Bicyclic pyridines and pyrimidines as kinase p38 inhibitors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

 

The present invention relates to certain derivatives of bicyclic pyridine and pyrimidine as inhibitors of protein kinase R. The present invention primarily relates to 2-substituted aminobenzylidene pyridinium and pyrimidines, method of production thereof, to pharmaceutical preparations containing these compounds and to methods of their use.

Mitogen-activated protein kinase (MAP) are a family of Proline-activated serine/trainingin who activate their substrates by dual phosphorylation. Kinases are activated under the influence of many signals that include stress, nutritional and osmotic stress, UV irradiation, growth factors, endotoxin and inflammatory cytokines. One group of MAP kinases is a group of kinases R, which includes various isoforms (for example, Rα, Rβ, Rγ and Rδ). Kinase R exercise fosforanowanie and activation of transcription factors and other types of kinases, and kinases are activated by physical and chemical stress, proinflammatory cytokines and bacterial lipopolysaccharide.

Furthermore, it is established that the products of phosphorylation by kinases R mediate the production of inflammatory tsitokinov, including TNF, IL-1 and IL-6, and cyclooxygenase-2. Each of these cytokines is in involved in the development of many diseases and pathological conditions. For example, TNF-α is a cytokine produced primarily activated monocytes and macrophages. It is assumed that his excessive or unregulated production is the cause of the development of the pathogenesis of rheumatoid arthritis. Recently found that inhibition of production of TNF finds wide application in the treatment of inflammatory process, inflammatory bowel disease, Alzheimer's disease, Crohn's disease, multiple sclerosis and asthma.

In addition, TNF is involved in the development of viral infections such as HIV, influenza virus and herpes virus, including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr, human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), human herpes virus 8 (HHV-8), the virus pseudoleskeella (virus Auski), rhinotracheitis virus.

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

Inhibition of these cytokines through inhibition of the kinase R will allow you to carry out treatment, the decrease in the intensity of symptoms, and alleviating many of these pathological conditions.

<> The first object of the present invention (I) are the compounds of formula

where a represents N or CH,

R1means hydrogen, alkyl or aralkyl,

R2means alkyl, hydroxyalkyl, (R)2NCO-alkylen- (where each R" is independently mean hydrogen or alkyl), cycloalkyl, heterocyclyl, aryl, heteroaryl or heteroalkyl,

X is O, N(R3or S, where R3means hydrogen, alkyl or aryl,

Y represents a chemical bond, O, N(R'), C(=O), CH(OR'), CHR', or S(O)nwhere n is 0, 1 or 2, and R' denotes hydrogen or alkyl, and

R is aryl or heteroaryl, and

their isomers, pharmaceutically acceptable salts, esters or prodrugs.

For professionals it is obvious that, if a represents CH, then the neighboring double bond becomes a simple connection.

In addition, objects of the present invention are the following compounds.

(II) the Compound according to item (I), in which all substituents have the meanings specified in paragraph (I), except that R2does not mean heteroalkyl.

(III) the Compound according to item (I), where

A represents N or CH,

R1means hydrogen, alkyl or aralkyl,

R2means alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,

X is O, N(R3or S, where R3means hydrogen or methyl, and

Y means O, N(R'), C(=O), CH(OR')CH' or S(O) nwhere n is 0, 1 or 2, and

R' means hydrogen or alkyl, and

R is aryl or heteroaryl.

(IV) the Compound according to any one of items (I)to(III), where

And means N

R1means hydrogen,

R2means hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroalkyl,

X represents O, NR3or S, where R3means alkyl or aryl, and

Y represents a chemical bond, O, S(=O), CH(OR'), CHR', or S, and R' is hydrogen and

R is aryl.

(V) the Compound according to any one of items (I)to(IV), where Y represents CH2or C(=O), a R is optionally substituted phenyl.

(VI) the Compound according to any one of items (I)to(V), where a represents N.

(VII) the Compound according to any one of items (I)to(VI), where X is S.

(VIII) the Compound according to any one of items (I)to(VII), where R is phenyl, optionally substituted by alkyl group, hydroxyalkyl, halogen, trifluoromethyl, alkoxy, triptoreline, cyano, nitro or amino.

(IX) the Compound according to any one of items (I)to(VIII), where Y represents C(=O).

(X) the Compound according to any one of items (I)to(IX), where R1means hydrogen.

(XI) the Compound according to any one of items (I)-(X), where R2selected from the group including cycloalkyl, heterocyclyl, aryl or heteroaryl.

(XII) the Compound according to any one of items (I)to(XI), where R2means heterocyclyl.

(XIII) the Compound according to any one of items (I)to(IV), where Y denotes O or S.

XIV) the Compound according to item (XIII), where a represents N.

(XV) the Compound according to clause (XIII) or (XIV), where X is S.

(XVI) a Compound according to any one of items (XIII)-(XV), where R2means heterocyclyl.

(XVII) a Compound according to any one of items (XIII)-(XVI), where R is aryl.

(XVIII) a Compound according to any one of items (XIII)-(XVII), where R is optionally substituted phenyl.

(XIX) a Compound according to any one of items (XIII)to(XVIII), where R1means hydrogen.

(XX) a Compound according to any one of items (I), (II) or (IV)where Y denotes a chemical bond.

(XXI) the Connection point (XX), where X is O or NR3.

(XXII) the Connection point (XX) or (XXI), where R2means heterocyclyl or aryl.

(XXIII) a Compound according to any one of items (XX) (XXIII), where R3means phenyl.

(XXIV) the Compound according to any one of items (I)to(IV), where R is aryl.

(XXV) the Compound according to item (XXIV), where R is optionally substituted phenyl.

(XXVI) the Compound according to item (XXIV) or (XXV), where a represents N.

(XXVII) the Compound according to any one of items (XXIV)to(XXVI), where R1means hydrogen.

(XXVIII) the Compound according to any one of items (XXIV)-(XXVII), where R2means alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl or aryl.

(XXIX) the Compound according to any one of items (XXIV)-(XXVII), where R3means methyl or phenyl.

(XXX) the Compound according to any one of items (I)to(IV), where a represents N.

(XXXI) the Compound according to item (XXX), where R means the AET aryl.

(XXXII) the Compound according to item (XXX) or (XXXI), where R2means alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl or aryl.

(XXXIII) the Compound according to any one of items (XXX)to(XXXII), where R1means hydrogen.

(XXXIV) the Compound according to any one of items (I)to(III), where R is thiophene.

(XXXV) the Compound according to any one of items (I)to(III), where

R1means hydrogen, R2means 4-hydroxycyclohexyl, And means N, X is S, Y represents C(=O), and R is phenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 4-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 2-chlorophenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2 means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means 1-(1,1-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 4-chlorophenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 4-forfinal;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 4-chlorophenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 2-chlorophenyl;

R1means hydrogen, R2means 4-tetrahydro-1,1-dioxide-2-N-dipiradol, And means N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means 4-tetrahydro-1,1-dioxide-2-N-dipiradol, And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1,1-dimethyl-2-hydroxy)the Tyl, And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1-methyl-2-methoxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1-methyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=)O, and R is 3-forfinal;

R1means hydrogen, R2means 1-(1-methyl-2,2-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 2-chlorophenyl;

R1means hydrogen, R2means 1-(1-methyl-2,2-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), R' represents hydrogen, a represents N, X is S, Y means CHR', and R is phenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), R' represents hydrogen, a represents N, X is S, Y represents CH(OR'), a R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, R' represents hydrogen, a represents N, X is S, Y represents CH(OR'), a R mean 2-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, R' represents hydrogen, a represents N, X is S, Y means CHR', a R mean 2-forfinal;

R1means hydrogen, R2means 4-tetr hydroporini, And means N, X is S, Y represents C(=O), and R is 2-were;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 2-methoxyphenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 3-methoxyphenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, R' is hydrogen, And N means That X is Oh, Y means CHR', a R is phenyl;

R1means hydrogen, R2means perlopentut, R' is hydrogen, And N means That X is Oh, Y means CHR', a R is phenyl;

R1means hydrogen, R2means 4-hydroxycyclohexyl, R' means hydrogen, And means NR3, X is Oh, Y means CHR', a R is phenyl;

R1means hydrogen, R2means isopropyl, R' is hydrogen, And N means That X is Oh, Y means CHR', a R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is NR3, R3means methyl, Y represents C(=O), and R is 2-methoxyphenyl;

R1means hydrogen, R2means cyclopentyl, R' is hydrogen, And N means That X is NR3, R3means methyl, means CHR', and R is phenyl;

R1means hydrogen, R2oznachaet-hydroxycyclohexyl, R' means hydrogen, And means NR3, X is N, R3means methyl, Y represents CHR', and R is phenyl or

R1means hydrogen, R2means 4-tetrahydropyranyl, R' is hydrogen, And N means That X is NR3, R3means methyl, Y represents CHR', a R is phenyl.

(XXXVI) a Compound of formula V

where a represents N or CH,

X is O, NR3or S, where R3means hydrogen, alkyl or aryl,

Y represents a chemical bond, O, NR', C(=O), CH(OR')CH(R') or S(O)nwhere n is 0, 1 or 2, and R' denotes hydrogen or alkyl,

R is aryl or heteroaryl, and

L mean Ra-S(O)n1where Rameans alkyl or aryl, and n1 is 0, 1 or 2.

(XXXVII) the Connection point (XXXVI), where n1 is 2.

(XXXVIII) the Compound of formula VI

where a represents N or CH,

R1means hydrogen, alkyl or arylalkyl,

R2means alkyl, hydroxyalkyl, heteroalkyl, (R)2NCO-alkylen- (where each R" is independently mean hydrogen or alkyl), cycloalkyl, heterocyclyl, aryl or heteroaryl,

X is O, NR3or S, where R3means hydrogen, alkyl or aryl, and

Z means a hydrogen or halogen.

(XXXIX) the Connection point (XXXVII) and (XXXVIII), where a represents N, and X is S.

(XXXX) Connection point (XXXVIII), where Rsup> 1means hydrogen, and R2means alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl or aryl.

(XXXXI) a Pharmaceutical composition comprising a therapeutically effective amount of one or more compound(s) according to any one of items (I)-(XXXV) in combination with a pharmaceutically acceptable carrier.

(XXXXII) a Method of obtaining the compounds of formula

where a represents N or CH,

R is aryl or heteroaryl,

R1means hydrogen, alkyl or arylalkyl,

R2means alkyl, heteroalkyl, hydroxyalkyl, (R)2NCO-alkylen- (where each R" is independently mean hydrogen or alkyl), cycloalkyl, heterocyclyl, aryl or heteroaryl,

X is O, NR3or S, where R3means hydrogen, alkyl or aryl, and

Y1means C(=O), CH(OR') or CH(R')where R' means hydrogen or alkyl, and the method includes

a) interaction of tiefer formula

where A, R, X, and Y1have the meanings indicated above, a Rameans alkyl or aryl, with the oxidant with the formation of alkylsulfonic formula

b) interaction of alkylsulfonic with an amine of the formula with other1R2where R1and R2have the meanings stated above, with the formation of compounds of formula IA.

