A method of obtaining a condensed polycyclic alkaloids, compounds, method of inducing apoptosis

 

The invention relates to a method for producing a condensed polycyclic alkaloids of General formula I, including new, including phase cyclization of azometynoylid General formula II, where a is optionally substituted aryl, Z is oxygen, n = 1, Y is optionally substituted aryl, W and X together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group, possibly substituted and possibly condensed with aryl, carbocyclic or heterocyclic group. The compounds I induce apoptosis in cells with multidrug resistance, which enhances the antitumor therapeutic effect of drugs. 5 C. and 50 C.p. f-crystals, 2 PL.

Description text in facsimile form (see graphic part).

Claims

1. A method of obtaining a condensed polycyclic alkaloids of General formula (I)or its pharmaceutically acceptable derivatives and salts, racemates, isomers and/or tautomers, including phase cyclization of azomethine an optionally substituted aryl group; Z represents oxygen; n is 1; Y is an optionally substituted aryl; and
W and X, together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group which may be optionally substituted or optionally condensed with a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group.

2. The method according to p. 1, where a represents an optionally substituted residue of benzene.

3. The method according to p. 1, where W and X, together with the respective nitrogen atoms and the carbon to which they are attached, form a group of the formula (i)

where = = is an optional double bond;
R1-R4and R14selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted, acyloxy, sulfate group, phosphate group, and cyano.

4. The method according to p. 3, where R1-R4and R14selected from the waters which represents an optionally substituted phenyl group of formula (ii)

where R9-R13selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy, optionally substituted, acyloxy, sulfate group, phosphate group, and cyano.

6. The method according to p. 5, where R9-R13selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy or acyloxy.

7. The method according to p. 6, where R9-R13selected from hydrogen, hydroxy, methoxy, isopropoxy, bromide and acetoxy.

8. The method according to p. 1, where the compound of formula (I) is a compound of formula (Ia)

and azomethine is a compound of the General formula (IIA)

where R1-R8and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted amino, neobyazatelno substituted aryl, acyl, sulfate group, phosphate group, and cyano;
Y, Z and n have the meanings specified in paragraph 1.

9. The method according to p. 1, where the compound of formula (I) is a compound of formula (Ib)

and azomethine is a compound of the General formula (IIb)

where R1-R4, R14, Y, Z and n have the meanings specified in paragraph 8;
RA1-RA4form a cyclic group, specified in paragraph 1.

10. The method according to p. 8 or 9, where Y is an optionally substituted phenyl group of formula (ii)

where R9-R13have the meanings indicated for R1-R8and R14in p. 8.

11. The method according to p. 10, where R1-R14selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, sulfate group or acyloxy.

12. The method according to p. 11, where R1-R14selected from hydrogen, hydroxy, isopropoxy, methoxy, methyl, acetoxy or sulphate group.

13. The method according to any of paragraphs. 1, 8 or 9, where the cyclization of azometynoylid carried out by thermal processing.

14. The method according to p. 13, where the heat treatment includes heating azometynoylid in tetrahyde metal salt.

16. The method according to p. 15, where the metal salt is a CuI.

17. The method according to any of paragraphs. 1, 8 or 9, where the cyclization should oxidative treatment.

18. The method according to p. 17, where oxidation treatment includes oxidation in the air.

19. The method according to p. 17, where the oxidation processing includes processing the quinone.

20. The method according to p. 19, where the quinone is selected from chloranil or 2,3-dichloro-5,6-dicyano-1,4-berekenen.

21. The method according to p. 17, where the oxidation treatment includes treatment of the catalyst based on metal.

22. The method according to p. 1, where the compound of formula (II) are obtained by treating the base compound of the formula (III)

where A, Z, X, W, Y and n have the meanings specified in paragraph 1;
the counterion Lis sustainable weakly basic anion.

23. The method according to p. 8, wherein the compound of formula (IIA) are obtained by treating the base compound of the formula (IIIa)

where R1-R8, R14, Y, Z and n have the meanings specified in paragraph 8;
the counterion Lis sustainable the main anion.

24. The method according to p. 22 or 23, where Lgn="BASELINE">selected from bromide, chloride or iodide anions.

26. The method according to p. 22 or 23, where the basis is derived alkali metal or base represents a mono-, di - or tizamidine Amin.

27. The method according to p. 26, where the base is acility or ability.

28. The method according to p. 26, where the base is an alkyl substituted amine.

29. The method according to p. 28, where the base is a triethylamine or diisopropylethylamine.

30. The method according to p. 1, where the cyclization stage is preceded by a stage, comprising: (a) the interaction of the compounds of formula (IV) with the compound of the formula (V)


with the formation of the compounds of formula (VI)

where PZnis a synthon for Zn,
b) removing the protecting group Zncompounds (VI) and interaction with connection L-CH2-C(O)-L' with the formation of compound (VII)

where L' is removed by the group or by Deputy, to be converted into a group to delete;
(C) treating compound (VII) Eminem formula (VIII)

d) receiving azometynoylid General formula (II)

31. The method according to p. 8, where the cyclization stage is preceded by a stage, comprising: (a) the interaction of the compounds of formula (IV) with the compound of the formula (Va)


with the formation of the compounds of formula (VIa)

where P represents a protective group,
(b) removing the protecting group Znthe compounds (VIa) and interaction with connection L-CH2-C(O)-L' with the formation of compound (VIIa)

(C) treating compound (VIIa) of the compound of formula (VIIIa)

(d) receiving azometynoylid the General formula (IIA),
where Hal, L, L', Zn, Y and Z have the values listed in paragraph 30;
R1-R8and R14have the values listed in paragraph 8.

