Quinazoline effective as ion channel modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula I:

or its pharmaceutically acceptable salt, in which:
R1and R2form together with the nitrogen atom substituted ring selected from:

or
where in the ring (A):
each of m1and n1independently equal to 0 to 3, provided that m1+n1well 3-4;
z1equal 0-4;
Sp1represents-O-, -S-, -NR'- or1-C4alkylidene linker, in which one methylene link is optionally and independently replaced by-O-, provided that Sp1connected to the carbonyl group through an atom other than carbon;
ring In1is a 5-6-membered saturated or aromatic, monocyclic heterocyclic ring,
containing 1-4 heteroatoms selected from O or N, with the ring In1optionally substituted w1independent options-R11and w1equal 0-1;
where in the ring (In):
G2represents CH;
each of m2and n2independently equal to 0 to 3, provided that m2+n2is 2-4;
p2equal 0-2;
q2equal to 0 or 1;
z2equal 0-4;
Sp2is a bond or C1-C6alkylidene linker, in which up to two methylene units optionally and independently replaced by-O-;
ring In2represents a 4-8 membered saturated, partially unsaturated or aromatic, monocyclic heterocyclic ring containing 1 heteroatom selected from O or N, where the ring In2optional Thames is but w 2independent options-R12where w2equal 0-2;
where in the ring (S) or ring (D):
G3represents-N-, -CH-NH - or-CH-CH2-NH-;
each of m3and n3independently equal to 0 to 3, provided that m3+n3is 2-4;
p3equal 0-2;
z3equal 0-4;
each RXXrepresents hydrogen, C1-6aliphatic group selected from alkyl or quinil, 3-8-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 1-2 heteroatoms independently selected from oxygen; where RXXoptionally substituted w3independent options-R13where w3equal to 0 to 3; provided that both RXXat the same time do not represent hydrogen;
RYYrepresents hydrogen, -CO2R' or-CON(R')2;
where in the ring (S):
each of m4and n4independently equal to 0 to 3, provided that m4+n4is 2-4;
p4equal 1-2;
z4equal 0-1;
ZYZrepresents a C1-C6aliphatic group selected from alkyl or cycloalkyl, optionally substituted w4independent options-R14where w 4equal 0-1;
each x and y independently equal to 0 to 4;
W represents a ORXY;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen;
each option R11, R12, R13and R14independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R independently represents hydrogen or C1-6aliphatic group containing up to three substituents, each R' independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

2. The compound according to claim 1, inwhich x is 1 and R 3is 6 - or 7-position chineselanguage rings.

3. The compound according to claim 2, in which R3selected from-Cl, -CH3, -CH2CH3, -F or-CN.

4. The compound according to claim 3, in which x is 1 and R3is 7-position chineselanguage ring and represents-CH3.

5. The compound according to claim 1, in which y is equal to 0.

6. The compound according to claim 1, in which y is equal to 1.

7. The connection according to claim 6, in which R5represents a halogen in the 6-position.

8. The compound according to claim 1, in which each of z1, z2, z3and z40.

9. The compound according to claim 1 in which the said compound has formula I-A:

where each of m1and n1independently equal to 0 to 3, provided that m1+n1well 3-4;
Sp1represents-O-, -S-, -NR1- or1-C4alkylidene linker, in which one methylene link is optionally and independently replaced by-O-, provided that Sp1connected to the carbonyl group through an atom other than carbon;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or-CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen;
each x and y independently equal to 0 to 4;
z1equal 0-4;
ring In1is a 5-6-membered saturated or aromatic, monocyclic heterocyclic ring containing 1-4 heteroatoms selected from O or N, with the ring In1optionally substituted w1independent options-R11and w1equal 0-1;
each option R11independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R' independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

10. The connection according to claim 9, in which Sp1represents-O-, -O-CH2-, -S - or-NH-, or-NH-CH2-.

11. The connection according to claim 9, in which each of m1and n1equal to 2.

12. The connection according to claim 9, in which1represents the t a 5-6-membered saturated monocyclic heterocyclic ring, containing 1-2 heteroatoms selected from O or N, with the ring In1optionally substituted w1independent options-R11and w1equal 0-1.

13. The connection section 12, in which the ring In1is tetrahydrofuranyl or tetrahydro[2H]pyranyl.

14. The connection according to claim 9, in which Sp1represents Oh or-O-CH2and n1and m1both equal to 2.

15. The connection according to claim 9, in which: each of n1and m1equal to 2;
RXYrepresents hydrogen;
y is 0 or 1, and R5represents fluorine;
x is equal to 1, and R3represents Me in the 7-position or fluorine at the 6-position;
z10;
Sp1represents-O-CH2-;
w1equal to 0; and
ring In1represents a tetrahydrofuran-3-yl, pyridin-3-yl, pyridine-4-yl or tetrahydro[2H]Piran-4-yl.