(XXXXIII) is a Method of obtaining connection is of formula IB

where a represents N or CH,

R is aryl or heteroaryl,

R1means hydrogen, alkyl or arylalkyl,

R2means alkyl, heteroalkyl, hydroxyalkyl, (R)2NCO-alkylen- (where each R" is independently mean hydrogen or alkyl), cycloalkyl, heterocyclyl, aryl or heteroaryl,

X is O, NR3or S, where R3means hydrogen, alkyl or aryl, and

Y1means O, NR' or S(O)nwhere n is 0, 1 or 2, and R' denotes hydrogen or alkyl,

moreover, this method involves reacting the compounds of formula

where A, X, R1and R2have the meanings indicated above, a Z means a halogen,

with an aromatic or heteroaromatic compound of the formula HY1-R, not necessarily in the presence of a base, with the formation of the compounds of formula IB, where Y1means O, NR' or S,

and, if Y1means S, the method also includes the interaction of the compounds of formula IB, where Y1means S, with the oxidant to form compounds of formula IB, in which Y1means S(O)nwhere n is 1 or 2.

(XXXXIV) is a Method of obtaining the compounds of formula IC

where n is 0, 1 or 2,

A represents N or CH,

R is aryl or heteroaryl,

R1means hydrogen, ALK is l or arylalkyl,

R2means alkyl, heteroalkyl, hydroxyalkyl, (R)2NCO-alkylen- (where each R" is independently mean hydrogen or alkyl), cycloalkyl, heterocyclyl, aryl or heteroaryl,

X is O, NR3or S, where R3means hydrogen, alkyl or aryl,

moreover, the method includes

(a) interactions of the compounds of formula

where R1, R2And X have the meanings indicated above, a Z means a halogen,

with an ORGANOMETALLIC reagent, and

(b) attaching an aryl - or heteroarylboronic formula

R-S-S-R

with the formation of tiefer formula

and, if n is 1 or 2, the method also includes

(C) interaction of tiefer with the oxidant to form compounds of formula IC, where n is 1 or 2.

(XXXXV) the Method according to any of items (XXXXII)-(XXXXIV), where X denotes methyl or phenyl, a R2does not mean heteroalkyl.

(XXXXVI) Compounds according to any one of items (I)-(XXXV), in each case obtained by the method according to any of items (XXXXII)-(XXXXIV).

(XXXXVII) a Method of treating disorders mediated by protein kinase R, including the introduction to a patient in need of such treatment, an effective amount of a compound according to any one of items (I)-(XXXV).

(XXXXVIII) the Method according to item (XXXXVII), where the violation is mediated by protein kinase R, ybiraut from the group including arthritis, Crohn's disease, Alzheimer's disease, irritable bowel syndrome, respiratory distress syndrome of adults (pulmonary edema), chronic obstructive pulmonary disease.

(XXXXIX) the Use of compounds according to any one of items (I)-(XXXV) to obtain a medicinal product intended for the treatment of disorders mediated by protein kinase R.

(V) the Application under paragraph (XXXXIX), where the violation is mediated by protein kinase R, selected from the group including arthritis, Crohn's disease, Alzheimer's disease, irritable bowel syndrome, respiratory distress syndrome of adults and chronic obstructive pulmonary disease.

The compounds of formula I and their aforementioned salts are inhibitors of protein kinases and exhibit high activity against R in vivo. Therefore, the compounds can be used for the treatment of diseases mediated by proinflammatory cytokines, such as TNF and IL-1.

Thus, another object of the present invention are methods of treating diseases or conditions mediated R, in accordance with which the patient who needs such treatment, introduces a therapeutically effective amount of compounds of formula I.

Another object of the present invention are methods of producing compounds of the above.

the school is one object of the present invention are methods of obtaining drugs for use in the treatment of diseases and conditions, indirect R.

The term "alkyl"used in the description of the application, means a linear or branched saturated monovalent hydrocarbon residue containing from one to six carbon atoms, for example methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl etc.

The term "alkylene"used in the description of the application, means a linear or branched saturated divalent hydrocarbon residue containing from one to six atomov carbon, for example methylene, ethylene, propylene, etc.

The term "aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon residue, optionally and independently substituted by one or more, preferably one, two or three substituents. Preferably each Deputy independently selected from the group including alkyl, halogenated, halogen, hydroxy, amino, halogenoalkane, heteroalkyl, methylendioxy, Ethylenedioxy, -Y-aryl, -Y-heteroaryl, -Y-cycloalkyl, -Y-heterocyclyl, -Y ORp, -Y,-NRpRq, -Y-C(O)-Rp, -YS(O)0-2Rp, -Y-N-S(O)2Rp, -Y,-S(O)2NRpRq, -Y-N-C(O)NRpPqwhere Y is absent or means C1-C3alkylen, a Rpand Rqindependently selected from the series hydrogen, alkyl, halogenated, hydroxy, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl. Prefer the ini primarily aryl substituents, selected from the group comprising alkyl, halogenated, halogen, hydroxy, amino, halogenoalkane and heteroalkyl. Other substituents are cyano and nitro. In this group Deputy first preferred halogen, alkyl and alkoxy. In more detail, the term aryl includes, without limitation, phenyl, chlorophenyl, methoxyphenyl, 1-naphthyl, 2-naphthyl and derivatives thereof.

The term "aralkyl" means the residue of formula RxRywhere Rxmeans alkylenes group, a Rymeans aryl group above. Examples of aralkyl include benzyl, phenylethylene etc.

The term "cycloalkyl"used in the description of the application, means a saturated monovalent cyclic hydrocarbon residue containing from in the cycle from three to seven carbon atoms, such as cyclopentyl, cyclobutyl, cyclohexyl, etc. Cycloalkyl optionally substituted one, two or three substituents. Preferably each Deputy independently selected from the group including alkyl, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, halogenated, halogen, cianelli, oxo (i.e. carbonyl oxygen), heteroalkyl, heterocyclyl, hydroxyalkyl and -(X)n-C(O)R' (where X is O or NR, n is 0 or 1, R" denotes hydrogen, alkyl, halogenated, amino, monosubstituted amino, disubstituted amino, Hydra is XI, alkoxy, alkyl or optionally substituted phenyl, and R' denotes hydrogen or alkyl) and-S(O)nR' (where n is 0 or 2). A more preferred group of substituents in cycloalkyl choose from a number of alkyl, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, halogenated and halogen. In this group Deputy first preferred alkyl, hydroxy, alkoxy, halogenated and halogen, the preferred hydroxyl. In more detail, the term cycloalkyl includes cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl etc.

The term "halogen" means such substituents as fluorine, chlorine, bromine or iodine.

The term "halogenated" means alkyl substituted by one or more identical or different Halogens, for example-CH2Cl-CF3, -CH2CF3, -CH2CCl3etc. and, in addition, includes alkyl groups, as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.

The term "heteroalkyl"used in the description of the application, means an alkyl residue, mentioned above, where one, two or three hydrogen atoms replaced by Deputy, is independently selected from the group comprising-ORa, -NRbRcand S(O)nRd(where n denotes an integer from 0 to 2), and assume that the Deputy is attached to heteroalkyl residue through a carbon atom, and Ra means hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl, Rband Rcnezavisimo from each other denote hydrogen, acyl, alkyl, cycloalkyl or cycloalkyl, or Rband Rctogether form cycloalkyl or aristically, and, if n is 0, Rdmeans hydrogen, alkyl, cycloalkyl or cycloalkenyl, and, if n is 1 or 2, Rdmeans alkyl, cycloalkyl, cycloalkenyl, amino, acylamino, monoalkylamines or dialkylamino. Typical examples include, without limitation, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol etc. If Rabalance-ORameans hydrogen, heteroalkyl" is denoted as "hydroxyalkyl" and includes, without limitation, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl.

"Monosubstituted amino group" means the group-otherewhere Remeans alkyl, heteroalkyl, halogenated, cycloalkyl, cycloalkenyl, hydroxyalkyl, aryl, Ara the keel, aralkyl, heteroaryl, heteroalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh, for example, methylamino, ethylamino, phenylamino, benzylamino etc. Similarly the term "disubstituted amino group" means the residue-NRgRhwhere Rgand Rhindependently of one another denote alkyl, heteroalkyl, halogenated, cycloalkyl, cycloalkenyl, hydroxyalkyl, aryl, aralkyl, aralkyl, heteroaryl, heteroalkyl, heteroalkyl, heterocyclyl or geterotsiklicheskikh, or Rgand Rhtogether with the nitrogen atom to which they are attached, form heterocyclyl cycle. Typical examples include, without limitation, dimethylamino, methylamino, di(1-methylethyl)amino, piperazinil, piperidinyl etc.

"Heterocyclyl" means a saturated cyclic residue in which one or two atoms in the cycle are heteroatoms selected from N, O or S(O)n(where n denotes an integer from 0 to 2), and the remaining atoms in the cycle are carbon atoms and one or two carbon atoms optionally contain a carbonyl group, for example one or two atoms in the cycle mean residue-C(=O)-. Heterocyclyl cycle optionally and independently substituted one, two or three substituents selected from the group comprising alkyl, hydroxy, hydroxyalkyl, alkoxy, heteroalkyl and halogen-free the keel. In more detail, the term heterocyclyl includes, without limitation, tetrahydropyranyl, piperidinyl, piperazinil, morpholinyl etc.

"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic residue containing in the cycle from 5 to 12 atoms, where one, two or three atoms are heteroatoms, each of which is independently selected from N, O or S and the remaining atoms in the cycle are carbon atoms. Heteroaryl cycle optionally substituted by one or more substituents, preferably one or two substituents, each of which is independently selected from the group comprising alkyl, halogenated, heteroalkyl, heterocyclyl, halogen, nitro, cyano, carboxy, acyl, -(alkylene)n-COOR (where n is 0 or 1, a R means hydrogen, alkyl, optionally substituted phenylalkyl or optionally substituted heteroalkyl) or(alkylen)n-COHRaRb(where n is 0 or 1, a Raand Rbindependently of one another denote hydrogen, alkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, aryl or Raand Rbtogether with the nitrogen atom to which they are attached, form heterocyclyl cycle). In more detail, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazole is, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, ethanolic, benzimidazolyl, benzisoxazole, benzothiophene, dibenzofuran and benzodiazepine-2-one-5-yl, and their derivatives (this list can be saved as such).

The term "acyl" means a group-C(O)Rrwhere Rrmeans alkyl, halogenated, heteroalkyl, aryl, heteroaryl, aralkyl or heteroalkyl.

"Alkoxy", "aryloxy", " aralkylated" or "heteroaromatics" means the balance-OR, where R is alkyl, aryl, aralkyl or heteroalkyl respectively, mentioned above, for example methoxy, phenoxy, pyridine-2-ylmethylene, benzyloxy, etc.

"Leaving group" means a group whose name is usually associated with its use in synthetic organic chemistry, i.e. means an atom or group which is 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 etc.