32. The method according to p. 30 or 31, where PZnrepresents the OAS and the removal of protection refers to the hydrolysis of the group SLA with the formation of IT.

33. The method according to p. 30 or 31, where PZnrepresents an aldehyde or acyl group, and deleting protection refers to the oxidation of the aldehyde or acyl group to the corresponding ester followed by hydrolysis.

34. The method according to p. 30 or 31, where L' represents a halogen or HE transformed p. 30 or 31, where the stage of interaction (a) is carried out in the presence of palladium catalyst.

37. The method according to p. 36, where the palladium catalyst is selected from dl2(h3)2or Pd(PPh3)4.

38. The method according to p. 36 or 37, where the interaction is mediated by the connection of Cu(I).

39. The method according to p. 30 that includes one or more of the following stages: (a) the interaction of the compounds of formula (IV) with the compound of the formula (V), (b) removing the protecting group Zncompounds (VI) and interaction with connection L-CH2-C(O)-L', (c) treating compound (VII) Eminem formula (VIII) is carried out by synthesizing the connection.

40. The compound of formula (I)

obtained by the method according to p. 1,
where a represents a cyclic group that represents optionally substituted aryl group;
Z represents oxygen;
n = 1;
Y represents an optionally substituted aryl;
W and X, together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group which may be optionally substituted, or optionally condensed with an aryl group;
or farmaceutyczne formula (Ia)

obtained by the method according to p. 8,
where R1-R8and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy;
Y, Z and n have the meanings specified in paragraph 40.

42. Connection on p. 40, represented by formula (Ib)

obtained by the method according to p. 9,
where R1-R4and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy;
Y, Z and n have the meanings specified in paragraph 40; and RA1-RA4form a cyclic group, which represents optionally substituted aryl group.

43. Connection on p. 1 of General formula (I)

where A, Z, X, W, Y and n s A-N and S-X, lamellarin I-acetate, lamellarin b, C, and G-diacetato, lamellarin A, D, E, G, K, L, M and N triacetate, lamellarin N-hexacyano, lamellarin T, U, V and Y-12 sulfate, lamellarin G-trimethylboron ether and lamellarin 1-methylate.

44. The compound according to any one of paragraphs. 40-42 as an active ingredient of a medicinal product for the treatment of tumors with multidrug resistance in need of this person or animal.

45. The compound according to any one of paragraphs. 40-42 as an active ingredient in medicines for inducing apoptosis in cells with multidrug resistance in need of this person or animal.

46. The compound according to any one of paragraphs. 40-42 as the active ingredient of the medicinal product to enhance antitumor chemotherapeutic action of drugs in multidrug resistance in need of this person or animal.

47. The compound of General formula (II)

where a represents a cyclic group that represents optionally substituted aryl group;
Z represents oxygen;
n = 1;
Y represents an optionally substituted to NUU nitrogen-containing heterocyclic group, which may be optionally substituted, or optionally condensed with an aryl group;
or its pharmaceutically acceptable derivatives or salts, racemates, isomers and/or tautomers.

48. Connection on p. 47, representing a compound of formula (IIA)

where R1-R8and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy;
Y, Z and n have the meanings specified in paragraph 47.

49. Connection on p. 47, representing a compound of formula (IIb)

where R1-R4and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy;
Y, Z and n have the meanings Yanou aryl group.

50. The compound of General formula (III)

where a represents a cyclic group that represents optionally substituted aryl group;
Z represents oxygen;
n = 1;
Y represents an optionally substituted aryl;
W and X, together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group which may be optionally substituted, or optionally condensed with an aryl group;
the counterion Lis sustainable weakly basic anion.

51. Connection on p. 50, representing a compound of formula (IIIa)

where R1-R8and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy;
Y, Z, n and Lhave the values listed in the
where R1-R4and R14may be the same or different and each is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted quinil, optionally protected hydroxy, optionally substituted alkoxy, optionally substituted, alkenone, optionally substituted, alkyloxy;
Y, Z and n have the meanings specified in paragraph 50;
RA1-RA4form a cyclic group, represents an optionally substituted aryl group; Lmatter specified in paragraph 50.

53. Method of inducing apoptosis in cells with multidrug resistance, including introduction to the needy in the human or animal an effective amount of a compound according to any one of paragraphs. 40-42.

54. The method according to p. 53 for the treatment of tumors with multidrug resistance.

55. The method according to p. 53 to enhance the antitumor therapeutic effects of drugs in multidrug resistance cells.

 

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