New hetero-aromatic inhibitors of fructose-1,6-bisphosphotase, pharmaceutical compositions containing them and method of inhibiting fructose-1,6-bisphosphotase

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

 

The text descriptions are given in facsimile form.

1. Heteroaromatic compounds with phosphonate group of the formula (I)

where R5choose from a group including:

and

where each G is independently selected from the group comprising C, N, O, S and Se, and where only one G may be O, S or Se, and not more than one G represents N;

each G' is independently selected from the group including C and N, and where no more than two G' denote N;

And are selected from the group including H, HE, -NR42, -CONR42, -CO2R3, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, phenyl, piperidyl, pyridyl, thienyl, (C1-C6)NH-, N-amino-N-methylamino-, N-tertbutoxycarbonyl, substituted, -CH2HE, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR3, -SR3, -N3, -NHC(S)NR42, -NHAc, and null;

each b and D are independently selected from the group comprising-H, -HE, (C1-C6)alkyl, optionally substituted by-OH, -CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, teinila, halogen, di-(C1-C6)alkylamino, cyclohexyl, morpholinyl; N,N-dimethylcarbamoyl, (C1-C6)alkoxycarbonyl, benzyloxycarbonyl, cyclopropanecarbonyl, (C2-C6)alkenyl; and (C2-C6)quinil, optionally substituted cyclohexylmethyl, CN; phenyl; and (C3-C6)t is cloacal; pyridyl; morpholinyl, thienyl; furanyl; benzyl, -C(O)R11, -C(O)OR3, -C(O)SR3, -S(O)R3, -CN, -NR92, -SR3, (C1-C6)perhalocarbon, a halogen and zero;

E is chosen from the group comprising-H, -HE, (C1-C6)alkyl, (C3-C6)cycloalkyl, -C(O)OR3, -CN, -NR92, -NO2, -SR3, (C1-C6)perhalocarbon, a halogen and zero;

J denotes zero;

X denotes furandi, peridinin -(C1-C6)alkyl-, -(C2-C6)quinil-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy (C1-C6)alkyl-, -(C1-C6)alkylthio-, -carbylamine(C1-C6)alkyl, (C1-C6)alkyl-carbylamine, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-, -(C1-C6)alkylthiomethyl-, -aminocarbonyl-(C1-C6)alkyl-, optionally substituted with halogen;

Y is independently selected from the group comprising-O - and-NR6-;

when Y represents-O-, then R1associated with-O-is independently selected from the group comprising: H, phenyl, which is optionally substituted with halogen, (C1-C6)alkoxy; benzyl, substituted (C1-C6)alkyl, (C1-C6)alkoxy, lower acyloxy; -C(R2)2-OC(O)R3-C(R2 )2-O-C(O)OR3, -C(R2)2-OC(O)SR3-(C1-C6)alkyl-S-C(O)R3; or (C1-C6)alkyl, which is optionally substituted by-C(R2)2-OC(O)R3;

when Y represents-NR6-, R1associated with-NR6is independently selected from the group comprising-H, -[C(R2)2]q-COOR3, -C(R4)2COOR3

or when each Y is independently selected from-O - and-NR6-, R1and R1together represent

where V, W and W' are independently chosen from the group comprising-H; phenyl, optionally substituted with halogen, CF3, (C1-C6)alkyl; benzyl, naphthyl, (C1-C6)alkoxyphenyl; pyridyl, etoxycarbonyl; or

together V and W are connected via an additional 3 carbon atom, form a cyclic group containing 6 carbon atoms and substituted by hydroxy, connected to one of said additional carbon atoms, which is the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2OH, -CHR2OC(O)R3, -CHR2OCO2R3, -CHR2N3, 'N;

q denotes an integer of 1 or 2;

provided that

a) V, Z, W, W' are not all represent H; and

b) when Z represents N, then at least one of V, W and W cannot specify-N, benzyl, pyridyl;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl and benzyl;

R4chosen independently from the group comprising-H, (C1-C2)alkyl, or together R4and R4form a cyclic alkyl group containing 3 atoms;

R6selected from the group comprising-H, lower alkyl or morpholinyl;

each of R9independently selected from the group including

-N and (C1-C6)alkyl;

R11selected from the group comprising (C1-C6)alkyl; -NR22; -OR2; phenyl, optionally substituted by fluorine, chlorine, stands, methoxy, or trifluoromethyl; naphthalenyl; thienyl or pyridinyl; and provided that

1) when G' denotes N, then the respective a, b, D or E denote null;

2) at least one of a and b, or a, b, D, and E cannot be selected from the group comprising-H or null;

3) when R5refers to six-membered cycle, then X cannot denote 2-atomic link, optionally substituted (C1-C6)alkyl or (C1-C6)alkylthio;

4) when G represents N, then the respective a or b cannot denote halogen or a group directly related to G via a heteroatom;

p num="43"> 5) R1does not denote unsubstituted (C1-C6)alkyl;

and its pharmaceutically acceptable salts.

2. Compounds according to claim 1, where R5selected from the group including

imidazolyl, oxazolyl, thiazolyl, isothiazolin, pyrazolyl, isoxazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, all of which contain at least one Deputy.

3. Compounds according to claim 1, where a is chosen from the group comprising-H, -NR42, -CONR42, -CO2R3, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, phenyl, -CH2HE, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -SR3, -N3, -NHC(S)NR42, -NHAc, and null;

each of b, D and E have the meanings indicated in claim 1, and each of R4represents-N.