16. The compound according to claim 1 in which the said compound has formula I-B:

where G2represents CH;
each of m2and n2independently equal to 0 to 3, provided that m2+n2is 2-4;
p2equal 0-2;
q2equal to 0 or 1;
z2equal 0-4;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or-CN;
R4represents the FDS is th (C 1-C4)aliphatic group-HE;
R5is a halogen; each x and y independently equal to 0 to 4;
Sp2is a bond or C1-C6alkylidene linker, in which up to two methylene units optionally and independently replaced by-O-;
ring In2represents a 4-8 membered saturated, partially unsaturated or aromatic, monocyclic heterocyclic ring containing 1 heteroatom selected from O or N, where the ring In2optionally substituted w2independent options-R12where w2equal 0-2;
each option R12independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R independently represents hydrogen or C1-6aliphatic group containing up to three substituents, each R1independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated with the th or fully unsaturated bicyclic ring system, containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

17. The connection clause 16, in which R2equal to 1 or 2.

18. The connection clause 16, in which each m2and n2equal to 1 or 2.

19. Connection P16, where m2equal to 1, and n2equal to 2.

20. Connection P16, where n2equal to 1, and m2equal to 3.

21. The connection clause 16, in which Sp2represents-O - or-O-CH2-.

22. The connection clause 16, in which the ring In2is a 5-6-membered saturated monocyclic heterocyclic ring containing 1 heteroatom selected from O or N, with the ring In2optionally substituted w2independent options-R12and w2equal to 0-4.

23. Connection p.22, in which the ring In2is tetrahydrofuranyl or tetrahydro[2H]pyranyl.

24. Connection P16, which
Sp2represents a bond, O or-O-CH2-;
p2equal to 1;
R represents hydrogen; and
n2equal to 1, and m2equal to 2 or 3.

25. Connection article 16, in which the said compound has formula I-B-i or formula I-B-ii:
or
in which m2is 2 or 3;
Sp2represents-O - or-O-CH2 ;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or-CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen; each x and y independently equal to 0 to 4;
ring In2represents a 4-8 membered saturated, partially unsaturated or aromatic, monocyclic heterocyclic ring containing 1 heteroatom selected from O or N, where the ring In2optionally substituted w2independent options-R12where w2equal 0-2;
each option R12independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R' independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents, selected from halogen.

26. The compound of formula I-B-i A.25, in which:
p2equal to 1;
m2equal to 3;
Sp2represents-O-;
y is 0 or 1, and R5represents fluorine;
x is equal to 1, and R3is a 7-IU; and
ring In2is tetrahydrofuranyl.

27. The compound of formula I-B-i A.25, in which:
p2equal to 0 or 1;
m2equal to 2;
Sp2represents-O - or-O-CH2-;
y is equal to 0;
x is equal to 1, and R3is a 7-IU; and
ring In2is tetrahydrofuranyl,
tetrahydro[2H]pyranyl or pyridyl.

28. The compound of formula I-B-ii A.25, in which:
p20;
m2equal to 2;
Sp2that is the link;
y is 0 or 1, and R5represents fluorine;
x is equal to 1, and R3is a 7-IU or 6-F; and
ring In2represents pyridyl.

29. The compound according to claim 1, in which the indicated compound has formula I-C or formula I-D:
,
where G3represents-N-, -CH-NH - or-CH-CH2-NH-;
each of m3and n3independently equal to 0 to 3, provided that m3+n3is 2-4;
p3equal 0-2; z3equal 0-4;
each RXXrepresents hydrogen, C1-6aliphatic group selected from alkyl is or quinil, 3-8-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 1-2 heteroatoms independently selected from oxygen; where RXXoptionally substituted w3independent options-R13where w3equal to 0 to 3; provided that both RXXat the same time do not represent hydrogen;
RYYrepresents hydrogen, -CO2R' or-CON(R')2;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen;
each x and y independently equal to 0 to 4;
each option R13independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each RXindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R independently represents hydrogen or C1-6aliphatic group containing up to three substituents, each R' independently represents hydrogen or the C 1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

30. The connection clause 29, in which one of RXXrepresents hydrogen and the other RXXis not hydrogen.

31. The connection clause 29, in which one of RXXrepresents hydrogen and the other RXXrepresents a C1-C6alkyl, optionally substituted with halogen.