"Pharmaceutically acceptable excipient" means excipient, which is used in obtaining pharmaceutical compositions and which usually assetmanagement, non-toxic and harmless to biological or other respects and includes excipient acceptable both in veterinary medicine and in the pharmaceutical industry. "Pharmaceutically acceptable excipient"used in the description and claims, includes one or more of such excipients.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the necessary pharmacological activity of the parent compound. Such salts include: (1) acid additive salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methansulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-tawassul the new acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 4,4'-Methylenebis(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid, etc. or (2) salts formed when replacing the acidic proton present in the original compound, metal ion, for example ion, alkaline metal ion, alkaline earth metal, aluminum ion, or in the formation of proton coordination compounds with organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like

The term "prodrug" means any compound which releases an active source drug of formula I in vivo when such prodrug is administered to a mammal. Prodrugs of compounds of the formula I is obtained by modification of one or more functional groups present in the compound of formula I, so that the modified group can rasaleela in vivo to release the parent compound. Prodrugs include compounds of formula I in which the hydroxyl group, amino group and a sulfhydryl group in the compound f is rmula I connected with any group, which can be chipped off in vivo with the formation of free hydroxyl groups, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate), carbamates (for example, N,N-dimethylaminoethyl) and ethers of hydroxyl functional groups of the compounds of formula I, etc.

"Protective group" means a group which upon binding with the reactive group in a molecule masks, reduces or suppresses the reactivity of this group. Examples of protective groups can be found in the monographs T.W.Green and P.G.Futs, Protective Groups in Organic Chemistry, Wiley, 2nded. (1991), and Harrison and Harrison and others, Compendium of Synthetic Organic Methods, V.1-8, John Wiley and Sons (1971-1996). Typical aminosidine groups include formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Vos), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), trityl and substituted triteleia group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NVOC), etc. Typical hydroxyamine groups include such groups, where the hydroxy-group allerban or alkylated such as benzyl, trifilova and alkalemia ethers, tetrahydropyranyl, trialkylsilyl and allyl ethers.

"Therapy" or "treatment" of the disease including the AET (1) the prevention of disease, i.e. the prevention of the development of clinical symptoms of the disease in a mammal that is susceptible or predisposed to the disease but in whom these symptoms are not detected or do not appear, (2) suppression of the disease, i.e. stopping or suppressing the development of the disease or its clinical symptoms, or (3) the weakening of the disease, for example, stimulation of temporary or long-term regression of the disease or its clinical symptoms.

"Therapeutically effective amount" means an amount of compound that when administered to a mammal for treating a disease, is sufficient to cure the disease. A therapeutically effective amount varies depending on the type of connection, type of illness, severity of disease, age, weight, etc. of a mammal in need of treatment.

One variant of the present invention are the compounds of formula

where A, R1, R2X, Y and R have the values specified above.

Some of the typical compounds of the formula I are given in table 1.

In one of the preferred groups of compounds of formula I R is aryl. Preferred aryl g is uppy not necessarily mean substituted phenyl. Preferred optionally substituted phenyl groups include phenyl (i.e. unsubstituted phenyl), mono - and dehalogenation family, alkyl substituted finely and alkoxy-substituted phenyl. Preferred optionally substituted phenyl group primarily means phenyl, 4-forfinal, 2-chlorophenyl, 2-forfinal, 3-forfinal, 4-chlorophenyl, 2-methoxyphenyl, 2-were, 3-methoxyphenyl, 4-methoxyphenyl, and 2,4-differenl.

In another preferred group of compounds of formula I, Y represents C(=O), CH2CH(HE), chemical bonding (i.e. no group or atom), S or O.

In another preferred group of compounds of formula I And means N.

In another preferred group of compounds of the formula I R1means hydrogen.

In another preferred group of compounds of the formula I R2means heterocyclyl, and heterocyclyl means preferably saturated N-, S- (SO or SO2or O-containing six-membered cyclic residue, which is optionally substituted, for example, means alkylsulfonyl, more preferred heterocyclyl means piperidinyl, tetrahydropyranyl or tetrahydrothiopyran or 1,1-dioxotetrahydrofuran; in addition, in this preferred group of compounds R2also means cycloalkyl, heteroalkyl, and preferred heteroalkyl OSN which denotes alkyl, the above and containing one or more, preferably from 1 to 4 substituents selected from a number of: alkyl, alkoxy or hydroxy; in addition, in this preferred group, R2also means alkyl and aryl, preferably phenyl. In this group, R2means 4-hydroxycyclohexyl, N-methylsulfonylmethane-4-yl, tetrahydropyran-4-yl, (1,1-dimethyl-2-hydroxy)ethyl, 1,1-dioxotetrahydrofuran-4-yl, 2-methoxy-1-methylethyl, 2-hydroxy-1-methylethyl, 1,2-dimethyl-2-hydroxypropyl, cyclopentyl, isopropyl, phenyl and 1-(2-hydroxyethyl)-3-hydroxypropyl. In addition, R2mean (1-methyl-2,2-dimethyl-2-hydroxy)ethyl or 1-(2,2-dimethyl-2-hydroxyethyl)ethyl.

In another preferred group of compounds of formula I, X is O, S or NR3and R3preferably denotes alkyl or aryl, and aryl means preferably phenyl.

In addition, combinations of the preferred groups described in the proposal form other preferred variants of the invention. Thus, the present invention includes many of the preferred compounds. Typical groups primarily preferred compounds are described below.

One preferred group of compounds of formula I includes compounds in which Y represents CH2or C(=O), and R is phenyl, optionally substituted with halogen, stands, triforma the sludge, alkoxy, triptoreline, cyano, nitro or amino.

In this embodiment, more preferred compounds of formula I, where a represents N, Y represents CH2or C(=O), and X is S. the Most preferred compounds of formula I, where a represents N, Y represents C(=O)R1means hydrogen, and R2means cycloalkyl, heteroseksualci or aryl.

Preferred primarily compounds of the formula I in which a represents N, X is S, Y represents C(=O), and R is phenyl, optionally substituted with halogen, alkyl, trifluoromethyl, alkoxy and hydroxyalkyl, R1means hydrogen, and R2means cycloalkyl, heteroseksualci or aryl.

The most preferred compounds of formula I, where a represents N, X is S, Y represents C(=O), R is phenyl, substituted with halogen, alkyl, trifluoromethyl, alkoxy and hydroxyalkyl, R1means hydrogen, and R2means heterocyclyl.

In another preferred embodiment, compounds of formula I, Y represents O or S. In this group of compounds of formula I And preferably means N. In this group of more preferred compounds in which X is S. more preferred compounds in which R2means heterocyclyl. In this group the most preferred compounds in which R is aryl, primarily R is optional for ewenny phenyl. Preferred primarily compounds in which R1means hydrogen.

In another preferred embodiment, compounds of formula I, Y represents a chemical bond, i.e. R is directly attached to a heteroaryl group via a carbon atom adjacent to the residue x In the specified version of the first preferred group of compounds in which X is O or NR3. The most preferred compounds, in which R2means heterocyclyl or aryl. A separate group of compounds within this group are compounds in which R3means phenyl.

In another preferred embodiment, compounds of the formula I R is aryl, preferably optionally substituted phenyl. Preferred above all the connections And means To N. more preferred compounds of this group include the compounds of formula I, where R1means hydrogen. Even more preferred group of compounds in which R2means alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl or aryl, with the most preferred compounds, in which R3means methyl or phenyl.

In another preferred embodiment, compounds of the formula I a represents N. In this group of preferred compounds in which R is aryl, especially preferred compounds in which R 2means alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl or aryl. The most preferred compounds, in which R1means hydrogen.

Compounds of the present invention may exist in resolutional and in solvated form, including gidratirovannuyu form, all of these forms are included in the scope of the invention. In addition, as indicated above, the present invention includes all pharmaceutically acceptable salts of the compounds, including prodrugs of the compounds, as well as all stereoisomers in pure chiral form, in the form of racemic mixtures or enantiomeric mixture.

The compounds of formula I form pharmaceutically acceptable acid-addicitive salt. As indicated above, the present invention includes all such forms.

Pharmaceutically acceptable additive salts of compounds of formula I include salts of inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, Hydrobromic, itestosterone, phosphoric acid, etc. and salts of organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid, arcangioli acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like, Such salts include the sulfate, persulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate disubstituted phosphate, monosubstituted phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, kaprilat, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like In the scope of the invention also includes salts of amino acids such as arginate and the like and gluconate, galacturonic (see, for example, Berge and others, Pharmaceutical Salts, J. of Pharmaceutical Science, 66, 1-19 (1977)).

Acid additive salts of the basic compounds get in the normal way when the interaction between the compounds in free base form with a sufficient amount of the appropriate acid with the formation of salts. The compound in free base form get in the interaction of salt with a base and subsequent isolation of the free base in a known manner. Compounds in free base form may differ from the corresponding salts in certain physical properties, such as solubility in polar solvents, but otherwise for the purposes of the present invention the salt is equivalent to the corresponding free base.

Pharmaceutically acceptable additive salts of the bases are formed by the interaction of ions with metals or amines, such as alkaline ions is alkali-earth metals or organic amines. Examples of ions of metals used as cations include sodium, potassium, magnesium, calcium, etc. are Examples of suitable amines include N,N'-dibenziletilendiaminom, chloroquin, choline, diethanolamine, Ethylenediamine, N-methylglucamine, and procaine (see, for example, above Berge and others).

Additive salts of the bases and acidic compounds receive the usual way when interacting compounds in the form of the free acid with a sufficient amount of the appropriate base with formation of salts. The connection in the form of the free acid get when interacting compounds in salt form with an acid, followed by separation of the free acid in the usual way. Connections in the form of the free acid may differ from their respective salt in certain physical properties such as solubility in polar solvents, but otherwise for the purposes of the present invention the salt is equivalent to the corresponding free acid.

Compounds of the present invention receive a number of methods, techniques known to experts in this field. Methods for obtaining compounds of the present invention is shown in the following diagrams. It uses the following abbreviations:

MSRAmeta-chloroperbenzoic acid,
NMP N-methylpyrrolidine,
THFtetrahydrofuran,
TLCthin-layer chromatography,the
EtOActhe ethyl acetate.

Scheme 1 shows a method of obtaining compounds of formula I(a) and its analogs I(b) and 1(C).

In the interaction of the compounds of formula 1 with potassium fluoride produces compound of formula 2, which is then converted into carboxaldehyde 3 using a known method (Ple N., A. Turck, Heynderickx, A., and Queguiner G.J., Heterocyclic Chem., 31, 1311 (1994)). Carboxaldehyde 3 condensed with substituted Penicillium and without additional purification receive compound of formula 4. Usually the reaction is carried out in the presence of a base triethylamine at a temperature of from about 0°C to room temperature.

The oxidation of compound 4 with an oxidant such as 3-chloroperbenzoic acid (for example, MSRWA) or exon get sulfon 5, of which the number of target compounds. Typically, the oxidation of compound 5 is carried out in a solvent which is inert under the oxidation conditions. For example, when using MSRV as oxidant, the preferred solvent is a halogenated aliphatic hydrocarbon, especially dichloromethane.

If the oxidant used Oxon, the solvent typically use mesh water and tetrahydrofuran. The reaction temperature depends on the used solvent. When using an organic solvent, the reaction temperature is usually from about -20°50°C, preferably from approximately 0°C to about room temperature. If the solvent used water, the reaction temperature mainly ranges from approximately 0°50°C, preferably from approximately 0°C to about room temperature.

In the interaction of compound 5 with an amine of formula R1R2NH, where R1and R2have the meanings indicated above, produces compound of formula I(a). The reaction can be carried out in the presence or in the absence of solvent. Usually the reaction is carried out at a temperature of from about 0°C to about 200°S, more preferably from about room temperature to about 150°C.

