Purine derivatives as inhibitors of tyrosine proteinase syk

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

 

This invention relates to organic compounds, their reception and their use as pharmaceuticals. More specifically, the present invention relates:

(a) to compounds of the formula

in free form or in salt form, where

X means an oxygen atom or sulfur or a group NR5,

R1means alkyl, alkenylphenol, cycloalkyl, benzocyclobutene, cycloalkylation or aracelio group, which optionally may be substituted by hydroxy, alkoxy, carboxy or alkoxycarbonyl or, when X is NR5alternative R1can mean heterocyclyl group or a group of the formula

R2, R3, R4, R6, R7and R8denote each independently from each other hydrogen, halogen, alkyl, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, carboxylic, alkoxycarbonylmethyl, -N(R9R10, -SO2N(R11R12, (C1-C4)alkylen-SO4N(R11R12or-CON(R13R14or, when two Deputy of R2, R3and R4or two substituent of R6, R7and R8attached to adjacent carbon atoms in the indicated benzene rings, together with the carbon atoms to which they are attached, they are about the means carbocyclic group, containing 5-10 ring atoms, or a heterocyclic group, containing from 5-10 ring atoms, of which one, two or three mean heteroatoms selected from nitrogen, oxygen and sulphur,

R5means hydrogen or alkyl,

R9means hydrogen or alkyl,

R10means hydrogen, alkyl or-COR15where R15means alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, carboxylic or alkoxycarbonylmethyl, or

R9and R10means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen or sulphur,

R11means hydrogen or alkyl,

R12means hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyethyl or alkoxycarbonylmethyl, or

R11and R12means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulfur, and R13and R14denote each independently from each other hydrogen or alkyl;

especially to compounds of formula I in free form or in the form of pharmaceutically acceptable salts for use as pharmaceuticals; and

(b) to whom soedinenijam formula I, as they mentioned above, in free form or in the form of pharmaceutically acceptable salts for use in the manufacture of medicaments for treating conditions mediated by syk kinase.

In formula I the substituent R9, R10, R11, R12, R13or R14may be the same as the corresponding group in R6, R7or R8or different from it.

In another aspect the present invention provides compounds of formula I, as they indicated above, in free form or in salt form, except 2-(n-n-butylaniline)-6-methoxypurine, 2-(n-n-butylaniline)-6-(methylthio)purine, 2,6-di(phenylamino)purine, 2,6-di(n-tolylamino)purine and 2-(n-tolylamino)-6-(phenylamino)purine.

In a further aspect the present invention provides compounds of formula I, as they indicated above, in free form or in salt form, with the exception of compounds of the formula I, where

(i) X is oxygen or sulfur, R1means alkyl, two Deputy of R2, R3or R4mean hydrogen and one of R2, R3and R4means alkyl, and

(ii) X is NH, R1means a group of the formula II, in which two of the substituents R6, R7and R8mean hydrogen, and one remaining means hydrogen or alkyl; one of R2, R3and R4means hydrogen, and the remaining two means each is hydrogen or alkyl.

In a further aspect the present invention provides compounds of formula I, as they indicated above, in free form or in salt form, where

(a) X is NR5and R1, R2, R3, R4and R5have the above meanings, with the proviso that when R1means a group of formula II, the substituents R6, R7and R8denote each independently from each other halogen, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, carboxylic, alkoxycarbonylmethyl, - N(R9R10, -SO2N(R11R12, (C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or when two of the substituents R6, R7and R8attached to adjacent carbon atoms in the indicated benzene ring, they mean together with the carbon atoms to which they are attached, a carbocyclic group containing from 5-10 ring atoms, or a heterocyclic group, containing from 5-10 ring atoms, of which one, two or three mean heteroatoms selected from nitrogen, oxygen and sulfur, or one or two substituent of R6, R7and R8mean hydrogen; or

(b) X is oxygen or sulfur and R1, R2, R3and R4have the above meanings, with the proviso that when R1means alkyl, R2, R3and R4mean of each of the y independently from each other hydrogen, halogen, alkoxy, carboxy, alkoxycarbonyl, carboxylic, alkoxycarbonylmethyl, -N(R9R10, -SO2N(R11R12(C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or when two Deputy of R2, R3and R4attached to adjacent carbon atoms in the indicated benzene ring, they mean together with the carbon atoms to which they are attached, a carbocyclic group containing from 5-10 ring atoms, or a heterocyclic group, containing from 5-10 ring atoms, of which one, two or three mean heteroatoms selected from nitrogen, oxygen and sulphur.

Terms used in this description have the following meanings.

“Alkyl” means a linear or branched alkyl chain, which may be, for example, (C1-C10)alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, linear or branched pentyl, linear or branched hexyl, linear or branched heptyl, linear or branched, nonyl either linear or branched decyl. Preferably, the alkyl means a (C1-C4)alkyl.

“Alkoxy” means a linear or branched CNS chain and may be, for example, (C1-C10)alkoxy, such as methoxy, ethoxy, n-propoxy, isoprop the si, n-butoxy, isobutoxy, Deut.-butoxy, tert.-butoxy, or a linear or branched, pentox, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy. Preferably alkoxy means (C1-C4)alkoxy.

“Alkenyl” means a linear or branched alkenylphenol chain, which may be, for example, (C2-C10)alkenyl, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, Isobutanol, or a linear or branched pentenyl, hexenyl, heptenyl, octenyl, nonanol or decenyl. Preferably alkenyl means (C2-C4)alkenyl.

“Cycloalkyl” means (C3-C10)cycloalkyl containing 3-8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, of which any may be substituted by one, two or more (C1-C4)alkyl groups, particularly methyl groups. Preferably cycloalkyl means (C3-C6) cycloalkyl.

“Benzocyclobutene” means cycloalkyl, for example one of the aforementioned (C3-C10)cycloalkyl groups attached to two adjacent carbon atoms in a benzene ring. Preferably benzocyclobutene means benzo(C5-C6)cycloalkyl especially benzocycloheptene (tetrahydronaphthyl).

“Cycloalkyl lcil” means (C 3-C10)cycloalkyl(C1-C10)alkyl, where (C3-C10)cycloalkyl group contains 3 to 8 carbon atoms and may be, for example, any one of the above (C1-C10)alkyl groups, in particular one from (C1-C4)alkyl groups, substituted one of the above (C3-C10)cycloalkyl groups. Preferably cycloalkenyl means (C3-C6)cycloalkyl(C1-C4)alkyl.

“Aralkyl” means (C6-C10)aryl(C1-C10)alkyl and may be, for example, any one of the above (C1-C10)alkyl group, especially one of (C1-C4)alkyl groups, substituted phenyl, talila, xilian or naphthyl. Preferably aralkyl means phenyl(C1-C4)alkyl, especially benzyl or 2-phenylethyl.

“Heterocyclyl” means a monovalent heterocyclic radical containing up to 20 carbon atoms and one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, and radical optionally contain alkyl, alkylcarboxylic, hydroxyalkyl, alkoxyalkyl or aracelio group attached to a carbon or nitrogen atom, and being linked to the remainder of the molecule via a ring carbon atom may mean, for example, radical, preferably Monaci the symbolic radical with one nitrogen atom, oxygen or sulfur, such as peril, pyridyl, piperidyl, furyl, tetrahydrofuryl or thienyl, or radical, preferably monocyclic radical with two heteroatoms selected from nitrogen, oxygen and sulfur, such as imidazolyl, pyrimidinyl, piperazinil, oxazolyl, isoxazolyl, thiazolyl, morpholinyl or thiomorpholine. Preferably heterocyclyl means a monocyclic radical containing 5 or 6 ring atoms and one or two nitrogen atom, or one nitrogen atom and one oxygen atom in the ring, optionally substituted on the ring nitrogen atom (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkylcarboxylic or phenyl(C1-C4)alkyl.

“Alkoxyalkyl” means a linear or branched alkyl chain substituted by one or more CNS groups, and may be, for example, (C1-C10)alkoxy(C1-C10)alkyl group, such as one of (C1-C10)alkyl groups, in particular one of the above (C1-C4)alkyl groups, substituted one of (C1-C10)alkoxygroup, preferably one of (C1-C4)alkoxygroup mentioned above. Preferably alkoxyalkyl means (C1-C4)alkoxy(C1-C4)alkyl.

“Carboxylic” means a linear or rasvet the military alkyl chain, for example (C1-C10)alkyl, such as one of the above (C1-C10)alkyl groups, substituted carboxyl group, preferably a primary carbon atom. Preferably carboxylic means (C1-C4)carboxyethyl.

“Alkylaryl” means the group R16CO in which R16means alkyl, for example (C1-C10)alkyl, such as one of the above (C1-C10)alkyl groups, preferably C1-C4. Preferably alkylaryl means (C1-C4)alkylsulphonyl, i.e. R16CO., where R16means (C1-C4)alkyl.

“Alkoxycarbonyl” means the group R17CO in which R17means alkoxygroup, for example (C1-C10)alkoxygroup, such as one of the above (C1-C10)alkoxygroup, preferably C1-C4. Preferably alkoxycarbonyl means (C1-C4)alkoxycarbonyl, i.e. R17CO., where R17means (C1-C4)alkoxy.

“Alkoxycarbonyl” means a linear or branched alkyl chain, for example (C1-C10)alkyl group, such as one of the above (C1-C10)alkyl groups, preferably C1-C4substituted alkoxycarbonyl group, as defined above. predpochtitelno alkoxycarbonylmethyl means (C 1-C4)alkoxycarbonyl(C1-C4)alkyl.

“Haloalkyl” means a linear or branched alkyl chain, for example (C1-C10)alkyl, such as one of the above (C1-C10)alkyl groups substituted by one or more, for example one, two or three halogen atoms, preferably fluorine atoms or chlorine. Preferably haloalkyl means (C1-C4)alkyl, substituted with one, two or three fluorine atoms or chlorine.

“Hydroxyalkyl” means a linear or branched alkyl chain, for example (C1-C10)alkyl, such as one of the above (C1-C10)alkyl groups, substituted one, two or three hydroxyl groups. Preferably hydroxyalkyl means (C1-C4)alkyl, substituted with one hydroxyl group.

If one of R2, R3and R4or one of R6, R7and R8means hydrogen, and the second and third of R2, R3and R4or the second and third of R6, R7and R8attached to adjacent carbon atoms in the respective benzene ring and together with said adjacent carbon atoms means a carbocyclic or heterocyclic group, the second and the third of R2, R3and R4or the second and third of R6, R7and R 8can denote, together with the benzene ring to which they are attached, (C9-C15)carbocyclic group, such as indenyl or naphthyl, optionally substituted by one or more (C1-C4)alkyl groups or (C1-C4)alkoxygroup, dihydronaphtho, tetrahydronaphthyl, fluorenyl, antrel or tenantry, preferably (C10-C15)carbocyclic aromatic group or tetrahydronaphthyl; or the second and third of R2, R3and R4or the second and third of R6, R7and R8can denote, together with the benzene ring to which they are attached, heterocyclic group containing 9 to 14 ring atoms, of which one, two or three mean heteroatoms selected from nitrogen, oxygen and sulfur, for example, indolenine, benzimidazolyl, indazolinone or carbazolyl group (which is optionally substituted on the nitrogen atom (C1-C4)alkyl, hydroxy(C1-C4)alkyl or phenyl(C1-C4)alkyl) or benzofuranyl, benzothiophene, chinoline, ethenolysis, naphthyridine, dioxaheptyl (benzodioxane), benzoxazolyl, benzothiazolyl, benzofuranyl or benzofurazanyl, preferably heterocyclic group containing 9 to 13 ring atoms, of which one, two or three mean heteroatoms, selected Isetta, oxygen and sulphur.

