7-member cyclic compounds, synthesis methods thereof and pharmaceutical application thereof

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

where Ar represents (1) phenyl or naftalina group or (2) pyridyloxy group,
where (1) the phenyl group of the above Ar may be optionally substituted by 1-3 groups selected from the group consisting of (i) halogen atom, (ii) nitro, (iii) cyano, (iv) (C1-C6)-alkyl, which may be, optionally, semese is 1 to 3 halogen atoms, (viii) hydroxyl, (ix) (C1-C6)-alkoxy which may be optionally substituted by 1-3 groups selected from (C1-C6)-alkoxy, mono - or di-(C1-C6)-allylcarbamate, carboxyl and (C1-C6)-alkoxycarbonyl, (x) (C1-C5)-alkylenedioxy, (xii) amino, or (xxvi) (C1-C6)-alkoxycarbonyl;
W represents (1) hydrogen atom, (2) phenyl or naftalina group (3), pyridyloxy, tetrazolyl, thienyl, follow or isoxazolyl group, (5) (C1-C6)-alkyl or (6) pyrrolidinyl group which may be optionally substituted by 1-3 groups selected from oxo and phenyl,
where the phenyl group of the above W may be optionally substituted by 1-3 groups selected from the group consisting of (i) halogen atom, (ii) nitro, (iii) cyano, (iv) (C1-C6)-alkyl, which may be optionally substituted by a halogen atom, amino, (C1-C6)-alkoxycarbonyl and carboxyla, (viii) hydroxyl, (ix) (C1-C6)-alkoxy, (xii) amino, (xiv) di-(C1-C6)-alkylamino, (xvii) carboxyl, (xviii) (C1-C6)-alkoxycarbonyl, (xxi) mono-(C1-C6)-allylcarbamate, which may be optionally substituted by 1-3 groups selected from hydroxyl and (C1-C6)-alkoxy, (xxii) di-(C1-C6)-allylcarbamate that m which may be optionally substituted by hydroxyl, (xxiii) a 5-6-membered cyclic aminocarbonyl, which may be optionally substituted (C1-C6-alkoxycarbonyl, (xxiv) of phenylcarbamoyl, (xxv) of pyridylcarbinol, (xxvii) of pyridylmethylamine, (xxviii) N-(C1-C6)-alkyl-N-(C6)-arylcarbamoyl, (xxix) (C3-C6)-cycloalkylcarbonyl, (xxx) sulfo, (xxxi) (C1-C6)-alkylsulfonyl, (xxxii) (C1-C6)-alkylsulfonyl, (xxxv) (C1-C6)-alkoxycarbonyl, (xxxvi) (C1-C6)-alkylcarboxylic, (xxxvii) a mono - or di-(C1-C6)-alkylaminocarbonyl, (xxxix) pyrazolyl, (xliv) aminosulfonyl and (xlvi) of benzyloxycarbonyl;
Peregrina group specified above W may be optionally substituted by one group selected from the group consisting of (i) halogen atoms and (xvii) carboxyl,
thienyl group specified above W may be optionally substituted by 1-2 groups selected from the group consisting of (i) halogen atoms, (xii) amino, and (xvii) carboxyl;
furilla group specified above W may be optionally substituted by one group (xvii) carboxyl; and
isoxazolidine group specified above W may be optionally substituted by one group (viii) hydroxyl;
X denotes (2) linear or branched (C1-C6-alkylene or (5) -S(O)mwhere m is equal to 0;
Y represents (1) -S(O)n-, where n is equal to 2, (4-C(=O)NH -, or (5) -C(=O)NR 14-where R14means (C1-C6)-alkyl group;
Z represents (1) a bond, provided that when W is hydrogen, Z is not a bond, or (2) CR7R8where R7and R8are independently:
(A) a hydrogen atom;
(B) (C1-C6)-alkyl, which may be optionally substituted by 1 group selected from the group consisting of (i) carboxyl, (ii) (C1-C6)-alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl;
(C) phenyl;
(D) (C3-C6-cycloalkyl;
(E) -COOR9where R9denotes a hydrogen atom, or
(F) CONR10R11where R10and R11are independently:
(a) a hydrogen atom;
(b) (C1-C6)-alkyl, which may be optionally substituted by 1 group selected from the group consisting of (iii) carboxyl and (iv) (C1-C6)-alkoxycarbonyl;
(c) OR12where R12denotes a hydrogen atom or (C1-C6)-alkyl, or
(d) (1) phenyl group, or (2) pyridyloxy, tetrazolyl or pyrrolidino group which may be substituted by carboxyla;
where each of (1) phenyl group may be optionally substituted by 1-3 groups selected from the group consisting of (i) halogen atom, (iv) (C1-C6)-alkyl, (viii) hydroxyl, (ix) (C1-C6)-alkoxy, (xii) amino, (xvii) carboxyl and (xxvii) aminosulfonyl;
1represents (1) hydrogen atom, (2) halogen atom, or (3) (C1-C6)-alkyl, or R1together with X form a-CH=;
R2and R3are independently (1) hydrogen atom or (3) (C1-C6)-alkyl;
R5and R6are independently (1) hydrogen atom or (2) (C1-C6)-alkyl, which may be optionally substituted by a group selected from the group consisting of (i) carboxyl, (ii) (C1-C6)-alkoxy, (iii) (C1-C6)-alkoxycarbonyl and (iv) benzyloxycarbonyl;
R5and R6can form cyclopropyl, and
R4represents (1) hydrogen atom, (C1-C6-allylcarbamate or (3) (C1-C6)-alkyl, which may be optionally substituted by one group selected from the group consisting of (i) carbamoyl, (iii) mono-(C6)-arylcarbamoyl, (iv) N-pyridylcarbinol, (v) N-(C1-C6)-alkyl-N-(C6)-arylcarbamoyl, (vii) benzylcarbamoyl, (ix) carboxyl and (x) (C1-C6)-alkoxycarbonyl;
or its pharmaceutically acceptable salt or MES.

2. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where in formula (I) X is a linear (C1-C6-alkylen, R1represents (1) hydrogen atom, (2) halogen atom, or (3) (C1-C6)-alkyl, or R1together with X form a-CH=, and represents-SO 2- or-C(=O)NH-.

3. The compound or its pharmaceutically acceptable salt or MES according to claim 1 or 2, where in the formula (I) Ar represents a phenyl group.

4. The compound or its pharmaceutically acceptable salt or MES according to claim 3, where in the formula (I) phenyl group may be optionally substituted by 1-3 groups selected from the group consisting of (i) halogen atom, (ii) nitro, (iii) cyano, (iv) (C1-C6)-alkyl, which may be optionally substituted by 1 to 3 halogen atoms, (v) hydroxyl, and (vi) (C1-C6)-alkoxy, and R2, R3, R4, R5and R6all represent hydrogen atoms.

5. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where in formula (I), W represents (1) phenyl group.

6. The compound or its pharmaceutically acceptable salt or MES according to claim 5, where in the formula (I), Z represents (1) a bond or (2) CR7R8where R7and R8are independently:
(A) a hydrogen atom,
(B) (C1-C6)-alkyl, which may be optionally substituted by a group selected from the group consisting of (i) carboxyl, (iii) phenyl, and (iv) hydroxyl.

7. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where in formula (I), W represents a hydrogen atom.

8. The compound or its pharmaceutically acceptable salt or with ivat according to claim 7, where in the formula (I), Z represents CR7R8where R7and R8are independently:
(A) a hydrogen atom,
(B) (C1-C6)-alkyl, which may be optionally substituted by a group selected from the group consisting of (i) carboxyl, (ii) (C1-C6)-alkoxycarbonyl, (iii) phenyl, and (iv) hydroxyl,
(E) -COOR9where R9denotes a hydrogen atom, or
(F) -CONR10R11where R10and R11are independently:
(a) a hydrogen atom,
(b) (C1-C6)-alkyl, which may be optionally substituted by 1 group selected from the group consisting of (iii) carboxyl and (iv) (C1-C6)-alkoxycarbonyl;
(c) OR12where R12denotes a hydrogen atom or (C1-C6)-alkyl, or
(d) (1) phenyl group, where the above group (1) may be optionally substituted 2 groups selected from the group consisting of (i) halogen atom, (iv) (C1-C6)-alkyl, (viii) hydroxyl, (ix) (C1-C6)-alkoxy, (xii) amino, (xvii) carboxyl and (xxvii) aminosulfonyl.

9. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where the compound is 3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)was 3.7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid.

10. The compound or its pharmaceutically acceptable salt or MES on the .1, where the compound is 2-amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)was 3.7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid.

11. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where the compound is 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)was 3.7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid.

12. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where the compound is a 6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione.

13. The compound or its pharmaceutically acceptable salt or MES according to claim 1, where the compound is 4-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione.

14. MES representing MES compound according to claim 1 or its pharmaceutically acceptable salt with at least one solvent selected from the group consisting of 2-propanol and acetic acid.

15. Pharmaceutical composition having activity to inhibit himizu and containing a compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt or MES.

16. The pharmaceutical composition according to § 15 for the prevention or treatment of atopic dermatitis.

17. The use of compounds according to claim 1 or its pharmaceutically acceptable salt or MES obtained for the I pharmaceutical for the prevention or treatment of atopic dermatitis.

18. The use of compounds according to claim 1 or its pharmaceutically acceptable salt or MES to obtain pharmaceutical agents that have activity to inhibit himizu.

19. A method of obtaining a compound, or its salt, or their solvate according to claim 1, comprising the reaction of cyclization in the presence of a base compound of the formula (II)

where Ar, W, X, Y, Z, R1, R2, R3, R4, R5and R6have the meanings indicated in claim 1, Q1denotes a halogen atom, (C6-C10)-arylsulfonate, which may be optionally substituted by 1-3 halogen atoms, or (C1-C4)-alkylsulfonates, which may be optionally substituted by 1 to 3 halogen atoms.

20. The method of obtaining the compounds of formula (I)or its salt, or their solvate according to claim 1, where Y represents-C(=O)NH-, including the reaction mix in the presence of a base compound of the formula (III) or its salt

where Ar, X, R1, R2, R3, R5and R have the meanings indicated above in claim 1, and
R denotes a protective group selected from the group consisting of (1) allyl, (2) allyloxycarbonyl, (3) 9-fluorenylmethoxycarbonyl, (4) (C1-C6)-allyloxycarbonyl, which may be optionally substituted by 1 to 3 halogen atoms, (5) (C1-C6-alkylsulphonyl is, which may be optionally substituted by 1 to 3 halogen atoms, (6) (C7-C16)-aralkyl, which may be optionally substituted by 1-3 groups selected from (i) halogen atom, (ii) (C1-C6)-alkyl, (iii) (C1-C6)-alkoxy and (iv) nitro, (7) (C5-C16)-arylcarbamoyl, which may be optionally substituted by 1-3 groups selected from (i) halogen atom, (ii) (C1-C6)-alkyl, (iii) (C1-C6)-alkoxy and (iv) nitro, (8) (C7-C16)-orelkinoservisa, which may be optionally substituted by 1-3 groups selected from (i) halogen atom, (ii) (C1-C6)-alkyl, (iii) (C1-C6)-alkoxy and nitro, or (9) (C5-C16)-arylsulfonyl, which may be optionally substituted by 1-3 groups selected from (i) halogen atom, (ii) (C1-C6)-alkyl, (iii) (C1-C6)-alkoxyl and (iv) nitro, or R4where R4matter specified in claim 1, provided that R4is not a hydrogen atom,
compounds (IV), formula (IV) or its salt

where Q2and Q3denote independently nitro, (C6-C10)-alloctype, which may be optionally substituted by 1 to 3 halogen atoms or nitro, or halogen atom, and Y' denotes C(=O),
and the compounds of formula (V) or its salt

the de W and Z have the meanings listed according to claim 1,
and the reaction of removing the protective group from the product of the combination described above, if it has a protective group.