4. Compounds according to claim 1, where R5means

5. The compound according to claim 4, where R5is

where A" denotes-H, -NR42, -CONR42, -CO2R3, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, phenyl, -CH2OH, -CH2NR4  2, -CH2CN, -CN, -C(S)NH2, -OR3, -SR3, -N3, -NHC(S)NR42and-NHAc;

In" refers to-N; N,N-dimethylcarbamoyl; and (C1-C6)alkoxycarbonyl; benzyloxycarbonyl; cyclopropylmethoxy-carbonyl; and (C2-C6)alkenyl; phenyl; and (C3-C6)cycloalkyl; pyridyl; morpholinyl; thienyl; furanyl; benzyl; -C(O)R11; -C(O)OR3C(O)SR3; -S(O)R3; -CN; -NR92; -SR3; halogen; (C1-C6)alkyl, optionally substituted-HE, CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, teinila, halogen, di-(C1-C6)alkylamino, cyclohexyl or morpholinyl; or (C2-C6)quinil, optionally substituted cyclohexylmethyl or CN.

6. The compound according to claim 5, where A" denotes-NH2, -Cl, -Br, or-CH3; "Denotes-H, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, optionally substituted-HE, CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, teinila, halogen, di-(C1-C6)alkylamino, cyclohexyl or morpholinyl; C(O)R11or halogen.

7. The connection according to claim 6, where A" denotes-NH2; In" means1-C6alkyl or C(O)R11where R11means (C1-C6)alkyl.

8. The compound according to claim 5, where X represents furan-2,5-diyl.

9. The compound according to claim 1, the de X represents furan-2,5-diyl.

10. The compound according to claim 1, where, when both Y groups represent-O-, then R1independently selected from the group comprising: H, phenyl, which is optionally substituted with halogen, (C1-C6)alkoxy; benzyl, substituted (C1-C6)alkyl, (C1-C6)alkoxy, lower acyloxy; -C(R2)2-OC(O)R3C(R2)2-O-C(O)OR3, -C(R2)2-OC(O)SR3-(C1-C6)alkyl-S-C(O)R3; or (C1-C6)alkyl, which is optionally substituted by-C(R2)2-OC(O)R3.

11. The connection of claim 10, wherein both Y groups represent-O -, and R1denotes N.

12. The compound according to claim 1, where, when Y represents NR6, R6selected from H or lower alkyl; and R1independently selected from the group comprising-H, -[C(R2)2]q-COOR3, -C(R4)2COOR3where R4independently represents (C1-C2)alkyl or H, or two R4together form a cyclic alkyl group containing 3 atoms, and R3means (C1-C6)alkyl, phenyl or benzyl.

13. The connection section 12, where Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

14. The compound according to claim 5, where A" denotes-NH2; In" refers to the 1-C6alkyl or C(O)R11where R11means (C1-C6)alkyl; and X represents furan-2,5-diyl.

15. The compound according to claim 5, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; and YR1IT refers.

16. The compound according to claim 5, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

17. The connection of claim 8, where X represents furan-2,5-diyl and YR1IT refers.

18. The connection of claim 8, where X represents furan-2,5-diyl; Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

19. The compound according to claim 5, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; X represents furan-2,5-diyl; and YR1IT refers.

20. The compound according to claim 5, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11putting the AET (C 1-C6)alkyl; X represents furan-2,5-diyl; Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

21. Compounds according to claim 1, where R5means

22. Compounds according to claim 1, where R5selected from the group including

,

and

;

where A" is chosen from the group comprising-H, -NR42, -CONR42, -CO2R3, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, halogen, phenyl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR3, -SR3, -N3, -NHC(S)NR42and-NHAc;

" And D" are independently selected from the group comprising-H, (C1-C6)alkyl, optionally substituted by-OH, -CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, halogen, dimethylamino, morpholino, tanila; and (C2-C6)alkenyl; and (C2-C6)quinil, optional samisen the th CN, cyclohexylmethyl; phenyl; and (C3-C6)cycloalkyl; -C(O)R11, -C(O)OR3, -C(O)SR3, -S(O)R3, -CN, -NR92, -OR3, -SR3, a halogen and zero, pyridyl; thienyl; furanyl; benzyl;

E is chosen from the group comprising-H, (C1-C6)alkyl, (C3-C6)cycloalkyl, -CN, -NR92, -SR3, (C1-C6)perhalocarbon, halogen and zero, and

each of R4means-N.

23. Connection p.22, where R5selected from the group including

,,

and

24. Connection p.22, where R5selected from the group including

,and

25. Connection p.22, where R5selected from the group including

,and

26. Compounds according to claim 1, where X is chosen from the group comprising -(C2-C6)quinil-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted, halogeno is, by phenyl; -(C1-C6)alkoxycarbonyl-.

27. Compounds according to claim 4, where X is chosen from the group comprising -(C2-C6)quinil-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-.

28. Compounds according to item 21, where X is chosen from the group comprising -(C1-C6)alkyl-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-.

29. Compounds according to claim 3, where X is chosen from the group comprising furandi, peridinin -(C1-C6)alkylcarboxylic-, -(C1-C6)alkoxycarbonyl - and -(C1-C6)alkoxy(C1-C6)alkyl-.

30. Join on clause 29, where X is chosen from the group including

furandi, peridinin and -(C1-C6)alkoxycarbonyl-.

31. Compounds according to claim 3, where the specified connection refers to the connection of the formula II or IV

or

32. Connection p.22, where X is chosen from the group comprising-C 1-C6)alkyl-, -(C2-C6)quinil-, purandar, peridinin, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-.