If R9and R10or R11and R12together with the nitrogen atom to which they are attached, denote a heterocyclic group, it may be, for example, a group containing one or two nitrogen atom in the ring, such as pyrrolidinyl, imidazolidinyl, imidazolidinyl, piperideine or piperazinilnom group, and a group containing two nitrogen atom in the ring, optionally substituted on the second nitrogen atom (C1-C4)alkyl group, hydroxy(C1-C4)alkyl group, (C1-C4)alkylcarboxylic group, (C1-C4)alkoxycarbonyl group or phenyl(C1-C4)alkyl group, or heterocyclic group may be a group containing one ring nitrogen atom and one oxygen atom, such as tetrahydrooxazolo, tetrahydroisoquinoline or morpholinopropan, which may be substituted by one or more carbon atoms of the ring (C1-C4)alkyl group.

Preferred compounds of formula I and their salts are the compounds of formula

in free form or in salt form, where

R1matter described above, and if it means a group of formula II, this group has the formula IV

R2/sup> , R3, R4, R6, R7and R8have the meanings given above.

In formula I and formula III

R1means preferably (C1-C10)alkyl, especially (C1-C4)alkyl, (C2-C10)alkenyl, especially (C2-C4)alkenyl, (C3-C10)cycloalkyl, especially (C3-C6)cycloalkyl, benzo(C3-C10)cycloalkyl, especially benzo(C5-C6)cycloalkyl, phenyl(C1-C10)alkyl, especially phenyl(C1-C4)alkyl or (C3-C10)cycloalkyl(C1-C4)alkyl, especially (C3-C6)cycloalkyl(C1-C4)alkyl group which is optionally substituted by hydroxyl, carboxyl or (C1-C4)alkoxycarbonyl group, or

R1means a heterocyclic radical containing 5 or 6 ring atoms and one or two nitrogen atom, or one nitrogen atom and one oxygen atom in the ring, and optionally substituted on a ring nitrogen atom (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkylcarboxylic or phenyl(C1-C4)alkyl, or

R1means a group of formula II or formula IV, respectively, in which one of R6, R7and R8means hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy, and

(i) the second and third of R 6, R7and R8denote each, independently of one another hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy, or

(ii) second from R6, R7and R8means hydrogen, and the third from R6, R7and R8means carboxy, (C1-C10)alkoxycarbonyl, preferably (C1-C4)alkoxycarbonyl, carboxy(C1-C10)alkyl, preferably carboxy(C1-C4)alkyl, (C1-C10)alkoxycarbonyl(C1-C10)alkyl, preferably (C1-C4)alkoxycarbonyl(C1-C4)alkyl, -N(R9R10, -SO2N(R11R12, (C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or

(iii) the second and third of R6, R7and R8attached to adjacent carbon atoms in the indicated benzene ring and together with said adjacent carbon atoms means a carbocyclic group containing 5 or 6 ring atoms, or a monocyclic heterocyclic group containing 5 or 6 ring atoms and one or two nitrogen atom in the ring, one of R2, R3and R4means hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy and

(a) the second and third of R2, R3and R4denote each, independently of one another hydrogen, (C1-C4)al is silt or (C 1-C4)alkoxy or

(b) the second of R2, R3and R4means hydrogen, and the third from R2, R3and R4means carboxy, (C1-C10)alkoxycarbonyl, preferably (C1-C4)alkoxycarbonyl, carboxy(C1-C10)alkyl, preferably carboxy(C1-C4)alkyl, (C1-C10)alkoxycarbonyl(C1-C10)alkyl, preferably (C1-C4)alkoxycarbonyl (C1-C4)alkyl, -N(R9R10, -SO2N(R11R12, (C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or

(C) second and third from R2, R3and R4attached to adjacent carbon atoms in the indicated benzene ring and together with said adjacent carbon atoms means a carbocyclic group containing 5 or 6 ring atoms, or a heterocyclic group, containing from 5-10 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulphur.

R9means hydrogen, (C1-C10)alkyl, preferably (C1-C4)alkyl, and

R10means hydrogen, (C1-C10)alkyl, preferably (C1-C4)alkyl or-COR15where R15means (C1-C10)alkyl, preferably (C1-C4)alkyl, (C1-C0 )haloalkyl, preferably (C1-C4)haloalkyl, (C1-C10)alkoxy(C1-C10)alkyl, preferably (C1-C4)alkoxy(C1-C4)alkyl, (C1-C10)alkoxycarbonyl, preferably (C1-C4)alkoxycarbonyl, carboxy(C1-C10)alkyl, preferably carboxy(C1-C4)alkyl or (C1-C10)alkoxycarbonyl(C1-C10)alkyl, preferably (C1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R9and R10means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms and one or two nitrogen atom, or one nitrogen atom and one oxygen atom in the ring,

R11means hydrogen or (C1-C10)alkyl, preferably (C1-C4)alkyl,

R12means hydrogen, (C1-C10)alkyl, preferably (C1-C4)alkyl, hydroxy(C1-C10)alkyl, preferably hydroxy(C1-C4)alkyl, (C1-C10)alkoxy (C1-C10)alkyl, preferably (C1-C4)alkoxy(C1-C4)alkyl, carboxy(C1-C10)alkyl, preferably carboxy(C1-C4)alkyl or (C1-C10)alkoxycarbonyl(C1-C10)alkyl, predpochtitel is but (C 1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R11and R12means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms and one or two nitrogen atom, or one nitrogen atom and one oxygen atom in the ring, and

R13and R14denote each independently from each other hydrogen or (C1-C10)alkyl, preferably (C1-C4)alkyl.

Preferred compounds of formula I or III and their salts include compounds in which:

X means a group NR5,

R1means (C1-C4)alkyl, (C2-C4)alkenyl, (C3-C5)cycloalkyl, benzo(C5-C6)cycloalkyl, phenyl(C1-C4)alkyl or (C3-C5)cycloalkyl(C1-C4)alkyl group which is optionally substituted by hydroxyl, carboxyl or (C1-C4)alkoxycarbonyl group, or

R1means a heterocyclic radical containing 5 or 6 ring atoms and the ring one or two nitrogen atom, or one nitrogen atom and one oxygen atom, and optionally substituted on a ring nitrogen atom (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkylcarboxylic or phenyl(C1-C4)alkyl, or

R1mean group forms the crystals IV, in which one of R6, R7and R8means hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy, and

(i) the second and third of R6, R7and R8denote each, independently of one another hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy, or

(ii) second from R6, R7and R8means hydrogen, and the third from R6, R7and R8means-N(R9R10, -SO2N(R11R12or-CON(R13R14or

(iii) the second and third of R6, R7and R8attached to adjacent carbon atoms in the indicated benzene ring and together with said adjacent carbon atoms means a carbocyclic group containing 5 or 6 ring atoms, or a heterocyclic group containing 5 or 6 ring atoms, of which one or two are nitrogen atoms,

one of R2, R3and R4means hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy and

(a) the second and third of R2, R3and R4denote each, independently of one another hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy or

(b) the second of R2, R3and R4means hydrogen, and the third from R2, R3and R4means carboxy, (C1-C4)alkoxycarbonyl, carboxy(C1-C4)Alki is, (C1-C4)alkoxycarbonyl(C1-C4)alkyl, -N(R9R10, -SO2N(R11R12, (C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or

(C) second and third from R2, R3and R4attached to adjacent carbon atoms in the indicated benzene ring and together with said adjacent carbon atoms, denote a heterocyclic group, containing from 5-10 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulphur,

R5means hydrogen or (C1-C4)alkyl,

R9means hydrogen or (C1-C4)alkyl, and

R10means hydrogen, (C1-C4)alkyl, or-COR15where R15means (C1-C4)alkyl, halogen(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl or (C1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R9and R10means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atom, or one ring nitrogen atom and one ring oxygen atom

R11means hydrogen or (C1-C4)alkyl, and

R12about the mean hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, or (C1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R11and R12means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atom, or one ring nitrogen atom and one ring oxygen atom, and

R13and R14denote each independently from each other hydrogen or (C1-C4)alkyl. Additional preferred compounds among the above, in which X stands for a group NR5are connections, where

R1means (C1-C4)alkyl, which is optionally substituted by hydroxy, (C2-C4)alkenyl, (C3-C5)cycloalkyl, which is optionally substituted by carboxy or (C1-C4)alkoxycarbonyl, benzo(C5-C6)cycloalkyl, phenyl(C1-C4)alkyl, optionally substituted hydroxy, (C3-C5)cycloalkyl(C1-C4)alkyl, heterocyclic radical containing 6 ring atoms and one or two nitrogen atom in the ring, optionally substituted on the ring nitrogen atom of the phenyl(C1-C4)alkyl, or a group of the formula IV, in which one of R6, R7and R8 represents hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy, and

(i) the second and third of R6, R7and R8denote each hydrogen or

(ii) second from R6, R7and R8means hydrogen, and the third from R6, R7and R8means-N(R9R10where

R9means hydrogen or (C1-C4)alkyl and R10means-COR15where

R15means (C1-C4)alkyl, (C1-C4)alkoxy, -SO2N(R11R12where R11and R12denote each hydrogen, (C1-C4)alkyl, or-CON(R13R14where R13and R14denote each hydrogen, or

(iii) the second and third of R6, R7and R8attached to adjacent carbon atoms in the indicated benzene ring, and means together with said adjacent carbon atoms, carbocyclic group containing 6 ring atoms, or a heterocyclic group containing 5 ring atoms, of which two are nitrogen atoms, one of R2, R3and R4means hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy and

(a) the second and third of R2, R3and R4denote each, independently of one another hydrogen, (C1-C4)alkoxy or

(b) the second of R2, R3and R4means hydrogen, and the third from R2, R3 and R4means carboxy, (C1-C4)alkoxycarbonyl, carboxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl(C1-C4)alkyl, -N(R9R10where

R9means hydrogen or (C1-C4)alkyl and

R10means hydrogen, (C1-C4)alkyl or-COR15where

R15means (C1-C4)alkyl, halogen(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl or (C1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R9and R10means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atoms, preferably piperazinil, piperidino, pyrrolidinyl, or one ring nitrogen atom and one ring oxygen atom, preferably morpholinopropan, heterocyclic group having two ring nitrogen atom, optionally containing (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkylsulphonyl, (C1-C4)alkoxycarbonyl or (C1-C4)alkoxycarbonylmethyl group attached to the nitrogen atom in the radical R9-R10-, and heterocyclic group having one to whom Lavoy nitrogen atom and one ring oxygen atom, optionally containing one or two (C1-C4)alkyl group attached to a ring carbon atom, or

the third of R2, R3and R4means-SO2N(R11R12where R11means hydrogen or (C1-C4)alkyl and R12means hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl or (C1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R11and R12means together with the nitrogen atom to which they are attached, heterocyclic group containing 6 ring atoms, including one or two ring nitrogen atoms, for example piperidino or piperazinil, or one ring nitrogen atom and one ring oxygen atom, for example, morpholino, heterocyclic group having two ring nitrogen atom, optionally containing (C1-C4)alkyl group attached to the nitrogen atom in the radical R11-R12-or

the third of R2, R3and R4means (C1-C4)alkylen-SO2N(R11R12where

R11and R12denote each independently from each other hydrogen or (C1-C4)alkyl, or a third of R2, R3and R4means-CON(R13R14where

R13and R14mean everyone follows the IMO from each other hydrogen or (C 1-C4)alkyl, or

(C) second and third from R2, R3and R4attached to adjacent carbon atoms in the indicated benzene ring, and means together with said adjacent carbon atoms of the heterocyclic group containing 5-9 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulfur, especially indazolinone, benzothiazolyl, pinolillo, indolenine, benzofuranyl or dioxaheptyl group, and R5means hydrogen or (C1-C4)alkyl.

