Quinazoline derivatives

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new compounds with formula (I), their esters, carbamates and pharmaceutically used salts, which can be used as inhibitors of p38 kinase, which means they can be used for curing diseases and conditions for which p38 is the mediator. In formula (I): Q represents -C(R1R2R3); R1 is chosen from hydrogen, C1-C8 alkyl, hydroxyC1-C8alkyl, and C1-C8alkoxy C1-C8alkyl; R2 and R3 are chosen: (i) independently from: (a) hydrogen, under the condition that, if R1 represents hydrogen, then only one of R2 and R3 can be chosen from hydrogen; (b) C1-C8alkyl; C1-C8alkyl, substituted with one or two radicals halogen, -OR8, -S(O)pR10;(c) -OR8; or (ii) R2 and R3 together with the carbon atom to which they are bonded, form optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system; R4 and R5 are independently chosen from halogen; R8 and R9 are independently chosen from hydrogen, C1-C8alkyl; R10 represents C1-C8alkyl; m equals 0, n equals 0; and p equals 2; where the term "substituted cycloalkyl" stands for a cycloalkyl group, containing one or two substitutes, which are independently chosen from a group, consisting of -Y-ORs, -Y-S(O)0-2RS, C(=O)ORs, where Y is absent; Rs is independently chosen from hydrogen, C1-C8alkyl, except when the said substitute represents -Y-S(O)1-2Rs, then RS represents hydrogen; the term "heterocyclic ring system" stands for a saturated non-aromatic monocyclic fragment, consisting of 5 to 6 atoms, which are part of the ring system, from which one atom, which is part of the ring system, is a heteroatom, chosen from N, O, and the rest of the atoms in the ring system are carbon atoms; the term "substituted heterocyclic ring system" stands for a heterocyclic fragment mentioned above, containing one substitute, chosen from the group, -Y-Rs, -Y-ORs, -Y-C(O)2Rs, -Y-S(O)0-2Rs, where Y is absent or represents a C1-C4alkylene group, Rs represents the same as was defined above for the substituted cycloalkyl group.

EFFECT: used for treating diseases and conditions.

13 cl, 2 dwg, 5 tbl, 17 ex

 

The present invention relates to certain derivatives of hintline, which can be used as inhibitors R protein kinase. In particular, the present invention relates to 2-amino-6-phenoxyphenyl derived hintline, pharmaceutical compositions containing these compounds, and to methods for their preparation.

Mitogenactivated protein kinase (map) are a family of Proline-directed serine/threonine kinases that activate their corresponding substrates by dual phosphorylation. Kinases are activated when exposed to a variety of signals, including signals, as nutrient loading and osmotic stress, UV radiation, exposure to growth factors, the effects of endotoxin and inflammatory cytokines. One of the groups of map kinases is a group R kinases, which includes various isoforms (for example, 38α, 39β, 38γ and 38δ). R-Kinase responsible for the phosphorylation and activation of transcription factors (as well as other kinases), and are activated by physical and chemical stress, under the influence of proinflammatory cytokines and bacterial lipopolysaccharide.

More importantly, the products R phosphorylation, as detected are mediated production of inflammatory cytokines, including TNF (TNF -). from necrosis factor swollen what?), IL-1 (IL - abbr. from interleukin), IL-6 and cyclooxygenase-2 (SOH-2). Each of these cytokines is associated with many illnesses and diseases. For example, TNF-α is a cytokine primarily produced by activated monocytes and macrophages. Excessive or unregulated production of TNF-α, as I believe, plays a decisive role in the pathogenesis of rheumatoid arthritis. Recently it was shown that the inhibition of production of TNF has wide application in the treatment of inflammatory conditions, inflammatory diseases of the gastrointestinal tract, Alzheimer's disease, Crohn's disease (granulomatous disease), multiple sclerosis and asthma.

In addition, TNF correlated with viral infections, such as HIV (human immunodeficiency virus), influenza virus and herpes virus, including the simplex herpes virus type-1 (HSV-1 -)). herpes simplex virus type-1), simplex-herpes simplex virus type-2 (HSV-2 - abbr. from the English. herpes simplex virus type-2), cytomegalovirus (CMV -). from the English. cytomegalovirus), the virus varicella - zoster (VZV - abbr. from the English. varicella-zoster virus, Epstein-Barr virus 6 human herpes (HHV-6 - abbr. from the English. human herpes virus-6), virus-7 human herpes (HHV-7 - abbr. from the English. human herpes virus-7), virus-8 human herpes (HHV-8 - abbr. from the English. human herpes virus-8), the virus Aujeszky's disease (infectious bulbar paralysis) and in the originate rhinotracheitis, etc.

Similarly IL-1 is produced by activated monocytes and macrophages and plays a role in many pathophysiological reactions, including rheumatoid arthritis, disease, the main symptom of which is a very high temperature, fever, loss of bone resorption.

Inhibition of these cytokines through inhibition R kinase could be useful for monitoring, facilitating and easing many of these painful conditions. Inhibitors R map kinase have shown efficacy in the study of models of several diseases, including arthritis and other joint diseases, sepsis, stroke, myocardial injury, inflammatory respiratory diseases such as chronic obstructive pulmonary disease and asthma, as well as a large range of inflammatory conditions. In accordance with the present invention offers some 2-amino-6-phenoxypyridine derivatives hintline that can be used for inhibition R kinase. In the patent application U.S. No.60/463467, according to which the priority of the present application, discloses 2-amino-6-phenoxypyridine derivatives of 7-azathiaprine, which may be useful as inhibitors R kinase.

In accordance with the first aspect of the present invention is proposed connection is ormula (I)

and its isomers, prodrugs and pharmaceutically acceptable salts, where

Q means-C(R1R2R3);

R1selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl;

R2and R3choose:

(i) independently from

(a) hydrogen, provided that if R1means hydrogen, only one of R2and R3can be selected from hydrogen;

(b) alkyl;

(C) alkyl substituted with one, two or three radicals halogen, cyano, -OR8, -SR8, -C(=O)R8, -C(O)2R8, -C(=O)NR8R9, -S(O)pR10, -C(O)2NR8R9, -S(O)2NR8R9and/or-NR8R9;

(d) -OR8, -SR8, -C(=O)R8-C(O)2R8, -C(=O)NR8R9, -S(O)pR10, -C(O)2NR8R9and-S(O)2NR8R9;

(d) cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkenyl, geterotsiklicheskie and substituted geterotsiklicheskie,

or alternatively,

(ii) R2and R3together form an optionally substituted cycloalkyl or heterocyclic ring system;

R4and R5independently selected from hydrogen, halogen, cyano, halogenoalkane and halogenoalkane provided that R4 and R5both signify hydrogen;

R6can be attached to carbon atoms C5, C7 and/or C8 khinazolinov ring system and in the case when it is attached to the carbon atom C5, represents lower alkyl, and in that case, when attached to the carbon atom C7 and/or C8, his independently selected from alkyl, halogen, cyano, nitro, hydroxy, alkoxy, halogenoalkane, amino, alkylamino and alkyl substituted by one or two radicals halogen, cyano, nitro, hydroxy, alkoxy, halogenoalkane, amino and/or alkylamino;

R7attached to any available carbon atom of phenyl ring in each case independently selected from alkyl, substituted alkyl, halogen, cyano, alkoxy, halogenoalkane;

R8and R9

(i) independently chosen from hydrogen, alkyl, halogenoalkane, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle or

(ii) in the case when R8and R9attached to the same nitrogen atom (as in-C(O)2NR8R9, -S(O)2NR8R9and-NR8R9), R8and R9may together form an optionally substituted ring system heterocycle;

R10represents alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted CEC shall alkyl, heterocycle or substituted heterocycle;

m means 0, 1, 2 or 3;

n means 0, 1 or 2 and

p is 1 or 2.

In addition, among the compounds, the structure definition above, [hereinafter they will be referred to as (I)], preferred are the following compounds:

(II) a compound of formula (I), in which

R1selected from hydrogen and C1-C4of alkyl;

R2and R3(i) independently selected from C1-C6the alkyl and C1-C6of alkyl, substituted by one or two hydroxy groups, -O(C1-C4alkyl), -S(O)2(C1-C4alkyl) and/or-S(O)p(C1-C4alkyl), or (ii) R2and R3together form3-C7cycloalkyl or five - or six-membered monocyclic heterocyclic ring system, where each of these ring systems is optionally substituted by a group R12in the amount of from 0 to 1 and/or R14in the amount of from 0 to 1;

R4and R5both represent halogen;

R12and R14independently selected from C1-C4of alkyl, hydroxy, oxo (=O), -O(C1-C4the alkyl), -C(=O)H, -C(=O)(C1-C4the alkyl), -S(O)2H, -C(O)2(C1-C4the alkyl) and-S(O)2(C1-C4alkyl);

m means 0, and

n means 0.

(III) the Connection form is s (I), where R1selected from hydrogen and C1-C4the alkyl.

(IV) a Compound of formula (I), where m and n both represent 0.

(V) a Compound of formula (I), where

R2and R3choose

(i) independently from

1) alkyl substituted by one or two atoms of halogen, cyano, -OR8, -SR8, -C(=O)R8, -C(O)2R8, -C(=O)NR8R9, -S(O)pR10, -C(O)2NR8R9-S(O)2NR8R9and/or-NR8R9,

2) -S(O)pR10, -C(O)2NR8R9or-S(O)2NR8R9and

3) cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkenyl, geterotsiklicheskie and substituted geterotsiklicheskie,

or alternatively,

(ii) R2and R3together form an optionally substituted cycloalkyl or ring group heterocycle.

(VI) a Compound of formula (I), where

R2and R3independently selected from hydrogen, C1-C6the alkyl groups and hydroxy(C1-C6alkyl).

(VII) a Compound of formula (I), where

R2and R3together form an optionally substituted C3-C7cycloalkyl or optionally substituted heterocyclic ring system.