21. The compound of formula (Va)

or its salt, or MES,
where in this formula, W represents a group, such as W, the definitions for which are given according to claim 1, provided that W is not hydrogen, naftilos group, tetrazolyl group, thienyl group, shriley group and isoxazolyl group,
R18means (C2-C4)-alkyl group, and R19denotes a hydrogen atom or (C1-C6)-alkyl group.

22. The compound of formula (VIa)

or its salt, or MES,
where in this formula, R1, R2and R3have the meanings indicated in claim 1,
R has the values listed in item 21,
X' denotes a methylene, or X' with R1form a-CH=,
R' denotes a hydrogen atom,
R20represents (1) halogen atom, (2) nitro, (3) cyano, (4) (C1-C6)-alkyl, which may be optionally substituted by 1 to 3 halogen atoms, (5) hydroxyl, or (6) (C1-C6)-alkoxy which can be substituted by 1-3 groups selected from (C1-C6)-alkoxy, carboxyl and (C1-C6)-alkoxycarbonyl,
R21, R22, R23and R24imagine the fight independently (1) a halogen atom, (2) nitro, (3) cyano, (4) (C1-C6)-alkyl which can be substituted by 1-3 halogen atoms, (5) hydroxyl, or (6) (C1-C6)-alkoxy which may be optionally substituted by 1-3 groups selected from among (C1-C6)-alkoxy, carboxyl and (C1-C6)-alkoxycarbonyl, or a hydrogen atom, except for the following compounds:
(1) compounds where R20and R24represent chlorine atoms, and R21, R22and R23represent hydrogen atoms,
(2) compounds where R20, R22and R24represents a metal group, and R21and R23represent hydrogen atoms, and
(3) compounds, where R20represents a chlorine atom or a bromine atom, and R21, R22, R23and R24represent hydrogen atoms,
(4) compounds, where R20represents a fluorine atom, R22represents a bromine atom, and R21, R23and R24represent a hydrogen atom.

23. The compound or its salt of the General formula (III)

where Ar, X, R1, R2, R3, R5and R6have the values specified above for claim 1, and
R denotes a protective group selected from the group consisting of (6) (C7-C16)-aralkyl, which may be optionally substituted by 1-3 groups selected from (i) atom ha is ogena, (ii) (C1-C6)-alkyl, (iii) (C1-C6)-alkoxy, (iv) nitro, or R4where R4matter specified in claim 1, provided that R4is not a hydrogen atom.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the chemistry of N,N-disubstituted nicotinamide-(Z)-O-methyloximes with the general formula I where if X denotes a methylene group, then R denotes phenyl, benzyl or 2-furyl, R' denotes methyl or n-chlorophenyl, if X denotes a carbonyl group, then R denotes styryl, n-chlorostyryl or benzyl, R' denotes methyl that is characterized by the fungicidal activity.

EFFECT: new compounds that can be efficient against maleficent fungi.

1 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula I in which R1 is chosen from the group including: H; alkyl; alkylenearyl and pyridin; R2 is chosen from the group including: cycloalkyl; aryl; CO-NH-cycloalkyl; CO-NH-aryl either unsubstituted or substituted with the help of halogen, CF3; SO2-aryl either unsubstituted or substituted with the help of alkyl; or in which R1 and R2 together form a 5- or 6-membered ring that does not need to contain 1 additional nitrogen heteroatom and that may also be substituted with the help of aryl; and that may also contain a carbonyl group; and that may also be condensed with aryl; R3 and R4 denote H; and acid additions to their physiologically acceptable salts. Invention also refers to a pharmaceutical composition, to the way of production of the formula I compound, to application of the formula I compound, and to the way of treatment or prevention of fatty degeneration, type II diabetes, metabolic syndrome and associated and/or secondary diseases or pathologic conditions endured by mammals.

EFFECT: production of new bioactive compounds that inhibit the isoenzyme of hydroxy citric acid II (hCA II).

11 cl, 11 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

Up!