Other preferred compounds of formula I or III and their salts are such, where X means an oxygen atom

R1means (C1-C4)alkyl or (C3-C10)cycloalkyl, one of R2, R3and R4means hydrogen or

(i) the second of R2, R3and R4means hydrogen, and the third from R2, R3and R4means carboxy, (C1-C4)alkoxycarbonyl or-N(R9R10where R9and R10means together with the attached nitrogen atom a heterocyclic group containing 5 or 6 ring atoms, including two ring nitrogen atom or one ring nitrogen atom and one ring oxygen atom, or

(ii) the second and third of R2, R3and R4attached to adjacent carbon atoms in the specified b Solna ring and means together with the carbon atoms, to which they are attached, a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean nitrogen atoms.

Among the compounds of formula I or III additional preferred compounds and their salts, where X means an oxygen atom, are such, where

R1means (C1-C4)alkyl or (C3-C5)cycloalkyl, one of R2, R3and R4means hydrogen or

(a) the second of R2, R3and R4means hydrogen, and the third from R2, R3and R4means carboxy, (C1-C4)alkoxycarbonyl or-N(R9R10where

R9and R10means together with the attached nitrogen atom a heterocyclic group containing 6 cyclic atoms, including one ring nitrogen atom and one ring oxygen atom, or

(b) the second and third of R2, R3and R4attached to adjacent carbon atoms in the indicated benzene ring and the mean together with the carbon atoms to which they are attached, a heterocyclic group containing 5 ring atoms, of which two mean nitrogen atoms.

Another group of preferred compounds of formula I or III and their salts are such, where

X is a sulfur atom,

R1means (C1-C4)alkyl, two of R2, R3and R4Osnach who are hydrogen, and the third of R2, R3and R4means carboxy, (C1-C4)alkoxycarbonyl or-N(R9R10where

R9means hydrogen or (C1-C4)alkyl and

R10means-COR15where

R15means (C1-C4)alkyl, or

R9and R10means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atoms or one ring nitrogen atom and one ring oxygen atom, preferably a heterocyclic group containing 6 ring atoms, including one ring nitrogen atom and one ring oxygen atom.

Compounds represented by formula I, are capable of forming acid additive salts, in particular pharmaceutically acceptable acid additive salts. Pharmaceutically acceptable acid additive salts of the compounds of formula I include salts of inorganic acids, for example galoidvodorodnykh acids, such as hydrofluoric acid, hydrochloric acid, Hydrobromic acid or uudistoodetena acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, triperoxonane acid, propio the OIC acid and butyric acid, aliphatic hydroxyacids, such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, n-chlorbenzene acid, diphenyloxy acid or triphenylarsine acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, n-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids, such as methanesulfonate acid or benzolsulfonat acid. These salts can be obtained from compounds of the formula I by known methods for the formation of salts.

The compounds of formula I which contain acidic, i.e. carboxyl groups capable of forming salts with bases, in particular pharmaceutically acceptable bases, such as those well known in the art; such applicable salts include metal salts, particularly alkali metal salt or alkaline earth metals such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamine or pyridine. These salts can be obtained from the compounds is of the formula I by known methods for the formation of salts.

Specific especially preferred compounds according to the invention are compounds described in the examples below. Among them, the most preferred compounds include those of formula III, in which

(i) X is NH,

R1means cyclopropyl, R2and R4denote each hydrogen and R3means N(CH3)3; or

(ii) X is NH,

R1means cyclopropyl, R2and R4denote each hydrogen and R3means morpholino; or

(iii) X is NH,

R1means cyclobutyl, R2and R4denote each hydrogen and

R3means 4-tert.-butoxycarbonyl-1-piperazinil; or

(iv) X is NH,

R1means cyclobutyl, R2and R4denote each hydrogen and R3means-N(CH3Of PINES3; or

(v) X is NH,

R1means isopropyl,

R2and R4denote each hydrogen and

R3means-SO2N(CH3)3; or

(vi) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means 4-acetyl-1-piperazinil; or

(vii) X is NH,

R1means tert. -butyl,

R2means hydrogen and

R3and R4mean along-CH2OCO-; or

(viii) X is Oh,

R1means cyclobuta is,

R2and R4denote each hydrogen and

R3means-N(CH3Of PINES3; or

(ix) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means 4-methyl-1-piperazinil; or

(x) X is NH,

R1means tert.-butyl,

R2and R4denote each hydrogen and

R3means-N(CH3Of PINES3; or

(xi) X is NH,

R1means isopropyl,

R2and R4denote each hydrogen and

R3means-N(CH2CH3Of PINES3; or

(xii) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means-N(CH3Of PINES2CH3;

moreover, the compounds are in free form or in the form of pharmaceutically acceptable salts, especially in the form of cleaners containing hydrochloride or trifenatate salts.

The present invention also provides a method of obtaining compounds of formula I and their salts, which includes

(A) the interaction of the compounds of formula

with the compound of the formula

where X, R1, R2, R3and R4have the meanings previously defined, and Y represents a leaving group, preferably halogen, such as bromine, iodine or osobennogo, and as a free functional group in the compounds of formulas V and VI are different from those involved in the reaction, is protected, if necessary, removing the protective group; or

(B) to obtain the compounds of formula I in which R2, R3or R4means carboxyl or carboxialkilnuyu group, cleavage of the corresponding compounds of formula I in which R2, R3or R4means alkoxycarbonyl or alkoxycarbonylmethyl group, respectively; or

(C) to obtain the compounds of formula I in which R2, R3or R4means alkoxycarbonyl or alkoxycarbonylmethyl group, respectively, the esterification of the corresponding compounds of formula I in which R2, R3or R4means carboxyl or carboxialkilnuyu group; or

(D) to obtain the compounds of formula I in which R2, R3or R4means a group of the formula-SO2N(R11R12whose values previously defined, respectively, by amination of the corresponding compounds of formula

in which R1shall have the meaning given above, R

2
a
, R
3
a
and R
4
a
mean respectively the same as R2, R3and R4as defined above, except that at least one of them means a group of the formula-SO2l, where Hal means halogen, preferably chlorine or bromine; or

(E) for obtaining the compounds of formula I in which R2, R3or R4means a group of the formula-CON(R13R14as previously defined, respectively, by amination of the corresponding compounds of formula I, where R2, R3or R4mean carboxypropyl;

and optional conversion of the compounds of formula I in protected form in the appropriate connection in unprotected form;

and regeneration of the compounds of formula I in free form or in salt form.

Protective groups, their introduction and their removal are described, for example, in the monograph "Protective Groups in Organic Synthesis, by T.W. Greene and others, published by John Wiley & Sons Inc., second edition, 1991.

Variant of the method (A) can be carried out using standard techniques. Convenient to carry it out in an inert organic solvent, preferably in a polar solvent such as dioxane or N-metalpro icon. A suitable reaction temperature is from 50 to 250°C, preferably from 100 to 150°C. the Reaction can kataliziruetsa a strong acid, the tertiary base or preferably metal ions, such as Ag, Cu, Li, Ni, Zn, La, Yb, or Sn. The reaction is conveniently performed using 1-5 equiv., for example 1-3 equiv., the compounds of formula VI in EQ. the compounds of formula V.

Compounds of formulas V and VI are known or can be obtained by methods similar to those used for known compounds. Thus, the compounds of formula V can be obtained, for example as described in WO 97/16452 or as described in the examples below.

Variant of the method (C) can be carried out using standard techniques cleavage of ester, for example using conventional hydrolysis catalyzed by acid or base, or in the same way as described in the examples below.

Variant of the method (C) can be carried out using standard methods of esterification, or similarly as described in the examples below.

Variant of method (D) can be done using standard techniques, for example by reaction haloalkaliphilic derivative of formula VII with the compound of the formula HN(R11R12in which R11and R12have the previously defined meanings, in certain circumstances, or in the same way as described in the examples below. Connected to the I of the formula VII are known or can be obtained by means similar to those used to obtain the known compounds, for example, the interaction of the compounds which are unsubstituted in the position of benzene ring, in which must be entered haloalkaliphilic group, with galoidovodorodami agent such as chlorosulfonic acid, for example, as described later in examples.

Variant of the method (E) can be carried out by standard methods, for example by transformation of the corresponding carboxypropanoyl to the acid chloride and the interaction of the carboxylic acid with the compound of the formula HN(R13R14in which R13and R14have the previously defined meanings, in certain circumstances, or in the same way as described in the examples below.

The compounds of formula I in free form may be converted into the salt form, or Vice versa, in a standard way. Compounds in free form or in salt form can be obtained in the form of hydrate or solvate solvent used for crystallization.

The compounds of formula I can be isolated from the reaction mixture and purified by a commonly known method. Isomeric mixtures can be separated into individual isomers, such as enantiomers, in a standard way, for example by fractional crystallization.

The compounds of formula I in free form or in salt form PR is important as pharmaceuticals. Accordingly, the invention also provides a compound of formula I in free or pharmaceutically acceptable salt form for use as a pharmaceutical product. The compounds of formula I in free form or in the form of pharmaceutically acceptable salts, hereinafter alternatively referred to as “agents of the invention inhibit the activity of tyrosylprotein syk, which is an activator of Pro-inflammatory cells that cause allergic reactions. The inhibitory property agents according to the invention can be illustrated by the following analysis.

In this analysis determines the effect of the agent according to the invention on the phosphorylation of the peptide kinase syk. The phosphate is transferred from the end phosphate group of adenosine triphosphate (ATP) on a modified Biotin peptide Biotin-EDPDYEWPSA (available from the company Genosys), which is a known specific substrate for the kinase syk. When32R-phosphorylated peptide is associated with streptomycinresistant (PVT) balls scintillation analysis of spatial proximity (SPA) (available from the company Amersham)radiated β-particles excite the fluorophore in the balls and lead to the glow. Free32P-ATP in the solution does not excite the fluorophore, because the balls are separated from the solution by flotation, and therefore he is not in question is rastenii proximity to the balls. Thus, scintillation account is a measure of the degree of inhibition of the studied compound phosphorylation by syk kinase.

In wells Optiplate (Canberra Packard) was added (i) an investigational compound in a mixture of DMSO/distilled water (10 μl), (ii) 20 μl of a composition formed by mixing 1 mm Biotin-EDPDYEWPSA (5,5 ml), 300 μm ATP (18,3 mm) and32P-ATP in a quantity sufficient to add 0.1 µci32P-ATP per well (1,1 μl per day), and brought volume up to 2.2 ml of a buffer (buffer A), obtained by dissolving Tris-base (0.36 g) in distilled water (80 ml), bringing the pH to 7.5 with 1 M hydrochloric acid, adding 1 M aqueous solution of MgCl2(1.5 ml), 50 mm aqueous solution of orthovanadate sodium (30 μl) and 1 M aqueous solution of dithiothreitol (150 μl) and bringing the volume with distilled water up to 120 ml, (iii) a 0.5% wt./about. kinase syk in buffer A (20 µl). Tablet incubated at room temperature for 30 min with shaking, and then the reaction was stopped by adding all wells with 150 ál of the mixture obtained by dilution of 500 mg of beads streptavidin PVT SPA 373 ml of physiological solution with Tris buffer containing 673,6 mg of caesium chloride, 20 ml of 0.5 M EDTA (ethylenediaminetetraacetic acid) and 27.5 mg of ATP (disodium salt) per litre. The tablet again incubated at room temperature for 30 min with Strahan and, then sealed using the fixture Top Seal-S (Canberra Packard) according to the manufacturer's instructions and left to stand at room temperature for 1 h the resulting scintillation considered using the device Packard TopCount, and each well was shortchanged for 1 minute

The methodology was repeated for different concentrations of the investigated compounds, selected to cover the range of inhibition from 0% to 100%, and the concentration at which 50% inhibition of kinase syk (IC50), for each connection defined in the usual way on the curve according to the concentration-inhibition.