33. Connection p, where X is chosen from the group comprising: purandar, peridinin -(C1-C6)alkylcarboxylic-, -(C1-C6)alkoxycarbonyl - and -(C1-C6)alkoxy(C1-C6)alkyl-.

34. Connection p, where the specified connection refers to the connection of the formula II

35. Connection p, where A" is chosen from the group comprising-NH2, -CONH2, -CH3, -CF3, halogen, -CH2-halogen, -CN, -och3, -SCH3and Mr..

36. Connection p, where A" is chosen from the group comprising-Cl, -NH2and CH3.

37. Connection p, where one is" chosen from the group comprising-H, -C(O)R11, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, phenyl, halogen, -CN, -SR3and-NR92.

38. Join on clause 37, where each" chosen from the group comprising-H, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, halogen, pyridinyl, thienyl, furanyl and-SR3.

39. Connection p, where D" Vybir the Ute from the group comprising-H, -C(O)R11, -C(O)SR3, (C1-C6)alkyl, phenyl, halogen, -NR92and-SR3.

40. Connections 39, where D" is chosen from the group comprising-H, (C1-C6)alkyl and halogen.

41. Connection p, where E is chosen from the group comprising-H, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen, -CN, and-SR3.

42. Compounds according to paragraph 41, where E is chosen from the group comprising-H, -Br and-Cl.

43. Compounds according to claim 1, wherein both of the group Y denotes-O-.

44. Compounds according to claim 4, wherein both of the group Y denotes-O-.

45. Compounds according to item 21, wherein both of the group Y denotes-O-.

46. Compounds according to claim 1, where one Y represents-NR6-and the other Y represents-O-.

47. Compounds according to claim 4, where one Y represents-NR6-and the other Y represents-O-.

48. Compounds according to item 21, where one Y represents-NR6-and the other Y represents-O-.

49. Compounds according to claim 1, where, when Y represents-O-, then R1associated with-O-is independently selected from the group comprising-H, optionally substituted with halogen phenyl, -C(R2)2-O-C(O)OR3, -C(R2)2OC(O)SR3-(C1-C6)alkyl-S-C(O)R3;

when Y represents-NR6-, R1associated with-NR6is independently selected from the group comprising: -H, -[C(R2)2]q-COOR3, -C(R4)2COOR3;

or codecity of Y is independently selected from-O - and-NR 6something along R1and R1mean

where V, W and W' are independently chosen from the group comprising-H, phenyl substituted with halogen, CF3, (C1-C6)alkyl, (C1-C6)alkoxyphenyl; benzyl, naphthyl, pyridyl; or

together V and W are connected via an additional 3 carbon atoms, form an optionally substituted cyclic group containing 6 carbon atoms and substituted by hydroxy, connected to one of said additional carbon atoms, which is the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2HE, -CHR2OC(O)R3, -CHR2OCO2R3;

q denotes an integer of 1 or 2;

provided that

a) V, Z, W, W' are not all represent H;

b) when Z represents N, then at least one of V, W and W' cannot denote-H, benzyl, pyridyl;

c) both groups Y can't identify-NR6-;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl and benzyl;

R6selected from the group comprising-H and lower alkyl.

50. Connections 49, where, when both groups Y denotes-O-, R1independently selected from the group including optional someseni the halogen phenyl, -C(R2)2OC(O)OR3and-H; and

when Y represents-NR6-, R1associated with the specified group-NR6-choose from a group comprising-C(R4)2COOR3and-C(R2)2COOR3; and when the other group, Y represents-O-, then R1associated with the specified-O-is independently selected from the group: optionally substituted with halogen phenyl, -C(R2)2-OC(O)R3, -C(R2)2-O-C(O)OR3.

51. Compounds according to item 50, wherein both of the group Y denotes-O -, and R1denotes N.

52. Connection p, where both groups Y denotes-O -, and R1denotes phenyl.

53. Connection p, where both groups Y denotes-O -, and at least one R1denotes-C(R2)2-O-C(O)OR3.

54. Connection p, where both groups Y denotes-O -, and at least one R1denotes -(C1-C6)alkyl-S-C(O)R3.

55. Connection p, where at least one Y denotes-O - and together R1and R1form

where V, W and W' are independently chosen from the group comprising-H; phenyl substituted with halogen, CF3, (C1-C6)alkyl; benzyl, naphthyl, (C1-C6)alkoxyphenyl; pyridyl, etoxycarbonyl; or

together V and W are connected via an additional 3 carbon atoms, form a neo is Astelin substituted cyclic group, containing 6 carbon atoms and substituted by hydroxy, United with one of these carbon atoms being the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2HE, -CHR2OC(O)R3, -CHR2OCO2R3;

provided that

a) V, Z, W, W' are not all represent H;

b) when Z represents N, then at least one of V, W and W' cannot denote-H, benzyl, pyridyl, and

c) both groups Y should not be-NR6-;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl and benzyl;

R6selected from the group comprising-H and lower alkyl.

56. Compounds according to item 50, where one Y represents-O -, and R1denotes optionally substituted with halogen phenyl; and the other Y represents-NR6-where R1associated with the specified group-NR6-choose from a group comprising-C(R4)2COOR3and-C(R2)2C(O)OR3.

57. Connection p, where R1associated with-O-, selected from the group comprising phenyl, substituted by 1-2 substituents which are selected from the group comprising-F, -Cl, -Br; and where R1associated with-NR6-denotes-C(R2)2COOR3; each R2independently selected from the group comprising SN3,-CH 2CH3and N.