(VIII) a Compound of formula (I), where

R2and R3(i) independently selected and is hydrogen, With1-C4the alkyl and groups

hydroxy(C1-C4alkyl), provided that R2and R3both signify hydrogen, or (ii) R2and R3together form a cyclohexyl, piperidine-4-yl or tetrahydropyran-4-yl, where each of these ring systems formed by groups of R2and R3taken together, is optionally substituted groups in number to two, such as lower alkyl, -OH, -S(O)2(C1-C4alkyl) and/or a group-S(O)2(CH3).

(IX) a Compound of formula (I), where R4and R5both represent halogen.

(X) the Compound (I) of the formula

(XI) the Compound (I) of the formula

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

R12aselected from hydrogen, C1-C4of alkyl, -C(=O)R15, -C(O)2R15and groups

-S(O)2(C1-C4alkyl);

R12bselected from hydrogen, C1-C4of alkyl, -OR15, -C(=O)R15-C(O)2R15and the group-S(O)2(C1-C4alkyl);

R14selected from C1-C4of alkyl, oxo (=O)- OR15, -C(=O)R15, -C(O)2R15and groups

-S(O)2(C1-C4alkyl);

R15in each case independently selected from hydrogen and C1-C4of alkyl;

q oz is achet 0 or 1, and

r is 0, 1, or 2.

(XII) the Compound (XI)in which

R4and R5both represent fluorine.

(XIII) the Compound (XI) or (XII), where X is-N(R12a)-, R12ameans-S(O)2(C1-C4alkyl and q is 1.

(XIV) the Compound of formula (Ip)

or its isomer, prodrug or pharmaceutically acceptable salt, where

Q preferably represents-C(R1R2R3or optionally substituted cycloalkyl or heterocycle;

R1selected from hydrogen and alkyl;

R2and R3independently selected from-Y-R8, -Y OR8, -Y,-SR8, -Y,-S(O)pR10, -Y-C(=O)R8and the group-Y-C(O)2R8where Y represents C1-C6alkylen;

R4and R5both represent halogen;

R8selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle provided that R8not is arylalkyl or heteroaromatic;

R10represents alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle or substituted heterocycle provided that R10does not mean arylalkyl or heteroaromatic and

p is 1 or 2.

(XV) to Compound (XIV)wherein R4and R5both represent fluorine.

Connect the out (XIV) or (XV), where at least one of R2and R3choose from

-Y OR8, -Y,-S(O)pR10, -Y-C(=O)R8and-Y-C(O)2R8where Y represents C1-C4alkylen.

(XVII) Any of the compounds (XIV)-(XVI), where Q does not necessarily represent substituted monocyclic cycloalkyl or cyclic system heterocycle.

In accordance with the second aspect of the present invention features a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I) or its salt and a filler.

In accordance with a third aspect of the present invention features a compound of formula (II) as a medicinal product

or its isomer, prodrug or pharmaceutically acceptable salt, where

Qaselected from alkyl, substituted alkyl, heteroalkyl or optionally substituted cycloalkyl or heterocyclic ring system, provided that Q does not arylalkyl or heteroaromatic;

Y represents-O-, -S - or-NR'-, where R' is hydrogen, lower alkyl or lower alkyl substituted by a group of IT;

R represents alkyl, substituted alkyl or optionally substituted aryl, heteroaryl, cycloalkyl or heterocycle;

R6attached to any available carbon atom khinazolinov Kohl the eve of the system and in each case it is chosen independently from alkyl, substituted alkyl, halogen, cyano, nitro, hydroxy, alkoxy, halogenoalkane, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl and

m means 0, 1, 2, or 3.

In the compounds of formula (II) preferably

Y represents-O-;

R represents a C1-C6alkyl or phenyl, optionally substituted by one or two groups selected from halogen, halogenoalkane, halogenoalkane;

Q is chosen from (i) C1-C6of alkyl, (ii) C1-C6of alkyl, substituted by one or two groups selected from hydroxy, groups,- O(C1-C4alkyl), -S(=O)(C1-C4alkyl), -S(O)2(C1-C4alkyl) and/or-S(O)2(C1-C4alkyl), or (iii) of cyclohexyl, piperidinyl or tetrahydropyranyl, each of these ring systems optionally substituted one of the groups HE, -C(O)2(C1-C4alkyl) or-S(O)2(C1-C4alkyl), and

m means 0.

In accordance with the fourth aspect of the present invention proposes a method of producing compounds of the formula (I).

In accordance with the fifth aspect of the present invention offers a new intermediate compounds disclosed in the text of this application, which can be used to obtain compounds the s of the formula (I).

In accordance with the sixth aspect of the present invention features a compound of formula (I) or its pharmaceutically acceptable salt for use in medical therapy or diagnosis, in particular in the treatment of diseases, the mediator which is R.

In accordance with the seventh aspect of the present invention features a compound of formula (I) or its pharmaceutically acceptable salt for the manufacture of drugs suitable for treatment of diseases associated with R.

Unless otherwise stated, the following terms in the description and in the claims have the following meanings.

In the text of this application, the term "alkyl" means a linear or branched saturated monovalent hydrocarbon fragment, consisting of from one to eight carbon atoms (preferably containing from one to six carbon atoms)such as methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl. "Lower alkyl" means alkyl containing from one to four carbon atoms. When in the text of this application after the carbon atom is subscript, this subscript refers to the number of carbon atoms, which may contain the specified group. Thus, for example, C1-C4alkyl means alkyl containing from one to four atoms of plastics technology : turning & is Yes (i.e. lower alkyl, including methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

"Alkylene" means a linear or branched, saturated bivalent hydrocarbon fragment containing from one to eight carbon atoms (preferably containing from one to six carbon atoms), such as methylene, ethylene, propylene. In that case, when you specify Allenova linking group, as in the-Y-S(O)2R-Y-C(O)2NRR, -Y,-S(O)2NRR and similar groups, where Y is alkylene, you must understand that this alkylen can be alkylenes with a linear or branched chain, and referred to the Deputy can be attached to any carbon atom of alkylene having a linear or branched chain. Thus, for example, the group-Y-S(O)2R may include, without limitation, -CH2-S(O)2R, -CH2CH[S(O)2R]-CH3, -CH2-SN{CH2CH[S(O)2R]CH3}CH3.

In that case, when the term "alkyl" used as a suffix after another term, such as in terms of "phenylalkyl" or "hydroxyalkyl"means an alkyl group as defined above, substituted by one or more (preferably one) Deputy chosen from specially selected groups. Thus, phenylalkyl" includes benzyl, phenylethyl, 2-phenylbutyl. "G is taxiarchis" includes 2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl, 3,4-dihydroxybutyl. In accordance with this, in the text of this application, the term "hydroxyalkyl" is used to denote the subset heteroalkyl groups listed below. In the case of the use of the term "substituted cycloalkenyl" this term, as expected, refers to an alkyl group, as defined above, which is substituted by one or two substituted cycloalkyl groups, as defined below, and similarly the term "substituted geterotsiklicheskikh" refers to an alkyl group, as defined above, which is substituted by one or two substituted groups heterocycle, as defined below.

The term "substituted alkyl" refers to alkyl group, as defined above containing one, two, three or four substituent (preferably one or two substituent), which are independently selected from the group consisting of halogen, halogenoalkane, trifloromethyl, cyano, nitro, -ORa, -SRa, -S(O)Rc, -S(O)2Rc, -C(=O)Ra, -C(=O)NRaRb, -C(O)2Ra, -C(O)2NRaRb, -S(O)2NRaRb, -NRaRb, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle and/or substituted heterocycle, where Raand Rbindependently selected from water the ode, C1-C6of alkyl, aryl, heteroaryl, cycloalkyl and heterocycle and Rcselected from C1-C6of alkyl, aryl, heteroaryl, cycloalkyl and heterocycle, and each of Ra, Rband Rcin turn is optionally substituted one, two or three radicals alkyl, halogen, halogenated, hydroxy, alkoxy, halogenoalkane, cyano, amino, alkylamino, SO2(alkyl), CO2N, CO2(alkyl), C(=O)N and/or C(=O)alkyl, and/or C1-C4alkyl, substituted by one or two radicals halogen, hydroxy, alkoxy, halogenoalkane, cyano, amino, alkylamino, -SO2(alkyl), CO2N, CO2(alkyl), C(=O)N and/or C(=O)alkyl.

"Alkoxy" refers to a group OR', where R' is an alkyl or substituted alkyl. The term "lower alkoxy" refers to a group-OR', where R' represents C1-C4alkyl.

"Alkoxycarbonyl" refers to a group COOR', where R' is an alkyl or substituted alkyl, as defined above.

"Alkylsulfonyl" refers to the group-S(O)2R', where R' is an alkyl or substituted alkyl, as defined above.

In that case, when the term "hydroxy" is used as a suffix after the other designated groups, for example, as in "aryloxy", "heteroaromatic" or "arylalkyl", this means that the oxygen atom is present as the link is to her group (linker) on the other, specifically identified by the group. Thus, for example, "aryloxy" refers to the group-O-R, where R is aryl; "heteroaromatic" refers to the group-O-R', where R' denotes heteroaryl, and arylalkyl" refers to the group-O-R", where R" means arylalkyl, such as benzyl. Similarly, the term "substituted, aryloxy" means the group-O-R, in which R is a substituted aryl, and substituted heteroaromatic" means the group-O-R', where R' represents a substituted heteroaryl.

"Amino" refers to the group of NH2. Thus, the term “aminoalkyl” refers to an alkyl group having Deputy amino, for example to the group-CH2-NH2, -CH2-CH2-NH2, -CH2-CH(NH2)-CH3. The term “alkylamino” refers to monoalkylamines having the formula-other, and dialkylamino having the formula-NRR where each R is independently alkyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl or alkyl substituted with one or two groups selected from halogen, halogenoalkane, hydroxy, alkoxy, halogenoalkane, cyano, amino, SO2(alkyl), CO2N, CO2(alkyl), C(=O)N and/or C(=O)alkyl. In accordance with this acylaminoalkyl refers to an alkyl group substituted by one or two radicals other and/or-NRR where each R is one who by such as defined directly above. The term "lower aminoalkyl" refers to the group-other' or-NR'r R'where each R' represents a C1-C4alkyl.

In the case where the text of this application indicates carboxamidine group-CO2NRR (such as-C(O)2NR8R9), you need to understand that this instruction belongs to the group-O-C(=O)-NRR.