The compounds in the examples below have the meanings IC50of the order of 1 μm or less in the above analysis. For example, compounds of the following examples 1 to 7 have values IC50equal to 3 nm, 4 nm, 5 nm, 5 nm, 9 nm, 10 nm and 10 nm, respectively, the compounds of examples 102-104 matter IC50equal to 5 nm, 2 nm and 3.6 nm, respectively, and the compounds of examples 138, 141, 170, 172, 188 and 201 are set IC50equal to 14 nm, and 4.5 nm, 10 nm, 6 nm, 5 nm and 5 nm, respectively.

With regard to the inhibition of their kinase syk and suppression, mediated by IgE (immunoglobulin E) degranulation of mast cells, the agents according to the invention is applicable in the treatment of conditions which are mediated by syk kinase, in particular inflammatory or allergic the ski conditions. In accordance with the invention, the treatment may be symptomatic or preventive.

Accordingly, the agents according to the invention is applicable in the treatment of inflammatory or obstructive diseases of the respiratory tract. Inflammatory or obstructive diseases of the respiratory tract to which the present invention is applicable, includes asthma of any type or Genesis including both hereditary (non-allergic) asthma and acquired (allergic) asthma. Treatment of asthma should also be understood as therapy, covering subjects, for example, in the age of 4-5 years, with symptoms of shortness of breath and diagnosed or diagnosable as “children with breathing difficulties”, a recognized category of patients is of paramount medical importance and are now frequently identified as asthma patients in the initial or early stage. (For convenience, this particular asthmatic condition is defined as “a syndrome of child shortness of breath”).

Prophylactic efficacy in the treatment of asthma is confirmed by the decrease in the frequency or severity of symptomatic attack, such as acute asthma attack attack or bronchostenosis. It can be further confirmed by the reduced need for other symptomatic therapy, i.e. therapy limited to what I or attempt to limit or termination of symptomatic attack, when it happens, for example anti-inflammatory (e.g., the use of corticosteroid or bronchodilator therapy. Prophylactic use in asthma may be particularly noticeable in subjects prone to “morning dipping”. The term “morning dive” means a recognized asthmatic symptoms common to a significant percentage of asthmatics and characterized in that an asthma attack occurs approximately between 4-6 hours of the morning, i.e. at a time substantially distant from any previously held the symptomatic treatment of asthma.

Other inflammatory or obstructive disease or condition of the respiratory tract to which the present invention is applicable, include respiratory distress syndrome in adults (ARDS), chronic obstructive pulmonary disease or respiratory (COPD or COAD), including chronic bronchitis and associated with shortness of breath, emphysema, and increased hyperresponsiveness of the Airways as a consequence of other drug therapy, especially therapy other inhaled drug. The invention is applicable also to the treatment of bronchitis of any type or Genesis, including, for example, acute, arachidonic (arachidic), catarrhal, lobar, or chronic purulent tuberculous bronchitis. Further inflammatory or obstructive diseases of the respiratory tract, to catherinemunro the present invention, include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by obstruction of the respiratory tract, chronic or acute, and the resulting repeated inhalation of dusts) of any type or Genesis, including, for example, aluminas, antraks, helicos, Philos, sideros, silicosis, tabacos and bissines.

As for their anti-inflammatory activity, particularly in relation to suppress activation of eosinophils, the agents according to the invention is also applicable to the treatment of disorders associated with eosinophils, such as eosinophilia, especially those related to eosinophils disorders of the respiratory tract (e.g., pathological eosinophilic infiltration of pulmonary tissues)including hypereosinophilia as it affects the respiratory tract and/or lungs, as well as, for example, associated with eosinophils disorders of the respiratory tract caused by or related syndrome Leffler, eosinophilic pneumonia, parasitic (especially in the case of multicellular) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarthritis thickening (including syndrome Bokson-Strauss), eosinophilic granuloma and associated with eosinophils disorders affecting the respiratory tract and is caused by a reaction to the drug.

The agents according to the invention are also applicable to the treatment of the AI inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphic erythema, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitive of angiitis, urticaria, bubble of pemphigoid, lupus erythematosus, ordinary water, acquired bullous of bullosa and other inflammatory or allergic conditions of the skin.

The agents according to the invention can also be applied in the treatment of other diseases or conditions, particularly diseases or conditions having an inflammatory component, for example in the treatment of diseases or conditions of the eye such as conjunctivitis, dry keratoconjunctivitis and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory bowel disease such as ulcerative colitis and Crohn's disease.

The effectiveness of the agent according to the invention in suppressing inflammatory conditions such as inflammatory diseases of the respiratory tract, can be demonstrated in animal models, such as mouse or rat model of airway inflammation or other inflammatory conditions, as described, for example, Szarka, etc., J. Immunol. Methods (1997) 202: 49-57; Renzi and other Am. Rev. Respir. Dis. (1993) 148: 932-939; Tsuyuki, etc., J. Clin. Invest. (1995) 96: 2924-2931; and Cernadas and others, (1999) Am. J. Respir. Cell Mol. Biol. 20: 1-8.

The agents according to the invention pressitakse as therapeutic agents for joint use in combination with anti-inflammatory or bronchodilator drug especially in the treatment of obstructive or inflammatory diseases of the respiratory tract, such as those mentioned above, such as amplifiers therapeutic activity of certain drugs or as a means to reduce the required dose or potential side effects of such drugs. The agent according to the invention can be blended with anti-inflammatory or bronchodilator drug in a fixed pharmaceutical composition or it may be introduced separately, before, simultaneously or after anti-inflammatory or bronchodilator drug. Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone or mometazon, and dopamine receptor agonists, such as cabergoline, parlodel or ropinirole. Such bronchodilatory drugs include anticholinergic or antimuskarinovoe act occurs agents, in particular ipratropium bromide, bromide oxytrope and Tiotropium bromide. Combinations of agents according to the invention and steroids can be applied, for example, in the treatment of COPD or, in particular, asthma. Combinations of agents according to the invention and anticholinergic antimuskarinovoe act occurs or agents or agonists dopamine receptor can be used, for example, in the treatment of asthma, particularly COPD.

In accordance with the foregoing, and the acquisition also provides a method of treatment of a condition, mediated by syk kinase, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive diseases of the respiratory tract, which includes an introduction to the subject, in particular seeker in this introduction, an effective amount of the compounds of formula I in free form or in the form of pharmaceutically acceptable salts, as described previously for use in the manufacture of the drug in the treatment of condition mediated by a kinase syk.

The agents according to the invention can be introduced by any suitable route, for example orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example, in the treatment of inflammatory or obstructive diseases of the respiratory tract; intranasal, for example, in the treatment of allergic rhinitis; local on the skin, for example, in the treatment of atopic dermatitis; or rectally, for example, in the treatment of inflammatory bowel disease.

In a further aspect the invention also provides a composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, together with its pharmaceutically acceptable diluent or carrier. The composition may contain additional therapeutic agent, such as anti-inflammatory or bronchodilator agent as described above. Such compositions can be prepared using conventional diluents or fillers and techniques known in pharmacology. Thus, the oral dosage forms may include tablets and capsules. Dosage forms for topical application can be in the form of creams, ointments, gels and transdermal delivery systems, such as patches. Compositions for inhalation may include an aerosol or other spray form or in a dry powder mixture.

The invention includes (A) the agent according to the invention in an inhaled form, for example in the form of an aerosol or other spray compositions or in the form of respirable particles, for example, in fine form; (B) the drug for inhalation, comprising the agent according to the invention in an inhaled form; (C) a pharmaceutical product comprising the agent according to the invention in an inhaled form, together with the device for inhalation; and (G) a device for inhalation containing the agent according to the invention in an inhaled form.

Doses of the agents according to the invention is used in practice of the present invention will, of course, vary depending, for example, from the individual to the state, which must be treated, the intended effect and the method of introduction. In General, an acceptable daily dose for administration by inhalation have is adok of 0.1-100 mg/kg, while oral administration is acceptable dose of the order of 1-1000 mg/kg

The invention is illustrated by the following examples.

Examples

Intermediate compounds used in the examples was prepared as follows.

1. meta-(3,5-Dimethylmorpholine)aniline

A. meta-(3,5-Dimethylmorpholine)nitrobenzene

1-Fluoro-3-nitrobenzene (2.8 g, 0.02 M) and 2,6-dimethylmorpholine (12.5 g, 0.12 M) was heated in DMSO (33 ml) at 100°C for 66 hours, the Cooled mixture was poured into water (300 ml). The precipitate was collected by filtration, washed with water and dried in a vacuum; ES+(the ionization in mass spectrometry by electrocapillary with the formation of a positive ion (M+Na) 258,96; tpl.126,6-127,8°C.

B. meta-(3,5-Dimethylmorpholine)aniline

meta-(3,5-Dimethylmorpholine)nitrobenzene (1A) (2 g, 8.5 mmole) was first made in ethanol (50 ml) over 10% Pd/C (200 mg) for 1.5 hours, the Catalyst was removed by filtration, the solvent was evaporated, getting oil. Enantiomers can be separated by column chromatography on silica gel. ES+(M+1) 207,36.

Beta-Morpholinoethyl

A. meta Morpholinopropan

Was obtained from 1-fluoro-3-nitrobenzene (10 g, of 0.07 M) and research (33,5 g, 0.38 M) in DMSO (116 ml)using the method described G.G. Brown and others, Tet. Lett. 40 (1999) 1219-1222. Filtration of the precipitate gave the product; tpl.113,8-115,5°C.

B. meta-Morpholinyl

meta-Morpholinoethyl ESOL (2A) (2 g, 9.6 mmole) was first made in a mixture of ethanol and ethyl acetate (50 ml/10 ml) over 10% Pd/C (200 mg) for 1 h, the Catalyst was separated by filtration, the solvent was removed by evaporation, getting a solid, which was dried in a vacuum; ES+(M+1) 179,35; tpl.125,4-uniforms, 127.6°C.

3. meta-(1-Methylpiperazin)aniline

A. meta-(1-Methylpiperazin)nitrobenzene

1-Fluoro-3-nitrobenzene (8.5 ml, 0.08 M) and 1-methylpiperazine (22.5 ml, 0,247 M) were heated in DMSO (100 ml) at 100°C for 48 hours, the Cooled mixture was poured into water (500 ml). Water the mixture was cooled at 0°and after 48 h the precipitate was collected by filtration, washed with cold water and dried in a vacuum; ES+(M+1) 222, tpl.107,5-to 108.2°C.

B. meta-(1-Methylpiperazin)aniline

meta-(1-Methylpiperazin)nitrobenzene (3A) (2 g, 0,009 M) was first made in ethanol (50 ml) over 10% Pd/C (100 mg) for 0.5 hours, the Catalyst was separated by filtration, the solvent was removed by evaporation, receiving oil; ES+(M+1) 191,5; tpl.87,6-89,0°C.

4. para-(1-Methylpiperazin)aniline

A. para-(1-Methylpiperazin)nitrobenzene

1-Fluoro-4-nitrobenzene (8.5 ml, 0.08 M) and 1-methylpiperazine (22.5 ml, 0,247 M) were heated in DMSO (100 ml) at 100°C for 60 hours, the Cooled mixture was poured into water (500 ml), the precipitate was collected by filtration, washed with water and dried in a vacuum; ES+(M+1) 222; tpl.57,4 to 58.9°C.

B. para-(1-Methylpiperazin)aniline

para-(1-Metile erasin)nitrobenzene (4A) (2 g, 0,009 M) was first made in ethanol (50 ml) over 10% Pd/C (250 mg) for 5 hours, the Catalyst was separated by filtration, the solvent was removed by evaporation, getting solid. ES+(M+1) 191,8; tpl.101,5-103,4°C.