58. Connections 57, where the substituents specified substituted phenyl chosen from the group comprising-Cl and-Br.

59. Connection p.22, where R5selected from the group including

,

and

;

where A" is chosen from the group comprising-NH2, -CONH2, -CH3, -CF3, -CH2-halogen, -CN, -och3, -SCH3and-N;

In" chosen from the group comprising: H, -C(O)R11, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, phenyl, halogen, -CN, -SR3and-NR92;

D is chosen from the group comprising: H, -C(O)R11, -C(O)SR3, -NR92, (C1-C6)alkyl, phenyl, halogen, and-SR3;

E is chosen from the group comprising: H, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen, -CN, and-SR3;

X is chosen from the group comprising: (C2-C6)quinil-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl, -(C1-C6)alkoxycarbonyl-;

when both g is uppy Y denotes-O-, R1is-H; or

when one Y represents-O-, R1associated with-O-, denotes optionally substituted with halogen phenyl; and when Y represents-NR6-, R1associated with-NR6-choose from a group comprising-C(R4)2COOR3and-C(R2)2C(O)OR3; or

when Y represents-O - or-NR6-, R1and R1together represent

where V, W and W' are independently chosen from the group comprising-H, phenyl substituted with halogen, CF3, (C1-C6)alkyl; benzyl, naphthyl; pyridyl; or

together V and W are connected via an additional 3 carbon atom, form a cyclic group containing 6 carbon atoms and substituted by one hydroxysultaine connected with one of these carbon atoms being the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2HE, -CHR2OC(O)R3, -CHR2OCO2R3;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl, benzyl;

R6selected from the group comprising H and (C1-C6)alkyl.

60. Connection p.22, where R5means

X is chosen from the group comprising furan-2,5-diyl; at least one group Y represents-O-; and their pharmaceutically acceptable salts.

61. Connection p, in which Y denotes-O-, R1associated with-O-, can be independently selected from the group comprising-H, optionally substituted with halogen phenyl, -CH2OC(O)Et, and-CH2OC(O)-iPr;

when Y represents-NR6-, R1associated with-NR6-may be independently selected from the group comprising: -C(R2)2COOR3, -C(R4)2COOR3or

when Y represents-O - or-NR6-and at least one Y represents-O-, then together R1and R1mean

where V is chosen from the group comprising optionally substituted with halogen phenyl and pyridyl; and Z, W' and W denote H; and

R6selected from the group comprising-H and lower alkyl.

62. Connection p where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-CH2CO2Et.

63. Connection p where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-C(Me)2CO2Et.

64. Connection p, where A" denotes-NH , X is furan-2,5-diyl and" denotes-CH2-CH(CH3)2.

65. Connection p where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-CH2CO2Et.

66. Connection p where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-C(Me)2CO2Et.

67. Connection p, where A" denotes-NH2X represents furan-2,5-diyl and" means-COOEt.

68. Connection p, where both Y denotes-O-, and R1means-N.

69. Connection p, where both Y denotes-O-, a R1denotes-CH2OC(O)OEt.

70. Connection p, where A" denotes-NH2X represents furan-2,5-diyl and" means-SMe.

71. Compounds according to item 70, where both Y denotes-O-, and R1means-N.

72. Compounds according to item 70, where both Y denotes-O-, a R' denotes-CH2OC(O)OEt.

73. Connection p, where A" denotes-NH2X denotes melanoxylon and" means-CH(CH3)2.

74. Connection p, where both Y denotes-O-, and R1means-N.

75. Connection p, where both Y denotes-O-, a R1denotes-CH2OS(O)OEt.

76. Connection p, where both groups Y denotes-O -, and R1putting the AET-N.

77. Connection p, where both groups Y denotes-O -, and R1denotes-CH2OC(O)OEt.

78. Connection p, where both groups Y denotes-O-, a R1and R1together represent

,

and V denotes phenyl, substituted with 1-3 Halogens.

79. Connection p, where V is chosen from the group comprising 3,5-dichlorophenyl, 3-bromo-4-forfinal, 3-chlorophenyl and 3-bromophenyl.

80. Connection p.22, where R5means

X represents furan-2,5-diyl and methylenecycloartanol, and A" represents-NH2and at least one group Y represents-O-; and their pharmaceutically acceptable salts.

81. Compounds according to item 80, where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-CH2CO2Et.

82. Connection p.22, where R5means

And" means-NH2, E" and D" represent-H, b" denotes n-propyl and cyclopropyl, X represents furan-2,5-diyl; at least one group Y represents-O-; and their pharmaceutically acceptable salts.

83. Connection p.22, where R5means

And" means-NH2D" denotes-H, b" denotes n-propyl, X denoted by the AET furan-2,5-diyl; at least one group Y represents-O-; and their pharmaceutically acceptable salts.

84. Heteroaromatic compounds with phosphonate group of the formula (X):

where G represents-S-;

A2L2E2and J2selected from the group including-NR42, -H, -OR2, halogen, -COR11, phenyl, (C1-C5)alkyl, cyclopropyl, -SCN, CH2HE, or together E2and J2form anilinophenol cyclic group containing 4 carbon atoms;

X2denotes-O-(C1-C6)alkylene-; -(C1-C6)alkylen; -S-;

Y represents-O-;

R' represents H;

or together R1and R1mean

where W, W' and Z are N;

V is phenyl, substituted with halogen;

R2means R3;

R3means (C1-C6)alkyl;

R4denotes-N;

R11means-OR2;

and their pharmaceutically acceptable salts.