32. The connection clause 29, in which both RXXat the same time represent a1-C6alkyl.

33. Connection p or 32, in which the said alkyl selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl.

34. The connection clause 29, in which R30.

35. The connection clause 29, in which each m3and n3equal to 2.

36. The connection clause 29, in which R represents hydrogen.

37. The connection clause 29, in which the said compound has formula I-C-i or formula I-D-i:

where each of m3and n3independently equal to 0 to 3, provided that m3+n3is 2-4;
p3equal 0-2;
z3equal 0-4;
each RXXrepresents hydrogen, C1-6aliphatic group selected from alkyl or quinil, 3-8-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 1-2 heteroatoms independently selected from oxygen; where RXXoptionally substituted w3independent options-R13where w3equal to 0 to 3; provided that both RXXat the same time do not represent hydrogen;
RYYrepresents hydrogen, -CO2R' or-CON(R')2;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen; each x and y independently equal to 0 to 4;
each option R13independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxthe independent is IMO chosen from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R independently represents hydrogen or C1-6aliphatic group containing up to three substituents, each R' independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

38. The connection clause 37, in which RXXrepresents a C1-C6alkyl.

39. The connection clause 37, in which x is 1, and R3represents a C1-C4alkyl in the 7-position.

40. The connection clause 37, in which x is 1, and R3represents F, CN or CF3in the 6-position.

41. The connection clause 37, in which RXXrepresents methyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

42. Connection § 39, in which R3represents methyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

43. The connection clause 37, to which m is equal to 0.

44. The connection clause 37, which is equal to 1, and R5represents a 6-F.

45. The connection clause 29, in which the said compound has formula I-C-ii:

where RXXrepresents hydrogen, C1-6aliphatic group selected from alkyl or quinil, 3-8-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 1-2 heteroatoms independently selected from oxygen; where RXXoptionally substituted w3independent options-R13where w3equal 0-3;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or CN;
each option R13independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
R' independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatom is a, independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

46. Connection § 45, in which R3represents a methyl 7-position chineselanguage rings.

47. Connection § 45, in which RXXrepresents CH2(A)HE or CH2C(O)NH2.

48. The compound according to claim 1 in which the said compound has formula I-E:

where each of m4and n4independently equal to 0 to 3, provided that m4+n4is 2-4;
p4equal 1-2;
z4equal 0-1;
RYZrepresents a C1-With6aliphatic group selected from alkyl or cycloalkyl, optionally substituted w4independent options-R14where w4equal 0-1;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen; each x and y independently equal to 0 to 4;
each option R14independently represents a Q-Rx; where Q is Soboh the bond or C 1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, COR', -CO2R', -OCOR', -CON(R')2;
each option R independently represents hydrogen or C1-6aliphatic group containing up to three substituents, each R1independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

49. Connection p, in which R4equal to 1.

50. Connection p, in which each m4and n4equal to 2.

51. Connection p, where n4equal to 1, m4equal to 3, z40, R4equal to 1, y is 0 or 1, and x is equal to 1.

52. Connection p, where n4equal to 1, m4equal to 2, z40, R4equal to 1, y is 0 or 1, and x is equal to 1.

53. Connection p, where n4equal to 1, m4equal to 3, z40, R4equal to 1, y is 0 or 1, x rave is 1, and R and RXYboth represent hydrogen.

54. Connection p, where n4equal to 1, m4equal to 2, z40, R4equal to 1, y is 0 or 1, x is 1, and R and RXYboth represent hydrogen.

55. Connection p, in which RYZrepresents a C1-C4alkyl group, optionally substituted w4independent options-R14and w4equal 0-1.

56. Connection p, in which:
n4equal to 1, and m4equal to 3;
p4equal to 1; z40;
RYZrepresents a C1-C6alkyl;
y is 0 or 1, and R5represents 6-fluoro; and
x is equal to 1, and R3represents a C1-C4alkyl.

57. Connection p, in which:
n4equal to 1, and m4equal to 2;
p4equal to 1; z40;
RYZrepresents a C1-C6alkyl;
y is 0 or 1, and R5represents 6-fluoro; and
x is equal to 1, and R3represents a C1-C4alkyl.

58. Connection p, in which:
n4equal to 1, and m4equal to 3;
p4equal to 1;
z40;
RYZrepresents benzyl;
y is 0 or 1, and R5represents 6-fluoro; and
x is equal to 1, and R3represents a C1-C4alkyl.