Intermediate compounds 5A-8b formula

where Z means NO2or NH2and substituted piperazinilnom the group is in the meta or paraprotein to Z, obtained as described above. They are listed in the following table 1 together with the similar method of delivery:

/tr>
Table No. 1
No.Zmeta/paraRMethodES+(M+1)tpl.(°C)
5ANO2m-PINES33(a) 151, 3mm-153,6
5BNH2m-PINES33(b)220127,8-129,4
6ANO2nPINES34(a)250of 98.2-1-1,3
6bNH2nPINES34(b)220138,8-140.7
7aNO2m-SOS(CH3)33(a) 146,1-147,0
7bNH2m-SOS(CH3)33(b)  
8ANO2nSOS(CH3)34(a) 88,4-90,1
8bNH2nSOS(CH3)34(b)278 

9. N-Acetyl-N-ethyl-4-aminoaniline

A. N-Acetyl-N-ethyl-4-nitroaniline

To a suspension of N-ethyl-4-nitroaniline (1.5 g, 9,026 mmole) in benzene (15 ml) were added acetylchloride (10 ml), the mixture was heated at boiling for 40 minutes, the Solvent was removed by evaporation. The residue was dissolved in ethyl acetate before washing with 2 N. sodium bicarbonate and water, drying (MgSO4and the process of evaporation. The product was dried in a vacuum; ES+(M+1) 208,57.

B. N-Acetyl-N-ethyl-4-aminoaniline

Was first made of N-acetyl-N-ethyl-4-nitroaniline (9a) (1.8 g, 8,64 mmole) in THF (30 ml) over 10% Pd/C (100 mg) for 1.5 hours, the Catalyst was separated by filtration, the solvent was removed by evaporation. The product crystallized upon standing in hexane, after filtration was dried in a vacuum is; ES+(M+1) 178,88.

10. N-Propionyl-N-methyl-4-aminoaniline

A. N-Propionyl-N-methyl-4-nitroaniline

The reaction was carried out using a method analogous to (9a), using N-methyl-4-nitroaniline (5 g, 32,86 mmole) in benzene (30 ml), treated with propionylcarnitine (15 ml). ES+(M+1) 208,88.

B. N-Propionyl-N-methyl-4-aminoaniline

The reaction was carried out using a method analogous to (9b), using N-propionyl-N-methyl-4-nitroaniline (10A) (6.8 g, 32,86 mmole), 10% Pd/C (447 mg) in THF (75 ml). Hydrogenation gave the oil. ES+(M+1) 178,87.

11. 4-(ETHYLACETYLENE)aniline

A. 4-(ETHYLACETYLENE)-1-(tert.-butylcarbamoyl)aniline

To a solution of N-tert.-butylcarbamoyl-1,4-phenylenediamine (1 g, 4.8 mmole) and triethylamine (of 1.34 ml) in dichloromethane (15 ml) was added ethyl ester of the acid chloride oxalic acid (0,655 g, 4.8 mmole) in 10°C. the Mixture was stirred at ambient temperature for 10 minutes the Mixture was distributed between dichloromethane and water. The organic layer was separated and washed with water, dried (MgSO4) and was evaporated. The residue is suspended in a mixture of diethyl ether and hexane. After filtration and washing with additional quantity of a mixture of diethyl ether/hexane, the product was dried in vacuum.

B. 4-(ETHYLACETYLENE)aniline

To a solution of 4-(ETHYLACETYLENE)-1-(tert.-butylcarbamoyl)aniline (11a) (1.3 g, 4.2 mmole) in dichloromethane (25 ml) at 10°With probable and triperoxonane acid (5 ml) and was stirred for 48 h at 5° C. the Mixture was podslushivaet the addition of concentrated ammonium hydroxide and diluted with ethyl acetate (200 ml). The resulting solution was washed with a mixture of water/ice and a saturated solution of salt, dried (MgSO4) and evaporated before purification by chromatography on a column of silica gel. Received the product as orange crystals; tpl.110-113°C.

12. 4-(Methylmaleimide)aniline

A. 4-(Methylmaleimide)-1-(tert.-butylcarbamoyl)aniline

To a solution of N-tert.-butylcarbamoyl-1,4-phenylenediamine (1 g, 4.8 mmole) and triethylamine (2 ml) in dichloromethane (15 ml) was added methyl ester acid chloride of malonic acid (1 ml, 9.6 mmole) in 10°C. the Mixture was stirred at ambient temperature for 1 h, then at 40°C for 30 minutes the Suspension was distributed between dichloromethane and water. The organic layer was separated and washed with water, dried (MgSO4) and was evaporated. The product was purified by chromatography on a column of silica gel.

B. 4-(Methylmaleimide)aniline

To a solution of 4-(methylmaleimide)-1-(tert.-butylcarbamoyl)aniline (12A) (1.3 g, 4.2 mmole) in dichloromethane (25 ml) at 10°With added triperoxonane acid (5 ml) and was stirred for 48 h at 5°C. the Biphasic mixture was stirred at 0°and podslushivaet the addition of concentrated ammonium hydroxide and diluted with ethyl acetate (200 ml). Polucheniya washed with a mixture of water/ice and a saturated solution of salt, dried (MgSO4) and evaporated before purification by chromatography on a column of silica gel. Received the product as yellow crystals; tpl.103-105°C.

13. 4-(Butylamino)aniline

A. 4-(Butylamino)-1-(tert.-butylcarbamoyl)aniline

To a solution of N-(tert.-butylcarbamoyl)-1,4-phenylenediamine (0.6 g, 2.88 mmole) and triethylamine (0,803 ml) in dichloromethane (10 ml) was added the acid chloride butyric acid (0,299 ml, 2.88 mmole) in 10°C. the Mixture was stirred at ambient temperature for 1 h, the Suspension was distributed between dichloromethane and water. The organic layer was separated and washed with water, dried (MgSO4) and was evaporated, obtaining crystalline product; ES+(M+Na) 301,23.

B. 4-(Butylamino)aniline

To a solution of 4-(butylamino)-1-(tert.-butylcarbamoyl)aniline (13A) (0,77 g, 2,77 mmole) in dichloromethane (75 ml) at 10°With added triperoxonane acid (2 ml) and was stirred for 18 h at ambient temperature. A two-phase mixture was stirred at 0°and podslushivaet the addition of concentrated ammonium hydroxide. The mixture was washed with water, dried (MgSO4) and evaporated before purification by chromatography on a column of silica gel. Received the product in crystalline form.

14. N-Methylcyclopropene

A. N-Carbencillin

Synthesis of N-carbencillin conducted with the availa able scientific C of the way, described in J. Heterocycl. Chem. (1983) 1035 using carbobenzoxy (56,3 g, 0.33 M), cyclopropylamine (19.6 g, 0,344 M), sodium carbonate (36,1 g, 0.34 M) in toluene (400 ml) and water (400 ml). Received the product as colourless crystals; ES+(M+1) 192,6.

B. N-Methyl-N-carbencillin

Synthesis of N-carbencillin conducted in accordance with the method described in J. Heterocycl. Chem. (1983) 1035, using N-carbencillin (14a) (10.5 g, to 0.055 M) in DMF (80 ml), sodium hydride (1.4 g) and methyl iodide (4 ml). The product was purified by vacuum distillation; tKip.86-92°s at 0.02 mm Hg

C. N-Methylcyclopropene

Synthesis of N-methylcyclopropene conducted in accordance with the method described in J. Heterocycl. Chem. (1983) 1035, using N-methyl-N-carbencillin (14b) (of 11.45 g, to 0.055 M), concentrated hydrochloric acid (4,32 ml), 10% Pd/C (700 mg) in ethanol (135 ml). Received and used the product in the form of a solution in ether.

15. para-(1-Ethylpiperazin)aniline

A. para-(1-Ethylpiperazin)nitrobenzene

1-Fluoro-4-nitrobenzene (0.54 ml, 0.005 M), 1-ethylpiperazine (1.9 ml of 0.015 M) and potassium carbonate (0,69 g, 0.005 M) was heated in acetonitrile (7 ml) at 85°in a stream of nitrogen for 24 hours, the Cooled mixture was distributed between dichloromethane and water. The organic layer was separated, the aqueous layer was twice extracted with dichloromethane. Obyedinenie the e organic layers washed twice with saturated salt solution, dried (MgSO4), filtered and evaporated, obtaining a solid substance, which may, if desired, be further purified column chromatography. ES+(M+1) 236; tpl.79-81°C.

B. para-(1-Ethylpiperazin)aniline

Was first made pair-(1-ethylpiperazin)nitrobenzene (0.5 g, of 0.002 M) in a mixture of ethanol/ethyl acetate (12.5 ml/2.5 ml) over 10% Pd/C (50 mg) for 24 hours, the Catalyst was separated by filtration, the solvent was removed by evaporation, getting a solid, which was dried in vacuum. ES+(M+1) 206; tpl.77-78°C.

Intermediate compounds 16A-18b formula VIII received similar compounds 15A and 15B. The data shown in the following table No. 2:

No.Zmeta/paraRMethodES+(M+1)tpl.(°C)
16ANO2nCH2CH2HE15(a)25298-100,5
16BNH2nCH2CH2HE15(b)222-
17ANO2nCH2SOON2CH315(a)--
17B NH2nCH2SOON2CH315(b)264-
18aNO2nSOON2CH315(a)-114-117
18bNH2nSOON2CH315(b)--

para-(1-Hydroxypiperidine)nitrobenzene (19(a)) was obtained from 1-fluoro-4-nitrobenzene and 4-hydroxypiperidine similar to the connection 15(a); ES+(M+1) 223.

para-(1-Hydroxypiperidine)aniline (19(b)) was obtained similarly to compound 15(b) of compound 19(a); TOF (time-of-flight mass spectrometry) ES+(M+1) 193.

20. 1-(4-Aniline)-2-pyrrolidinone

Was first made 1-(4-nitrophenyl)-2-pyrrolidine (1 g, of 0.004 M) in ethyl acetate (75 ml) over 5% Pd/C (160 mg) for 18 hours, the Catalyst was separated by filtration, the solvent was removed by evaporation, getting solid. ES+(M+1) 177; tpl.129-130°C.

21. 3,3-Dimethyl-1-(4-aniline)-2-azetidinone

Was first made 3,3-dimethyl-1-(4-nitrophenyl)-2-azetidinone (985 mg, of 0.004 M) in ethyl acetate (100 ml) over 5% Pd/C (150 mg) for 1 h, the Catalyst was separated by filtration, the solvent was removed by evaporation, getting solid. ES+(M+1) 191; tpl.113-114°C.

The compounds of formula III p who were given one of the following General methods.

Method And

The corresponding 2-chloro-6-substituted purine of the formula V was heated with 1.5-3 EQ. the appropriate aniline of formula VI at a temperature of 90-190°over time 3-78 including the Desired product was isolated (i) by precipitation from the reaction mixture, washing with methanol, ethanol, water or dioxane and optional allocation hydrochloric salt upon treatment with Hcl in dioxane or (ii) the concentration of methanol or ethanol solution, or (iii) the concentration of the solution and subsequent flash chromatography on silica gel or a direct clearing preparative HPLC.

Method In

As in method A, except that the purine of formula V was heated with 1.5 EQ. aniline of the formula VI and 1.5 EQ. diisopropylethylamine at 130°for 16-96 h and the product was isolated distribution between ethyl acetate and water, followed by extraction with ethyl acetate, the concentration of the solution and purified flash chromatography on silica gel.

Way

As in method A, except that the reaction mixture was distributed between ethyl acetate and water were podslushivaet 1 N. NaOH or saturated aqueous Panso3was extracted with ethyl acetate, concentrated solution and was purified flash chromatography on silica gel.

Method D

The corresponding ester in ethanol, a mixture of THF/water methanol or THF/water was treated with 2,5-13 EQ. 1 N. NaOH or LiOH at room te is the temperature. The mixture was neutralized with 1 N. hydrochloric acid, the solvent was removed. The product was isolated by dissolving in ethanol, filtration and evaporation of the filtrate.

Method In

As in method A, with the addition to the heated reaction mixture with concentrated hydrochloric or triperoxonane acid.

