METHOD FOR TREATMENT OF STATES CAUSED BY p38 KINASES AND PYRROLOTRIAZINE COMPOUNDS USED AS KINASE INHIBITORS Russian patent published in 2008 - IPC C07D487/04 C07D519/00 A61K31/53 A61P29/00 

FIELD: organic chemistry, medicine, pharmacy, biochemistry.

SUBSTANCE: invention relates to a method for treatment of states caused by activity of p38 kinase. Method involves administration to a patient needed in this treatment of at least one compound of the formula (I): or its pharmaceutically acceptable salt or solvate wherein R₃ means hydrogen atom, methyl, perfluoromethyl, methoxy-group, halogen atom, cyano-group or NH₂-group; X is chosen from -O-, -OC(=O)-, -S-, -S-, -S(=O)-, -SO₂-, -C(=O)-, -CO₂-, -NR₁₀-, -NR₁₀C(=O)-, -NR₁₀C(=O)NR₁₁-, -NR₁₀CO₂-, -NR₁₀SO₂-, -NR₁₀SO₂NR₁₁-, -SO₂NR₁₀-, -C(=O)NR₁₀, halogen atom, nitro- and cyano-group, or X is absent; Z is chosen from oxygen (O), sulfur (S), nitrogen (N) atoms, and -CR₂₀ being wherein Z means -CR₂₀ optionally substituted bicyclic aryl or heteroaryl with R₄ or R₅; R₁ means hydrogen atom, -CH₃, -OH, -OCH₃, -SH, -SCH₃, -OC()=O)R₂₁, -S(=O)R₂₂, -SO₂NR₂₃R₂₅, -CO₂R₂₁, -C(=O)NR₂₄R₂₅, -NH₂, -NR₂₄R₂₅, -NR₂₁SO₂NR₂₄R₂₅, -NR₂₁SO₂R₂₂, -NR₂₄C(=O)R₂₅, -NR₂₄CO₂R₂₅, -NR₂₁C(=O)NR₂₄R₂₅, halogen atom, nitro- or cyano-group; R₂ is chosen from the following group: (a) hydrogen atom under condition that R₂ doesn't mean hydrogen atom if X means -S(=O)-, -SO₂-, -NR₁₀CO₂- or -NR₁₀SO₂-; (b) alkyl, alkenyl and alkynyl comprising up to four R₂₆ groups or pentafluoroalkyl as substitutes; (c) aryl and heteroaryl comprising up to three groups R₂₇ as substitutes, and (d) heterocyclo-group or heteroalkyl optionally comprising keto-group (=O), up to three groups R₂₇ as substitutes, and/or comprising carbon-carbon bridge comprising 3-4 carbon atoms, or (e) R₂ is absent if X means halogen atom, nitro- or cyano-group; R₄ means substituted aryl, aryl comprising NOSE-alkyl, substituted heteroaryl or optionally substituted bicyclic 7-11-membered saturated or unsaturated carbocyclic or heterocyclic fragment as a substitute, and R₅ means hydrogen atom, alkyl or substituted alkyl with exception of cases when Z means O or S and then R₅ is absent, or R₄ and R₅ in common with Z form optionally substituted bicyclic 7-11-membered aryl or heteroaryl; R₆ means hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group, substituted heterocyclo-group, -NR₇R₈, -OR₇ or halogen atom; R₁₀ and R₁₁ are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo-group and substituted heterocyclo-group; R₇, R₈, R₂₁, R₂₄ and R₂₅ are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group and substituted heterocyclo-group; R₂₀ means hydrogen, lower alkyl or substituted alkyl, or R₂₀ can absent if carbon atom to which is bound and in common with R₄ and R₅ represents part of bicyclic aryl or heteroaryl; R₂₂ means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group or substituted heterocyclo-group; R₂₆ is chosen from the following group: halogen atom, trifluoromethyl, halogenalkoxy-group, keto (=O)-, nitro-, cyano-group, -SR₂₈, -OR₂₈, -NR₂₈R₂₉, -NR₂₈SO₂, -NR₂₈SO₂R₂₉, -SO₂R₂₈, -SO₂NR₂₈R₂₉, -CO₂R₂₈, -C(=O)R₂₈, -C(=O)NR₂₈R₂₉, -OC(=O)R₂₈, -C(=O)NR₂₈R₂₉, -NR₂₈C(=O)R₂₉, -NR₂₈CO₂R₂₉,=N-OH, =N-O-alkyl; aryl optionally comprising as a substitute from one to three R₂₇ groups; cycloalkyl optionally comprising a substituted keto-group (=O), from one to three R₂₇ groups, or carbon-carbon-containing bridge comprising of 3-4 carbon atoms; and heterocyclo-group comprising optionally as a substitute keto-group (=O), from one to three R₂₇ groups or comprising carbon-carbon bridge comprising 3-4 carbon atoms, and wherein each R₂₈ and R₂₉ is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-heterocycle, or they can form in common (C₃-C₇)-heterocycle; and each R₂₈ and R₂₉, in turn, can comprise optionally up to two substitutes representing alkyl, alkenyl groups, halogen atoms, halogenalkyl groups, halogenalkoxy-, cyano-, nitro-, amino-, hydroxy-, alkoxy-, alkylthio-groups, phenyl, benzyl, phenyloxy- and benzyloxy-groups; and R₂₇ is chosen from the following group: alkyl, R₃₂ and (C₁-C₄)-alkyl comprising as substitutes from one to three R₃₂groups and wherein each R₃₂ group is chosen independently from the following group: halogen atom, halogenalkyl, halogenalkoxy-, nitro-, cyano-groups, -SR₃₀, -OR₃₀, -NR₃₀R₃₁, -NR₃₀SO₂, -NR₃₀SO₂R₃₁, -SO₂R₃₀, -SO₂NR₃₀R₃₁, -CO₂R₃₀, -C(=O)R₃₀, -C(=O)NR₃₀R₃₁, --OC(=O)R₃₀, -OC(=O)NR₃₀R₃₁, -NR₃₀C(=O)R₃₁, -NR₃₀CO₂R₃₁ and from 3-7-membered carbocyclic or heterocyclic ring comprising optionally as a substitute alkyl, halogen atom, hydroxy-, alkoxy-group, halogenalkyl, halogenalkoxy-, nitro-, amino- or cyano-group, and wherein each R₃₀ and R₃₁ is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C₃-C₇)-cycloalkyl, and heterocycle, or they in common can form (C₃-C₇)-heterocycle. Also, invention describes pyrrolotriazine compounds, a pharmaceutical composition based on thereof and a method for treatment of inflammatory diseases using above proposed compounds and pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 14 tbl, 152 ex