The term "aryl" refers to monovalent, monocyclic or bicyclic fragment consisting of from 6 to 10 carbon atoms incorporated in the ring system in which at least one of the rings is an aromatic, carbocyclic fragment. Thus, the term "aryl" includes phenyl, 1-naphthyl and 2-naphthyl. The term "aryl" also includes phenyl rings, which are associated with the second non-aromatic carbocyclic ring or a heteroaryl or heterocyclic ring system, such as benzothiazyl, benzimidazolyl, benzopyranyl, benzocycloheptene, however, that the attachment point must belong to the phenyl ring. Preferred "aryl" represents a monocyclic or bicyclic aromatic hydrocarbon radical comprising from 6 to 10 carbon atoms incorporated in the ring system.

The term "substituted aryl" refers to aryl group, as defined above, keyseating or more (preferably one, two or three) substituents that are independently selected from the group consisting of halogen, halogenoalkane, halogenoalkane, cyano, nitro, -Y-Rp, -Y-aryl, -Y-heteroaryl, -Y-cycloalkyl, -Y-heterocyclyl, -Y ORp, -Y,-NRpRq, -Y-C(=O)Rp, -Y-C(O)2Rp, -Y-C(=O)NRpRq, -Y-C(O)2NRpRq, -Y,-S(O)0-2Rp, -Y,-NRS(O)2Rq, -Y,-S(O)2NRpRqand/or-Y-NRC(=O)NRpRqwhere Y is either missing or means C1-C4alkylenes group, R represents hydrogen, lower alkyl or hydroxy, C1-C4alkyl, and Rpand Rqindependently selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl and heterocycle, except in those cases when the Deputy is a-YS(O)1-2Rpor-Y-NRS(O)2RPthen Rpin these cases, does not mean hydrogen. In each case, each of Rpand/or Rqin turn is optionally substituted by one or two alkyl radicals, halogen, cyano, hydroxy, alkoxy, amino, alkylamino, halogenated, halogenoalkane, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, -SO2(alkyl), CO2N, CO2(alkyl), C(=O)N and/or C(=O)alkyl. A preferred group of substituents of the aryl represents such substituents, which are selected from alkyl, GoLoG is nalkyl, of halogen, hydroxy, amino, alkylamino, halogenoalkane and alkoxy. Within this group, particularly preferred aryl substituents are halogen, alkyl and alkoxy. More specifically, the term "substituted aryl" includes, but is not limited to such radicals as forfinal, differenl, chlorophenyl, methoxyphenyl.

The term "carbocyclic" means a cyclic fragment, containing from 3 to 10 carbon atoms incorporated in the ring system in which all the atoms are carbon atoms, including saturated, partially unsaturated or unsaturated ring system.

The term "cycloalkyl" in the text of the present application refers to a saturated or partially unsaturated, monovalent, monocyclic carbocyclic fragments, consisting of from three to seven carbon atoms included in the ring system, which optionally include a ring system, in which a carbon-carbon bridge of one, two or three bridging carbon atoms and/or which contain second conjugate ring, provided that the second conjugate ring may be non-aromatic carbocyclic or heterocyclic ring system, and in this case, the attachment point will belong to non-aromatic carbocyclic cyclic fragment. Thus, the term "qi is loukil includes a ring system, as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl. Additionally, one or two carbon atom cycloalkyl groups may optionally contain a carbonyl oxygen group, for example one or two atoms in the ring system may represent a fragment of formula. Preferably cycloalkyl" is a saturated monovalent cyclic hydrocarbon moiety consisting of from three to seven carbon atoms included in the ring system, and one or two carbon atom cycloalkyl groups may optionally contain a carbonyl oxygen group.

"Substituted cycloalkyl" is cycloalkyl group as defined above containing one, two or three substituent which is independently selected from the group consisting of halogen, halogenoalkane, halogenoalkane, cyano, nitro, -Y-Rs, -Y-cycloalkyl, -Y-heterocyclyl, -Y ORs, -Y,-NRsRt, -Y-C(=O)Rs, -Y-C(O)2Rs,

-Y-C(=O)HRsRt, -Y-C(O)2NRsRt, -Y,-S(O)0-2Rs, -Y,-NRS(O)2Rs, -Y,-S(O)2NRsRtand/or the group-Y-NRC(=O)NRsRtwhere Y is absent or represents a C1-C4alkylenes group, R represents hydrogen, lower alkyl or hydroxy, C1-C4alkyl, and Rsand R tindependently selected from hydrogen, alkyl, cycloalkyl and heterocycle, except in those cases when the Deputy is a-YS(O)1-2Rsor-Y-NRS(O)2Rsthen Rsin these cases, does not mean hydrogen. In each case, each of Rsand/or Rtin turn is optionally substituted by one or two radicals of lower alkyl, halogen, cyano, hydroxy, alkoxy, amino, alkylamino, halogenated, halogenoalkane, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, -SO2(alkyl), CO2N, CO2(alkyl), C(=O)N and/or C(=O)alkyl. Preferred substituents for substituted cycloalkyl groups include -(alkylene)nis hydroxy, -(alkylene)n-lower alkoxy, -(alkylene)n-S(O)2(lower alkyl) and -(alkylene)n-CO2(lower alkyl), where n means 0, 1, or 2.

The term "halogen", "halide", when they refer to the Deputy, means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine).

The term "halogenated" means alkyl substituted by one or more identical or different halogen atoms, such as-CH2Cl-CF3, -CH2CF3, -CH2CCl3and the like, and further includes such alkyl groups as perfluoroalkyl in which all the alkyl hydrogen atoms of the substituted atom and fluorine.

The term "halogenoalkane" means halogenating group, as defined above, attached via an oxygen atom, for example, the term includes-O-CH2Cl, -O-CF3, -O-CH2CF3, -O-CH2CCl3.

The term "heteroalkyl" in the text of this application means C1-C8the alkyl fragment defined above, where one, two or three hydrogen atoms replaced by the Deputy, which is independently selected from the group consisting of-ORd, -NRdReand S(O)nRd(where n denotes an integer from 0 to 2), provided that the connection point is heteroalkyl fragment is a carbon atom, where Rdand Reselected from hydrogen, alkyl, substituted alkyl (excluding arylalkyl or heteroaromatic), cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle, except in those cases where Rdattached to S(O)nRdand n denotes 1 or 2, then Rddoes not mean hydrogen. Additionally, in the case when Rdand Reattached to the same nitrogen atom they may together form an optionally substituted heterocyclyl or heteroaryl ring system. Typical examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-g is troxerutin, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxymethylation, 2,3-dihydroxypropyl.

"Heterocycle," "heterocyclyl" or "heterocyclic" refers to a saturated or partially unsaturated non-aromatic monocyclic or bicyclic fragment consisting of from 3 to 10 atoms incorporated in the ring system, from which one or two atoms incorporated in the ring system, are heteroatoms selected from N, O or S(O)n(where n denotes an integer from 0 to 2), the remaining atoms included in the ring system, are carbon atoms and optionally one or two carbon atoms may optionally contain a carbonyl oxygen group, for example one or two atoms in the ring system may represent a fragment of formula. Thus, the term heterocycle includes the following ring systems as tetrahydropyranyl, tetrahydrofuryl, piperidinyl, piperazinil, morpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl. In the case of a bicyclic fragment heterocycle one of the two rings may be non-aromatic carbocyclic, is, however, the attachment point belongs heterocyclic ring system.

The term "substituted heterocycle" or "substituted heterocycle" refers to a group heterocycle, as defined above, which contains one, two or three substituent (preferably one or two substituent)selected from the group consisting of halogen, halogenoalkane, halogenoalkane, cyano, nitro, -Y-Rs, -Y-cycloalkyl, -Y-heterocyclyl, -Y ORs, -Y,-NRsRt, -Y-C(=O)Rs, -Y-C(O)2Rs, -Y-C(=O)NRsRt, -Y-C(O)2NRsRt, -Y,-S(O)0-2Rs, -Y,-NRS(O)2Rs, -Y,-S(O)2NRsRtand/or-Y-NRC(=O)NRsRtwhere Y, R, Rsand Rtare as defined above for substituted cycloalkyl group, so that Rsand Rtin turn, in each case independently are optionally substituted with one or two additional groups, as indicated above in the definition of the substituted cycloalkyl. Preferred substituents for the substituted groups heterocycle include -(alkylene)nis hydroxy, -(alkylene)n-lower alkoxy, -(alkylene)n-S(O)2(lower alkyl) and -(alkylene)n-CO2(lower alkyl), where n means 0, 1 or 2.

"Heteroaryl" means a monovalent, monocyclic aromatic fragment consisting of 5 or 6 atoms incorporated in the ring system containing one, two, three or four members of calcev the th system heteroatom, each of which is independently selected from N, O or S and the remaining atoms are carbon atoms, and the term also includes ring systems containing a second, conjugate ring, consisting of five or six members ring atoms, where the second conjugate ring may be aromatic or non-aromatic and may represent a carbocyclic, heterocyclic or heteroaryl ring system, provided however, that in this case, the attachment point will belong to the aromatic ring containing at least one heteroatom. Thus, the term heteroaryl includes, but not limited to, pyridyl, furyl, thiophenyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isooxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuran, isobenzofuran, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, ethanolic, benzimidazolyl, benzisoxazole, benzothiophene, dibenzofuran and benzodiazepine-2-one-5-yl, and their derivatives.

"Substituted heteroaryl" is a heteroaryl ring system, as defined above containing one, two or three (preferably one or two) substituent selected from the group consisting of halogen, halogenoalkane, halogenoalkane, cyano, nitro, -Y-Rp, -Y-aryl, -Y-heteroaryl, -Y-cyclol the sludge, -Y-heterocyclyl, -Y ORp, -Y,-NRpRq, -Y-C(=O)Rp, -Y-C(O)2Rp, -Y-C(=O)NRpRq, -Y-C(O)2NRpRq, -Y,-S(O)0-2Rp, -Y,-NRS(O)2Rq, -Y,-S(O)2NRpRqand/or-Y-NRC(=O)NRpRqwhere Y, R, Rpand Rqare as defined above for substituted aryl groups, such that Rpand Rqin turn, in each case independently optionally are substituted by one or two additional substituents, as indicated above in the definition of the substituted aryl. Preferred substituents for the substituted heteroaryl groups include alkyl, halogenated, heterocyclyl, halogen, nitro, cyano, and -(alkylene)n-CO2R (where n means 0 or 1 and R represents hydrogen or alkyl).