Method F

As in method A, followed by treatment of the product chlorosulfonic acid. Was added 400 μl of a solution obtained sulphonylchloride to a 1 M solution of the appropriate amine of the formula HN(R11R12and after 2 h the solvent was removed and product was purified preparative HPLC.

Method G

As in method A, with the addition of silver triflate (1 EQ.) the hot reaction mixture.

Way N

Stirred the appropriate carboxylic acid in DMF with 1 EQ. suitable amine of formula HN(R13R14dissolved in THF, and equivalent quantities of N-dimethylaminopyridine and hexaphosphate benzotriazol-1-yl-oxtriphylline at 20°C for 16 hours the Product was isolated by precipitation from the reaction mixture during processing with 1 N. hydrochloric acid, followed by purification on a flash chromatography on silica gel.

The way I

The corresponding carboxylic acid is reacted with excess thionyl chloride, giving the corresponding acid chloride of the acid, which was treated in b is sole appropriate amine of the formula HN(R 13R14or a suitable alcohol. The product was isolated by evaporation and purification preparative HPLC.

Method J

The corresponding 2-chloro-6-substituted purine of the formula V and the appropriate aniline of formula VI (2.2 EQ.) was heated in a microwave oven at 140°and 50% power for 10 min followed by treatment with methanol. The product was isolated by filtration.

The compounds of formula III, examples identified 1-221, listed in the following table along with used General way. In table 3 Surg means cyclopropyl, suvi means cyclobutyl, Sura means cyclopentyl and Uprr means N-benzylpiperidine.

Getting some compounds of the above examples is described in more detail neither the E.

Used the following abbreviations:

NMP: N-organic

DCM: dichloromethane

THF: tetrahydrofuran

Rumor: hexaphosphate benzotriazol-1-yl-oxtriphylline

DMAP: N,N-dimethyl-4-aminopyridine

DMF: dimethylformamide

HPLC: high performance liquid chromatography

TLC: thin layer chromatography

Example 5

A. Cyclopropylamine (6,65 g, 0,116 M) and N,N-diisopropylethylamine (20,8 ml, 0,116 M) was added to a suspension of 2,6-dichloropurine (20 g, 0,106 M) in n-butanol (200 ml). The mixture was stirred at 60°C for 20 hours the Mixture was cooled and the precipitate was isolated by filtration, washed with n-butanol and dried in vacuum, obtaining 6-cyclopropylamino-2-globulin; ES+(M+1) of 209.5; tpl.249,7°C (decomp.).

B. A solution of 6-cyclopropylamino-2-chloropurine (0,535 g, 2.5 mmole) and 4-morpholinopropan (0,683 g, 3.8 mmole) in NMP (2.5 ml) was stirred at 130°C. After the solid dissolved, was added N,N-diisopropylethylamine (0,65 ml, 3.8 mmole), the mixture was stirred at 130°C for 48 hours the Mixture was cooled and distributed between ethyl acetate and water. The layers were separated, the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic layers were evaporated, the residue was purified by chromatography on a column of silica gel (4% methanol:D). The product was isolated as a brown solid, which was dried in a vacuum; ES+(M1) 352; tpl.reach 201.9-203,7°C.

Example 6

A. Cyclobutylamine (20 g 0,28 M) and N,N-diisopropylethylamine (50,4 ml of 0.28 M) was added to a suspension of 2,6-dichloropurine (48,4 g, 0.25 M) in n-butanol (480 ml). The mixture was stirred at 60°C for 20 hours the Mixture was cooled, the precipitate was isolated by filtration, washed with n-butanol and dried in vacuum, obtaining 6-cyclobutylamine-2-globulin; ES+(M+1) 222,5; tpl.237,8°C (decomp.).

B. A solution of 6-cyclobutylamine-2-chloropurine (100 mg, 0,447 mmole), 4-amino-N-methylacetamide (220 mg, 1.34 mmole) in NMP (1 ml) was stirred at 145°C under argon. After 7 h, the solvent was removed by evaporation, the residue is suspended in methanol and the suspension was irradiated with ultrasound for 3 minutes, the Solid was separated by filtration, washed with chilled methanol and dried in a vacuum; ES+(M+1) 350; tpl.314-318°C.

Example 19

A. A solution of 6-cyclopropylamino-2-chloropurine (5A) (0,209 g, 1 mmol) and methyl ester of 4-aminobenzoic acid (0,377 g, 2.5 mmole) in NMP (2 ml) was stirred at 130°C for 16 hours the Mixture was diluted with water and treated with 4 N. sodium hydroxide to achieve a pH of 14. The solution was extracted with ethyl acetate (4×100 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated. The residue was purified further by chromatography on a column of silica gel, receiving a colorless oil; ES+ (M+1) 325,3.

Example 34

A. To a stirred ethereal solution of N-methylcyclopropene (50 ml) was added 2,6-dichloropurine (1.3 g, 6.8 mmole). After 15 min was added n-butanol (3 ml)and the suspension was irradiated with ultrasound at 40°C for 1 h was Added an additional aliquot share of n-butanol, and continued exposure to ultrasound for 2.5 hours, the Mixture was stirred at ambient temperature for 16 hours the Precipitate was separated by filtration, washed with a mixture of ether/methanol, dried in vacuum at 115°receiving 6-N-methylcyclopropyl-2-globulin; ES+(M+1) 223,5; tpl.234-235°C (decomp.)

B. To a hot solution of 6-N-methylcyclopropyl-2-chloropurine (0.2 g, of 0.89 mmole) in NMP (1.7 ml) was added N-aminoindazole (0.26 g, a 1.96 mmole) and concentrated hydrochloric acid (7.7 ml). The mixture was stirred at 107°C for 20 h and at ambient temperature for 48 hours the Solvent was removed by evaporation, the residue was treated with methanol. The solid was isolated by filtration, washed with water and methanol, dried in vacuum at 100°C. the Solid was purified further by chromatography on silica gel and was led from methanol; ES+(M+1) 321,3; tpl.289-292°C.

Example 75

A. A solution of 6-cyclobutylamine-2-chloropurine (6A) (5 g, to 22.35 mmole) and aniline (6,1 ml, 67 mmol) in NMP (25 ml) was heated at 150°in techenie h and allowed to cool. After standing for 16 h at ambient temperature the resulting crystals were isolated by filtration, washed with dioxane (50 ml) and dried, obtaining 6-cyclobutylamine-2-anilinophenol; ES+(M+1) 280,86; tpl.312-314°C.

B. 6 Cyclobutylamine-2-anilinophenol (200 mg, 0,631 mmole) was carefully added to chlorosulfonic acid (2 ml). The solution was stirred at 50°C for 2 hours After cooling to ambient temperature the mixture was added dropwise to a mixture of ice/water (20 ml). The precipitate was separated by filtration and washed with cold water (5 ml). Solid 6-cyclobutylamine-2-(4-chlorosulfonylphenyl)purine was dissolved in NMP (2 ml).

C. To a 1 M solution of methylamine in ethanol (1 ml) was added 400 μl of a solution of 6-cyclobutylamine-2-(4-chlorosulfonylphenyl)purine in NMP. After 2 h the solvent was removed, the residue was purified using preparative HPLC; ES+(M+1) 374,4.

Example 79

A. To a suspension of 2,6-dichloropurine (2 g, 10.6 mmole) in n-butanol (3 ml) was added ethylamine (2 M in THF) (15 ml). The solution was stirred at 84°C for 2.5 h, then was cooled to ambient temperature and was stirred for additional 2 hours the precipitate was isolated by filtration, washed with n-butanol, methanol and ethyl acetate. The solid was dried at 70°C in vacuum for 16 h, receiving 6 acylamino-2-globulin; ES+(M+) 197,5, 198,2; tpl.237-239°C.

B. A solution of 6-ethylamino-2-chloropurine (200 mg, 1 mmol), methyl ester of 4-aminobenzoic acid (382 mg, 2.5 mmole) in NMP (0,77 ml) was stirred at 123°C under argon. After 22 h the solvent was removed by evaporation, the residue is suspended in methanol, and the suspension was irradiated with ultrasound for 3 minutes, the Solid was separated by filtration, washed with chilled methanol and dried in vacuo before purification by chromatography on a column of silica gel. The product was led from methanol, getting 6-ethylamino-2-(methyl-4-aminobenzoate)purine; ES+(M+1) 312,84; tpl.229-230°C.

C. To a suspension of 6-ethylamino-2-(methyl-4-aminobenzoate)purine (0.7 g, 2 mmole) in a mixture of THF/water (1:1) (55 ml) was added a solution of the monohydrate of lithium hydroxide (1.1 g, 26 mmol) in water (17 ml). The mixture was stirred at 55°C for 48 hours the Solvent was removed by evaporation, the residue was irradiated by ultrasound in water. The solid was removed by filtration, the filtrate was neutralized with concentrated hydrochloric acid. The precipitate was isolated by filtration and dried in vacuum at 75°; ES+(M+1) 398,71; tpl.301-303°C.

Example 80

To a solution of 6-ethylamino-2-(methyl-4-aminobenzoate)purine (V) (50 mg, 0,1493 mmole) in DMF (1 ml) under stirring at 45°C was added DMAP (20 mg) and 2 M ethylamine in THF (0.5 ml). The mixture was cooled to 25°and probabl is whether Rumor (78 mg). The mixture was stirred at ambient temperature for 20 h before removing the solvent. The residue is suspended in water and irradiated with ultrasound for 2 minutes and the Mixture was acidified to pH 4 by addition of 1 N. hydrochloric acid. The product was isolated by filtration, washed with water and dried in vacuum. The product can be further purified using preparative TLC, giving a crystalline solid; ES+(M+1) 325; tpl.295°C (decomp.).

Example 89

A mixture consisting of 10 ml of a suspension of 6-ethylamino-2-(methyl-4-aminobenzoylamino)purine in benzene obtained in example a, and dimethylamine (33% solution in methanol) (2 ml)was irradiated with ultrasound for 40 min and was stirred at ambient temperature for 48 hours the Solvent was removed in vacuo, and the residue suspended in water. Water decantation, and the oily residue was purified preparative HPLC. The product was led from methanol and dried in vacuum at 70°; ES+(M+1) 325,64; tpl.262 to 264°C (decomp.).

Example 94

A. A suspension of 6-ethylamino-2-(methyl-4-aminobenzoate)purine (V) (150 mg, 0,502 mmole) in thionyl chloride (12 ml) was stirred, barbotine argon at ambient temperature for 16 hours was Added an additional portion of thionyl chloride (5 ml), and continued the reaction for 20 hours, the Residue, 6-ethylamino-2-(methyl-4-aminobenzoyl orid)purine, suspended in benzene (20 ml).

B. To 10 ml of a suspension of 6-ethylamino-2-(methyl-4-aminobenzoylamino)purine in benzene was added isopropanol (1.5 ml) and triethylamine (0.2 ml). The mixture was irradiated with ultrasound for 30 min and stirred at ambient temperature for 48 hours the Solvent was removed in vacuo, and the residue was heated in water. The resulting crystalline solid was isolated by filtration and washed with water. Then was purified preparative HPLC, obtaining a colorless solid; ES-(M-1)340.

Example 96

A. Dissolved sodium metal (1,53 g 0,067 M) in a mixture of cyclobutanol (8 g, 0,11 M) and anhydrous THF (20 ml) at 90°C under nitrogen for 4 hours the Mixture was cooled to 0°and was added 2,6-dichloropurine (4,39 g 0,024 M). The mixture was stirred at ambient temperature for 0.5 h before addition of glacial acetic acid (10 ml) and water (30 ml). The precipitate was isolated by filtration, washed with water and dried in vacuum, obtaining a colorless solid, 6-O-cyclobutyl-2-globulin; ES+(M+1) 224,74; tpl.247,6-249,7°C (decomp.).

