Pyrazolylaminopyridine derivatives applicable as kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I):

in which:
R1represents a C1-6alkyl, C1-6alkoxy, cyclopropyl;
R2represents hydrogen;
X3or X4is a =N, X1and X2and the other of X3and X4independently selected from =CR8-, =CR9and =CR10-;
R3represents hydrogen or C1-6alkyl;
R4and R34independently selected from hydrogen or C1-6of alkyl; R4and R34independently may be optionally substituted at carbon atoms by one or more R12where R12represents a hydroxy-group;
Rather it represents a simple bond;
the ring is a phenyl, pyridyl or pyrimidinyl;
R5may be the same or different and independently selected from halogen, C1-6alkanolamine, C1-6alkylsulfonate or cyclopropyl-R37-; where R37represents-C(O)N(R31)-, where R31represents hydrogen;
n is 1 or 2;
R8, R9and R10independently selected from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl,1-6of alkyl, C1-6alkanoyl, N-(C1-6alkyl)amino or cyclopropyl-R25-; where R8, R9and R10the independent is IMO from each other optionally may be substituted at carbon atoms by one or more R 18;
R18independently selected from hydroxy, amino, N-(C1-6alkyl)amino, C1-6alkanolamine,1-6alkylsulfonamides, carbocyclic-R27or heterocyclyl-R28-; where R18optionally may be substituted at carbon atoms by one or more R20; and where, if the specified heterocyclyl contains an-NH-portion, a nitrogen atom optionally may be substituted by a group selected from R21;
R20independently selected from halogen, amino, C1-6of alkyl, N,N-(C1-6alkyl)2amino, C1-6alkylsulfonyl-N-(C1-6alkyl)amino, carbocyclic-R35or heterocyclyl-R36-; where R20optionally may be substituted at carbon atoms by one or more R23;
R21represents a C1-6alkylsulfonyl;
R23represents dimethylamino or phenyl;
R25represents-NH=CH-;
R27, R28, R35and R36independently selected from a simple link, -C(O)N(R31)- or-SO2N(R32)-;
where R31and R32independently selected from hydrogen or C1-6of alkyl; where the specified carbocycle selected from cyclopropyl or phenyl, and the specified heterocyclyl is a 5-6-membered saturated, partially saturated or unsaturated ring containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, and where the group is a-CH 2- optional, can be replaced by a group-C(O)-;
or its pharmaceutically acceptable salt.

2. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1, where R3represents hydrogen.

3. The compound of formula (I) according to claim 1

in which:
R1represents methyl, tert-butyl, isopropoxy or cyclopropyl;
R2represents hydrogen;
X3or X4is a =N, X1and X2and the other of X3and X4independently selected from =CR8-, =CR9and =CR10-;
R3represents hydrogen;
R4and R34independently selected from hydrogen, methyl or hydroxymethyl;
Rather it represents a simple bond;
the ring is a phenyl, pyrid-2-yl, pyrid-3-yl or pyrimidine-2-yl;
R5selected from fluorine, acetylamino, methylamino or cyclopropanecarboxylate;
n represents 1 or 2; where the values of R5may be the same or different;
R8, R9and R10independently selected from hydrogen, fluorine, chlorine, iodine, nitro, cyano, amino, carboxy, carbamoyl, formyl, methylamino, hydroxymethyl, acetamidomethyl, (2-aminoacetyl)aminomethyl,
(2-morpholinoethyl)aminomethyl,
(R)-2-oxopyrrolidin-5-yl-carbonylmethyl,
(S)-2-oxopyrrolidin-5-yl-carbonylmethyl,
(R,S)-2-oxopyrrolidin-5-yl-carbonylmethyl,
isoxazol-5-yl-carbonylmethyl, methylaminomethyl,
of morpholinomethyl, benzylaminopurine,
pyrid-3-yl-carbonylmethyl, 6-dimethylaminophenyl-3-yl-carbonylmethyl, 6-morpholinomethyl-3-yl-carbonylmethyl, pyrid-4-yl-carbonylmethyl,
5-methylisoxazol-4-yl-carbonylmethyl,
Tien-2-yl-carbonylmethyl, 4-dimethylaminocarbonylmethyl,
2-(N-(isopropyl)-N-(mesyl)amino)acetylaminophenol,
2-(N-(phenethyl)-N-(mesyl)amino)acetamidomethyl,
1-methylpiperidin-4-incorporatingthe,
2-(pyrid-3-yl)acetamidomethyl,
tetrahydro-2H-thiopyran-4-yl-carbonylmethyl,
2-(Tien-2-yl)acetamidomethyl,
2-(Tien-3-yl)acetamidomethyl,
3-phenylpropionylamino,
2-(N-benzene-N-methylamino)acetamidomethyl,
4-dimethylaminobenzophenone, phenylsulfonylacetate,
2-amino-3-methylbutylamine,
cyclopropanecarboxylate,
pyrrol-2-yl-carbonylmethyl,
tetrahydrofuran-2-yl-carbonylmethyl,
furan-2-yl-carbonylmethyl, cyclopropylacetylene (cyclopropylamino)bromide, methylaminomethyl,
triptoreline, isopropyl, isopropylamino or methylamino;
or its pharmaceutically acceptable salt.

