Indolylmaleimide derivatives as protein kinase c (pkc) inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

in which Radenotes N or C1-C4alkyl;
one of Rb, Rc, Rdand Restands With1-C4alkyl, and the other three Deputy denote H; or Rb, Rc, Rdand Reall represent H; and
R denotes a radical of the formula (a), (b) or (C)



where R1represents -(CH2)n-NR3R4,
where each of R3and R4independently represents N or C1-C4alkyl; or R3and R4together with the nitrogen atom to which they are bound, form a 5-8-membered heterocyclic residue, where, including the linking nitrogen atom, one or two atoms With substituted on the N atom, optionally substituted C1-C4by alkyl;
n is 0, 1 or 2; and
R2represents H; halogen or1-C4and the keel;
each of R10and R10aindependently denotes a 5-8 membered saturated heterocyclic ring, which, including the linking nitrogen atom, one or two atoms With substituted on the N atom, optionally substituted C1-C4by alkyl;
and each of R20and R20aindependently represents H; halogen; C1-C4alkyl; CF3; or a nitro-group;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, which is selected from
3-[5-chloro-2-(4-methylpiperazin-1-yl)-pyridin-4-yl]-4-(1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-dimethylaminonaphthalene-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethyl-2-chloronaphthalene-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-methylaminomethyl-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-methylaminomethyl-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-methylaminomethyl-1-yl)-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-methylaminomethyl-1-yl)-4-(6-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-methylaminomethyl-1-yl)-4-(5-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-dimethylaminonaphthalene-1-yl)-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-dimethylaminonaphthalene-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-dimethylaminonaphthalene-1-yl)-4-(6-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-dimethylamino ethylnaphthalene-1-yl)-4-(5-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-{2-chloro-7-[(ethylmethylamino)-methyl]-naphthalene-1-yl}-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-diethylaminomethyl-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-ethylaminomethyl-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-[2-chloro-7-(isopropylaminomethyl)-naphthalene-1-yl]-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-[2-chloro-7-(4-methylpiperazin-1-ylmethyl)-naphthalene-1-yl]-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(2-chloro-7-pyrrolidin-1-illiterately-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethyl-2-methylnaphthalene-1-yl)-4-(1,7-dimethyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethyl-2-methylnaphthalene-1-yl)-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethyl-2-methylnaphthalene-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethyl-2-methylnaphthalene-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethylation-1-yl)-4-(1-H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminomethylation-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminonaphthalene-1-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-aminonaphthalene-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-dimethylaminomethyl-2-fornatale-1-yl)-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(7-dimethylaminomethyl-2-fornatale-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione;
3-(1-methyl-1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-pyridin-3-yl]-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-pyridin-3-yl]-Pirro is -2,5-dione;
3-(7-methyl-1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-2-triptorelin-3-yl]-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-2-triptorelin-3-yl]-pyrrole-2,5-dione;
3-(1-methyl-1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-2-triptorelin-3-yl]-pyrrole-2,5-dione;
3-(7-methyl-1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-pyridin-3-yl]-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[5-(4-methylpiperazin-1-yl)-2-nitropyridine-3-yl]-pyrrole-2,5-dione;
3-[2-chloro-5-(4-methylpiperazin-1-yl)-pyridin-3-yl]-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[5-methyl-2-(4-methylpiperazin-1-yl)-pyridin-4-yl]-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-5-nitropyridine-4-yl]-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)-5-triptorelin-4-yl]-pyrrole-2,5-dione in free form or in the form of pharmaceutically acceptable salts.

3. The compound according to any one of claim 1 or 2, in free form or in the form of a pharmaceutically acceptable salt intended for use as a inhibits protein kinase C (SW) tools.

4. The compound according to any one of claim 1 or 2, inhibiting the protein kinase C (SW).

5. The pharmaceutical composition inhibiting the protein kinase C (CSWs)including the compound according to any one of claim 1 or 2, in free form or in the form of a pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

6 the Use of compounds according to any one of claim 1 or 2, in free form or in the form of pharmaceutically acceptable salts, or pharmaceutical composition according to claim 5 for the preparation inhibits protein kinase C (CSW), an agent intended for the treatment or prevention of diseases or disorders mediated by T lymphocytes and/or the RCC that in the particular transplant rejection, graft versus host.

7. A method of obtaining a compound according to claim 1, including the interaction of the compounds of formula II

in which Ra-Reare as defined in claim 1,
with the compound of the formula III

in which R is as defined in claim 1,
and, if necessary, converting the resulting compounds of the formula I obtained in free form, in salt, or Vice versa in accordance with what is appropriate.

8. A method of treating or preventing disorders or diseases mediated by T lymphocytes and/or the RCC that in the particular transplant rejection, graft versus host, the subject in need of such treatment, comprising the introduction of a specified subject an effective amount of a compound according to any one of claim 1 or 2, or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: chemistry.

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

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

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydrochinoline derivatives represented by general formula , where t is equal 0, 1 or 2; each R independently represents H, alkyl, alkenyl or cycloalkyl; n is equal 0; R is selected from group, consisting of H, alkyl, halogenalkyl, cycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5 or group - Racycloalkyl, and where R2 is not substituted with amine or alkylamine; each R4 independently represents halogen; m is equal 0, 1 or 2; each R5 independently represents H, alkyl, alkenyl, alkinyl, cycloalkyl; p is equal 0 or 1; y represents -NR10-, -O-, -S-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, -RaHetRaN(R10)2, -HetRaAy or -HetRaHet; each Ra independently represents alkylene, possibly suibstituted with one or more than one alkyl or hydroxyl, cycloalkylene, possibly substituted with one or more than one alkyl or hydroxyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl or -Ra-cycloalkyl; each Ay independently represents possibly substituted phenyl or naphtyl group; each Het independently represents possibly substituted 3-12-member mono- or polycyclic heterocyclyl group, containing as heteroatoms N, or 5-7-member possibly substituted heteroaryl group, containing as heteroatom N; or its pharmaceutically acceptable salts or ethers. Also described are methods of obtaining compounds of formula (I-G).