B. To a suspension of 6-O-cyclobutyl-2-chloropurine (0,22 g, and 0.98 mmole) in NMP (2 ml) was added, triplet silver (0,252 g to 0.98 mmole). The mixture was heated to 120°to achieve dissolution. To this solution was added 4-amino-N-methylacetanilide (0,402 g of 2.4 mol)and the mixture was stirred at 120°With those who tell 16 PM The mixture was cooled, and water was added (10 ml) and ethyl acetate (20 ml). The phases were separated, and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (30 ml), saturated salt solution (50 ml), dried (MgSO4), filtered and evaporated. The residue was purified further by chromatography on a column of silica gel; ES+(M+1) 352,72.

Example 131

A. To a solution of ethanthiol (0,93 ml, 12.5 mmole) in anhydrous THF (8 ml) was added sodium hydride (0,48 g, 12.5 mmole). As soon as the rapid foaming decreased, was added 2,6-dichloropurine (0,945 g, 5 mmol). The mixture was stirred at ambient temperature under nitrogen for 1.5 h, then was heated at boiling for 2 hours the Mixture was cooled, the solvent was removed by evaporation, the residue was purified by chromatography on a column of silica gel, receiving 6-etanercept-2-globulin; ES+(M+1) 215,3, 217,2; tpl.262-263°C.

B. A solution of 6-etanercept-2-chloropurine (107 mg, 0.5 mmole) and 4-amino-N-methylacetanilide (246 mg, 1.5 mmole) in NMP (0.5 ml) was heated at 140°C for 17 hours, the Cooled mixture was poured into water and was extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on a column of silica gel, receiving a colorless crystalline product; ES+(M+1) 342,76/343,46; tpl.219-220°C.

Por the measures 220

The product from example 6 (500 mg, of 1.42 mmole) suspended in a mixture of dichloromethane (5 ml) and water (5 ml). Added 4 N. aqueous sodium hydroxide solution to bring the pH value to 10 in the water layer. The organic layer is discarded, the aqueous layer was extracted with ethyl acetate. The solvent was removed, obtaining a solid substance that is suspended in dichloromethane, filtered and dried, obtaining a colorless solid. When analyzing by HPLC retention time was 2,669 min (Hewlett Packard Chemstation, λ=254 nm, column 50 mm×0.2 mm, adsorbent Phenomenex Luna C8, pore size 3 µm, 50°; And means citrate-phosphate buffer, pH 3; B means acetonitrile; gradient of 0 to 95% B for 3 min at a speed of 0.7 ml/min

Other examples were performed similarly to the corresponding detailed above examples in accordance with synthetic methods (A-J)that are listed in the table above.

The following table No. 4 shows the data characterizing the mass spectrometric techniques and the melting temperature for the above examples, along with the specification of the acid involved in the formation of salt, and if the example described salt.

1. The compound of the formula

in free form or in salt form, where

X means an oxygen atom or sulfur or a group NR5,

R1means alkyl, alkenylphenol, cycloalkyl, benzocyclobutene, cycloalkylation or aracelio group, which optionally may be substituted by hydroxy, carboxy or alkoxycarbonyl or, when X is NR5alternative R1could mean a heterocyclic group selected from benzylpiperidine or

or a group of the formula

R2means hydrogen, alkyl or alkoxy;

R3means hydrogen, alkoxy, carboxy, carboxylic, alkoxycarbonyl, -N(R9R10, (C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or when two Deputy R2and R3attached to adjacent carbon atoms in the indicated benzene ring together with the carbon atoms to which they are attached, they represent a heterocyclic group containing 5-10 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulfur;

R4means hydrogen, alkoxy, carboxy, carboxylic, -SO2N(R11R12, -N(R9R10or-CON(R13R14or

when two C is the Deputy R 3and R4attached to adjacent carbon atoms in the indicated benzene ring together with the carbon atoms to which they are attached, they represent a heterocyclic group containing 5-6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulfur;

R5means hydrogen or alkyl;

R6, R7and R8mean hydrogen, or one of these radicals means-SO2NH2, -N(CH3Of PINES3, -CONH2and the other two denote hydrogen;

R9means hydrogen or alkyl;

R10means hydrogen, -COR15; where R15means alkyl, alkoxy, or R9and R10together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen;

R11means hydrogen or alkyl,

R12means hydrogen, alkyl, hydroxyalkyl, carboxyethyl or alkoxycarbonylmethyl, or

R11and R12together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen; and R13and R14each independently from the other means hydrogen or alkyl;

with the exception of 2-(para-n-butylaniline)-6-methoxypurine, 2-(para-n-butylaniline)-6-(methylthio)purine, 2,6-di(phenylamino)purine, 2,6-di(para-tolylamino)purine and 2-(para-tolylamino)-6-(phenylamino)purine.

2. The compound according to claim 1, which means the compound of the formula

in free form or in salt form, where

R1matter described above, and if it means a group of formula II,

this group has the formula

and R2, R3, R4, R6, R7and R8have the meanings given above.

3. The compound according to claim 1 or 2, where

R1means preferably (C1-C10)alkyl, (C2-C10)alkenylphenol, (C3-C10)cycloalkyl, benzo(C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C4)alkyl or phenyl(C1-C10)alkyl group which is optionally substituted by hydroxy, carboxy or (C1-C4)alkoxycarbonyl, or

R1means benzylpiperidine, or

R1means a group of formula II or formula IV, respectively, in which

R6, R7and R8mean hydrogen, or

one of R6, R7and R8means SO2NH2, -CONH2and the other two denote hydrogen,

R2means hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy or

one of R3and R4means hydrogen or (C1-C4)alkoxy and

(a) the second and third of R2, R3and R4denote each independently from each other hydrogen or (C1-C4)alkoxy or if R2, R2may mean (C1-C4)alkyl, or

(b) the second of R2, R3and R4means hydrogen, and the third from R3and R4means carboxy, carboxy(C1-C4)alkyl, -N(R9R10or-SOP(R13R14or if R3, R3may mean (C1-C10)alkoxycarbonyl, (C1-C4)alkylen-SO2N(R11R12or

(C) R3and R4attached to adjacent carbon atoms in the indicated benzene ring and together with the carbon atoms to which they are attached, denote a heterocyclic group containing 5-6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulphur,

R9means hydrogen or (C1-C10)alkyl, and

R10means hydrogen or-COR15where R15means (C1-C10)alkyl, or R9and R10together with the nitrogen atom to which they are attached, signify geterotsiklicheskikh the group, containing 5 or 6 ring atoms and one or two nitrogen atom, or one nitrogen atom and one oxygen atom in the ring,

R11means hydrogen or (C1-C10)alkyl,

R12means hydrogen, (C1-C10)alkyl, hydroxy(C1-C10)alkyl, carboxy(C1-C10)alkyl or (C1-C10)alkoxycarbonyl(C1-C10)alkyl, or

R11and R12together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms and one or two nitrogen atom, or one nitrogen atom and one oxygen atom in the ring, and

R13and R14each independently of one another denotes hydrogen or (C1-C10)alkyl.

4. The compound according to claim 1 or 2, where X stands for a group NR5,

R1means (C1-C4)alkyl, (C2-C4)alkenyl, (C3-C5)cycloalkyl, benzo(C5-C6)cycloalkyl, (C3-C5)cycloalkyl(C1-C4)alkyl or phenyl(C1-C4)alkyl group which is optionally substituted by hydroxy, carboxy, (C1-C4)alkoxycarbonyl, or R1means benzylpiperidine, or R1means a group of the formula IV in which R6, R7and R8mean hydrogen or one of R6, R7and R8means-SO2NH2/sub> , -CONH2and the other two denote hydrogen,

R2means hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, or one of R3and R4means hydrogen or (C1-C4)alkoxy and

(a) the second and third of R2, R3and R4denote each independently from each other hydrogen or (C1-C4)alkoxy, or if R2, R2may mean (C1-C4)alkyl,

(b) the second of R2, R3and R4means hydrogen, and the third from R3and R4means carboxy, carboxy(C1-C4)alkyl, -N(R9R10or-SOP(R13R14or if R3, R3may mean (C1-C10)alkoxycarbonyl, (C1-C4)alkylen-SO2N(R11R12or

(C) R3and R4attached to adjacent carbon atoms in the indicated benzene ring and together with the carbon atoms to which they are attached, denote a heterocyclic group containing 5-6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulphur,

R5means hydrogen or (C1-C4)alkyl,

R9means hydrogen or (C1-C4)alkyl, and

R10means hydrogen or-COR15where R15means (C1-C4)alkyl, (C1 -C4)alkoxy, or R9and R10together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atom, or one ring nitrogen atom and one ring oxygen atom

R11means hydrogen or (C1-C4)alkyl, and

R12means hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl(C1-C4)alkyl, or

R11and R12means together with the nitrogen atom to which they are attached, a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atom, or one ring nitrogen atom and one ring oxygen atom, and

R13and R14denote each independently from each other hydrogen or (C1-C4)alkyl.

5. The compound according to claim 1 or 2, where X means an oxygen atom, R1means (C1-C4)alkyl or (C3-C10)cycloalkyl, one of R2, R3and R4means hydrogen or (i) the second of R2, R3and R4means hydrogen, and the third from R3and R4means carboxy, or-N(R9R10, R9and R10together with the attached nitrogen atom denote a heterocyclic group containing 5 or 6 ring the volumes, including two ring nitrogen atom or one ring nitrogen atom and one ring oxygen atom, or if R3, R3may mean (C1-C4)alkoxycarbonyl, or

(ii) R3and R4attached to adjacent carbon atoms in the indicated benzene ring and the mean together with the carbon atoms to which they are attached, a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean nitrogen atoms.

6. The compound according to claim 1 or 2, where X denotes a sulfur atom, R1means (C1-C4)alkyl, two of R2, R3and R4mean hydrogen, and the third of R3and R4means carboxy, or-N(R9R10or if R3, R3may mean (C1-C4)alkoxycarbonyl,

R9means hydrogen or (C1-C4)alkyl and

R10means-COR15where

R15means (C1-C4)alkyl, or

R9and R10together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms including one or two ring nitrogen atoms or one ring nitrogen atom and one ring oxygen atom.