4. The compound of formula (I) according to claim 1

selected the th of:
(S)-6-(5-cyclopropyl-1H-pyrazole-3-ylamino)-5-fluoro-2-(1-(4-forfinal)ethylamino)-4-(methylamino)nicotinanilide;
(S)-6-(5-cyclopropyl-1H-pyrazole-3-ylamino)-5-fluoro-2-(1-(5-herperidin-2-yl)ethylamino)nicotinanilide;
(S)-5-fluoro-2-(1-(5-herperidin-2-yl)ethylamino)-6-(5-isopropoxy-1H-pyrazole-3-ylamino)nicotinanilide;
(S)-6-(5-cyclopropyl-1H-pyrazole-3-ylamino)-5-fluoro-2-(1-(4-forfinal)ethylamino)-4-(isopropylamino)nicotinanilide;
(S)-5-chloro-6-(5-cyclopropyl-1H-pyrazole-3-ylamino)-2-(1-(5-herperidin-2-yl)ethylamino)nicotinanilide;
6-[(5-cyclopropyl-1H-pyrazole-3-yl)amino]-2-{[(1S)-1-(3,5-differencein-2-yl)ethyl]amino}-5-fornicationis;
(S)-5-fluoro-2-(1-(4-forfinal)ethylamino)-6-(5-isopropoxy-1H-pyrazole-3-ylamino)nicotinanilide;
(S)-6-(5-cyclopropyl-1H-pyrazole-3-ylamino)-5-fluoro-2-(1-(4-forfinal)ethylamino)nicotinanilide;
(R)-6-(5-cyclopropyl-1H-pyrazole-3-ylamino)-5-fluoro-2-(1-(4-forfinal)-2-hydroxyethylamino)nicotinanilide; or
(R)-5-fluoro-2-(1-(4-forfinal)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazole-3-ylamino)nicotinanilide;
or its pharmaceutically acceptable salt.

5. The method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt according to claim 1, which includes the interaction of the compounds of formula (VI):

where L represents a displaced group;
with an amine of formula (VII):

and then, the ri need:
ii) removing any protective groups;
iii) formation of pharmaceutically acceptable salts.

6. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4, for use as drugs having inhibitory activity against Trk kinase.

7. The use of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 for preparing a medicinal product for use for the inhibition of Trk activity.

8. The use of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 for the preparation of a medicine for use for the treatment or prevention of malignant neoplasm is selected from breast cancer, colorectal cancer and prostate cancer.

9. The use of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 for preparing a medicinal product for use to obtain antiproliferative action.

10. The method of inhibition of Trk activity, which includes the introduction of a host in need of such treatment, a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4.

11. Method for the treatment or prevention of malignancy, which includes the introduction is of a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4.

12. The method of obtaining antiproliferative action in warm-blooded animal, such as man, in need of such treatment, which provides for the introduction of specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4.

13. A pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4, together with at least one pharmaceutically acceptable carrier, diluent or excipient, for use in inhibiting the activity of the Trk.

14. A pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4, together with at least one pharmaceutically acceptable carrier, diluent or excipient, for use for the treatment or prevention of malignant tumors.

15. A pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4, together with at least one pharmaceutically acceptable carrier, diluent or excipient, for use to obtain antiproliferative action in warm-blooded animal such as man.

16. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 DL is applied for the inhibition of Trk activity.

17. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 for use for the treatment or prevention of malignant neoplasm is selected from breast cancer, colorectal cancer and prostate cancer.

18. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 for use to obtain antiproliferative action.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound 3-{[5-(azetidine-1-ylcarbonyl)pyrazine-2-yl] oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazine-5-yl)benzamide or to its pharmaceutically acceptable salt. Also, it refers to a pharmaceutical composition for treating insulin-independent diabetes or obesity containing said compound.

EFFECT: there is produced and described a new compound which can be effective in treating insulin-independent diabetes and obesity.

5 cl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where the dotted line is either absent or denotes a double bond; R1 denotes H or C1-6-alkyl, possibly substituted with a CN group, or denotes a phenyl or sulphonyl phenyl, substituted with one or more B groups, or denotes -(CH2)m-Ra, where Ra denotes: NRiRii, C3-6-cycloalkyl, 6-member heterocycloalkyl, which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, aryl, which can be substituted with one or more B groups, or denotes -(CH2)n-(CO)-Rb or -(CH2)n-(SO2)-Rb, where Rb denotes: NRiRii, 5-6-member heterocycloalkyl, which denotes a univalent saturated group containing one or more heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms, aryl or 5- or 6-member heteroaryl, which denotes an aromatic ring containing two heteroatoms as ring members, the said heteroatoms selected from N or O, the rest are carbon atoms; which can possibly be substituted with one or more B groups, R2 denotes one or more H, halo, C1-6-alkyl, C1-6-alkoxy, R3 denotes H or-(CO)-Rc, where Rc denotes: C1-6-alkyl, 5-member heterocycloalkyl, which denotes a univalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms possibly substituted with C1-6-alkyl, or denotes C1-6-alkyl; R4 denotes H; R5 denotes H, C1-6-alkyl, -(CH2)m-NRiRii, -(CH2)n-(CO)-Rb, where Rb denotes NRiRii or a 6-member heterocycloalkyl which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, when the dotted line is absent or is absent when the dotted line denotes a double bond; R6 is absent, when the dotted line denotes a double bond; R7 denotes Cl or NReRf, where Re and Rf denotes H or C1-6-alkyl, or Re and Rf together with the nitrogen atom to which they are bonded form a 6-member heterocycloalkyl which denotes a univalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms; which can be substituted with C1-6-alkyl, or R6 and R7 together form a C=O group, when the dotted line is absent; B denotes halogen, C1-6-alkoxy, (CRiiiRiv)n-phenyl; Ri and Rii denote H, C1-6-alkyl -C(O)-C1-6-alkyl; Riii and Riv denote C1-6-alkyl; m equals to 1 or 2, n equals 0 or 1; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, as well as to use of compounds of formula (I), (I-a) or (1-b).

EFFECT: obtaining novel biologically active compounds having activity on V1a receptor.