The term "tsepliaeva group" has the meaning generally accepted in the field of synthetic organic chemistry, i.e refers to an atom or a group which may be substituted by a nucleophile and includes halogen (such as chlorine, bromine and iodine), alkanesulfonyl, arenesulfonyl, alkylcarboxylic (for example, acetoxy), arylcarboxylic, mesilate, tosyloxy, tripterocalyx, aryloxy (for example, 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamine.

“Optional” or “optionally” means that the specified afterthis term event or circumstance may but it doesn't have to happen and that the description includes examples of where such event or circumstance occurs and examples of when it doesn't. For example, the term "optionally substituted cycloalkyl" refers to cycloalkyl groups, and substituted cycloalkyl groups, as defined above. In that case, when the term "optionally substituted" is preceded by a number of different types of ring systems listed in one row or in one row, for example, as the "optionally substituted cycloalkyl or heterocycle" or "optionally substituted carbocyclic or heterocyclic ring system, or optionally substituted aryl, heteroaryl, cycloalkyl or heterocycle", it is assumed that the term "optionally substituted" refers to each of the ring systems listed in the same row or in the same row.

In that case, when the term "optionally substituted" used in respect of specified cyclic group, for example, as the "optionally substituted cyclohexyl or optionally substituted piperidinyl you have to understand that optional Deputy of such specified cyclic ring systems may be selected from the group of substituents listed above for the group, expressed a generalized term, specifically if the convoy is Uchenna group falls under this term. Thus, for example, "optionally substituted cyclohexyl may be an unsubstituted cyclohexyl or tsiklogeksilnogo group containing one, two or three substituent selected from the substituents mentioned above for substituted cycloalkyl.

In that case, when you specify carbon atoms C5, C7 or C8 khinazolinov ring system, the numbering of the atoms of the ring system is as follows:

Preferred radicals are substituents chemical groups, determine which of the above are specified in the examples illustrating the invention.

The term "pharmaceutically acceptable excipient" means an excipient that can be used to obtain a pharmaceutical composition that is generally safe, non-toxic and is not undesirable neither biological, nor in any other sense. The term includes excipients that are acceptable for use in veterinary medicine, as well as fillers that may be used in the manufacture of medicinal products intended for humans. The term "pharmaceutically acceptable excipient" as used in the description of this application and in the claims includes both one or more fillers.

The term "pharmaceutically acceptable salt" link which means salt, which in General is a safe, non-toxic and is not undesirable neither biological, nor in any other sense, and which has the necessary pharmaceutical activity of the parent compound. Such salts include : (1) additive salts with acids (salt - addition products of acids), formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like acids, or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic (β-phenylacrylate) acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 4,4'-methylenbis-(3-hydroxy-2-EN-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic (octadecanoic) acid, Mukanova acid; (2) salts formed when an acidic proton present in the original compound, substituted or metal ion, for example an alkali metal ion, alkali earth metal ion or an aluminum ion; or are coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine.

The term "prodrug" in the text of this application refers to any compound which releases an in vivo source of active medicinal compound of formula I or II, in the case when such prodrug is administered to the patient is a mammal. Prodrugs based on the compounds of formula I or II receive by modifying one or more functional groups present in the compound of formula I or II so that the modifying group or a modifying group can be chipped off in vivo to release the source connection. Prodrugs include compounds of formula I or II, where the group hydroxy, amino or sulfhydryl in the compound of formula I or II attached to any group, which m which can be derived in vivo regeneration of free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (for example, derivatives such as acetate, formate and benzoate), carbamates (for example, N,N-dimethylaminoethyl) or hydroxyquinoline group in compounds of formula I or II.

"Protective group" refers to an atom or group of atoms that are attached to the reactive group in the molecule and are masking, reducing or eliminating the reactivity of the group to which they are joined. Examples of protective groups can be found in Green, Wuts, Protective Groups in Organic Chemistry (Wiley, 2nded. 1991); Harrison, Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8 (John Wiley and Sons, 1971-1996). Typical protective groups for amino groups include formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), trityl and substituted triteleia group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NVOC). Typical protective groups for hydroxy groups include such groups that are either acelerou or alkylate the hydroxy-group, for example, groups such as benzyl or lower alkalemia and trifilova ether group, and alkalemia ether group, tetrahydropyranyl ether group, Tria is Kiselyova ether group and an allyl ether group.

The term “treatment” of a disease includes:

(1) preventing the disease, i.e. treatment leads to the fact that mammals do not develop clinical symptoms to the appearance or manifestation which predisposes to the disease, but which have not yet felt or not manifest as the symptoms of the disease;

(2) the suppression of the disease, i.e. suspension or weakening of the development of the disease or its clinical symptoms, or

(3) the weakening of the disease, i.e. the regression of the disease or its clinical symptoms

“Therapeutically effective amount” means an amount of compound that, in the case of the introduction to a mammal for treating a disease, is sufficient to cause said treatment of the disease. “Therapeutically effective amount” will vary depending on such factors as the type of compound that is administered, the type of disease to be treated, and the severity of symptoms, and the age, weight and General health of the mammal undergoing treatment.

Compounds that correspond to the same molecular formula but differ in the nature or sequence of arrangement of the atoms or the arrangement of atoms in space are referred to as “isomers”. For isomers, to the which differ in the arrangement of atoms in space using the term “stereoisomers”. In the case of stereoisomers that are not mirror images of each other, using the term “diastereomers”and, in the case of such stereoisomers that are not overlapping each other, mirror images - the term “enantiomers”. In the case where the compound has an asymmetric center, for example, if the carbon atom is linked to four different groups may exist as pairs of enantiomers. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described as R - and S - rule ordering by Kanu and Prelog (Cahn, Prelog), or specify the method, according to which the molecule rotates the plane of polarized light and designated as programalso or levogyrate (e.g., as (+) or (-)isomer, respectively). Chiral compound can exist in the form of an individual enantiomer, or a mixture of enantiomers. A mixture containing equal amounts of the enantiomers is called a “racemic mixture”.

Compounds that are the subject of the present invention can possess one or more asymmetric center and therefore can be obtained in the form of individual R - or (S)-stereoisomers or mixtures thereof. If not specified, it is assumed that the description in the form of the e invention the name or description of the compounds include both individual enantiomers, and their mixtures (racemic or any other). Ways of establishing the stereochemistry and the separation of stereoisomers are well known from the prior art (see March, Advanced Organic Chemistry, Chap. 4, 4thedition, John Wiley and Sons, New York [1992]).

Although the above presented description of the invention, certain compounds of formula (I) are preferred.

Preferred compounds according to the present invention are the compounds of formula (Ip)

and their isomers, prodrugs and pharmaceutically acceptable salts, where

Q means-C(R1R2R3);

R1selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl;

R2and R3(i) independently chosen from alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle and alkyl substituted with one, two or three groups OR8, -SR8, -S(O)pR10, -C(O)2R8cycloalkyl, substituted cycloalkyl, heterocycle and/or substituted heterocycle or (ii) R2and R3together form an optionally substituted non-aromatic carbocyclic or heterocyclic ring system;

R4and R5represent halogen, cyano, trifluoromethyl or triptoreline;

R8and R9independently selected from hydrogen, alkyl, hydroxyalkyl of alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle;

R10represents alkyl, cycloalkyl, substituted cycloalkyl, heterocycle or substituted heterocycle and

p is 1 or 2.

More preferred are the compounds of formula (Ip), which has just been described above, in which

R1selected from hydrogen and C1-C4of alkyl;

R2and R3(i) independently chosen from hydrogen, C1-C6the alkyl and C1-C6of alkyl, substituted hydroxy group, -O(C1-C4alkyl) or-S(O)2(C1-C4alkyl), or (ii) R2and

R3together form3-C7cycloalkyl or five - or six-membered monocyclic heterocyclic ring system, where each of these ring systems is optionally substituted by one group R12and/or one group R14;

R4and R5both represent halogen and

R12and R14independently selected from C1-C4of alkyl, hydroxy, oxo (=O)- O(C1-C4alkyl), -C(=O)H, -C(=O)(C1-C4alkyl), -S(O)2H, -C(O)2(C1-C4alkyl) and-S(O)2(C1-C4alkyl).

As for the compounds of formulas (I) and (Ip), the preferred such compounds in which R1selected from hydrogen and C 1-C4the alkyl.

In the case of compounds of formulas (I) and (Ip) preferred such compounds, in which one of R2and R3selected from alkyl, substituted with one, two or three groups OR8, -SR8, -C(=O)R8, -C(O)2R, -C(=O)NR8R9, -S(O)pR10, -C(O)2NR8R9, -S(O)2NR8R9, -NR8R9cycloalkyl, substituted cycloalkyl, heterocycle and/or substituted heterocycle (where R8and R9independently selected from alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycle and substituted heterocycle). A more preferred group of compounds is that group of compounds, where R2and R3selected from alkyl, hydroxyalkyl, alkoxyalkyl, the group -(C1-C4alkylene)-S(O)pR10and -(C1-C4alkylene)-S(O)2R8(where R8and R10represent lower alkyl). Also preferred are such compounds where R2and R3together form an optionally substituted C3-C7cycloalkyl or optionally substituted heterocyclic ring system. Among this group of preferred compounds, more preferred are such compounds where R2and R3together form an optionally substituted cyclohexyl, piperidine-4-yl and the and tetrahydropyran-4-yl. Preferably specified cycloalkyl and heterocyclic group formed by the radicals R2and R3are unsubstituted or substituted with groups, -O(C1-C4alkyl), -C(O)2(C1-C4alkyl) and/or-S(O)2(C1-C4alkyl), more preferably a group-C(O)2(Et) or-S(O)2(CH3).