Scheme 1

Compound I(a) reduced to the alcohol of formula I(b), the reaction is carried out in the presence of a reducing agent, such as borohydride sodium in ethanol at room temperature. From compound I(b) receive the compound of formula I(C). Recovery is usually carried out in dichloromethane in the presence of triethylsilane and triperoxonane acid.

Drugom variant (not shown) in the interaction of compound 5 with ammonia to obtain the compound of formula I(a)' (i.e. the compound of formula I, where R1and R2mean hydrogen). Subsequent alkylation of compound I(a)' get the compounds of formula I, where R1and R2mean hydrogen. The reaction is carried out in the presence or in the absence of solvent. Usually the reaction is carried out at a temperature of from about 0°C to about 200°S, more preferably from about room temperature to about 150°C. In another embodiment (not shown) in some cases, instead of the sulfone 5 use the sulfide 4, which interacts directly with the amine (R1R2NH), you get a compound of formula I(a).

Scheme 2 shows a method of obtaining errorcodehex analogue of compound I(a). By condensation of aminoaldehyde 6 with substituted penacerrada get the connection 7. The reaction is usually carried out in NMP at 80°C. Then compound 7 are oxidized by sulfona 8 by the method described above for scheme 1. Then sulfon 8 is introduced into reaction with the appropriate amine, as described above, with the formation of the compounds of formula II.

Scheme 2

Parapaguridae similar to the compounds of formula I(a) are obtained according to the method shown in scheme 3. Compound 8 (obtained as described in article Sakamoto T., Kondo Y., Watanabe R., Yamanaka H., Chem. Pharm. Bull., 34, 2719 (1986)) is transformed into compound 9 by condensation with alkynes catalyzed by the palladium with subsequent cyclization (see Sakamoto T., Kondo Y., Watanabe R., Yamanaka H., Chem. Pharm. Bull., 34, 2719 (1986)). Then the connection 9 are oxidized to compound 10 by the method described above. The connection 10 is introduced into reaction with the desired amine of the formula with other1R2will get a connection formula III.

Scheme 3

In another embodiment, the compound 8 is converted into californiamean formula 11, which condense with arilaldegidov with the formation of the alcohol of formula 12 to the described method (see Aquila V.M., Tetrahedron Lett., 38, 2795 (1997)). Then the connection 12 in turn sulfon 13, which when interacting with an amine of the formula with other1R2get the compound of formula III(a). Then from compound III(a) receive other derivatives, as shown in figure 1, and when using a variety of methods known to experts in this field.

Scheme 3A

The compound of the formula IV are given as shown in scheme 4. The compound of formula 14 (obtained as described in article Sakamoto T., Kondo Y., Watanabe R., Yamanaka H. Chem. Pharm. Bull., 34, 2719 (1986)) is converted into a compound of formula 15 by condensation with Alcina catalyzed by palladium. Then the connection 15 is treated with methylamine with the formation of compound 16. The cyclization of compound 16 with the formation of compound 17 is performed during the processing of a mixture of CuI and PdCl2(PPh3)2. ZAT is m connection 17 in turn sulfon 18 and finally, in the compound of formula IV using the methods shown in the above schemes.

Scheme 4

Compounds of formulas Va and Vb are given as described in scheme 5. The compound of formula 5-1 is introduced into reaction with α-cyanoacetamide formula 5-2 with education TypeProvider formula 5-3. Then thienprasiddhi 5-3 interacts with the potassium salt of O-propyl ether dithiocarbonic acid of formula 5-4 with the formation of thienopyrimidine-4-it formula 5-5. When the methylation thienopyrimidine-4-it formula 5-5 methyliodide receive appropriate thioether formula 5-6. This is followed by oxidation with simultaneous chlorination of tiefer formula 5-6 in the presence of POCl3will get thienopyrimidine formula 5-7. Oxidation of tiefer formula 5-7 to sulfanilamidnov formulas 5-8 carried out using an oxidant, such as Oxon. Then chargroup in the pyrimidine ring is reactivated by hydrogenation in the presence as catalyst of palladium on coal with the formation of 2-methanesulfonamido[2,3-d]pyrimidine of the formula 5-9. Methanesulfonyl group in the compound of formula 5-9 replacing the amino group with an appropriate amine. For example, as shown in scheme 5, methanesulfonyl group substituted in the presence of 4-aminotetrahydrofuran formula 5-10, this produces the t 2-(tetrahydropyran-4-yl)aminosilanes thienopyrimidine formula 5-11. Then the connection 5-11 halogenous, for example, using copper oxide(II), and iodine, with the formation of Izumisano of thienopyrimidine formula 5-12. Izlesene thienopyrimidine formula 5-12 enter into reaction with a number of compounds, such as phenols (for example, the compound of formula 5-13 and its corresponding tiffanypreston not shown) and after metallation in the processing of ORGANOMETALLIC reagent (e.g., alkylate) and subsequent reaction with disulfides (e.g., a compound of formula 5-14) receive condensed products, such as compounds of formulas Va and Vb, respectively.

Scheme 5

To a person skilled in the art it is obvious that in the scope of the present invention are possible modifications of the above described circuits. For example, in some stages, you can use protective groups for functional groups that exhibit reactivity in a particular reaction conditions.

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicines, for example, in the form of pharmaceutical preparations. Pharmaceuticals can enter enteric way, for example, by oral way in the form of tablets, coated tablets, dragées, hard and agcih gelatin capsules, solutions, emulsions or suspensions, nazalnam way, for example, in the form of nasal sprays, or rectal means, for example, in the form of suppositories. However, the compounds can be administered by parenteral way, for example, in the form of injection solutions.

The compounds of formula I and the above-described pharmaceutically acceptable salts can be converted into pharmaceutical preparations in a mixture with pharmaceutically inert, organic or inorganic carriers. For example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like are Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like, however, depending on the nature of the active ingredient is usually to obtain soft gelatin capsules carrier is not required. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like are Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like

The pharmaceutical preparations can also contain preservatives, with jubilatory, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffer substances, masking agents or antioxidants. Along with the compounds of formula I and the above-described pharmaceutically acceptable salts preparations may also contain other therapeutically valuable substances.

Objects of the present invention are also medicinal product containing a compound of formula I or its pharmaceutically acceptable salt of the compound of formula I and the acid in the mixture with a compatible pharmaceutical carrier and a method of obtaining such medicines, which includes processing one or more of such compounds or salts, and optionally one or more other therapeutically valuable substances in a mixture with a compatible pharmaceutical carrier in herbal form for injection.

As indicated previously, the compounds of formula I and their pharmaceutically acceptable salts can be used according to the present invention as therapeutically active substances, especially as anti-inflammatory agents, or for the prevention of rejection of grafts after transplantation. The dose can be changed in a wide range, and the dose depends on the individual requirements in each particular case. The OS is the RAM with the introduction of adults usual daily dose is from about 0.1 mg/kg to about 100 mg/kg, preferably from about 0.5 mg/kg to about 5 mg/kg Daily dose can be administered as a single dose or divided doses, moreover, the upper limit mentioned above, can be exceeded when indicated.

Finally, an object of the present invention is the use of compounds of the formula I and their aforementioned pharmaceutically acceptable salts to obtain drugs intended primarily for the treatment or prevention of inflammatory, immunologicaly, Oncology, pulmonary, dermatological and cardiovascular disorders, for the treatment of asthma, CNS disorders or complications of the diabetes or to prevent rejection of grafts after transplantation.

The compounds of formula I also apply, without limitation, for the treatment of any disorders or diseases in human or other mammal, which is caused by or aggravated in the body of this mammal in connection with excessive or unregulated production of TNF or kinase R. The compounds of formula I inhibit the kinase R in the analysis of in vitro and inhibit the release of α-TNF in the analysis using cells as described in examples 12 and 13. In this regard, the present invention describes a method of treating diseases mediated by cytokines, which include the AET introduction the compounds of formula I or its pharmaceutically acceptable salt or tautomer, in an effective amount to suppress cytokines.

The compounds of formula I also apply, without limitation, for the treatment of inflammation in a subject and as an antipyretic for the treatment of fever. Compounds of the present invention is also used to treat arthritis, including, without limitation, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, and other conditions of arthritis. In addition, the compounds of the present invention is used to treat lung disease or pneumonia, including respiratory distress syndrome in adults, pulmonary sarcoidosis, asthma, silicosis, and chronic pneumonia. Moreover, the compounds of the present invention is also used for the treatment of viral and bacterial infections, including sepsis, septic shock, gram-negative sepsis, malaria, meningitis, secondary atrophy as a result of infection or malignant disease, secondary atrophy as a result of acquired immunodeficiency syndrome (AIDS), AIDS, complications of AIDS, pneumonia and herpes virus. Moreover, the compounds of the present invention used for the treatment of diseases associated with bone resorption, such as osteoporosis, endotoxic the definition of shock, toxic shock, damage due to reperfusion injury, autoimmune disease, comprising the reaction to the graft in the host organism and allograft rejection, cardiovascular disease including atherosclerosis, thrombosis, congestive heart failure, damage to the heart tissue as a result of reperfusion, kidney damage as a result of reperfusion, liver disease and nephritis, and myalgia due to infection.

Compounds of the present invention used for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus, skin diseases such as psoriasis, eczema, burns, dermatitis, formation of keloid scars. Compounds of the present invention used for the treatment of diseases of the gastrointestinal tract, such as colitis, Crohn's disease, gastritis syndrome level becomes too low, colon cancer, and ulcerative colitis. Compounds of the present invention used for the treatment of ophthalmic diseases such as retinitis, retinopathy, uveitis, ocular photophobia, and of acute damage to the eye tissues. Compounds of the present invention used for the treatment of angiogenesis including neoplasia; metastasis; ophthalmological conditions such as the rejection of transportation is anatov of the cornea, ocular neovascularization, retinal neovascularization including neovascularization as a result of injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant conditions, such as hemangioma, including child hemangioma, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy, as well as disorders of the reproductive system in women, such as endometriosis. In addition, the compounds of the present invention is used to suppress the production of cyclooxygenase-2.

In addition to the use of compounds of the present invention for medical purposes, they can be used in veterinary practice for the treatment of domestic animals, exotic and farm animals, including mammals, rodents, etc. To the most preferred animals include horses, dogs and cats.

In addition, the compounds of the present invention can also be used for combination therapies, partially or completely, instead of the usual anti-inflammatory drugs, such as together with steroids, inhibitors of cyclooxygenase-2, non-steroidal anti-inflammatory drugs, DMARDS, immunosuppressants, and inhibitors of 5-lipoxy is easy, antagonists LTB4and inhibitors hydrolases LTA4.

The term "mediated TNF violation"used in the description of the application, refers to any and all disorders and diseases in which TNF exerts the function of regulating the release of TNF or the release of other monokines, such as, without limitation, IL-1, IL-6 or IL-8. The disease in which, for example, IL-1 is a major component, the production or effect of which is amplified or call its secretion in response to TNF, also applies to mediated TNF disease.

The term "indirect R disease"used in the description of the application, refers to any and all disorders and diseases in which R shows the function of regulating the release of R or release of other factors, such as, without limitation, IL-1, IL-6 or IL-8. The disease in which, for example, IL-1 is a major component, the production or effect of which is amplified or call its secretion in response to R also applies to indirect R disease.