12 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula: or to its pharmaceutically acceptable salt, where: Ar2 represents phenyl or pyridyl, each of which is substituted by 0-4 substituents, independently selected from R2; X and Z represent N; Y represents CRX; D represents N; F represents N, CH or carbon, substituted by substituent, representing R1 or R10; Rx in each case is independently selected from hydrogen, halogen, C1-C4alkyl, amino, cyano and mono- or di-(C1-C4alkyl)amino; R1 represents 0-3 substituents, independently selected from: (a) halogen, cyano and nitro; (b) groups of formula -Q-M-Ry; R10 represents one substituent, selected from: (a) groups of formula -Q-M-Ry; so that R10 is not hydroxy, amino or unsubstituted group, selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, C1-C6aloxy, C2-C6alkyl, ether, C2-C6alkanoyl, C3-C6alcanone, C1-C6halogenalkyl, C1-C6halogenoalkoxy, mono- or di-(C1-C6alkyl)amino, C1-C6alkylsulfonyl, mono- or di-(C1-C6alkyl)aminosulfonyl or mono- or di-(C1-C6alkyl)aminocarbonyl; each Q is independently selected from C0-C4alkylene; each M is independently absent or is selected from O, C(=O), OC(=O), C(=O)O, S(O)m, N(RZ), C(=O)N(Rz), C(=NH)N(Rz), N(Rz)C(=O), N(Rz)C(=NH), N(Rz)S(O)m, S(O)mN(Rz) and N[S(O)mRz]S(O)m, where m equals 2; and Rz in each case is independently selected from hydrogen, C1-C8alkyl and groups, which taken together with Ry, form possibly substituted (4-7)-member heterocycle; and each Ry independently represents hydrogen, C1-C8halogenalkyl, C1-C8alkyl, C2-C8alkenyl, (C3-C8carbocycle)C0-C4alkyl, ((4-7)-member heterocycle)C0-C4alkyl or taken together with Rz forms (4-7) member heterocycle, where each alkyl, carbocycle and heterocycle is substituted by 0-4 substituents, independently selected from hydroxy, halogen, amino, cyano, nitro, -COOH, aminocarbonyl, aminosulfonyl, C1-C6alkyl, C3-C7cecloalkyl, C2-C6alkyl ether, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C8alkoxy, C1-C8hydroxyalkyl, mono- and di-(C1-C6alkyl)aminocarbonyl, mono- and di-(C1-C6alkyl)aminosulfonyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkanoylamino and phenyl; so that Ry is not hydrogen, if Q represents C0alkyl and M is absent; each R2: (a) is independently selected from (1) hydroxyl, amino, cyano, halogen, -COOH, nitro and (2) C1-C6alkyl, (C3-C8cycloalkyl)C0-C4alkyl, C1-C6halogenalkyl; R3 is selected from: (1) hydrogen; (2) C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl; and (3) groups of formula: where L represents C0-C6alkylene; R5 and R6: (a) are independently selected from C1-C12alkyl, (C3-C8cycloalkyl)C0-C4alkyl; or (b) are combined with formation of (4-6)-member heterocycle, containing one or two heteroatoms independently selected from O and N; and where each of (2) and (3) is substituted by 0-4 substituents, independently selected from: C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl, each of which is substituted by 0-4 secondary substituents, independently selected from hydroxy, C1-C4alkyl and C1-C4alkoxy; and R4 represents 0-2 substituents, independently selected from C1-C3alkyl.

EFFECT: claimed are pharmaceutical compositions for modulation of capsaicin receptor activity and methods of applying said compounds for treatment of such disorders as pain, itch, cough, hiccup, urinary incontinence or obesity.

65 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a sodium salt N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide in form of a polymorph, characterised by peaks on an x-ray powder diffraction (XRD) pattern at approximately 22.38 and 23.38 degrees 2-theta. The invention also relates to methods of producing said polymorph and to a pharmaceutical composition based on said polymorph, having endothelin antagonist activity.

EFFECT: polymorphous form is more stable and can be used in medicine to treat pulmonary hypertension.

17 cl, 9 tbl, 31 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where R2 denotes H, [(C1-C6) alkylene]0-1-R'; R3 denotes H; R4 denotes H, halogen or (C1-C6) alkyl; R5 denotes H or halogen; R6 denotes H, (C1-C8) alkyl, R', (C1-C6) alkylene-R'; R7 and R8 independently denote H, halogen, (C1-C6) alkyl, O-(C1-C6) alkyl, R'; R9 denotes (C1-C6)alkyl; n equals 0 or 1; L denotes O or O-(C1-C6)alkylene; where R' denotes (C3-C8) cycloalkyl; (C5-C10)heterocyclyl, which denotes an aromatic or saturated mono- or bicyclic ring system which, besides a carbon atom, includes one or more heteroatoms such as nitrogen, oxygen and sulphur atoms; or (C6-C10) aryl; where in the heterocyclyl is unsubstituted or substituted with (C1-C6)alkyl, and the aryl is unsubstituted or substituted with a halogen, (C1-C4)alkyl, -O-(C1-C4)alkyl, SO2- (C1-C4) alkyl or N[(C1-C4) alkyl]2; and where in groups R4, R6 and R7 the alkyl can be halogenised in one or more positions; or pharmaceutically acceptable salts and/or stereo isomer forms thereof. The invention also relates to use of formula (I) compounds, as well as a medicinal agent.

EFFECT: obtaining novel biologically active compounds having Rho-kinase inhibiting activity.

21 cl, 320 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

Dna-pk inhibitors // 2408596

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I: and salts thereof, where R1 and R2 together with a nitrogen atom with which they are bonded can form a morpholine group; Q denotes -NH-C(=O)- or -O-; Y denotes a saturated aliphatic group C1-5alkylene group; X is selected from SR3 or NR4R5, where R3 denotes triazolyl; R4 and R5 are described in the claim.

EFFECT: compounds are DNA-PK inhibitors.

5 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

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