In the case of compounds of formulas (I) and (Ip) preferably both radicals R4and R5represent halogen. More preferred compounds in which R4and R5both represent fluorine.

In addition, combinations of the preferred groups described in the text of this application form other preferred embodiments of the invention. Thus, there are many preferred compounds included in the scope of the present invention.

Another group of preferred compounds are the compounds of formula

where Q denotes-C(R1R2R3); R1selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl; R2and R3(i) independently chosen from hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle and C1-C6of alkyl, substituted by one or two groups OR8, -SR8, -S(O)pR10, -C(O)2/sub> R8, -NR8R9cycloalkyl, substituted cycloalkyl, heterocycle and/or substituted heterocycle or (ii) R2and R3together form an optionally substituted non-aromatic carbocyclic or heterocyclic ring system.

Another group of preferred compounds are the compounds of formula

where R4and R5both represent halogen (preferably fluorine);

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

R12Aselected from hydrogen, C1-C4of alkyl, -C(=O)R15-C(O)2R15and the group-S(O)2(C1-C4alkyl);

R12bselected from hydrogen, C1-C4of alkyl, -OR15, -C(=O)R15-C(O)2R15and the group-S(O)2(C1-C4alkyl);

R14selected from C1-C4of alkyl, hydroxy, oxo (=O)- OR15, -C(=O)R15, -C(O)2R15and the group-S(O)2(C1-C4alkyl);

R15selected from hydrogen and C1-C4of alkyl;

q is 0 or 1, and

r is 0 or 1.

Even more preferred compounds which have just been defined above in which X represents-NR12a-, R12ameans S(O)2(C1-C4alkyl), q is 1 and R is 0.

The compounds of formula I to III can be used to treat any medical conditions and diseases of the human or other mammal, which is caused or enhanced by excessive or unregulated activation of Pro-inflammatory cytokines (i.e. TNF, IL-1 etc) or R kinase in these mammals. Compounds of formulas I and II inhibit R kinase in vitro studies and inhibit the release of TNF-α or IL-1B in the study of cells.

Due to the presence of activity against inhibition R kinase compounds according to the present invention can be used for the treatment of inflammatory diseases, autoimmune diseases, destructive bone disorders, and disorders, proliferative disorders, and disorders, angiogenic disorders, and disorders, infectious diseases, neurodegenerative diseases and viral diseases. Compounds according to the present invention can be used to treat arthritis, including but not limited to, rheumatoid arthritis, spondylitis, gouty arthritis, osteoarthritis, systemic lupus erythematous (SLE -)). systemic lupus lupus), juvenile arthritis and other conditions associated with arthritis. In addition, the compounds according to the present invention can be used for the treatment of lung disorders or inflammation of the lungs, including respiratory distress syndrome in adults, pulmonary sarcoidosis, asthma, silicosis, and chronic obstructive dis is evanie easy. In addition, the compounds according to the present invention can be used in the treatment of viral and bacterial infections, including sepsis, septic shock, gram-negative sepsis, malaria, meningitis, cachexia, evolved as a result of infectious disease or malignant condition, cachexia, evolved as a result of acquired immunodeficiency syndrome (AIDS), AIDS, ARC (complex associated with AIDS), pneumonia and herpes virus. In addition, the compounds according to the present invention can be used in the treatment of diseases associated with bone resorption, such as osteoporosis, in the treatment of endotoxic shock, toxic shock, disorders reperfusion injury, autoimmune diseases including graft rejection - graft-versus-host and allograft rejection, cardiovascular diseases, including myocardial infarction, atherosclerosis, thrombosis, congestive heart failure, impaired cardiac reperfusion, impaired renal reperfusion, for the treatment of liver disease and nephritis, and myalgia, which developed as a result of the infection.

Compounds according to the present invention can also be used to treat influenza, diabetes, systemic lupus erythematous (SLE), skin diseases and injuries, such as psoriasis, eczema,burns, dermatitis, keloid formation and scars. Compounds according to the present invention can also be used to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, symptoms of increased irritability of the intestines and ulcerative colitis. Compounds according to the present invention can also be used to treat ophthalmic diseases such as retinitis, retinopathy, uveitis, photophobia (photophobia) and acute damage to the eye tissues. Compounds according to the present invention can be useful for the treatment of cancer and angiogenesis including neoplasia and metastasis; ophthalmological conditions such as graft rejection corneal tumors of the blood vessels of the eyes, neovascularization of the retina, including neovascularization after trauma or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; for the treatment of ulcerative diseases such as gastric ulcer; pathological, but benign tumors such as hemangiomas, including child hemangioma, angiofibroma of the nasopharynx and avascular necrosis of bone; for the treatment of diabetic nephropathy and cardiomyopathy, disorders of the female reproductive system, such as endometriosis.

Soy is inane according to the present invention may also be useful for the treatment of diseases of the Central nervous system, for example, such as Alzheimer's disease, multiple sclerosis and depression.

In addition, the compounds according to the present invention may also be useful to prevent the production of cyclooxygenase-2 (MOR-2), and thus, can be used to treat such diseases, the course of which responds to inhibition of MOR-2, such as fever, swelling, and pain, including headache, neuromuscular pain, dental pain, arthritis pain and pain in cancer.

Besides the fact that the compounds are suitable for treatment of humans, the compounds according to the present invention can also be used in veterinary medicine for treatment of animals, such as domestic, exotic and farm animals, including mammals, rodents. The most preferred animals include horses, dogs and cats.

In addition, the compounds according to the present invention can be used for combination therapies, partially or completely instead of other conventional anti-inflammatory agents such as together with steroids, inhibitors of cyclooxygenase-2, non-steroidal anti-inflammatory drugs (NSAID), aspirin, DMARDS, immunosuppressive agents, inhibitors of 5-lipoxygenase, LTB4antagonists and inhibitors LTA4hydrolases.

In Tex the e of this application, the term "disease, the mediator which is TNF" refers to any and all diseases and morbid conditions under which plays the role of TNF or by control through the TNF, or caused by TNF release of other cytokines, such as (but not limited to) IL-1, IL-6 or IL-8. A painful condition in which, for example, IL-1 is a major component of its production or the impact of increases or occurs in response to TNF, thus, will be treated as a disease state, a mediator which is TNF.

In the text of this application, the term "disease, a mediator which is R" refers to any one and to all diseases and morbid conditions under which plays the role of R, or due to the control by R, or caused by R release another factor, such as (but not limited to) IL-1, IL-6 or IL-8. A painful condition in which, for example, IL-1 is a major component, and its production or the impact of increases or occurs in response to R, thus, will be treated as a disease state, a mediator which is R.

As TNF-β has close structural homology with TNF-α (also known as cachectin) and since each induces CX is derivative of biological reactions and is associated with the same cellular receptors, synthesis of TNF-α and TNF-β inhibited by compounds according to the present invention. In the case where the text of this application is indicated in General TNF - inhibition, it is assumed that you have in mind as TNF-α and TNF-β inhibition, unless specifically stated otherwise.

In all cases use the following abbreviations when describing the General synthesis schemes and in the examples in the text of this application abbreviations have the following meanings:

EtOH = ethanol

Meon = methanol

EtOAc = ethyl acetate

EDC = 1,2-dichloroethane

DHM = dichloromethane

DMF = dimethylformamide

NaOH = sodium hydroxide

N-MP = 1-methyl-2-pyrrolidin

The tea or Et3N = triethylamine

TFU = triperoxonane acid

THF = tetrahydrofuran

TPL = melting point

h = hour (time)

CT = room temperature

Compounds according to the present invention can be obtained in a variety of ways known to the person skilled in the art. Preferred methods include, but are not limited to, the General synthetic methods described below. Schemes are intended primarily for illustration. Various modifications of the above methods are quite possible and they are obvious to a person skilled in this technical field.

Used reference substances and reagents are the Xia or commercially available from manufacturers, such as Aldrich Chemical Co.” (Milwaukee, Wisconsin, USA), Bachem (TORRANCE, California, USA), Enika Chemie, or Sigma (St. Louis, Missouri, USA), “Maybridge” (Dist: Ryan Scientific, P.O. Box 6496, Columbia, S.C. 92960), etc. or they can be obtained using methods known to the expert in the art and described in the literature. Source materials and intermediate compounds resulting from the interaction, can be isolated and purified, if necessary, using conventional techniques, including, but not limited to, such techniques as filtration, distillation, recrystallization, chromatography. Such compounds may be characterized by conventional methods, including the determination of physical constants and spectroscopic characteristics. In the given schema variables Q, R1, R2, R3, R4, R5, R6etc. are determined in the same manner as described above in the description and as indicated in the claims.

The General scheme 1

Methyl ester of 5-chloro-2-nitrobenzoic acid (1) is subjected to interaction with the appropriately substituted phenol (2) and a base such as potassium carbonate, in an environment of a solvent, such as N-MP, obtaining thus the corresponding methyl ether Fenox the-2-nitrobenzoic acid (3). Connection (3) hydrolyzing when processing an alkaline solution such as NaOH in a mixture of water/Meon, obtaining thus benzoic acid (4). Benzoic acid (4) is treated with thionyl chloride in the environment of a solvent, such as DMF, to obtain the intermediate compound - carboxylic acid, which when processed with the use of NH4OH in the environment of a solvent, such as THF, allows to obtain benzamide (5). Nitrobenzamide (5) may be subjected to hydrogenation in the environment of a solvent, such as EtOH, to obtain this aminobenzamide (6).

Aminobenzamide (6) may be subjected to cyclization with getting at this hinzelin-2,4-dione (7) in the processing of urea in the medium solvent, such as N-MP. Compound (7) can be treated with N,N-diethylaniline and POCl3obtaining this 2,4-dichloroaniline (8)from which, after processing using the NH3in the environment of a solvent, such as Meon, get a connection (9). Compound (9) may be subjected to interaction with tert-butylnitrite in THF with getting this connection (10)from which after condensation with the appropriate amine NH2Q, for example, in the environment of N-MP, get the compounds of formula (I). The Cl group in the compounds (8) and (9) represents tsepliaeva group, and may be COI is used and the other tsepliaeva group.