Because β-TNF homologous α-TNF (also known as cachectin), both factors induce similar biological response upon binding to the same cell receptor and the synth is C both α (TNF- β-TNF is inhibited by compounds of the present invention, unless otherwise specified in the description of the application both factors referred to under the General title "TNF".

Examples

Example 1

2-(Tetrahydropyran-4-ylamino)-6-(2-chlorobenzoyl)thieno[2,3-d]pyrimidine

This example describes how to obtain the compounds of formula I by the method described for scheme 1.

Stage 1

4-fluoro-2-methylthiopyrimidin

To a solution 35,7 g (0,22 mole) 4-chloro-2-methylthiopyrimidine (company Aldrich Chemical Co., Milwaukee, Wisconsin, USA) in 135 ml tetragona was added 18-crown-6 (1,33 g) and potassium fluoride (80 g, anhydrous, Aldrich Chemical company Co., Milwaukee, Wisconsin, USA) and the mixture was stirred at 150°C for 16 hours Then the reaction mixture was cooled and distilled under reduced pressure, was obtained 20 g (62%) of 4-fluoro-2-methylthiopyrimidine in liquid form.

Stage 2

4-fluoro-2-methylthiopyrimidin-5-carboxaldehyde

To THF (100 ml) at -78°C was added a 2.5 M solution of n-utility (20.4 ml). The mixture was heated to 0°and was slowly added Diisopropylamine (8.2 ml). The mixture was stirred at 0°C for 30 min, cooled to -78°C, was slowly added a solution of 4-fluoro-2-methylthiopyrimidine (3,76 g of 22.2 mmole) in 5 ml of THF and was stirred for 2 h Then was added ethyl formate (4.3 ml, 444 mmole) and the reaction mixture was stirred for another 2 hours To the mixture was slowly added 4 N. HCl (25 ml), ethanol (25 ml) and THF (100 ml), the cooling bath was removed and the mixture was stirred for a further 10 minutes the Reaction mixture was diluted with ethyl acetate (250 ml), water (200 ml) and sodium bicarbonate solution (100 ml). The organic layer was separated, washed with brine (2×50 ml), dried over MgSO4and filtered. The solvent was removed, it was obtained a viscous oil (to 5.66 g).

Stage 3

2-(Methylthio)-6-(aroyl)thieno[2,3-d]pyrimidine

To a solution of crude 4-fluoro-2-methylthiopyrimidin-5-carboxaldehyde obtained in stage 2 (2.8 g, approximately 11 mmol) and triethylamine (of 1.44 ml) in THF (40 ml) at 0°C was slowly added a solution of 2'-chloro-2-thioacetate (1,93 g, obtained as described below on the stage) in THF (30 ml). Then the reaction mixture was slowly heated to room temperature and was stirred overnight. The resulting solution was added to a mixture of ethyl acetate (500 ml) and water (250 ml). The organic layer was separated, washed with saline solution and sodium bicarbonate solution, dried and evaporated. The crude product was purified by chromatography on a column of silica gel (eluent: 5-10% EtOAc/hexane), was obtained the desired product (1,82 g). tpl.137-140,4°C. MS: 321 (M+H).

Stage 3A

2'-Chloro-2-thioacetate

A mixture of 2'-chloroacetophenone (25 g, rate £ 0.162 mol) and bromide m is di (72,8 g) in ethyl acetate (90 ml) and chloroform (90 ml) was boiled under reflux for 2 hours The mixture was cooled to room temperature, filtered through a layer of celite and washed with ethyl acetate. The solvent was removed, it was obtained the crude 2-bromo-2'-chloroacetophenone (35 g).

The mixture specified bromide (14,67 g) and thioacetate potassium (7.5 g) in acetone (250 ml) was stirred at room temperature overnight. Then added an additional portion of thioacetate potassium (3.7 g) and the mixture was stirred overnight. The reaction mixture was filtered, the filter cake washed with acetone. The filtrate was evaporated, the residue was diluted with ethyl acetate (200 ml) and brine (150 ml). The organic layer was separated, dried and evaporated, to receive the crude 2-(acetylthio)-2'-chloroacetophenone (14.4 g).

To a solution of the obtained product (to 2.29 g, 10 mmole) in methanol (100 ml) was slowly added a solution of timelocked sodium (0.7 g, 10 mmole) in methanol (10 ml). The reaction mixture was stirred for 2 h, poured into 200 ml of 0.1 M HCl and was extracted with dichloromethane (2×150 ml). The organic phase is washed with brine (150 ml), dried and evaporated, to receive the crude 2'-chloro-2-thioacetate (1,93 g).

Stage 4

2-(Methanesulfonyl)-6-(aroyl)thieno[2,3-d]pyrimidine

To a solution of sulfide (1.6 g)obtained in stage 3, in THF (80 ml) at 0°solution was added oxone (6,13 g, the firm Aldrich) in water (40 ml) and the reactions is nnow the mixture was stirred at room temperature for 5 hours Then to the mixture was added ethyl acetate (250 ml) and water (150 ml). The organic phase was separated, washed with water (2×150 ml), dried and evaporated, to receive sulfon (1.56 g). tpl.164,1-165,4°C. MS: 352,9 (M+H).

Stage 5

2-(Tetrahydropyran-4-ylamino)-6-(2-chlorobenzoyl)thieno[2,3-d] pyrimidine

A mixture of sulfone (352 mg), obtained as described above, and 4-aminotetrahydrofuran (152 mg) in NMP (0.1 ml) was heated at 100°C for 3 hours Then to the mixture was added ethyl acetate (180 ml) and water (50 ml). The organic layer was separated, washed with brine, dried and evaporated. The crude product was purified preparative TLC on silica gel (eluent: 65% EtOAc/hexane), was obtained 253 mg of the final product. The compound was treated with 1 N. HCl solution in ether (1.5 equiv.) it was obtained the hydrochloride of the final product. MS: 374 (M+H).

Example 2

2-(Tetrahydropyran-4-ylamino)-6-(2-perbenzoic)thieno[2,3-d]pyrimidine

The specified connection was obtained in the same way as described in example 1.

Example 2A

2-(Tetrahydropyran-4-ylamino)-6-[(2-forfinal)hydroxymethyl]thieno[2,3-d]pyrimidine

To a solution of 2-(tetrahydropyran-4-ylamino)-6-(2-perbenzoic)thieno[2,3-d]pyrimidine (300 mg) in ethanol (30 ml) at room temperature was added borohydride sodium (0.4 g) and the mixture was stirred over night. To the reaction mixture were added ethyl acetate (50 ml). The organic layer was separated, washed with brine, dried and evaporated. The crude product was purified preparative TLC on silica gel (eluent: 50% EtOAc/hexane), was obtained 140 mg of alcohol. MS: 360,2 (M+H).

Example 2B

2-(Tetrahydropyran-4-ylamino)-6-[(2-forfinal)methyl]thieno[2,3-d]pyrimidine

Alcohol (140 mg), obtained as described in example 2A, was stirred with triethylsilane (1.0 ml) and triperoxonane acid (1.5 ml) in dichloromethane (5 ml) for 4 h and the solvent was removed. The residue was diluted with toluene (5 ml) and the mixture was concentrated. The process of dilution/concentration was repeated three times. The crude product was purified preparative TLC (eluent: 50% EtOAc/hexane), to receive the final product. The compound obtained was treated with 1 N. HCl solution in ether, was obtained 65 mg of the hydrochloride of the final product. tpl.217-219°C. MS: 344 (M+H).

Example 3

2-(Tetrahydropyran-4-ylamino)-6-(2-methoxybenzoyl)-7-methylpyrrole[2,3-d]pyrimidine

This example describes how to obtain the compounds of formula I according to the method described for scheme 2.

Stage 1

Ethyl ester of 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid

To a solution of 20 g (86 mmole) of Atila the CSOs ether 4-chloro-2-methylthiopyrimidine-5-carboxylic acid (company Aldrich Chemical Co., Milwaukee, Wisconsin, USA) in 250 ml of dichloromethane at 0°slowly added 35 ml (281 mmole) 33% solution of methylamine in ethanol. The reaction mixture was stirred for 30 min, then was added 150 ml of water and the phases were separated. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, obtained 19 g (97%) of ethyl ester of 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid in the form of a solid white color.

Stage 2

4-Methylamino-2-methylthiopyrimidine-5-methanol

To a suspension of sociallyengaged (9 g, 237 mmole) in 300 ml dry tetrahydrofuran was added dropwise a solution of 34 g (143 mmole) ethyl ester 4-methylamino-2-methylthiopyrimidine-5-carboxylic acid in 300 ml of dry tetrahydrofuran and kept for 15 minutes the Mixture was cooled in an ice bath and was added dropwise 18 ml of water, 36 ml of 2 M sodium hydroxide solution and 48 ml of water. The resulting suspension was stirred at room temperature for 17 h, and then filtered. The residue on the filter is washed twice with 100 ml of ethyl acetate, the combined filtrate and wash fractions were evaporated under reduced pressure. The residue is suspended in 200 ml of dichloromethane/hexane (2:1), solid substance was separated by filtration and dried, to receive 23,5 g (86%) 4-methylamino-2-methylthiopyrimidin is n-5-methanol in the form of a solid yellow color.

Stage 3

4-Methylamino-2-methylthiopyrimidine-5-carboxaldehyde

To a solution of 4-methylamino-2-methylthiopyrimidine-5-methanol (20 g, 108 mmole) in 1 l of dichloromethane was added 87 g (1 mol) of manganese dioxide. The resulting suspension was stirred for 24 h and then filtered through a layer of sorbent. The filter residue was washed with 100 ml of dichloromethane, and the combined filtrate and wash fractions were evaporated under reduced pressure, it was given to 15.8 g (80%) 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde in a solid white color.

Stage 4

2-(Methylthio)-6-(2-methoxybenzoyl)-7-methylpyrrole[2,3-d]pyrimidine

A mixture of the obtained aldehyde (0,792 g), 2'-methoxybenzophenone (1,17 g, the firm Aldrich) and potassium carbonate (1.6 g) in NMP (5 ml) was stirred at 70-80°With during the night. Then added another portion of 2'-methoxybenzophenone (0.88 g) and the mixture was stirred at 100°With during the night. Added another portion of 2'-methoxybenzophenone (0.65 g) and potassium carbonate (1.12 g) and the mixture was stirred at 100°With during the night. The reaction mixture was cooled, diluted with ethyl acetate (150 ml), washed with brine (3×50 ml), dried and concentrated. The product was purified by chromatography on a column of silica gel (eluent: 10-30% EtOAc/hexane)and then preparative TLC n is silica gel (eluent: 30% EtOAc/hexane), to receive 100 mg of product. MS: 334 (M+H).

Stage 5

2-(Tetrahydropyran-4-ylamino)-6-(2-methoxybenzoyl)-7-methylpyrrole[2,3-d]pyrimidine

Sulfide (0.1 g)obtained in stage 4, was mixed with axonom (0.5 g) in THF/N2About (2 ml/2 ml) for 4 h After treatment of an aqueous solution with ethyl acetate and extraction of saline was given untreated sulfon.

