Steroid derivatives, methods for their preparation, pharmaceutical composition, method of treatment, the method of suppressing the growth of microbes

 

Described a number of new steroid derivatives of formula 1, which are antibacterial agents and also make the bacteria sensitive (sensibiliser) to other antibiotics, including erythromycin and novobiocin, where R3, R7and R12independently represent IT, =O,1-10hydroxyalkyl, optionally substituted C1-10aminoalkyl possibly protected With1-10hydroxyalkyloxy, where HE is the group could be protected, With2-10acyloxy, possibly substituted C1-10aminoacylase, possibly substituted C1-10aminoalkylsilane, where the amino group may secure or quaternion, N2N-HC(Q5)-C(O)-O, where Q5 is a side chain of any amino acid and the amino group may secure, possibly substituted C1-10guanidinoacetate,2-10alkenylacyl,1-10cyanoacrylate,1-10azidoethoxy; R17- may be substituted With1-10hydroxyalkyl, where HE is optionally protected, or optionally substituted C1-10alkyloxy-C1-10alkyl, optionally substituted C1-10aminoalkyl,2-10acyl or Catalunya derivative, or a linking group attached to a second steroid in position 17 where the binding group before-ly, 8 table.

Description text in facsimile form (see graphic part).

Claims

1. Steroid derivatives of General formula I

where R3, R7and R12each independently selected from the group comprising hydroxy, oxo, (C1-C10)hydroxyalkyl, optionally substituted (C1-C10)aminoalkyl, where the amino group optionally protected, (C1-C10)hydroxyalkyloxy, where the hydroxy-group optionally protected, (C2-C10)acyloxy, optionally substituted (C1-C10)aminoacylase, optionally substituted (C1-C10)aminoalkylsilane, where the amino group optionally protected or quaternion, H2N-HC(Q5)-C(O)-O-, where R5 denotes a side chain of any amino acid and the amino group optionally protected, optionally substituted (C1-C10)guanidinoacetate, (C2-C10)alkenylamine, (C1-C10)cyanoacrylate and (C1-C10)azidoethoxy;

R17represents an optionally substituted (C1-C10)hydroxyalkyl, where the hydroxy-group optionally protected, optionally substituted (C1-C10)alkyloxy(C1-C10)alkyl, optionally substituted (C1-C10)aminoalkyl, (C2-C10)acyl or Catalunya of proizvodi the position 17, where the linking group is a (C1-C10)alkylene(C1-C10)alkylene,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where the second steroid is a compound of formula I.

3. Connection on p. 1 where the binding group is a (C1-C10)alkylene(C1-C10)alkylene.

4. Connection on p. 1, where each of R3, R7and R12independently selected from the group comprising-O-(CH2)n-NH2, -O-CO-(CH2)n-NH2and-O-(CH2)n-NH-C(NH)-NH2where n is 1-3.

5. Connection on p. 4, where each of R3, R7and R12independently selected from the group consisting of-O-OC-(CH2)n-NH2where n is 1 or 2.

6. Connection on p. 4, where each of R3, R7and R12independently selected from the group consisting of-O-(CH2)n-NH-C (NH)-NH2where n is 1-3.

7. Connection on p. 1, where each of R3, R7and R12denotes-O-(CH2)n-NH2where n is 1-4.

8. Steroid derivatives of General formula I

where R3, R7and R12each independently selected from the group comprising optionally substituted (C1-C10)alkyloxy(C1-C10)alkyl, optionally substituted (C1-C10)Amin is on, and optionally substituted (C1-C10)guanidinoacetate;

R17represents an optionally substituted (C1-C10)hydroxyalkyl, optionally substituted (C1-C10)aminoalkyl or linking group attached to a second steroid in position 17 where the binding group is an optionally substituted (C1-C10)alkylene(C1-C10)alkylene,

or its pharmaceutically acceptable salt.