The General scheme 2

The compounds of formula (II) receive thus, as shown in scheme 2, in accordance with the same General method, which is shown above in figure 1.

Examples

Example 1

2-[6-(2,4-Divergence)hinzelin-2-ylamino]-2-ethylpropane-1,3-diol

1A. Methyl ester 5-(2,4-divergence)-2-nitrobenzoic acid

Methyl ester of 5-chloro-2-nitrobenzoic acid (73 g, 0.34 mol), 2,4-diferena (of 51.1 g of 0.39 mol) and potassium carbonate (73 g of 0.53 mol) in N-MP (200 ml) was stirred at 160°C for 2 h, the Reaction mixture was cooled to room temperature, poured into water (250 ml) and extracted using EtOAc (2×100 ml). The organic layer is washed several times with water, dried over sodium sulfate, concentrated in vacuo, then the residue purified Express chromatography, elwira a mixture of hexane:EtOAc (ratio 95:5) and thus to 66.8 g of methyl ester of 5-(2,4-divergence)-2-nitrobenzoic acid (1A).

1B. 5-(2,4-Divergence)-2-nitrobenzoic acid

To a solution of compound (1A) (66 g, 0.21 mol) in a mixture of water/Meon (180/180 ml) is added NaOH (27 g, of 0.68 mol) and then the resulting mixture is refluxed for 2 hours After cooling to room temperature the reaction mixture was podcas Aut, using a 10%HCl solution, then extracted using EtOAc. The organic layer was washed with saturated salt solution, dried over sodium sulfate, concentrated in vacuo and recrystallized using a mixture of ether/hexane and receiving with 53 g of 5-(2,4-divergence)-2-nitrobenzoic acid (1B).

1B. 5-(2,4-Divergence)-2-nitrobenzamide

A mixture of compound (1B) (53 g, 0.18 mol), thionyl chloride (51,3 ml) and DMF (1 ml) was stirred at room temperature for 18 h, then concentrated in vacuo to dryness. The obtained acid chloride of acid (60,7 g) dissolved in THF (400 ml) and add NH4HE (235 ml). Then the resulting mixture was stirred for 18 h and concentrated in vacuo. The residue is purified Express chromatography, elwira a mixture of hexane:EtOAc (ratio 4:1), while receiving 27,7 g of 5-(2,4-divergence)-2-nitrobenzamide (1B).

1G. 2-Amino-5-(2,4-divergence)benzamid

To the compound (1B) (27 g, 0.09 mol) in EtOH added palladium on activated carbon (2.7 g) and then the resulting mixture was stirred in an atmosphere of hydrogen for 18 hours, the resulting suspension is filtered through celite and then the filtrate is concentrated and dried in vacuum, to thereby obtain 23 g of 2-amino-5-(2,4-divergence)benzamide (1 G).

1D. 6-(2,4-Divergence)-1H-hinzelin-2,4-dione

The compound (1G) (23 g, 0.09 mol) and urea (25,42 g, 0.41 mol) in N-MP (150 ml) is heated to 170°C for 18 hours After cooling to room temperature the reaction mixture was poured into water (200 ml) and stirred for 1 h the precipitate is filtered off, washed with water and dried, thus obtaining an increase of 22.7 g of 6-(2,4-divergence)-1H-hinzelin-2,4-dione (1D).

1E. 2,4-Dichloro-6-(2,4-divergence)hinzelin

The compound (1D) (22,6 g, 0.08 mol), N,N-diethylaniline (7.2 ml) and POCl3(248 ml) is heated at 120°C for 4 h After cooling to room temperature the excess POCl3evaporated and the residue is alkalinized using 10% NaHCO3then extracted using EtOAc (2×100 ml). The combined organic layers dried over sodium sulfate and evaporated in vacuum. The crude product is purified by chromatography (silica gel, hexane:EtOAc, in the ratio 4:1), while receiving 21.1 g of 2,4-dichloro-6-(2,4-divergence)hintline (1E).

1G. 2-Chloro-6-(2,4-divergence)hinzelin-4-ylamine

The compound (1E) (21 g, 0.06 mol) is suspended in ammonia (100 ml, 2.0 M solution in Meon) and then the resulting solution over 30 minutes, stirred at room temperature for 18 hours the precipitate is filtered, concentrated the filtrate is triturated with EtOAc, then the organic layers are combined to receive the I of 21.5 g of 2-chloro-6-(2,4-divergence)hinzelin-4-ylamine (1G).

1Z. 2-Chloro-6-(2,4-divergence)hinzelin

The compound (1G) (21 g, 0.07 mol) is dissolved in THF (200 ml) and the resulting solution is added dropwise to a solution of tert-butylnitrite with 16.5 ml, 0.14 mol) in THF (100 ml). The resulting mixture was refluxed for 4 h and then, after cooling to room temperature the reaction mixture was poured into water and extracted using EtOAc (2×100 ml). The combined organic layers dried over sodium sulfate and evaporated in vacuum. The crude product is purified by chromatography (silica gel, hexane:EtOAc, in the ratio 4:1), while receiving 9,05 g of 2-chloro-6-(2,4-divergence)hintline (1Z).

1I. 2-[6-(2,4-Divergence)hinzelin-2-ylamino]-2-ethylpropane-1,3-diol (Example 1)

The compound (1G) (250 mg, 0.85 mmol) and 2-amino-2-ethyl-1,3-propandiol (298 mg, 2.5 mmol) in N-MP (0.25 ml) was stirred at 120°C for 4 h After cooling to room temperature the reaction mixture was poured into water and extracted using EtOAc (2×25 ml). The combined organic layers dried over sodium sulfate and evaporated in vacuum. The crude product is purified by chromatography (silica gel, mixture of CH2Cl2:MeOH, in the ratio 95:5), while receiving 150 mg specified in the title compound (Example 1). TPL=110-112,9°C. the Molecular mass (M+N)+=376.

Examples 2-5

The compounds of formula I(a)above, where R2and R3have the values listed in tables 1 and 2, obtained using the same methodology described above in example 1, or a similar technique, except that at the second stage, instead of 2-amino-2-ethyl-1,3-propane diol using the appropriate amine.

Table 1
Example No.R2R3Connection nameTPL (°C)Molecular weight
2-CH3-CH36-(2,4-Divergence)hinzelin-2-yl]-
(isopropyl)amine
160-162,6315,32
3-CH2CH2OH-CH2CH2OH3-[6-(2,4-Divergence)hinzelin-2-ylamino]
pentane-1,5-diol
112,9-113,6375,37
Table 2
Example No. R2R3Connection nameTPL (°C)Molecular weight
4-N3-[6-(2,4-Divergence)hinzelin-2-ylamino]
propane-1,2-diol
161,5-162,7347,32
5-N6-(2,4-Divergence)hinzelin-2-yl]-
(2-methansulfonate)Amin
160,1-161,5379,39

Example 6

[6-(2,4-Divergence)hinzelin-2-yl]-(1-methanesulfonamido-4-yl)Amin

2-Chloro-6-(2,4-divergence)hinzelin (250 mg, 0.85 mmol) (compound 1, obtained as described in example 1, stage A-C) and 1-(methylsulphonyl)piperidine-4-amine (228 mg, 1.25 mmol) in N-MP (0.25 ml) was stirred at 120°C for 18 hours After cooling to room temperature the reaction mixture was poured into water and extracted using EtOAc (2×25 ml). The combined organic layers dried over sodium sulfate and evaporated in vacuum. The crude product is purified by chromatography (silicagel is, a mixture of hexane:EtOAc, 1:1 ratio), while receiving 105 mg of the compounds specified above in the header of example 6. TPL=173,9-177,1°C. Molecular weight (M+N)+=435.

Examples 7-10

The compounds of formula (IB)above, where X has the values listed in table 3, obtained using the same methodology described above in example 6, or a similar method, except that instead of 1-(methylsulphonyl)piperidine-4-amine used appropriately substituted amine.

Table 3
Example No.XConnection nameTPL (°C)Molecular weight
7-O-[6-(2,4-Divergence)hinzelin-2-yl]-(tetrahydropyran-4-yl)Amin179-180,9357,36
84-[6-(2,4-Divergence)hinzelin-2-ylamino]cyclohexanol176,2-176,8371,39
9 Ethyl ester of 4-[6-(2,4-divergence)hinzelin-2-ylamino]piperidine-1-carboxylic acid154,1-155,0428,44
10-N(H)-6-(2,4-Divergence)hinzelin-2-yl]piperidine-4-ylamine163,0-165,3356,37

Example 11

(6-Ethoxyquinoline-2-yl)-(2-methansulfonate)Amin

2-Chloro-6-ethoxyquinoline (500 mg, 2.4 mmol) and 2-methylsulfonylamino (of 0.67 ml of 7.25 mmol) in N-MP (0.5 ml) was stirred at 80°C for 18 hours After cooling to room temperature the reaction mixture was poured into water and extracted using EtOAc (2×25 ml). The combined organic layers dried over sodium sulfate and evaporated in vacuum. The crude product is dissolved in DHM (5 ml) and cooled in a bath with ice. Then add 3-chloroperoxybenzoic acid (911 mg, 5.2 mmol), after which the reaction mixture is stirred for 5 h, diluted with using EtOAc (15 ml), washed with 5%solution of NaHCO3(10 ml), dried over sodium sulfate and evaporated in vacuum. The crude product is purified by chromatography (silica gel, EtOAc first 100%, then the mixture is CH2Cl2:Meon [where is Oseni 95:5]), while receiving 250 mg of the compounds specified above in the header of the example 11. TPL=152,7-154, 6mm°C, molecular weight (M+N)+=280.

Examples 12-15

The compounds of formula II(a)above, in which Q has the values listed in table 4, obtained using the same methodology described above in example 11, or a similar method, except that instead of 2-methylsulfonylamino using the appropriate amine.

Table 4
Example No.XConnection nameTPL (°C)Molecular weight
123-(6-Ethoxyquinoline-2-ylamino)pentane-1,5-diol291
13(6-Ethoxyquinoline-2-yl)-(1-methanesulfonamido-4-yl)Amin168,0-173350,44
14 Ethyl ester of 4-(6-ethoxyquinoline-2-ylamino)piperidine-1-carboxylic acid164,4-165,0345
15(6-Ethoxyquinoline-2-yl)-(2-methansulfonate)Amin296

Example 16

The following shows a typical pharmaceutical compositions based on compounds of formula (I) or (II).