Received sulfon and 4-aminotetrahydrofuran (0.18 g) in NMP (0.2 ml) was heated at 140°With during the night. When processing water was obtained the crude product, which was purified preparative TLC, it was obtained the desired product (2 mg). MS: 367 (M+H).

Example 4

2-(Cyclopentylamine)-6-benzylguanine[2,3-d]pyrimidine

This example describes how to obtain the compounds of formula I according to the methods shown in scheme 3.

Stage 1

2-(Methylthio)-6-benzylguanine[2,3-d]pyrimidine

A mixture of 2-methylthio-4-hydroxy-5-iodopyrimidine (2.65 g), 3-phenyl-1-propyne (1,49 ml), copper iodide(I) (90 mg) and dichloride bis(triphenylphosphine)palladium(II) (160 mg, the company Fluka) in 20 ml of triethylamine and NMP (7 ml) was stirred at 40°C for 6 hours, the Reaction mixture was diluted with ethyl acetate (100 ml), washed with brine (3×50 ml), concentrated and was purified by chromatography on a column (eluent: 5% EtOAc/hexane), et the m received 0,57 g of solid product. tpl.69-72,2°C. MS: 257,2 (M+H).

Stage 2

2-(Cyclopentylamine)-6-benzylguanine[2,3-d]pyrimidine

A solution of sulfide (0,57 g), obtained as described above in stage 1, in THF (15 ml) was stirred with axonom (2.2 g) in water (15 ml) at 0°C for 3 h and at room temperature for 1 h After treatment water received untreated sulfon (containing sulfoxide) (0,63 g).

A solution of sulfone (60 mg), obtained as described above, in 1 ml of aminocyclopentane was stirred at 100°C for 2 hours the Excess aminocyclopentane removed. The crude product was purified preparative TLC (eluent: 40% EtOAc/hexane), was obtained 47 mg of solid product. MS: 294,2 (M+H).

Example 5

2-(Cyclopentylamine)-6-benzyl-7-methylpyrrole[2,3-d]pyrimidine

This example describes how to obtain 2-(cyclopentylamine)-6-benzyl-7-methylpyrrole[2,3-d]pyrimidine by the method shown in scheme 4.

Stage 1

2-Methylthio-5-(3-phenylpropen-1-yl)-6-methylaminopropyl

A mixture of 2-mutanty-4-chloro-5-iodopyrimidine (6.5 g), 3-phenyl-1-propyne (3.4 ml), copper iodide(I) (130 mg)dichloride bis(triphenylphosphine)palladium(II) (322 mg) and triethylamine (25 ml) were heated in NMP at 40°C for 2 hours Then the mixture was cooled to 0°C, was added 25 ml of 4% solution of methylamine (Aldrich company) in acetonitrile (15 ml), the resulting mixture was stirred at room temperature for 2 h, and then concentrated. The residue was diluted with ethyl acetate (200 ml) and washed with brine (3×100 ml). The organic layer was separated, dried and evaporated, to receive the oil. The crude product was purified by chromatography on a column (eluent: 5-12% EtOAc/hexane), was obtained 3.8 g of solid product. MS: 270 (M+H).

Stage 2

2-(Methylthio)-6-benzyl-7-methylpyrrole[2,3-d]pyrimidine

A mixture of alkyne (3,47 g), obtained as described above, triethylamine (15 ml), copper iodide(I) (200 mg)dichloride bis(triphenylphosphine)palladium (200 mg) in NMP (10 ml) was boiled under reflux for 6 hours After treatment water received 4 g of the residue is a dark color. The crude product was purified by chromatography on a column (eluent: 10-13% EtOAc/hexane), was obtained 1.0 g of product. MS: 270,2 (M+H).

Stage 3

2-(Methanesulfonyl)-6-benzyl-7-methylpyrrole[2,3-d]pyrimidine

The resulting sulfide (0.3 g) in THF (10 ml) was stirred with a solution oxone (0.9 g) in water (10 ml) at 0-5°C for 3 hours After treatment water received sulfoxide (containing sulfon).

Stage 4

2-(Cyclopentylamine)-6-benzyl-7-methylpyrrole[2,3-d]pyrimidine

A mixture of sulfoxide (50 mg), obtained as described in the process 3, and cyclopentylamine (1 ml) was stirred at 100°With during the night. Excess cyclopentylamine was removed, the residue was purified preparative TLC (eluent: 25% EtOAc/hexane), was obtained the desired product (26 mg). MS: 307,3 (M+H).

Example 6

(Tetrahydropyran-4-yl)thieno[2,3-d]pyrimidine-2-ylamine

Stage 1

Amide 2-aminothiophene-3-carboxylic acid

2,5-Dihydroxy-1,4-dition (76 g) and cyanoacetamide (84 g) was added to a mixture of methanol (180 ml), water (10 ml) and triethylamine (10 g). The resulting mixture was heated, stirred at 35-40°C for approximately 30 min, and then stirred at 50-60°for a further 30 minutes the mixture is Then cooled to room temperature and was poured into a mixture of ice/water (100 g:300 ml). It was formed of fine suspension, which was separated by filtration and dried during the night, when it got mentioned in the title compound (100,6 g) in the form of powder light grey. tpl.159,0-159,6°C. MS:

143 (M+N)+.

Stage 2

2 Thioxo-2,3-dihydro-1H-thieno[2,3-d]pyrimidine-4-one

Amide 2-aminothiophene-3-carboxylic acid (28.4 g, 0,2 mol) and ethylxanthate potassium (96 g, 3 EQ.) mixed and added to DMF (1000 ml). The resulting mixture was heated at 150°C for approximately 6 hours, the Solvent (DMF) deletion is whether on a rotary evaporator under high vacuum at 90° C. the Residue was diluted with 600 ml of citric acid solution (5%), cooled to 0°and then was stirred for approximately 30 minutes, the Powder is light brown in color was separated by filtration and dried during the night, when it got mentioned in the title compound (25.6 g). tpl.>300°C. MS: 185 (M+N)+.

Stage 3

2-Methylsulfanyl-3H-thieno[2,3-d]pyrimidine-4-one

To a solution of 2-thioxo-2,3-dihydro-1H-thieno[2,3-d]pyrimidine-4-it (25.4 g, was 0.138 mol) in 1 N. NaOH (600 ml) at room temperature was added methyliodide (10.3 ml, 1.2 EQ.) and the resulting mixture was intensively stirred for about 2.5 hours Then the mixture was cooled to 0°and was added acetic acid (approximately 80 ml) to approximately pH 4.5. The obtained fine suspension was separated by filtration and dried during the night, when it got mentioned in the title compound (24.8 g) in the form of fine powder light brown. tpl.231,6-235,0°C. MS: 198 M+.

Stage 4

4-Chloro-2-methylsulfonylamino[2,3-d]pyrimidine

2-Methylsulfanyl-3H-thieno[2,3-d]pyrimidine-4-one (12 g, 60,5 mmole) was mixed with POCl3(56 ml) and the resulting mixture was boiled under reflux for about 1 h the Reaction mixture was concentrated under reduced pressure the ri 50° C. the Residue was diluted with ethyl acetate (700 ml) at 0°C, the solution was slowly added to a saturated solution of sodium bicarbonate (600 ml) and the resulting mixture was intensively stirred at 0°C for 1 h, the Layers were separated, the organic layer at 0°C was added a saturated solution of sodium bicarbonate (600 ml) and the mixture was intensively stirred for 20 minutes, the Layers were separated, the organic layer was added brine (600 ml) and the mixture was intensively stirred for 5 minutes, the Layers were separated, the organic layer was dried over magnesium sulfate, filtered and concentrated, this has been indicated in the title compound (10.7 g) in powder form is dark brown. tpl.105,0-107,4°C. MS: 216 M+.

Stage 5

4-Chloro-2-methanesulfonamido[2,3-d]pyrimidine

To a solution of 4-chloro-2-methylsulfonylamino[2,3-d]pyrimidine (10 g, 46,15 mmole) in tetrahydrofuran (350 ml) at 0°With dropwise with stirring solution was added oxone (59,6 g, 2.1 EQ.) in water (300 ml). The resulting mixture was gradually heated from 0°C to room temperature over night.

The reaction mixture was diluted with ethyl acetate (1000 ml) and water (300 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (1×300 ml). The organic layers were combined, washed with brine (2×300 ml), dried over magnesium sulfate is, was filtered and concentrated, this has been indicated in the title compound (10.7 g) in powder form yellow-brown color. MS: 249 (M+H)+.

Stage 6

2-Methanesulfonamido[2,3-d]pyrimidine

Through a solution of 4-chloro-2-methanesulfonamido[2,3-d]pyrimidine (2.8 g) in ethanol (400 ml) and tetrahydrofuran (75 ml) missed nitrogen for 5 minutes To the specified solution was added 10% palladium on charcoal (2.8 g). The resulting mixture was placed on a rocking chair Parra at hydrogen pressure of 30 psi. After 16 h was added an additional portion of catalyst (1 g), the mixture was placed on a rocking chair Parra at hydrogen pressure of 30 psi and maintained for a further 6 hours, the Reaction mixture was filtered through a layer of celite 3 cm thick, a layer of celite washed with dichloromethane. The filtrate was concentrated, this has been indicated in the title compound (2.2 g).

Stage 7

(Tetrahydropyran-4-yl)thieno[2,3-d]pyrimidine-2-ylamine

A mixture of 2-methanesulfonamido[2,3-d]pyrimidine (1,58 g, 7,37 mmole), 4-aminotetrahydrofuran (2.24 g, 3 EQ.) and 1-methyl-2-pyrrolidinone (2 ml) was stirred at 100°C for approximately 7 h and then at 80°With during the night. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate/water (180 ml:60 ml). The layers were separated, org the organic layer was sequentially washed with water (4× 60 ml) and brine (1×60 ml), dried over magnesium sulfate, filtered and concentrated, to receive the crude product (1.7 g). The crude product was purified by chromatography on a column of silica gel (eluent: 25% ethyl acetate/hexane), was obtained is listed in the title compound as white powder (1,264 g). tpl.127,0-130,0°C. MS: 236 (M+N)+.

Example 7

6-Otieno[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)Amin

Stage 1

6-Otieno[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)Amin

To a solution of (tetrahydropyran-4-yl)thieno[2,3-d]pyrimidine-2-ylamine (786 mg, 3,34 mmole) in benzene (40 ml) was added mercuric oxide(II) (854 mg, 1,18 equiv.) and then iodine (1,00 g of 1.18 EQ.) and the resulting mixture was intensively stirred at room temperature overnight. Then added another portion of the oxide mercury(II) (427 mg, 0.6 EQ.) and iodine (500 mg, 0.6 EQ.) and the mixture was intensively stirred at room temperature for another 1 day. Then the mixture was filtered through a layer of celite thickness of 3 cm and the celite was washed with ethyl acetate (180 ml). The filtrate was sequentially washed with saturated solution of Na2S2O3(4×50 ml), water (2×50 ml) and brine (1×50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated, this is m has been specified in the title compound in the form of powder reddish color (823 mg). MS: 362 (M+N)+.