9. Connection on p. 8, having the following formula:

10. Connection on p. 8, having the following formula:

11. Connection on p. 8, having the following formula:

12. Connection on p. 8, having the following formula:

13. Connection on p. 8, having the following formula:

14. Connection on p. 8, having the following formula:

15. Connection on p. 8, having the following formula:

16. Connection on p. 8, having the following formula:

17. The method of obtaining compounds of General formula I on p. 1, where3, R7and R12such as specified in paragraph 1, and the camping is the method involves reacting the compounds of formula IV:

where at least two of R3, R7and R12are hydroxyl and the remaining have the values specified above for formula I,

with the electrophile with the formation of Olkiluoto ester compounds of the formula IV, where at least two of R3, R7and R12are alkalemia ether groups;

conversion Olkiluoto ester compounds of the formula IV in aminosidine predecessor, where at least two of the3, R7and R12independently selected from the group comprising (C1-C10)azidoethoxy and (C1-C10)cyanoacrylate; and recovering the amino compounds of the predecessor with the formation of compounds of formula I.

18. The method according to p. 17, where the electrophile is allylbromide.

19. The method of obtaining compounds of General formula I on p. 1, where3, R7, R12and R17such as specified in paragraph 1, and at least two of R3, R7and R12represent (C1-C10)guanidinoacetate, namely, that the method includes the interaction of the compounds of formula IV:

where at least two of R3, R7and RLom education Olkiluoto ester compounds of the formula IV, where at least two of R3, R7and R12are alkalemia ester group; conversion Olkiluoto ester compounds of the formula IV in aminosidine predecessor, where at least two of the3, R7and R12independently selected from the group comprising (C1-C10)azidoethoxy and (C1-C10)cyanoacrylate; and recovering the amino compounds of the predecessor with the derivatization aminoalkylated simple ether, where at least two of R3, R7and R12represent (C1-C10)aminoacylase; and contacting derived aminoalkylated simple ether forming guanidino the electrophile with the formation of compounds of formula I.

20. The method according to p. 19, where forming guanidino the electrophile is S3-C(NH)-NH2.

21. The method of obtaining compounds of General formula I on p. 1, where3, R7, R12and R17such as specified in paragraph 1, and at least two of R3, R7and R12represent H2N-HC(Q5)-C(O)-O-, where R5 denotes a side chain of any amino acid, which consists in the fact that the method involves reacting the compounds of formula IV

where at least two of R3, R7is isenau amino acid with the formation of the protected amino acid derivative compounds of formula IV with a protected amino acid, where at least two of R3, R7and R12represent (P. G.-HN-C(Q5)-C(O)-O-), where Q5 is a side chain of any amino acids and P. G. means aminosidine group; and removing the protective group of the compounds of the protected amino acid derivative compounds with the formation of compounds of formula I.

22. Pharmaceutical composition having antimicrobial properties, containing an effective amount of the compounds under item 8.

23. The pharmaceutical composition according to p. 22, optionally containing antibiotics.

24. The pharmaceutical composition according to p. 22, further containing a substance to be introduced into the cell.

25. The pharmaceutical composition according to p. 24, in which the substance to be introduced into the cell, is an antimicrobial substance.

26. The pharmaceutical composition according to p. 24, in which the specified connection and a specified substance are mixed with a pharmaceutically acceptable carrier.

27. The pharmaceutical composition according to p. 25, in which the antimicrobial agent is an antibiotic.

28. A method of treating microbial infection of the host by the introduction of this master effective amount of an antimicrobial composition containing the compound under item 1.

30. The method according to p. oroe antimicrobial substance for delivery in the microbial cell.

31. The method according to p. 30, where the second antimicrobial substance is an antibiotic.

32. The method according to any of paragraphs.28-30, where the infection is a bacterial infection.

33. The method according to p. 32, where the infection is an infection caused by gram-negative bacteria.

34. The method according to p. 33, where the bacterial infection is an infection by a bacterium, characterized in that its outer membrane contains a significant percentage of lipid A.

35. The method of suppressing the growth of microbes involving contacting the microbe with an effective amount of an antimicrobial composition containing the compound under item 1.

36. The method according to p. 35, where the antimicrobial composition comprises an additional antimicrobial agent.

37. The method according to p. 36, where the specified substance is a disinfectant, an antibiotic, an antiseptic.

 

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