7. The compound of formula III

in free form or in the form of Pharma is efticiency acceptable salt, where

(i) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means N(CH3)3; or

(ii) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means morpholino; or

(iii) X is NH,

R1means cyclobutyl,

R2and R4denote each hydrogen and

R1means 4-tert-butoxycarbonyl-1-piperazinil; or

(iv) X is NH,

R1means cyclobutyl,

R2and R4denote each hydrogen and

R3means-N(CH3Of PINES3; or

(v) X is NH,

R1means isopropyl,

R2and R4denote each hydrogen and

R3means-SO2N(CH3)3; or

(vi) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means 4-acetyl-1-piperazinil; or

(vii) X is NH,

R1means tert-butyl,

R2means hydrogen and

R3and R4mean along-CH2OCO-; or

(viii) X is Oh,

R1means cyclobutyl,

R 2and R4denote each hydrogen and

R3means-N(CH3Of PINES3; or

(ix) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means 4-methyl-1-piperazinil; or

(x) X is NH,

R1means tert-butyl,

R2and R4denote each hydrogen and

R3means-N(CH3Of PINES3; or

(xi) X is NH,

R1means isopropyl,

R2and R4denote each hydrogen and

R3means-N(CH2CH3Of PINES3; or

(xii) X is NH,

R1means cyclopropyl,

R2and R4denote each hydrogen and

R3means-N(CH3Of PINES2CH3;

8. The compound of the formula I

in free form or in salt form, where

X means an oxygen atom or sulfur or a group NR5,

R1means alkyl, alkenylphenol, cycloalkyl, benzocyclobutene, cycloalkylation or aracelio group, which optionally may be substituted by hydroxy, carboxy or alkoxycarbonyl or, when X is NR5alternative R1can mean geterotsiklicheskikh, selected from benzylpiperidine or

or a group of the formula

R2means hydrogen, alkyl or alkoxy;

R3means hydrogen, alkoxy, carboxy, carboxylic, alkoxycarbonyl, -N(R9R10, (C1-C4)alkylen-SO2N(R11R12or-CON(R13R14or when two Deputy R2and R3attached to adjacent carbon atoms in the indicated benzene ring together with the carbon atoms to which they are attached, they represent a heterocyclic group containing 5-10 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulfur;

R4means hydrogen, alkoxy, carboxy, carboxylic, -SO2N(R11R12, -N(R9R10or-CON(R13R14or

when two substituent R3and R4attached to adjacent carbon atoms in the indicated benzene ring together with the carbon atoms to which they are attached, they represent a heterocyclic group containing 5-6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen and sulfur;

R5means hydrogen or alkyl;

R6, R7and R8mean hydrogen, is whether one of these radicals means-SO 2NH2, -N(CH3Of PINES3, -CONH2and the other two denote hydrogen;

R9means hydrogen or alkyl;

R10means hydrogen, -COR15where R15means alkyl, alkoxy, or

R9and R10together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms, of

which one or two mean heteroatoms selected from nitrogen, oxygen;

R11means hydrogen or alkyl,

R12means hydrogen, alkyl, hydroxyalkyl, carboxyethyl or alkoxycarbonylmethyl, or

R11and R12together with the nitrogen atom to which they are attached, denote a heterocyclic group containing 5 or 6 ring atoms, of which one or two mean heteroatoms selected from nitrogen, oxygen; and

R13and R14each independently of one another denotes hydrogen or alkyl; for use as pharmaceuticals.

9. Pharmaceutical composition having anti-inflammatory and antiallergic activity, comprising a compound according to any one of claims 1 to 8 together with its pharmaceutically acceptable diluent or carrier.

10. Compounds of General formula (I) according to any one of claims 1 to 8 to obtain a drug that has anti-inflammatory is or antiallergic action.

11. Method of producing compounds of the formula I according to claim 1 and their salts, which includes:

(A) interactions of the compounds of formula

with the compound of the formula

where X, R1, R2, R3and R4have the meanings previously defined, and Y represents a leaving group, free functional group in the compounds of formulas V and VI, other than those involved in the reaction are protected, if necessary, removing the protective group; or

(B) to obtain the compounds of formula I in which R3or R4means carboxyl or carboxialkilnuyu group, cleavage of the corresponding compounds of formula I in which R3or R4means alkoxycarbonyl or alkoxycarbonylmethyl group, respectively; or

(C) to obtain the compounds of formula I in which R3means alkoxycarbonyl group, respectively, the esterification of the corresponding compounds of formula I in which R3means carboxyl group; or

(D) to obtain the compounds of formula I in which R4means a group of the formula-SO2N(R11R12whose values previously defined, respectively, by amination of the corresponding compounds of formula

in which R1, R2, R3have the meanings previously defined, ameans a group of the formula-SO2Hal, where Hal means halogen; or

(E) for obtaining the compounds of formula I in which R3or R4means a group of the formula-CON(R13R14as previously defined, respectively, by amination of the corresponding compounds of formula I, where R3or R4mean carboxypropyl;

and optional conversion of the compounds of formula I in protected form in the appropriate connection in unprotected form;

and isolation of the compounds of formula I in free form or in salt form.



 

Same patents:

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to new compounds of General formula I

< / BR>
where R is chosen from the group comprising R2, R2NH - or R3R4N-R5-, where R2selected from the group including9-C12-alkyl,

< / BR>
and

< / BR>
where each R6independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m = integer 0-8; x = 1-8 integer; n = 0-8 integer; z is chosen from the group comprising phenyl, heterocycle, cycloalkyl and naphthalene, and M is chosen from the group comprising hydrogen, C1-C4-alkyl,

< / BR>
and

< / BR>
where each R6' are independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m' = integer 0-8; n' = integer 0-8; x' = 1-8 integer; Q is hydrogen or C1-C4-alkyl, and Z' is chosen from the group comprising phenyl, heterozygote selected from the group including D, E,

< / BR>
and

< / BR>
where each D is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E is independently selected from the group including Hal, HE and1-C8-alkyl; Z is chosen from the group comprising phenyl, cycloalkyl and naphthalene; each R6"is hydrogen, n = integer 0-8; x" = 1-8 integer, and M' is hydrogen, Z' may be optionally substituted by groups D', E', each D' is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E' is independently selected from the group including Hal, HE and1-C8-alkyl; R3and R4selected from the group including hydrogen, C1-C4-alkyl and (CH2)y-phenyl, where y = 0-8 integer, provided that R3and R4both denote hydrogen; R5- C1-C8-alkylene and R1selected from the group including cyclopentyl, cyclopentenyl and isopropyl, and their pharmaceutically acceptable salts, optical isomers and hydrates, provided that when R2refers to a group

< / BR>
< / BR>
< / BR>
and

< / BR>
where D, b, R6", x", n", M' and Z" accept above values

the method of treatment of a patient with proliferative disorders by assigning the compounds I, the method of preventing apoptosis of nerve cells, ways of protecting nerve cells from apoptosis and destruction caused by antitumor agents, and pharmaceutical composition

The invention relates to new derivatives of purine of formula I, II, III and IV, pharmaceutical compositions and method of treatment of a pathological state characterized by thrombotic activity

The invention relates to new compounds of General formula I, in which R is selected from the group consisting of R2, R2NH or H2N-R3 where R2 is selected from the group consisting of C1-C8the alkyl and formula (II), where Z is selected from the group consisting of phenyl, heterocycle and cycloalkyl, each R4 independently represents hydrogen or C1-C4alkyl, and n is an integer equal to 1 to 8; where each1-C8alkyl, and Z optionally substituted by 1-3 substituents, which may be the same or different, selected from the group consisting of Hal, HE and1-C4of alkyl; R3 represents C1-C8alkylene; and R1 is selected from the group consisting of cyclopentyl and isopropyl, and their pharmaceutically acceptable salts, optical isomers and hydrates

The invention relates to a method for producing analogues of nucleosides dimethoxyaniline

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutical composition eliciting anti-inflammatory and analgetic activity for oral administration and containing compound of the formula (I): A-X1-NO2 wherein A and X1 are given in cl. 1 of the invention claim and representing in the amorphous state or partially amorphous state. Method involves the following steps: stirring compound of the formula (I) with at least one filling agent that is able to confer the amorphous state to obtained mixture wherein this filling agent is taken among group consisting of (C5-C6)-polyalcohols, mono- and disaccharides and their derivatives, oligosaccharides comprising from 3 to 10 monosaccharide units, polysaccharides, their derivatives involving their salts, cyclodextrins and their derivatives, noncyclic derivatives of β-cyclodextrin, polymers and copolymers based on vinyl monomeric links, and/or comprising the carboxyl function, or methacrylic monomers wherein the mass ratio between amount of compound of the formula (I) and the amount of at least one filling agent is in the range = (1:20)-(1:0.5), and providing the amorphous state of obtained mixture by combined grinding, stirring, spraying drying and lyophilization. Also, invention relates to a pharmaceutical composition eliciting an anti-inflammatory and analgetic activity. Invention provides preparing a pharmaceutical composition for oral administration and medicinal agents based on thereof for treatment of inflammatory diseases.

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

10 cl, 1 tbl, 10 ex

FIELD: medicine, phytotherapy, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing agent eliciting immunocorrecting and anti-inflammatory activity. Method for preparing the phytopreparation eliciting immunocorrecting and anti-inflammatory activity involves milling common horse radish fresh roots, extraction of raw by maceration method in the definite ratio of ratio raw : extractant for definite time at room temperature, at periodic stirring, clarification of extract under definite conditions and filtration. Method provides preparing the phytopreparation from common horse radish roots for carrying out pharmacotherapy of immune deficient states and inflammatory diseases.

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

4 tbl, 3 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the agent comprising the following components: lidazum (16-32 U), proserinum 0.05% solution, 0.00025-0.0005 g; methylprednisolone succinate sodium, 0.02-0.04 g; lidocaine 10% solution, 0.05-0.1 g, and glucose 40% solution, 3-4 ml. Also, invention relates to a method for administration of agent and a method for treatment of inflammatory diseases. Invention provides expanding assortment of medicinal agents and improving the regional transport of medicinal preparations.

EFFECT: improved and valuable properties of agent.

6 cl, 5 ex

FIELD: pharmaceutical industry.

SUBSTANCE: rectal- and vaginal-administration suppositories contain 1,3-diethylbenzimidazolium triiodide as active principal, polyvinylpyrrolidone as solubilizer and stabilizer, and lipophilic base with specified proportions of components.

EFFECT: extended therapeutical activity and reduced occurrence of side effects.

4 cl, 2 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with curative ointments of antiphlogistic and wound-healing action and could be applied for treating hemorrhoid, burns, bruises, fractures, wounds, chronic bronchitis, polyarthritis, periarthritis, radiculitis, trophic ulcer and psoriasis. Three variants of ointments have been suggested. They contain oily extract of plant components and, also, honey, mumiye, propolis and bear oil. This innovation enables to widen the assortment of ointments of antiphlogistic and wound-healing and the range of curative action upon a body.

EFFECT: higher efficiency of application.

3 cl, 11 ex

Therapeutic agents // 2246294

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes composition of a pressed tablet comprising multiple of hardened melted granules of nonsteroid anti-inflammatory preparation (NSAID) with a melting point in the range 30-300oC and comprising a loosening agent dispersed uniformly in it. Granules comprise a continuum phase of indicated nonsteroid anti-inflammatory preparation and the table composition comprises additionally silicon dioxide in the amount 0.05-5.0% of composition mass. Preferably, the composition comprises also a nongranulated component containing silicon dioxide and excipient. The preferable NSAID represents ibuprofen that has a melting point in the range 75-77oC. Method provides preparing tablet showing useful industrial properties and ability for dissolving.

EFFECT: improved preparing method, valuable pharmaceutical properties of agent.

34 cl, 16 tbl, 64 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new spiroimidazolidine derivatives of the formula (1):

wherein R1 represents hydrogen atom or methyl; R2 represents phenyl or (C1-C4)-alkyl; X represents -CH2-CH2- or -CH2-CH2-CH2-; W represents isopropyl or cyclopropyl; V represents hydrogen atom or methoxy-group; E represents -CO-R3 wherein R3 represents hydroxy-group, (C1-C4)-alkoxy- or amino-group; phenyl represents unsubstituted phenyl residue or phenyl residue substituted with one or some similar or different substitutes taken among the group consisting of (C1-C4)-alkoxy-, methylenedioxy- and ethylenedioxy-group in all its stereoisomeric forms and their mixtures in all ratios, and to its physiologically acceptablesalts. Also, invention relates to a method for preparing compounds of the formula (1) and pharmaceutical composition based on these compounds. Invention provides preparing new compounds eliciting the inhibitory effect with respect o leukocytes adhesion.

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

16 cl, 1 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

The invention relates to 3’-Destinationin-9 oxyimino macrolides of formula (I):

in which R represents hydrogen or methyl; R1and R2both represent hydrogen or together form a chemical bond; R3represents hydrogen or linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated and contains from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups, X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group; r is an integer from 1 to 6; m is an integer from 1 to 8; n is an integer from 0 to 2; and their pharmaceutically acceptable salts; except for compounds of the oxime of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-descimated the

FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

The invention relates to the pharmaceutical industry, in particular the production of medicines used for colds, relieving headaches and neuralgia
The invention relates to medicine, namely to pharmacy
The invention relates to medicine, gynecology, and can be used for the treatment of primary dysmenorrhea

The invention relates to medicine, namely to the development of new combinations Antiherpes virus effect of actions
Up!