Example 8

[6-(2,4-Divergence)thieno[2,3-d]pyrimidine-2-yl](tetrahydropyran-4-yl)Amin

Stage 1

[6-(2,4-Divergence)thieno[2,3-d]pyrimidine-2-yl](tetrahydropyran-4-yl)Amin

A mixture of 2,4-differenoe (0.5 ml, 38 equiv.) of sodium hydride (205 mg, 37 EQ.) and 1-methyl-2-pyrrolidinone (0.6 ml) in a vessel with a volume of 2.5 ml microwave reactor was stirred for approximately 5 minutes To this mixture was added 6-Otieno[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)amine (50 mg, of 0.14 mmole), the mixture was placed in a microwave reactor and maintained for 75 minutes at 150°C. Then the reaction mixture was cooled to room temperature, diluted with ethyl acetate (85 ml) and then washed with water (3×30 ml) and brine (1×30 ml). The ethyl acetate layer was concentrated, the residue was purified preparative TLC on two plates with silica gel (20×20 cm, 1000 μm, eluent: 40% ethyl acetate/hexane). Specified in the title compound was obtained in the form of powder off-white color (8 mg). MS: 364 (M+N)+.

Example 9

[6-(2,4-Differentsurfaces)thieno[2,3-d]pyrimidine-2-yl](tetrahydropyran-4-yl)Amin

Stage 1

[6-(2,4-Differentsurfaces)thieno[2,3-d]pyrimidine-2-yl](tetrahydropyran-4-yl)Amin

To 6-Otieno[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)amine (100 mg, 0,277 mmole) was added 2,4-differentation (0.35 ml, 10.8 equiv.) and the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was stirred at 100°C for 5 h, was added 1-methyl-2-pyrrolidinone (0.2 ml)and then potassium carbonate (415 mg, 10.8 equiv.). The resulting mixture was stirred at 150°C for another 5 h and Then the reaction mixture was cooled to room temperature and was diluted with ethyl acetate/water (35 ml:20 ml). The layers were separated, the organic layer was sequentially washed with water (3×20 ml), brine (1×20 ml), dried over magnesium sulfate, filtered and concentrated, to receive the crude product (452 mg). The crude product was purified preparative TLC on four plates with silica gel (20×40 cm, 1000 μm, eluent: 55% ethyl acetate/hexane), to receive specified in the title compound in the form of powder off-white color (16 mg). MS: 380 (M+N)+.

Example 10

(6-Fenilalanina[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)Amin

Stage 1

(6-Fenilalanina[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)Amin

To a solution of 6-Otieno[2,3-d]pyrimidine-2-yl)(tetrahydropyran-4-yl)amine (100 mg, 0,277 mmole) in tetrahydrofuran (3 m is) at -78° With was added dropwise a 2.5 M solution of n-utility in hexane (0,23 ml, 2.1 equiv.) this red color of the reaction mixture had become yellow. The resulting mixture was stirred at -78°C for 45 min, then slowly at -78°solution was added phenoldisulfonic (242 mg, 4 equiv.) in tetrahydrofuran (3 ml). The reaction mixture gradually over 4 hours, heated from -78°to room temperature and the reaction was stopped by adding water (5 ml). The resulting mixture was diluted with ethyl acetate/water (35 ml:25 ml). The layers were separated, the organic layer washed with brine (1×20 ml), dried over magnesium sulfate, filtered and concentrated, to receive the crude product. The crude product was purified preparative TLC on two plates with silica gel (20×20 cm, 1000 μm, eluent: 50% ethyl acetate/hexane), to receive specified in the title compound in the form of powder off-white color (16 mg). MS: 344 (M+N)+.

Example 11

The following are examples of pharmaceutical compositions containing a compound of formula I.

The tablet formulation

The following ingredients are thoroughly mixed and pressed into tablets with a single notch.

IngredientThe number of 1 tablet mg
The connection according to the present invention400
Corn starch50
Nitrocresols25
Lactose120
Magnesium stearate5

The capsules

The following ingredients are thoroughly mixed and the mixture is filled hard gelatin capsules.

IngredientAmount per 1 capsule mg
The connection according to the present invention200
Lactose, dried in the spray dryer148
Magnesium stearate2

The composition of the suspensions

The following ingredients are mixed prior to the formation of 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
Veegum K (Vanderbilt Co.)1.0 g
Flavora 0.035 ml
Dye0.5 mg
Distilled waterq.s. to 100 ml

The composition for injection

The following ingredients are mixed to form a 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)q.s. to the desired pH
Water (distilled, sterile)q.s. to 20 ml

All of the above ingredients, except water, are mixed and heated with stirring to a temperature of 60-70°C. Then add a sufficient quantity of water at 60°With vigorous stirring to form an emulsion of the ingredients and add the required amount of water to 100 g

The composition of the suppository

A suppository of total weight 2.5 g of the following composition are obtained when mixing the compounds according to the invention with the base Witepsol® H-15 (triglycerides of saturated vegetable fatty acids, the firm Riches-Nelson, Inc., New-York).

The connection according to the present invention500 mg
Witepsol® H-15to balance

Example 12

Analysis of in vitro inhibition of kinase R (MAP)

Inhibitory activity of the compounds of the present invention in relation kinase R MAP was determined in vitro according to the degree of transfer (under the action of kinases R) γ-phosphate from γ-33P-ATP on myelin basic protein (MBP) by a modified method described in the article N.G. Ahn and others, J. Biol. Chem., 266 (7), 4220-4227 (1991).

Phosphorylated form of recombinant kinase R MAP expressed in vectors SEK-1 and MEKK in E. coli (see A. Khokhlatchev, etc., J. Biol. Chem., 272 (17), 11057-11062 (1997) and was isolated by affinity chromatography on a Nickel column.

Phosphorylated recombinant kinase R MAP was diluted in kinase buffer solution (20 mm 3-(N-morpholino)propanesulfonic acid, pH of 7.2, 25 mm β-glycerophosphate, 5 mm etilenglikoli(beta aminoacylase ether)-N, N,N',N'-tetraoxane acid, 1 mm sodium Vanadate, 1 mm dithiotreitol, 40 mm magnesium chloride). Then added the analyzed compound, dissolved in DMSO, or only DMSO (control) and samples were incubated for 10 min at 30°C. the Kinase reaction was initiated by adding the substrate mixture containing MBP and γ-33P-ATP. After incubation for a further 20 min at 30°the reaction was stopped by the addition of 0.75% phosphoric acid. Then phosphorylated MBP CTD is ranged from residual γ -33P-ATP on phosphocellulose membrane (firm Millipore, Bedfrod, MA) and radioactivity was determined by scintillation counter (Packard company, Meriden, CT).

Inhibiting R activity (expressed as the value of the IC50, i.e. the concentration at which there is 50% inhibition of the analyzed enzyme R) for compounds listed in table 1, ranges from 0.01 to 10 microns.

Table 2

ConnectionStructurep38 IC50(nM)
1104
3221
23128
30744
33135
41226

Example 13

In the example described the in vitro assays no inhibition of the production of α-TNF induced by LPS in the cells TNR-1.

The ability of the compounds of the present invention to inhibit the release of αa (TNF-a was determined using a modified method described in the article Blifeld and other Transplantation, 51: 498-503 (1991)./p>

(a) Induction of the biosynthesis of TNF

Cells TNR-1 suspended in culture medium (RPMI, the company Gibco-BRL, Gailthersburg, MD, USA)containing 15% fetal calf serum, 0.02 mm 2-mercaptoethanol, at a concentration of 2.5×106cells/ml and then added to 96-well plates (0.2 ml in each well). The compounds were dissolved in DMSO and then diluted in culture medium to the final concentration of DMSO 5%. To each well was added 25 μl of a solution of tested compound or only a mixture of medium and DMSO (control). Cells were incubated for 30 min at 37°C. Then the wells were added LPS (firm Sigma, St. Louis, MO, USA) at a final concentration of 0.5 μg/ml and cells were incubated for a further 2 hours At the completion of incubation, supernatant culture medium was collected and determined the amount of αa (TNF-a by ELISA, as described below.

(b) Enzyme-linked immunosorbent assay (ELISA)

Number α-TNF present in supernatant, was determined by the modified ELISA using two antibodies against α-TNF (2TNF-H12 and 2TNF-H34), as described in article Reimund J.M. and others, GUT, t (5), 684-689 (1996).

96-well tablets made of polystyrene covered with antibodies 2TNF-H12 in PBS buffer solution (10 µg/ml)by adding to each well 50 μl of the indicated antibody solution and incubated in a humid chamber at 4°With during the night. The tablets were washed in PBS,then blocked with a solution of 5% nonfat dry milk in PBS for 1 h at room temperature and washed with 0.1% BSA (bovine serum albumin) in PBS.

Standard solutions of TNF was prepared from the original solution of recombinant α-TNF person (firm R&D Systems, Minneapolis, MN, USA). For the analysis used a set of standard solutions, obtained by serial dilution (ratio of breeding is 6.5 log) solution with initial concentration of 10 ng/ml.

The above culture solution supernatant (25 μl) or standards TNF or only medium (control) was mixed with 25 μl of a solution of biotinylated monoclonal antibodies 2TNF-H34 (2 μg/ml in PBS containing 0.1% BSA), then the mixture was added to each well. Samples were incubated for 2 h at room temperature with mild shaking, and then washed three times with 0.1% BSA in PBS. To each well was added 50 ál of conjugate solution peroxidase-streptavidin (firm Zymed, S. San Francisco, CA, USA)containing 0,416 μg/ml conjugate peroxidase-streptavidin and 0.1% BSA in PBS. Samples were incubated for another 1 h at room temperature and washed four times with 0.1% BSA in PBS. To each well was added 50 μl of a solution of O-phenylenediamine (1 mg/ml O-phenylenediamine and 0.03% hydrogen peroxide in 0.2 M citrate buffer solution, pH 4.5) and the samples were incubated in the dark for 30 min at room temperature. The optical density of the sample and standard were measured at 450 and 650 nm, respectively. Level α-TNF was determined by the graphics zavisimost and optical density at 450 nm concentration.

The value of the IC50defined as the concentration of tested compound at which there is 50% reduction of the maximum absorption at 450 nm.

1. The compound of the formula I

where a represents N or CH,

R1means hydrogen, alkyl or aralkyl,

R2means C1-6alkyl, hydroxy1-6alkyl, (R)2NCO-alkylen- (where each R" is independently mean hydrogen or C1-6alkyl), optionally substituted hydroxy-group3-7cycloalkyl, 6-membered heterocyclyl containing as heteroatoms nitrogen, oxygen, or sulfur, or its oxides, with nitrogen-containing heterocyclyl may be substituted With1-4alkylsulfonyl group, optionally substituted phenyl, the substituents of which are selected from halogen atoms and lower alkoxy,

X is O, NR3or S, where R3means C1-6alkyl or phenyl, and

Y represents a chemical bond, O, S(=O), CH(OR'), CHR', or S and R' means hydrogen, and

R is optionally substituted by one or more substituents phenyl, the substituents of which are selected from halogen atoms, lower alkyl and lower alkoxy,

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where

A represents N or CH,

R1means hydrogen,

2means C1-6alkyl, hydroxys1-6alkyl, optionally substituted hydroxy-group3-7cycloalkyl, 6-membered heterocyclyl containing as heteroatoms nitrogen, oxygen, or sulfur, or its oxides, with nitrogen-containing heterocyclyl may be substituted With1-4alkylsulfonyl group, optionally substituted phenyl, the substituents of which are selected from halogen atoms and lower alkoxy,

X is O, NR3or S, where R3means methyl,

Y represents O, C(=O), CH(OR'), CHR', or S and R' means hydrogen, and

R is optionally substituted by one or more substituents phenyl, the substituents of which are selected from halogen atoms, lower alkyl and lower alkoxy, and

its pharmaceutically acceptable salt.