Preparation of tablets

The following ingredients are thoroughly mixed and pressed, while receiving the tablets with a single notch.

Ingredient tabletsQuantity per tablet, mg
the connection according to the present invention400
corn starch50
crosscarmelose sodium25
lactose120
magnesium stearate5

Cooking capsules

The following ingredients are thoroughly mixed and placed in a hard gelatin capsule.

Ingredient capsulesQuantity per capsule, mg
the connection according to the present invention200
lactose, dried
spray drying148
magnesium stearate2

Preparation of suspension

The following ingredients are mixed, thus obtaining a suspension for oral administration

IngredientNumber
the connection according to the present invention1.0 g
fumaric acid0.5 g
sodium chloride2.0 g
methylparaben0.15 g
propylparaben0.05 g
granulated sugar25,5 g
sorbitol (70%solution)is 12.85 g
The Whigs To Veegum K, Vanderbilt Co.)1.0 g
flavora 0.035 ml
tinted substance0.5 mg
distilled waterto bring up to 100 ml

Composition for injection

The following ingredients are mixed to give the composition for injection.

IngredientNumber
the connection according to the present invention0.2 g
sodium acetate buffer solution, 0.4 M2.0 ml
HCl (1 BC) or NaOH (1 BC)for adjusting the pH of
water (distilled, sterile)to bring up to 20 ml

All of the above ingredients, except water, are combined and heated to 60-70°C under stirring. Then add water at 60°C in sufficient quantity to emulsify the ingredients, and then the amount of water adjusted to 100 g

Preparation of suppositories

A suppository of total weight 2.5 g privotal which provide a mixture of compounds according to the present invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York, suppository has the following composition:

the connection according to the present invention500 mg
Witepsol® H-15the basis, the rest

Example 17

Inhibition of p-38 (map) kinase - an in vitro study

Inhibitory activity of the compounds according to the present invention in vitro against p-38 map kinase is determined by measuring the transfer of γ-phosphate from γ-33P-ATP by p-38 kinase to myelin basic protein (MBP -). from the English. Myelin Basic Protein) using a slight modification of the techniques described in Ahn et al., J. of Biol. Chem., Vol.266 (7), 4220-4227 (1991).

Phosphorylated form of recombinant R map kinase Express using the SEK-1 and MEKK in E.Coli (see Khokhlatchev et al., J. of Biol. Chem. Vol.272(17), pp.11057-11062 (1997)), and then purified by affinity chromatography using columns Nickel column.

Phosphorylated R map kinase was diluted with a buffer for kinase (20 mm 3-(N-morpholino)propanesulfonic acid, pH of 7.2, 25 mm β - glycerophosphate, 5 mm ethylene glycol-bis(beta-aminoacylase simple ether)-N,N,N',N'-tetraoxane acids, 1 mm sodium Vanadate, 1 mm dithiothreitol, 40 mm magnesium chloride). Add test compounds dissolved in DMSO or only LCA is (control), and then the samples are incubated for 10 min at 30°C. the Kinase reaction is initiated by addition of the substrate mixture containing MBP and γ33P-ATP. After incubation for an additional 20 min at 30°C the reaction is stopped by the addition of 0.75%phosphoric acid. Phosphorylated MBP then separated from the remaining γ-33P-ATP using phosphocellulose membrane (“Millipore, Bedford, mA, USA) and performed quantitative determination with the use of scintillation counter (Packard, Meriden, CT, USA).

Compounds described in the examples presented in the text of this application, is tested in accordance with the above-described method, it was found that these compounds have measured the level of inhibitory activity against p-38. As an illustration, table 5 below reports the estimated inhibitory activity against p-38 for some compounds according to the present invention (expressed as IC50i.e. as the concentration causing 50% inhibition in relation to the investigated p-38 enzyme).

Table 5
Example No.IC50Example No.IC50
1<,106<,001
2<,038<,03
4<212>10
5≅2

The above discussion of the present invention are presented for purposes of illustration and description. It is assumed that the above does not limit the invention to those forms, which are described in the text of this application. Although the description of the present invention comprises one or more embodiments and certain modifications and variations, other modifications and variations that are included in the scope of the present invention, for example, which can be performed within the knowledge and experience of the expert in this field. It is assumed to have the same rights that apply to all alternatives in extent permitted, including alternate, interchangeable and/or equivalent structures, functions, intervals or stages in relation to declared, regardless of the fact, disclosed by such alternative, inter is aenemia and/or equivalent structures, functions, intervals or stages in the text of this application, and without intending to publicly disclose any patentable subject. All publications, patents and patent applications, cited throughout this application are included in all their volume only as a reference.

1. The compound of formula (I):

or its esters, carbamates, or its pharmaceutically acceptable salt,
where Q denotes-C(R1R2R3);
R1selected from hydrogen, C1-C8of alkyl, hydroxys1-C8of alkyl, and C1With8alkoxyl1-C8of alkyl;
R2and R3choose:
(i) independently from:
(a) hydrogen, provided that if R1means hydrogen, only one of R2and R3can be selected from hydrogen;
(b) C1-C8of alkyl;
(C) C1-C8of alkyl, substituted by one or two radicals halogen, -OR8, -S(O)pR10;
(d) -OR8;
or (ii) R2and R3together with the carbon atom to which they are attached, form an optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system;
R4and R5independently selected from halogen;
R8and R9independently selected from hydrogen, C1-C8of alkyl;
R10represents a C1-C8and the keel;
m means 0;
n is 0; and
p represents 2;
where the term "substituted cycloalkyl" means cycloalkyl group containing one or two substituent which is independently selected from the group consisting of-Y ORs, -Y,-S(O)0-2RsC(=O)OR8where Y is absent; a, Rsindependently selected from hydrogen, C1-C8of alkyl, except in those cases when the Deputy means
-Y-S(O)1-2Rsthen Rsin these cases, does not mean hydrogen;
the term "heterocyclic ring system" means a saturated non-aromatic monocyclic fragment consisting of 5 to 6 atoms incorporated in the ring system, of which one atom included in the ring system is a heteroatom selected from N, O, and the remaining atoms included in the ring system, are carbon atoms;
the term "substituted heterocyclic ring system" means a heterocyclic fragment above, containing one Deputy, selected from the group-Y-Rs, -Y ORs, -Y-C(O)2Rs, -Y,-S(O)0-2Rswhere Y is absent or means1-C4alkylenes group, Rsis the same as defined above for substituted cycloalkyl group.

2. The compound according to claim 1,
where R1selected from hydrogen and C1-C4of alkyl;
R and R3(i) independently selected from C1-C6the alkyl and C1-C6of alkyl, substituted by one or two radicals of hydroxy, -O(C1-C4alkyl), - and/or-S(O)p(C1-C4alkyl); or
(ii) R2and R3together form3-C7cycloalkyl or five - or six-membered monocyclic heterocyclic ring system, where each of these ring systems is optionally substituted by the radical R12in the amount of from 0 to 1 and/or the radical R14in the amount of from 0 to 1;
R and R5both represent halogen;
R12and R14independently selected from C1-C4of alkyl, hydroxy, -O(C1-C4alkyl),
-C(=O)O(C1-C4alkyl) and-S(O)2(C1-C4alkyl);
m means 0;
and n is 0.

3. The compound according to claim 1, where R1selected from hydrogen and C1-C4the alkyl.

4. The compound according to claim 1,
where R2and R3choose (i) independently from:
1) C1-C8of alkyl, substituted by one or two halogen atoms, a group-OR8, -S(O)pR10;
or R2and R3together form an optionally substituted C3-C7cycloalkyl or heterocyclic ring system.

5. The compound according to claim 1,
where R2and R3independently selected from hydrogen, C1-C6the alkyl and g is PPI hydroxy(C 1-C6alkyl).

6. The compound according to claim 1,
where R2and R3together form an optionally substituted C3-C7cycloalkyl or optionally substituted heterocyclic ring system.

7. The compound according to claim 1,
where R2and R3(i) independently chosen from hydrogen, C1-C4the alkyl and groups
hydroxy(C1-C4alkyl), provided that R2and R3both signify hydrogen; or (ii) R2and R3together form a cyclohexyl, piperidine-4-yl or tetrahydropyran-4-yl, where each of these ring systems formed by the radicals R2and R3taken together is optionally substituted up to two such radicals as HE, and/or-S(O)2(CH3).

8. The compound according to claim 1, corresponding to the formula:

9. The compound according to claim 1, corresponding to the formula:

where X represents-O-, -N(R12a)- or-CH(R12b)-;
R4and R5independently selected from halogen,
R12aselected from hydrogen, C1-C4of alkyl, -C(O)2R15and the group-S(O)2(C1-C4alkyl);
R12bselected from hydrogen, C1-C4of alkyl, -OR15, -C(O)2R15and the group-S(O)2(C1-C4alkyl);
R15in each case, independently wybir the Ute from hydrogen and C 1-C4of alkyl;
q indicates 0 or 1.

10. The connection according to claim 9,
where R4and R5both represent fluorine.

11. Connection to item 11, where X is N(R12a)-, R12ameans-S(O)2(C1-C4alkyl), and q is 1.

12. The compound according to any one of claims 1 to 11, or its pharmaceutically acceptable salt having the properties of an inhibitor R protein kinase.

13. Pharmaceutical composition having the properties of an inhibitor R protein kinase, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11, or its pharmaceutically acceptable salt and a filler.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns novel amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy3,4-dihydro-2N-chromen-6-yl of the general formula (I) where R1 is C1-C4alkyl, R2 is C1-C4alkyl, R3 is phenyl optionally once or twice substituted or substituted by halogen, C1-C4alkyl, C1-C4alkoxy group or trifluoromethyl, naphthyl or biphenyl, R4 is hydrogen, C1-C6alkyl or C3-C7cycloalkyl-C1-C4alkyl, R5 is hydrogen, and R6 is C1-C6 alkyl, phenyl-C1-C4alkyl, phenyl group optionally substituted by halogen, furyl-C1-C4alkyl or tetrahydronaphthyl, or R5 and R6 together with nitrogen atom linking them form piperazine ring optionally substituted by phenyl.