85. Connection p, where a2L2E2and J2independently selected from the group comprising-H, -NR42, -S-C≡N, halogen, -OR2and (C1-C5)alkyl.

86. Connection p,where a 2L2E2and J2independently selected from the group comprising-H, -NR42, -S-C≡N halogen.

87. Connection p, where a2denotes-NH2, -H, halogen.

88. Connection p, where L2and E2independently selected from the group comprising: -N, -S-C≡N, lower alkoxy, C1-C5alkyl and halogen.

89. Connection p, where J2selected from the group comprising: -H and C1-C5alkyl.

90. Connection p, where X2means (C1-C6)alkylen-O-.

91. Connection p, where X2means (C1-C3)alkylen-O-.

92. Connection p, where X2indicates metalinox-.

93. Connection p, where both groups Y denotes-O-.

94. Connection p, where Y represents-O-.

95. Connection p, where

R1denotes-N;

or together R1and R1mean

where W, W' Z are N;

V is phenyl, substituted with halogen;

R2means R3;

R3means (C1-C6)alkyl.

96. Connection p, where the substituents specified substituted phenyl chosen from the group comprising-Cl and-Br.

97. Connection p, where a is chosen from the group comprising-NH2, -N, and Br;

L2the seat is t-N, lower alkyl, halogen, lower alkyloxy;

E2selected from the group including H, halogen, SCN, or together with the J2forms anilinophenol cyclic group containing 4 carbon atoms; or

J2selected from the group including H, halogen, and (C1-C5)alkyl;

X2represents-och2-.

98. Connection p, where a2denotes NH2L2means-Et, E2means-SCN and J2means-N.

99. Connection p, where V is 3,5-dichlorophenyl.

100. Pharmaceutical composition having the properties of an inhibitor Fbpase, including pharmaceutically acceptable amount of the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt.

101. Pharmaceutical composition having the properties of an inhibitor Fbpase, including pharmaceutically acceptable amount of the compounds of formula (X) p or its pharmaceutically acceptable salt.

102. Method of inhibiting Fbpase, including the introduction of a composition containing a carrier and an inhibitor Fbpase according to claim 1 to a subject in an amount sufficient for inhibition Fbpase.

103. The method according to 102, where R5selected from the group comprising: imidazolyl, oxazolyl, thiazolyl, isothiazolin, pyrazolyl, isoxazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, and sectariat, at least one Deputy.

104. The method according to 102, where a is chosen from the group comprising-H, -NR42, -CONR42, -CO2R3, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, phenyl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -SR3, -N3, -NHC(S)NR42, -NHAc, and null;

each of b, D and E have the meanings indicated in claim 1, and

each of R4represents-N.

105. The method according to 102, where R5means

106. The method according to p where the specified R5means

where A" denotes-H, -NR42, -CONR42, -CO2R3, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, phenyl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR3, -SR3, -N3, -NHC(S)NR42and-NHAc;

In" refers to-N; N,N-dimethylcarbamoyl; and (C1-C6)alkoxycarbonyl; benzyloxycarbonyl; cyclopropanecarbonyl; and (C2-C6)alkenyl; phenyl; and (C3-C6)cycloalkyl; pyridyl; morpholinyl; thienyl;furanyl; benzyl; -C(O)R11; -C(O)OR3, -C(O)SR3; -S(O)R3; -CN; -NR92; -SR3; halogen; (C1-C6)alkyl, optionally substituted-HE, CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, teinila, halogen, di-(C1-C6)alkylamino, cyclohexyl or morpholinyl; or (C2-C6)quinil, optionally substituted cyclohexylmethyl or CN.

107. The method according to p, where A" denotes-NH2, -Cl, -Br, or-CH3; "Denotes-H, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, optionally substituted-HE, CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, teinila, halogen, di-(C1-C6)alkylamino, cyclohexyl or morpholinyl; C(O)R11or halogen.

108. The method according to p, where A" denotes-NH2; In" means1-C6alkyl or C(O)R11where R11means (C1-C6)alkyl.

109. The method according to p, where X represents furan-2,5-diyl.

110. The method according to 102, where X represents furan-2,5-diyl.

111. The method according to 102, where, when both Y groups represent-O-, then R1independently selected from the group comprising H, phenyl, which is optionally substituted with halogen, (C1-C6)alkoxy; benzyl, optionally substituted (C1-C6)alkyl, (C1-C6)alkoxy, lower acyloxy; -C(R2)2 -OC(O)R3C(R2)2-O-C(O)OR3, -C(R2)2-OC(O)SR3-(C1-C6)alkyl-S-C(O)R3; or (C1-C6)alkyl, which is optionally substituted by-C(R2)2-O-C(O)R3.

112. The method according to 111, where both Y groups represent-O -, and R1denotes N.

113. The method according to 102, where Y represents NR6, R6selected from H or lower alkyl; and R1independently selected from the group comprising-H, -[C(R2)2]q-COOR3, -C(R4)2COOR3where R4independently represents (C1-C2)alkyl or H, or two R4together form a cyclic alkyl group containing 3 atoms, and R3means (C1-C6)alkyl, phenyl or benzyl.

114. The method according to p, where Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

115. The method according to p, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; and X represents furan-2,5-diyl.

116. The method according to p, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; and YR1IT refers.

117. The method according to p, g the e a" denotes-NH 2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

118. The method according to p, where X represents furan-2,5-diyl and YR1IT refers.

119. The method according to p, where X represents furan-2,5-diyl; Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

120. The method according to p, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; X represents furan-2,5-diyl; and YR1IT refers.