3. The compound according to claim 1, where

And means N

R1means hydrogen,

R2means hydraxis1-6alkyl, optionally substituted hydroxy-group3-7cycloalkyl, 6-membered heterocyclyl containing as heteroatoms nitrogen, oxygen, or sulfur, or its oxides, with nitrogen-containing heterocyclyl may be substituted With1-4alkylsulfonyl group, optionally substituted phenyl, the substituents of which are selected from halogen atoms and lower alkoxy,

X is O, NR3or S, where R3 means C1-6alkyl or phenyl, and

Y represents a chemical bond, O, S(=O), CH(OR'), CHR', or S and R' means hydrogen, and

R is optionally substituted by one or more substituents phenyl, the substituents of which are selected from halogen atoms, lower alkyl and lower alkoxy.

4. The compound according to claim 1, where Y represents CH2or C(=O), and R is optionally substituted by one or more substituents phenyl, the substituents of which are selected from halogen atoms, lower alkyl and lower alkoxy.

5. The compound according to claim 1, where Y denotes O or S.

6. The compound according to claim 1, where Y denotes a chemical bond.

7. The compound according to claim 1, where a represents N.

8. The compound according to claim 1, where X is S.

9. The compound according to claim 1, where R is phenyl, optionally substituted with halogen, lower alkyl and lower alkoxy.

10. The compound according to claim 1, where R is selected from the group comprising optionally substituted hydroxy-group3-7cycloalkyl, 6-membered heterocyclyl containing as heteroatoms nitrogen, oxygen, or sulfur, or its oxides, with nitrogen-containing heterocyclyl may be substituted With1-4alkylsulfonyl group, optionally substituted phenyl, the substituents of which are selected from halogen atoms and lower alkoxy,

11. The compound according to claim 1, where

R1means hydrogen, R2means 4-GI is Toxicological, And means N, X is S, Y represents C(=O), and R is phenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 4-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 2-chlorophenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means 1-(1,1-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y oznachaet the C(=O), and R is 2-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), and R is 4-chlorophenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=0), and R is 4-forfinal;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 4-chlorophenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), And means N, X is S, Y represents C(=O), and R is 2-chlorophenyl;

R1means hydrogen, R2means 4-tetrahydro-1,1-dioxide-2-N-dipiradol, And means N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means 4-tetrahydro-1,1-dioxide-2-N-dipiradol, And means N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1,1-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1-methyl-2-methoxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1-methyl-2-hydroxy)ethyl, And N means That X oz is achet S, Y represents C(=O), and R is 3-forfinal;

R1means hydrogen, R2means 1-(1-methyl-2,2-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 2-chlorophenyl;

R1means hydrogen, R2means 1-(1-methyl-2,2-dimethyl-2-hydroxy)ethyl, a represents N, X is S, Y represents C(=O), and R is 2-forfinal;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), R' represents hydrogen, a represents N, X is S, Y means CHR', and R is phenyl;

R1means hydrogen, R2means of 4-(N-methylsulfonylbenzoyl), R' represents hydrogen, a represents N, X is S, Y represents CH(OR'), a R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, R' represents hydrogen, a represents N, X is S, Y represents CH(OR'), a R mean 2-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, R' represents hydrogen, a represents N, X is S, Y means CHR', a R mean 2-forfinal;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), a R mean 2-were;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), a R is 2-methoxyphenyl;

R1means hydrogen, R means 4-tetrahydropyranyl, And means N, X is S, Y represents C(=O), a R is 3-methoxyphenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, R' represents hydrogen, a represents N, X is O, Y represents CHR', a R is phenyl;

R1means hydrogen, R2means cyclopentyl, R' represents hydrogen, a represents N, X is O, Y represents CHR', a R is phenyl;

R1means hydrogen, R2means isopropyl, R' represents hydrogen, a represents N, X is O, Y represents CHR', a R is phenyl;

R1means hydrogen, R2means 4-tetrahydropyranyl, And means N, X is NR3, R3means methyl, Y represents C(=O), a R is 2-methoxyphenyl;

R1means hydrogen, R2means cyclopentyl, R' is hydrogen, And N means That X is NR3, R3means methyl, Y represents CHR', a R is phenyl;

or

R1means hydrogen, R2means 4-tetrahydropyranyl, R' is hydrogen, And N means That X is NR3, R3means methyl, Y represents CHR', a R is phenyl.

Priorities for items:

07.03.2002 and 03.12.2002 according to claims 1, 3, 4, 5, 7-11.

07.02.2002 according to claim 2.

03.12.2002 6.



 

Same patents:

FIELD: organic chemistry, biology, pharmacy.

SUBSTANCE: invention relates to derivatives of thieno[2,3-d]pyrimidine of the general formula (I): or their pharmaceutically acceptable salts wherein R1 and R2 in common with nitrogen atom to which they are added form a ring comprising from 2 to 6 carbon atoms and optionally comprising one or more heteroatoms chosen from nitrogen (N), oxygen (O) and/or sulfur (S) atoms. Proposed compounds possess ability to activate both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and can be used in therapy in aims for regulating fertility. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1): wherein each R1 and R2 represents independently (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C3-C6)-cycloalkyl wherein each of them can be substituted possibly with halogen atom in the amount from 1 to 3; R3 represents isoxyzolydine-2-ylcarbonyl or tetrahydroisoxazine-2-ylcarbonyl wherein each ring is substituted possibly with one hydroxy-group; Q represents -CO- or -C(R4)(R5)- (wherein R4 represents hydrogen atom or (C1-C4)-alkyl, and R5 represents hydrogen atom or hydroxy-group); Ar represents 5-10-membered aromatic ring system wherein up to 4 ring atoms can be represented by heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms and wherein this ring system is substituted possibly with one or more substitute. Proposed compounds can be used for modulation of autoimmune disease. Also, invention describes methods for synthesis of compounds of the formula (1) and pharmaceutical composition based on compounds of the formula (1).

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

14 cl, 44 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes glycine-substituted thieno[2,3-D]-pyrimidines of the formula (I): wherein X represents oxygen atom (O) or H,H; A represents sulfur atom (S), -NH, -N(R6), O or a bond; R1 represents (C1-C4)-alkyl, (C2-C4)-alkenyl, unsubstituted or substituted phenyl, thienyl, pyridyl; R2 represents hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-(C2-C4)-alkyl or hydroxy-(C2-C4)-alkyl; R3 and R4 are chosen independently from H, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl; R5 represents H or (C1-C4)-alkyl, and R6 represents (C1-C4)-alkyl. Compound possess agonistic activity with respect to glycoprotein hormone, in particular, to compounds possessing agonist activity with respect to luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Also, invention describes pharmaceutical compositions containing such compounds and using these compounds in medicinal therapy, in particular, for fertilization control.

EFFECT: valuable biological and medicinal properties of compounds.

11 cl, 1 tbl, 27 ex

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

SUBSTANCE: invention describes compounds of the formula (I):

wherein R1 means hydrogen atom; R2 means phenyl or phenyl mono- or di-substituted substituted with the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, perfluoro-(lower)-alkyl; R3 and R4 in common with carbon atoms to which they are bound form phenyl optionally and independently mono-, di- or tri-substituted with halogen atom or perfluoro-(lower)-alkyl, or form 5-, 6- or 7-membered saturated cycle optionally comprising heteroatom chosen from oxygen (O) and sulfur (S) atom and optionally and independently mono-substituted with (lower)-alkyl wherein indicated saturated cycle is condensed in ortho-position with 5-membered aromatic cycle optionally comprising S atom as a heteroatom, or with phenyl optionally and independently mono- di-substituted with the group: halogen atom, (lower)-alkyl, perfluoro-(lower)-alkyl or (lower)-alkoxy-group, and their pharmaceutically acceptable salts. Also, invention describes a method for synthesis of compounds, a pharmaceutical composition and using compounds for treatment and/or prophylaxis of DPP-IV-associated diseases. Compounds are used in treatment of such diseases as diabetes mellitus being first of all non-insulin dependent diabetes mellitus and damaged tolerance to glucose.

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

16 cl, 1 tbl, 39 ex

FIELD: agriculture, organic chemistry.

SUBSTANCE: invention relates to application of 2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno[2,3-b]pyridine of formula as stimulator of sunflower growth.

EFFECT: stimulation of sunflower seed germination; increased sunflower productivity.

2 tbl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

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

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

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

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

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

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

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

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of tetracyclic derivatives of isoquinolone. Invention describes a method for synthesis of derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isoquinoline-5-one of the general formula (1a-f): wherein (1a): R means hydrogen atom (H); R' means hydrogen atom (H); (1b): R means chlorine atom (Cl); R' means hydrogen atom (H); (1c): R means bromine atom (Br); R' means hydrogen atom (H); (1d): R means iodine atom (J); R' means hydrogen atom (H); (1e): R means methoxy-group (-OCH3); R' means hydrogen atom (H); (1f): R means -OCH3; R' means -OCH3. Method involves boiling derivatives of 3,5-dihydro-1,11-dimethylfuro[2',3':3,4]cyclohepta[c]isochromen-5-one in formamide medium in the ratio 0.01 mole of the parent substance per 45 ml of formamide for 25-120 min. Invention provides preparing new compounds that possess the potential useful biological properties.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 tbl, 6 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

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

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

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, peptides, medicine, pharmacy.

SUBSTANCE: invention relates to peptide derivatives named as memnopeptides that are used as an active component for manufacturing a medicinal preparation used in treatment of bacterial infection. Invention proposes compound of the formula (I): wherein radicals R1, R2, R3, R4, R5, R6, R7, R8 and (A)n have corresponding values, or its salt. Compounds of the formula (I) are prepared by culturing microorganism Memnoniella echinata FH 2272, DSM 13195 under suitable conditions in the nutrient medium containing at least one source of carbon atoms and at least one source of nitrogen atoms and the process is carrying out until the accumulation of at least one compound of the formula (I) in the nutrient medium followed by isolation of indicated compound. The attained technical result involves the development of a pharmaceutical composition eliciting an antibacterial activity. The development of the preparation provides expanding assortment of agents used in treatment of diseases said above.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

3-piperidine, methods for their preparation and pharmaceutical composition based on them" target="_blank">

The invention relates to tricyclic3-piperidinol General formula (1), where X is O or S, R1means hydrogen, halogen, C1-6alkyl or C1-4alkyloxy, Alk means C1-6alcander, a D such as defined in the claims

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

FIELD: organic chemistry, medicine, hepatology.

SUBSTANCE: invention relates to using 2-methylthiopyrimido[4,5-b]indole of the formula (1): showing melting point at 243°C (with decomposition) and value LD50 > 1000 mg/kg used in liver protection from poisoning with carbon tetrachloride. Proposed compound exceeds activity of the "Essentiale" as a comparison preparation.

EFFECT: valuable medicinal property of compound, enhanced effectiveness.

1 tbl

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