 nm against concentration.

Value IR50determined coconcentration test connection corresponding to the lower half of the maximum absorption at 450 nm.

Example 90

This example illustrates in vivo method for assessing the inhibition of LPS-induced production process in mice (or rats) TNF-α.

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

Female mice of BALB/c mice weighing 18-21 g (firm Charles River, Hollister, stilborne) acclimatized for one week. Each animal groups consisted of 8 mice was administered orally or test compound in suspension or dissolved in an aqueous medium containing a 0.9%sodium chloride and 0.5%sodium carboxymethyl cellulose, 0,4%Polisorb 80, and 0.9%benzyl alcohol (CMC media) or media (control group). After 30 min the animals by intraperitoneal injection was administered at 20 μg LPS (firm Sigma, St. Louis, stricture). After 1.5 h the animals were killed by inhalation of CO2and collected blood by puncture of the heart. Blood was osvetleni by centrifugation at 15600g for 5 min, the serum was transferred into a clean test tubes were frozen at -20°and kept up as long as you have not performed the analysis for TNF-α etodo ELISA, Biosource International, Camarillo, stilborne) according to the manufacturer's instructions.

It must be borne in mind that in the present description, the examples and embodiments of the invention are only illustrative purposes, therefore, taking them into account, sentence, specialists in the art can make various modifications or alterations that do not fall within the essence and scope of this application and scope of the attached claims.

1. Heterooligomerization derived dihydropyrimido[4,5-d] pyrimidinone selected from a series of compounds corresponding to the formula I

in which the subscript character n denotes an integer of 1;

R1represents C1-6alkyl (substituted by one or two substituents selected from the group comprising hydroxy, C1-6alkoxy, amino, di(C1-4alkyl)amino, C1-4alkanolamine and phenyl), piperidinyl-C0-4alkyl [where piperidinyl fragment optional monogamist a benzyl, carbamoyl,1-4alkanesulfonyl, C1-6the alkyl (which is optionally substituted by one or two substituents selected from the group comprising hydroxy, cyano, carbarnoyl, phenyl, carboxy, di(C1-4alkyl)aminocarbonyl,1-4alkoxycarbonyl, trifluoromethyl) or (C alkoxycarbonyl], morpholinyl-C0-4alkyl, tetrahydropyranyl-C0-4alkyl, 2-Oxymetazoline-C0-4alkyl, 2-oxo-pyrrolidinyl-C0-4alkyl or 1,1-dioxo-tetrahydrothieno-C0-4alkyl, C3-6cycloalkyl (monosubstituted hydroxy, C1-6alkoxy (optionally substituted by one or two substituents selected from the group comprising hydroxy and C1-4alkoxy), formyloxy,2-6alkenylacyl,1-4alkanoyloxy, carbamoylated,1-4alkoxycarbonyl,1-4alkylaminocarbonyl, hydroxy-C1-4alkyl, =O, =N-OH, amino, C1-4alkylsulfonate or di(C1-4alkyl)aminosulfonyl), 1,4-dioxaspiro[4.5]Decan-8-yl, 2,4-dione-1,3-diaza-Spiro[4.5]Decan-8-yl or (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro [5.5]undecane-9-yl,

R2stands With1-4alkyl, halo;

R3denotes hydrogen, C1-6alkyl (optionally substituted by one or two substituents selected from the group comprising From1-4alkoxy, pyrrolidinyl, di(C1-4alkyl)amino, C1-4alkylthio, di(C1-4alkyl)aminocarbonyl, carbarnoyl,1-4alkoxycarbonyl, carboxy, cyano, hydroxy and trifluoromethyl), phenyl, benzyl or piperidinyl (optionally N-substituted With1-4by alkyl);

R4denotes hydrogen;

as well as its individual Isom the market, racemic and nerezisca mixture of isomers, prodrugs and pharmaceutically acceptable salts.

2. The compound according to claim 1, in which -(R2)ndenotes the 2-halo.

3. The compound according to claim 1, in which -(R2)nrefers to 2-methyl.

4. The compound according to any one of claims 1 to 3, in which R3denotes hydrogen or methyl.

5. The compound according to any one of claims 1 to 3, in which R3means 2,2,2-triptorelin.

6. The compound according to claim 1, in which R1stands With1-6hydroxyalkyl.

7. The connection according to claim 6, in which R2represents halo or methyl, and R3denotes methyl.

8. The compound according to claim 1, in which R2represents halo or methyl, a, R3denotes methyl.

9. The connection of claim 8, in which R1stands With3-6hydroxycyclohexyl.

10. The compound according to claim 1, in which R2represents halo or methyl, and R3denotes methyl or hydrogen.

11. The compound according to claim 1, which is 3-(2-chlorophenyl)-7-(TRANS-4-hydroxycyclohexyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-he and its pharmaceutically acceptable salts.

12. The compound according to claim 1, selected from

3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she

7-[1-(2-hydroxyethyl)piperidine-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she

3-(2-chlorphen is)-7-[(TRANS-4-methoxycyclohexyl)methylamino]-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she

3-(2-chlorophenyl)-7-(4-oxocyclohexyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-she and their pharmaceutically acceptable salts.

13. The compound according to any one of claims 1 to 12, having inhibitory activity against R MAP kinase.

14. Pharmaceutical composition having inhibitory activity against R MAP kinases, including heterooligomerization derived dihydropyrimido[4,5-d]pyrimidinone formula (I), an isomer, racemic or prizemistuyu a mixture of isomers or its pharmaceutically acceptable salt in a mixture with at least one pharmaceutically acceptable carrier.



 

Same patents:

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: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

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

10 cl, 6 tbl, 337 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

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

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of α-aminohydroxamic acid of the formula (I):

wherein R1 means hydrogen atom, (lower)-alkyl or phenyl-(lower)-alkyl; R2 means hydrogen atom or (lower)-alkyl; R3 means (lower)-alkyl or phenyl; A means (C1-C3)-alkylene; q = 1-5; R means (C2-C7)-alkyl, (C3-C7)-alkenyl, (C3-C7)-alkynyl, and its pharmaceutically acceptable salts. These compounds are inhibitors of MMP and first of all inhibitors of MMP2 and can be used in treatment of inflammatory states, proliferative arthritis, osteoarthritis, oncological and pulmonary diseases. Also, invention describes a method for preparing compounds and a pharmaceutical composition.

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

18 cl, 1 tbl, 87 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

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

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of benzimidazole of general formulae (IV)

and

For compounds of the formula (IV): R represents hydrogen atom, (C1-C10)-alkyl and others; D represents phenyl or azaphenyl; n = 0; A, B and Q represent hydrogen atom, (C1-C10)-alkyl and others; Z represents a bond, (C1-C6)-alkylene or -CH2O-; R1 represents hydrogen atom, (C1-C10)-alkyl and others; R2 represents hydrogen atom. For compounds of the formula (IVA): n = 0; Z represents a bond, -CH2-, -CH2O-, -CH2CH2-; R represents hydrogen atom or (C1-C10)-alkyl; R1 represents hydrogen atom, (C3-C12)-cycloalkyl, benzyl and others; R2 represents hydrogen atom. Compounds of formulae (IV) and (IVA) possess affinity with respect to nociceptin and μ-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

18 cl, 5 tbl, 16 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, 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 benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 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

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