121. The method according to p, where A" denotes-NH2; In" means (a1-C6)alkyl or C(O)R11where R11means (C1-C6)alkyl; X represents furan-2,5-diyl; Y represents NR6and R6denotes H; and R1denotes-C(R4)2COOR3where R4independently denotes H or methyl; and R3means (C1-C6)alkyl.

122. The method according to 102, where R5means

123. The method according to 102 where R 5selected from the group including

,

and

;

where A" is chosen from the group comprising-H, -NR42, -CONR42, -CO2R3, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)perhalocarbon, (C1-C6)haloalkyl, phenyl, -CH2HE, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR3, -SR3, -N3, -NHC(S)NR42and-NHAc;

" And D" are independently selected from the group comprising-H, (C1-C6)alkyl, optionally substituted by-OH, -CN, oxo-(C1-C6)alkyl, (C1-C6)alkoxy, halogen, dimethylamino, morpholino, tanila; and (C2-C6)alkenyl; and (C2-C6)quinil, optionally substituted by CN, cyclohexylmethyl; phenyl; and (C3-C6)cycloalkyl; -C(O)R11, -C(O)OR3, -C(O)SR3, -S(O)R3, -CN, -NR92, -OR3, -SR3, a halogen and zero; pyridyl; thienyl; furanyl; benzyl;

E is chosen from the group comprising-H, (C1-C6)alkyl, (C3-C6)pilooski, -CN, -NR92, -SR3, (C1-C6 )perhalocarbon, halogen and zero, and

each of R4means-N.

124. The method according to p, where R5selected from the group including

and

;

125. The method according to p, where R5selected from the group including

and

126. The method according to p, where R5selected from the group including

and

127. The method according to 102, where X is chosen from the group comprising -(C2-C6)quinil-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-.

128. The method according to p, where X is chosen from the group comprising -(C2-C6)quinil-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alcox the carbonyl-.

129. The method according to p, where X is chosen from the group comprising -(C1-C6)alkyl-, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylthio-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-.

130. The method according to p, where X is chosen from the group comprising furandi, peridinin -(C1-C6)alkylcarboxylic-, -(C1-C6)alkoxycarbonyl - and -(C1-C6)alkoxy(C1-C6)alkyl-.

131. The method according to p, where X is chosen from the group comprising: purandar, peridinin and -(C1-C6)alkoxycarbonyl-.

132. The method according to p, where the specified connection refers to the connection of the formula II or IV

or

133. The method according to p, where X is chosen from the group comprising -(C1-C6)alkyl-, -(C2-C6)quinil-, purandar, peridinin, -1,1-diploid(C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylthio-, (C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-.

134. The method according to p, where X is chosen from the group comprising furandi, peridinin, (C 1-C6)alkylcarboxylic-, -(C1-C6)alkoxycarbonyl - and -(C1-C6)alkoxy(C1-C6)alkyl-.

135. The method according to p, where the specified connection refers to the connection of the formula II

136. The method according to p, where A" is chosen from the group comprising-NH2, -CONH2, -CH3, -CF3, halogen, -CH2-halogen, -CN, -och3, -SCH3and Mr..

137. The method according to p, where A" is chosen from the group comprising-Cl, -NH2and CH3.

138. The method according to p, where one is" chosen from the group comprising-H, -C(O)R11, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, phenyl, halogen, -CN, -SR3and-NR92.

139. The method according to p, where one is" chosen from the group comprising-H, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, halogen, pyridinyl, thienyl, furanyl and-SR3.

140. The method according to p, where D" is chosen from the group comprising-H, -C(O)R11, -C(O)SR3, (C1-C6)alkyl, phenyl, halogen, -NR92and-SR3.

141. The method according to p, where D" is chosen from the group comprising-H, (C1-C6)alkyl and halogen.

142. The method according to p, where E is chosen from the group comprising-H, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen, -CN, and-SR3.

143. The method according to p, where E is chosen from the group comprising-H, -Br, and Cl.

144. The method according to 102, where both groups Y denotes-O-.

145. The method according to p, where both groups Y denotes-O-.

146. The method according to p, where both groups Y denotes-O-.

147. The method according to 102, where one Y represents-NR6-and the other Y represents-O-.

148. The method according to p, where one Y represents-NR6-and the other Y represents-O-.

149. The method according to p, where one Y represents-NR6-and the other Y represents-O-.

150. The method according to 102, where, when Y represents-O-, then R1associated with-O-is independently selected from the group comprising-H, optionally substituted with halogen phenyl, -C(R2)2-O-C(O)OR3, -C(R2)2OC(O)SR3-(C1-C6)alkyl-S-C(O)R3;

when Y represents-NR6-, R1associated with-NR6is independently selected from the group comprising-H, -[C(R2)2]q-COOR3, -C(R4)2COOR3;

or when each Y is independently selected from-O - and-NR6something along R1and R1mean

where V, W and W' are independently chosen from the group comprising-H, phenyl substituted with halogen, CF3, (C1-C6)alkyl, (C1-C6)alkoxyphenyl; benzyl, naphthyl, pyridyl; or

together V and W are connected via an additional 3 carbon atoms, form an optionally substituted cyclic group, with whom containing a series of 6 carbon atoms and substituted by hydroxy, connected to one of said additional carbon atoms, which is the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2HE, -CHR2OS(O)R3, -CHR2OCO2R3;

q denotes an integer of 1 or 2;

provided that:

a) V, Z, W, W' are not all represent H;

b) when Z represents N, then at least one of V, W and W' cannot denote-H, benzyl, pyridyl;

c) both groups Y can't identify-NR6-;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl and benzyl;

R6selected from the group comprising-H and lower alkyl.