EFFECT: obtained are novel compounds, which demonstrate protective against HIV-infection effect on target-cells by means of specific binding with chemokine receptor and which influence binding of natural ligand or chemokine with target-cell receptor, such as CXCR4 and/or CCR5.

54 cl, 2 tbl, 90 ex

FIELD: chemistry.

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

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry; pharmacology.

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

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

3 cl, 5 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenyl substituted pyrrolidones of formula: , where R1 and R5 represent substitutes, which are independently chosen from a group which contains H, CN, halogen, C1-C4alkyl and OR8, where R8 represents C1-C4alkyl, R2 and R4 represent substitutes, which are chosen from a group which contains H, halogen, CN and C1-C4alkyl, R3 represents H, R6 represents a condensed phenyl heterocyclic ring system, chosen from , where R16 represents a substitute, chosen from a group which contains H, C(O)NR18R19 and S(O)2R20, where R18 and R19 represent H or C1-C6alkyl; R20 represents C1-C6alkyl or phenyl; and R17 represents a substitute, which is chosen from a group which contains H, NH2, (CH2)mOH, C(O)NR21R22, SO2R23 and NHSO2R23; where R21 and R22 represent substitutes, which are independently chosen from a group which contains H and substituted or unsubstituted C1-C6alkyl, or, together with a nitrogen atom to which they are bonded, optionally form a ring; R23 represents C1-C6alkyl; and m equals 1; or R6 represents a group, where R9 and R11 represent substitutes, which are independently chosen from a group which contains H, halogen, CN, C(O)NR12R12, NR12R12 and OR12, where each R12 represents H or C1-C4alkyl, and under the condition that, at least one of substitutes R9 and R11 is not hydrogen; R10 represents CN, NR13R14, SO2NHR13, NHSO2R13, O(CH2)nSO2R15, SO2R15, SO2(CH2)nNR13R14 or C(O)NR13R14, where R13 and R14 represent H or C1-C4alkyl; R15 represents C1-C4alkyl, n equals 1-2, and R7 represents halogen, C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl.

EFFECT: design of compounds and a pharmaceutical composition for inhibiting HIV growth.

19 cl, 12 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and describes novel roentgen-amorphous modification of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]benzamide of methane sulfonate (imatinib mesilate - international non-patented name) and method of obtaining it, consisting in evaporating initial substance of imatinib mesilate at temperature 170-215°C in vacuum 5×10-3 - 3×10-5 torr and condensing on cooled to (-)100 - (-)196°C surface.

EFFECT: obtaining of novel imatinib mesilate modification which can be used in pharmaceutical industry and medicine as anti-leucosis cytostatic medication for therapy of oncological diseases.

2 cl, 6 ex, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to aryl or heteroarylpiperazines with general formula II , where R2 is hydrogen or C1-4-alkyl (i) R1 is branched C4-6-alkyl, branched C4-6-alkenyl or branched C4-6-alkynyl, under the condition that R1 is not isobutyl, - C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl, -R1 and R2 together form a C3-6-alkylene bridge, and A is or or (ii) R1 - is ethyl, n-propyl or isopropyl, - R1 and R2 together form a C3-6-alkylene bridge, and A is or . Described also is a pharmaceutical composition based on formula II compounds, use of formula II compounds and method of treatment.

EFFECT: compounds exhibit high and selective bonding affinity to histamine H3 receptor and can be used for treating diseases and disorders, related to histamine H3 receptor.

49 cl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the new substituted dihydroquinazolines of formula (I) and to their pharmaceutically acceptable salts having antiviral properties. In general formula (I) , Ar is phenyl group which can be mono-, di- or trisubstituted. The substituting group are independently selected from the group including C1-6 alkyl-, C1-6 alkoxy-, trifluoromethyl groups and halogen atoms or two substituting groups together with linked carbon atoms form 1,3-dioxolane; R1 is hydrogen atom, amine group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R2 is hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R3 is C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; or one of the radicals R1, R2 and R3 is hydrogen atom and two others together with linked carbon atoms form cyclopentane or cyclohexane ring, R4 is hydrogen atom or C1-6 alkyl group, R5 is hydrogen atom or alkyl group, R6 is carboxyl, aminocarbonyl, alkoxycarbonyl groups, halogen atoms, cyanic or hydroxyl groups, R7 is hydrogen atom or halogen atoms and R8 is hydrogen atom or halogen atoms, its pharmaceutically acceptable salts.

EFFECT: claimed compounds can find application for treatment and prevention of diseases and as antiviral agents.

21 cl, 3 tbl, 201 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to experimental ophthalmology, and can be applied for suppression of positive regulation of short form of c-Maf transcription factor in processed with steroids or transforming growth factor β2 (TGF β2) cells of trabecular net. For this purpose introduced is antagonist c-Maf, also possessing inhibiting activity with respect to cyclin-dependent kinase cdk2, for instance purvalanol A.

EFFECT: invention explains mechanism and possible new approach to treatment of primary open-angle and steroid glaucoma.

4 cl, 1 tbl, 7 ex, 3 dwg

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