59. The compound of the following formula I-F:

in which
R1and R2form together with the nitrogen atom substituted ring selected from:

or
where in the ring (A):
each m1and n1independently equal to 0 to 3, provided that m1+n1well 3-4;
z1equal 0-4;
Sp1represents-O-, -S-, -NR'- or1-C4alkylidene linker, in which one methylene link is optionally and independently replaced by-O-, provided that Sp1attached to a carbonyl group through an atom other than carbon;
ring In1is a 5-6-membered saturated or aromatic, monocyclic heterocyclic ring containing 1-4 heteroatoms selected from O or N, with the ring In1optionally substituted wxindependent options-R11and w1equal 0-1;
where in the ring (In):
G2represents CH;
each of m2and n2independently equal to 0 to 3, provided that m2+n2is 2-4;
p2equal 0-2;
q2equal to 0 or 1;
z2equal 0-4;
Sp2is a bond or C1-C6alkylidene linker, in which up to two methylene units optionally and independently replaced by-O-;
ring In2pre is is a 4-8-membered saturated, partially unsaturated or aromatic, monocyclic heterocyclic ring containing 1 heteroatom selected from O or N, with the ring In2optionally substituted w2independent options-R12and w2equal 0-2;
where in the ring (S) or ring (D):
G3represents-N-, -CH-NH - or-CH-CH2-NH-;
each of m3and n3independently equal to 0 to 3, provided that m3+n3is 2-4;
p3equal 0-2;
z3equal 0-4;
each RXXrepresents hydrogen, C1-6aliphatic group selected from alkyl or quinil, 3-8-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 1-2 heteroatoms independently selected from oxygen; and RXXoptionally substituted w3independent options-R13and w3equal 0-3;
provided that both RXXare not both hydrogen;
RYYrepresents hydrogen, -CO2R' or-CON(R')2;
where in the ring (S):
each of m4and n4independently equal to 0 to 3, provided that m4+n4is 2-4;
p4equal 1-2;
z4Rawa is 0-1;
RYZrepresents a C1-C6aliphatic group selected from alkyl or cycloalkyl, optionally substituted w4independent options-R14and w4equal 0-1;
each x and y independently equal to 0 to 4;
W represents a ORXY;
RXYrepresents hydrogen;
R3represents a C1-C6alkylidene chain, halogen, -CO2R', or CN;
R4is a (C1-C4)aliphatic group-HE;
R5is a halogen;
each option R11, R12, R13and R14independently represents a Q-Rx; where Q is a bond or C1-C6alkylidene chain; each Rxindependently selected from-R', halogen, =O, -OR', -N(R')2, -COR', -CO2R', -OCOR', -CON(R')2;
each option R independently represents hydrogen or C1-6aliphatic group containing up to three substituents; each R' independently represents hydrogen or C1-6aliphatic group selected from alkyl containing up to three substituents, 3-6-membered saturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen or oxygen, or an 8-12 membered saturated, partially unsaturated or fully nenas is placed bicyclic ring system, containing 2 heteroatoms independently selected from oxygen, where R' contains up to four substituents selected from halogen.

60. The compound according to claim 1, where the specified connection choose from



















61. Pharmaceutical composition having the properties of an inhibitor of sodium channel NaV 1.8, containing the compound of the formula I according to claim 1 or connection p in an effective amount.

62. The compound according to claim 1, where the connection specified is a

63. The compound according to claim 1, where the connection specified is a

64. The compound according to claim 1, where the connection specified is a

65. The compound according to claim 1, where the connection specified is a

66. Connection p, where connection is a

67. Pharmaceutical composition having the properties of an inhibitor of sodium channel NaV 1.8, containing the compound of formula I-F in p or connection p in an effective amount.



 

Same patents:

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 a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 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 diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 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: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

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 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: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 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 describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 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: chemistry.

SUBSTANCE: invention relates to a compound of formula I , isomer thereof of formula IA , mixture of isomers thereof IA/C , synthesis method thereof, as well as methods of producing compounds of formula IVA from compounds of formula IA, involving reduction and removal of protection from compounds of formula IA via hydrogenolysis using H2 and a catalytic amount of Pd/C, in the presence of trifluoroacetic acid to obtain a compound of formula VA; further reaction of this compound with Cbz-t-leu-OH, EDC and HOBt to obtain a compound of formula VIA; reaction of compound VIA with H2 and a catalytic amount of Pd/C in the presence of citric acid to obtain an amine and reaction of said amine and 4-amino-3-chlorobenzoic acid in the presence of CDMT and NMM to obtain a compound of formula IVA.

EFFECT: fewer synthesis steps and high output while using dynamic crystallisation.

13 cl, 5 ex

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

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