151. The method according to p, where, when both groups Y denotes-O-, R1independently selected from the group comprising optionally substituted with halogen phenyl, -C(R2)2OC(O)OR3and-H; and

when Y represents-NR6-, R'associated with the specified group-NR6-choose from a group comprising-C(R4)2COOR3and-C(R2)2COOR3; and when the other group, Y represents-O-, then R1associated with the specified-O-is independently selected from the group: optionally substituted with halogen phenyl, -C(R2)2-OC(O)R3, -C(R2)2-O-C(O)OR3.

p> 152. The method according to p, where both groups Y denotes-O -, and R1denotes N.

153. The method according to p, where both groups Y denotes-O -, and R1denotes phenyl.

154. The method according to p, where both groups Y denotes-O -, and at least one R1denotes-C(R2)2-O-C(O)OR3.

155. The method according to p, where both groups Y denotes-O -, and at least one R1denotes -(C1-C6)alkyl-S-C(O)R3.

156. The method according to p, where at least one Y denotes-O - and together R1and R1form

where V, W and W' are independently chosen from the group comprising: H; phenyl substituted with halogen, CF3, (C1-C6)alkyl; benzyl, naphthyl, (C1-C6)alkoxyphenyl; pyridyl, etoxycarbonyl; or

together V and W are connected via an additional 3 carbon atoms, form an optionally substituted cyclic group containing 6 carbon atoms and substituted by hydroxy, United with one of these carbon atoms being the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2HE, -CHR2OC(O)R3, -CHR2OCO2R3;

provided that

a) V, Z, W, W' are not all represent H;

b) when Z represents N, then at least one of V, W and W' cannot denote-H, benzyl, who iridal, and

c) both groups Y should not be-NR6-;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl and benzyl;

R6selected from the group comprising-H and lower alkyl.

157. The method according to p where one Y represents-O -, and R1denotes optionally substituted with halogen phenyl; and the other Y represents-NR6-where R1associated with the specified group-NR6-choose from a group comprising-C(R4)2COOR3and-C(R2)2C(O)OR3.

158. The method according to p, where R1associated with-O-, selected from the group comprising phenyl, substituted by 1-2 substituents which are selected from the group comprising: -F, -Cl, -Br; and where R1associated with-NR6-denotes-C(R2)2COOR3; each R2independently selected from the group comprising SN3, -CH2CH3and N.

159. The method according to p, where the substituents specified substituted phenyl chosen from the group comprising-Cl and-Br.

160. The method according to p, where R5selected from the group including

,

and

;

And" ybiraut from the group including-NH2, -CONH2, -CH3, -CF3CH2-halogen, -CN, -och3, -SCH3and-N;

In" chosen from the group comprising-H, -C(O)R11, -C(O)OR3, -C(O)SR3, (C1-C6)alkyl, phenyl, halogen, -CN, -SR3and-NR92;

D is chosen from the group comprising-H, -C(O)R11, -C(O)SR3, -NR92, (C1-C6)alkyl, phenyl, halogen, and-SR3;

E is chosen from the group comprising-H, (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen, -CN, and-SR3;

X is chosen from the group comprising (C2-C6)quinil-, -1,1-diploid (C1-C6)alkyl-, -(C1-C6)alkoxy(C1-C6)alkyl-, -(C1-C6)alkylcarboxylic-, optionally substituted with halogen, phenyl; -(C1-C6)alkoxycarbonyl-;

when both groups Y denotes-O-, R1is-H; or

when one Y represents-O-, R1associated with-O-, denotes optionally substituted with halogen phenyl; and when Y represents-NR6-, R1associated with-NR6-choose from a group comprising-C(R4)2COOR3and-C(R2)2C(O)OR3; or

when Y represents-O - or-NR6-, R1and R1together represent

where V, W and W' are independently chosen from the group comprising-H, phenyl substituted with halogen, CF3, (C1-C6)alkyl; benzyl, naphthyl; pyridyl; or

together V and W are connected via an additional 3 carbon atom, form a cyclic group containing 6 carbon atoms and substituted by one hydroxysultaine connected with one of these carbon atoms being the third atom of Y associated with phosphorus;

Z is chosen from the group comprising-CHR2HE, -CHR2OC(O)R3, -CHR2CCA2R3;

R2selected from the group comprising R3and-N;

R3selected from the group comprising (C1-C6)alkyl, phenyl, benzyl;

R6selected from the group comprising H and (C1-C6)alkyl.

161. The method according to p, where R5means

X is chosen from the group comprising furan-2,5-diyl; at least one group Y represents-O-; and their pharmaceutically acceptable salts.

162. The method according to p, where, when Y represents-O-, R1associated with-O-, can be independently selected from the group comprising-H, optionally substituted with halogen phenyl, -CH2OC(O)Et, and-CH2OC(O)-iPr;

when Y represents-NR6-, R1associated with-NR6-may be independently selected from groups who, including: -C(R2)2COOR, -C(R4)2COOR, or

when Y represents-O - or-NR6-and at least one Y represents-O-, then together R1and R1mean

where V is chosen from the group comprising optionally substituted with halogen phenyl and pyridyl; and Z, W' and W denote H; and

R6selected from the group comprising-H and lower alkyl.

163. The method according to p where one Y represents-O-, and the corresponding R1means - phenyl, and the other Y represents-NH-, and the corresponding R1denotes-CH2CO2Et.