EFFECT: also invention claims method of obtaining claimed compounds, and intermediary products used in method implementation, as well as medicines containing compounds of the formula (I) with antiarrhythmic effect, and application of these medicines.

11 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds N-(2-furylalkyl)-NHR carbamides with formula 1: , exhibiting growth-regulating and immuno-modeling activity, and method of producing them. The method involves reacting furfuryl idenacetone with urea in hydroamination conditions in an autoclave, in the presence of skeletal nickel catalyst and an organic solvent at 70-90°C temperature, and ratio of substrate to reagent equal to 1:1 or 2:1.

EFFECT: invention can be used in agriculture.

2 cl, 9 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: in novel tocopherol-modified therapeutic drug compounds of formula 1 T-L-D, T is tocopherol, L is succinate, and D is camptotecin or its derivative, where all three fragments are bound covalently. Invention also relates to emulsions based on said compounds, formulations of micelles, including said compounds, methods of treating cell proliferative disease using said compounds and formulations, as well as to said compounds application for production of medication for treatment of cell proliferative disease.

EFFECT: increase of composition and treatment method efficiency.

18 cl, 17 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to 5-substituted alkylaminopyrazole derivatives of formula I , wherein R1 is CN; W is C-halogen; R1 is halogen; R3 is C1-C3-haloalkyl, C1-C3-haloalkoxy; R4 is hydrogen, C1-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, COR8; A is C1-C12-alkylene; R5 is hydrogen, C3-C6-alkenyl, -(CH )qR7 or NR10R11; R5 is C1-C6-haloalkyl; as well as method for animal exogenous and endogenous pest controlling; pesticide composition and application of said compounds for production of veterinary drug. 5-Substituted alkylaminopyrazole derivatives are useful in pest controlling, including insects, arachnids and helminthes, such as nematodes.

EFFECT: new pesticide derivatives.

9 cl, 12 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to anthranylamidepyridine amides of selective effect as inhibitors of VEGFR-2 and VEGFR-3. Invention describes compounds of the general formula (I): wherein A, B and D represent independently of one another nitrogen atom or carbon atom wherein at least one nitrogen atom is in a ring; E represents aryl comprising 6-12 ring carbon atoms or heteroaryl comprising 5 or 6 ring atoms and comprising in ring instead carbon atom similar or different heteroatoms chosen from nitrogen or sulfur atoms, or represents group -COOR8, -CONR2R3 or -C≡C-R9; G represents nitrogen atom or group -C-X; L represents nitrogen atom or group -C-X; M represents nitrogen atom or group -C-X; Q represents nitrogen atom or group -C-X and wherein a ring comprises maximally one nitrogen atom; X represents hydrogen atom; W represents hydrogen or halogen atom; R1 represents aryl similarly or differently optionally mono- or multi-substituted with halogen atom, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl or group =O and wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms and comprising in ring instead carbon one or more similar or different heteroatoms, such as oxygen, nitrogen or sulfur and it can be mono-, bi- or tricyclic and condensed additionally condensed with benzene ring; R2 and R3 represent independently of one another hydrogen atom or aryl similarly or differently mono- or multi-substituted with halogen atom, cyano-group, (C1-C6)-alkyl, phenyl, hydroxy-(C1-C6)-alkyl, halogen-(C1-C6)-alkyl or group -NR6R7, -OR5, (C1-C6)-alkyl-OR5-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms and comprising in ring instead carbon one or more heteroatoms, such as nitrogen or sulfur; or R2 and R3 in common with nitrogen atom form (C3-C8)-ring that can comprise optionally one more nitrogen or oxygen atom or it can comprise group -N(R10); R5 represents hydrogen atom; R6 and R7 represent independently of one another hydrogen atom or (C1-C6)-alkyl; R8 represents (C1-C6)-alkyl mono- or multi-substituted optionally with halogen atom or benzyl; R9 represents hydrogen atom or tri-(C1-C6)-alkylsilyl; R10 represents hydrogen atom or (C1-C6)-alkyl, and their isomers, enantiomers and salts also. Also, invention describes a medicinal agent based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

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

15 cl, 2 sch, 133 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of pyridinecarboxamides with formula (I), where the descriptions of radicals are given in the formula of the invention and its salts.

EFFECT: compounds exhibit insecticide activity.

7 cl, 5 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel pyrazole derivatives of the formula (IIIa) , where R1 is T-(ring D), where ring D is naphthyl or phenyl optionally substituted by -R5; Rx, Ry, R2, R2' and R5 are as defined in the claim; and pharmaceutical composition containing claimed compounds. Compounds inhibit protein kinases such as Aurora-2, GSK-3 or Src and can be applied in treatment methods for diseases mediated by the indicated protein kinases, such as cancer, diabetes and Alzheimer's disease.

EFFECT: compounds also applicable in methods of hyperphosphorylated protein Tau products inhibition and β-catenin phosphorylation inhibition.

24 cl, 12 tbl, 292 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed N-hydroxyformamide compound of formula (I) or its pharmaceutically acceptable salt where ring B represents phenyl, pyridinyl or pyrimidinyl; R2 represents the group chosen from C1-6alkyl, phenyl or naphthyl where the specified group is substituted with one or more fluoro group; n is equal to 1, 2 or 3; and R1 represents tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-, 2-pyrimidinyl-CH2CH2CH2-, SF-2-pyrimidinyl-CH2CH2-, C1-6alkyl or phenyl.

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds satisfying general formula (I): where: R1 stands for direct or branched (C1-C7)alkyl, X stands for hydrogen atom, R2 stands for the group chosen from naphthalenyl, pyridinyl, isoquinoleinyl, thienyl, imidazolyl, benzothienyl, benzimidazolyl, indolyl, benzotriazolyl and optionally substituted with one or more substitutes chosen from halogen atoms and following groups: (C1-C4)alkyls, thio(C1-C4)alkyls or phenyls, optionally substituted with one or more substitutes chosen from halogen atoms or trifluoromethyl, as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 3 ex, 1 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: object of the present invention are compounds: N-(2,3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl)piperidine-4-yl]methoxy}quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]-propoxy}quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, 2-{3-[(7-{3-[cycloamyl(2-hydroxyethyl)-amino]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}-N-(2,3-difluorophenyl)acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)-pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide and others named in formula of invention.

EFFECT: compounds are intermediate for synthesis of phosphonooxyquinazoline derivatives with properties of aurora-kinase-A and/or aurora-kinase-B inhibitor.

3 cl, 5 tbl, 50 ex

FIELD: medicine.

SUBSTANCE: in the formula I or it pharmaceutically comprehensible salt: m it is peer 3; n it is peer from 0 to 2; all R1 independently mean H; R2 means aryl, unessentially replaced 1-2 assistants chosen from group, including halogen, and C1-C12alcoxy; R3 means H, C1-C12alkyl; p it is peer 2 or 3; R5, R6, R7 and R8 independently mean H, C1-C12alkyl, or one of R5 and R6 together with one of R7 and R8 and the atoms located between them can form a 4-7-termed heterocyclic ring, or R7 and R8 together with atom of nitrogen to which they are attached, can form a 5-7-termed heterocyclic ring; or one of R5 and R6 together with R3 and the atoms located between them can form a 5-7-termed heterocyclic ring. Bonds I possess selective opposing activity in the relation of 5-NT6 receptor.

EFFECT: possibility to use bond in a pharmaceutical composition for treatment of CNS and gastroenteric tract.

16 cl, 8 dwg, 2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula I: , where L represents radical , in which R1 represents H, C1-4alkyl; n represents 0 or 1; or L represents radical , in which R1 represents H, C1-4alkyl; m equals 1; R represents H, halogen, C1-C4alkyl or C1-C4-alkoxy; Z represents a bond, -C(O)NH-, O or S; p is an integer from 1 to 5; Q represents a bond with the condition that, Z is not a bond, when p equals 1; or represents O, S or -C(O)NR6-, where R6 represents H, C1-4alkyl or C3-6cycloalkyl; or W and R6 together with a nitrogen atom, to which they are bonded, form or or Q represents -NR6-, or in the condition that, p is not equal to 1; W represents , , , , ,

, , ,

, , ,

, , , ,

, , , ,

, , , ,

, , , , ,

, , , , , and

.

EFFECT: obtaining compounds with agonistic activity towards PPAR receptors, which enables them to be used in pharmaceutical compositions and methods of treating conditions, mediated by these receptors.

12 cl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to application of indazole derivatives of general formula (I) , in which: R stands for O; R3 stands for radical (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, said radicals being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R4, R5, R6 and R7, independently on each other are selected from following radicals; hydrogen atom, halogen, CN, NO2, NH2, NHSO2R9, trifluoromethyl, trifluoromethoxygroup, (C1-C6)-alkyl, phenyl, phenyl-(C1-C6)-alkyl, pyridyl, possibly substituted with amino or hydroxygroup, thienyl, furanyl, morpholino, phenyl being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R8, R9, R10, R11, independently on each other, stand for hydrogen atom, (C1-C6)-alkyl, phenyl possibly substituted with halogen; their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts for obtaining medication, inhibiting phosphorylation of Tau-protein. Invention also relates to novel compounds of formula (I), particular indazole derivatives, their racemates, enantiomers, tautomers and pharmaceutically acceptable salts, pharmaceutical composition and based on them medication which inhibits Tau-protein phosphorylation, as well as to method of obtaining compounds of formula (I).

EFFECT: obtaining medication based on indazole derivatives, inhibiting Tau-protein phosphorylation.

9 cl, 118 ex, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, namely to medicated products normalising cardiac function, particularly being perspective for treatment of coronary heart disease (CHD). Peptide of general formula CH3CO-Lys-Lys-Arg-Arg-NH2 is disclosed as an anti-ischemic and antihypoxic agent.

EFFECT: declared invention ensures apparent anti-ischemic, antihypoxic and adaptive action and is being available in medical practice.

1 cl, 3 ex, 5 tbl

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