164. The method according to p where one Y represents-O-, and the corresponding R1means - phenyl, and the other Y represents-NH-, and the corresponding R1denotes-C(Me)2CO2Et.

165. The method according to p, where A" denotes-NH2, X is furan-2,5-diyl and" denotes-CH2-CH(CH3)2;

166. The method according to p where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-CH2CO2Et.

167. The method according to p where one Y represents-O-, and the corresponding R1means - phenyl, and the other Y represents-NH-, and the corresponding R1denotes-C(Me)2CO2Et.

168. The method according to p, where the" means-NH 2X represents furan-2,5-diyl and" means-COOEt.

169 the Method according to p, where both Y denotes-O-, a R1means-N.

170. The method according to p, where both Y denotes-O-, a R1denotes-CH2OC(O)OEt.

171. The method according to p, where A" denotes-NH2X represents furan-2,5-diyl and" means-SMe.

172. The method according to p, where both Y denotes-O-, a R1means-N.

173. The method according to p, where both Y denotes-O-, a R1denotes-CH2OC(O)OEt.

174. The method according to p, where A" denotes-NH2X denotes melanoxylon and" means-CH(CH3)2.

175. The method according to p, where both Y denotes-O-, a R1means-N.

176. The method according to p, where both Y denotes-O-, and R1denotes-CH2OC(O)OEt.

177. The method according to p, where both groups Y denotes-O -, and R1means-N.

178. The method according to p, where both groups Y denotes-O -, and R1denotes-CH2OC(O)OEt.

179. The method according to p, where both groups Y denotes-O-, and R1and R1together represent

,

and V denotes phenyl, substituted with 1-3 Halogens.

180. The method according to p, where V is chosen from the group comprising 3,5-dichlorophenyl, 3-bromo-4-forfinal, 3-chlorophenyl and 3-bromophenyl.

181. The method according to p, where R5means

X represents furan-2,5-diyl melanoxylon, and" means-NH2and at least one group Y represents-O-; and their pharmaceutically acceptable salts.

182. The method according to p where one Y represents-O-, and the corresponding R1means-phenyl, and the other Y represents-NH-, and the corresponding R1denotes-CH2CO2Et.

183. The method according to p, where R5means

And" means-NH2, E" and D" represent-H, b" denotes n-propyl and cyclopropyl, X represents furan-2,5-diyl; at least one group Y represents-O-; and their pharmaceutically acceptable salts.

184. The method according to p, where R5means

And" means-NH2D" denotes-H, b" denotes n-propyl, X represents furan-2,5-diyl; at least one group Y represents-O-; and their pharmaceutically acceptable salts.



 

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FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs

FIELD: synthesis of lubricant oiliness addends.

SUBSTANCE: claimed method includes reaction of equimolar amounts of 1-(N,N-dimethylaminomethyl)-benzotriazol and O-(n-butyl)-O-(3,4,5-trithiatricyclodez-8-yl-methyl))-dithiophosphoric acid at 80-100°C in toluene medium for 2-4 h to produce target product of general formula:

.

EFFECT: ash-free addend for lubricant oils processing under high pressure, in particular lubricant oiliness addend of improved antiscoring properties.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-benzotriazole salt of general formula 2 is disclosed. 1-(N,N-dimethylaminomethyl)-benzotriazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(n-butyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

The invention relates to new P,N-bidentate ligands of formula (I):

where a is S or NR,

where R represents a C1-C4alkyl,

R1and R2represent hydrogen, C1-C4alkyl, or R1and R2can be locked in the benzene ring,

R3and R4submit C1-C4alkyl or phenyl,

R5and R6submit C1-C4alkyl

The invention relates to new heteroaryl-alldifferent formulas (I) and (II) for compounds of formula (I) A=S if V=C; A=N, if B=N, R1is hydrogen or C1-C4alkyl, R2-R5-phenyl, R6and R7is hydrogen, n=0 or 1, R8-R11is hydrogen; compounds of f-crystals (II) A=N, if I=S, R1=C1-C4alkyl, A=C, if B= N, R1is hydrogen; A=N if I=N, R1=0; And=O, if=S, R1=0, R2-R5- phenyl, R8-R11is hydrogen or C1-C4alkyl

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: synthesis of lubricant oiliness addends.

SUBSTANCE: claimed method includes reaction of equimolar amounts of 1-(N,N-dimethylaminomethyl)-benzotriazol and O-(n-butyl)-O-(3,4,5-trithiatricyclodez-8-yl-methyl))-dithiophosphoric acid at 80-100°C in toluene medium for 2-4 h to produce target product of general formula:

.

EFFECT: ash-free addend for lubricant oils processing under high pressure, in particular lubricant oiliness addend of improved antiscoring properties.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-benzotriazole salt of general formula 2 is disclosed. 1-(N,N-dimethylaminomethyl)-benzotriazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

FIELD: synthesis of lubricant oil additives.

SUBSTANCE: method for production of O-(2-ethyl-n-hexil)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid 1-(N,N-dimethylaminomethyl)-1,2,4-triazole salt of general formula

is disclosed. 1-(N,N-dimethylaminomethyl)-1,2,4-triazole is brought into reaction with equimolar amount of O-(2-ethyl-n-hexyl)-O-3,4,5-trithiatricyclo[5.2.1.02,6]-dez-8-yl-methyl)-dithiophosphoric acid in toluene medium at 80-100°C for 2-4 h.

EFFECT: ash-free antiscoring lubricant oil additive operating under high pressure.

2 tbl, 1 ex

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