Binuclear coordination compounds of biologically active d-elements with aliphatic thiols as agents for increasing efficiency of medicinal drugs

FIELD: chemistry.

SUBSTANCE: in the compound of formula I, M denotes identical or different metal atoms selected from a group comprising: Pd, Fe, Mn, Co, Ni, Cu, Zn or Mo, R1 and R2 independently denote hydrogen, amino, hydroxyl, carboxy, cyano, C1-12alkyl, C2-12alkenyl, C2-12alkynyl, C1-12alkoxy, C1-12alkylamino, C1-12alkoxycarbonyl, C1-12alkylamido,arylamido. Alkyl groups in the said substitutes may in turn be substituted with one or more of the following groups: hydroxyl, oxo, carboxy, amino or amido, R3-R10 independently denote hydrogen, or NHR3R4 and NHR5R6, taken together, and(or) NHR7R8 and NHR9R10, taken together, denote a ligand (or ligands) containing one or more donor aliphatic or aromatic nitrogen atoms and which occupy the cis-position near metal (M) atoms. The invention also discloses a pharmaceutical composition, use of the compound to prepare a medicinal drug and a therapeutic treatment method.

EFFECT: obtaining compounds capable of boosting efficiency of medicinal drugs.

25 cl, 17 ex, 23 tbl

 

The text descriptions are given in facsimile form.

1. The compound of General formula

and its pharmaceutically acceptable salt and solvate, where M denotes the same or different metal atoms selected from the group comprising Pd, Fe, Mn, Co, Ni, Cu, Zn or Mo,
R1and R2- independently from each other denote hydrogen, amino, hydroxy, carboxy, cyano, C1-12alkyl, C2-12alkenyl,2-12quinil,1-12alkoxy, C1-12alkylamino,1-12alkoxycarbonyl,1-12alkylamino, arylamino, and alkyl groups that are part of these substituents can be, in turn, substituted od is Oh or more than one of the following groups: hydroxy, oxo, carboxy, amino or amido,
R3-R10independently of one another denote hydrogen or
Other3R4and other5R6taken together, and(or) other7R8and other9R10taken together, represent a ligand (or ligands)that contains one or more donor aliphatic or aromatic nitrogen atoms and which has the CIS-position of the metal atom (M).

2. The compound according to claim 1, characterized in that it allows (assuming their application in small and ultrasmall quantities) to speed up the process of homogeneous selective, mild oxidation tylnej groups diamination only before the formation of disulfide bonds using secondary mediators (endogenous reactive oxygen, nitrogen and other oxidants), which play an important role in the transduction of various signals;
able to act as an effective catalyst posttranslational oxidative modification of sulfur-containing proteins in the body;
is able to maintain its conformation in the transition from the solid phase into solution;
able to significantly alter the catalytic efficiency when replacing tiality bridging ligands;
able to form only weak intermolecular interactions (van der Waals) interaction with drugs;
can be used is in the form of ions or neutral particles.

3. The compound according to claim 1, where other3R4and other5R6taken together, and(or) other7R8and other9R10taken together, represent Ethylenediamine, 2,2'-bipyridyl (2,2'-bipy), 1,10-phenanthroline (1,10-phen) or their derivatives.

4. The compound according to claim 1, where R1R2CH-CH2S represents the residue of a compound selected from the group comprising 2-aminoethanethiol (group probably facilitates), 2-acetamidomethyl, cysteine, methyl ester of cysteine, ethyl ester of cysteine, acetylcysteine, methyl ester acetylcysteine, ethyl ester acetylcysteine, nitrile acetylcysteine, 3-mercaptopropionic acid, d-glutamine-cysteine-glycine, homocysteine or their derivatives.

5. The compound according to claim 1, having the formula

where M, R1and R2have the meanings indicated in claim 1.

6. The compound according to claim 1, which represents a compound selected from the group consisting of [Pd2(µ-S-L-Cys)(µ-S-L-CysH)(2,2'-dipy)2](NO3)3·4,5H2O [Pd2(aetH)2(phen)2](NO3)4·H2O [Pd2(µ-S-Accys)2(dipy)2]Cl2·H2O [Pd2(µ-S-Accys)2(NH3)4]Cl2, [Cu2(µ-S-Cys)2(dipy)2]Cl2.

7. The connection according to claim 6, representing [Pd2(µ-S-L-Cys)(µ-S-L-CysH)(2,2'-dipy)2](NO3)3·4,5H2O, crystallizing in the triclinic singani is with the space group P-1, with unit cell parameters: a=13,86, b=13,82,=12,17, α=122,13°, β=103,61°, γ=91,40°, V(Å3)=1887,0, Z=1, which is characterized by an IR spectrum (KBr tablet), vmaxcm-1: 419, 542, 590, 648, 689, 722, 765, 807, 977, 1022, 1036, 1072, 1107, 1164, 1174, 1204, 1226, 1240, 1272, 1312, 1353, 1364, 1384, 1447, 1469, 1563, 1601, 1666, 1728, 3073, 3108, 3221, 3283, 3427, 3953.

8. The connection according to claim 6, representing [Pd2(aetH)2(phen)2](NO3)4·H2O, crystallizing in the monoclinic crystal system with space group CC, unit cell parameters, Å: a=24,53, b=13,10,=22,65, β=104,26°, V(Å3)=7052,25, Z=4.

9. The connection of claim 6, representing [Pd2(µ-S-Accys)2(dipy)2]Cl2·H2O, characterized by an IR spectrum (KBr tablet), vmaxcm-1: 507, 640, 692, 774, 815, 879, 946, 1058, 1094, 1212, 1229, 1343, 1381, 1404, 1427, 1573, 1723, 2655, 2820, 2971, 3377, 3406, 3480.

10. The connection according to claim 6, representing [Pd2(µ-S-Accys)2(NH3)4]Cl2characterized by an IR spectrum (KBr tablet), vmaxcm-1: 512, 597, 692, 773, 839, 879, 946, 1094, 1212, 1229, 1254, 1343, 1403, 1521, 1572, 1594, 1723, 2655, 2925, 2971, 3119, 3460.

11. The connection according to claim 6, representing the [Cu2(µ-S-Cys)2(dipy)2]Cl2characterized by an IR spectrum (KBr tablet), vmaxcm-1: 520, 691, 815, 879, 1058, 1133, 1212, 1229, 1254, 1343, 1404, 1572, 1594, 1627, 2655, 2925, 2940, 2971, 3119, 3480.

12. The compound according to any one of claims 1 to 11 for use in therapy to enhance therapeutic activity of the pharmacologically active compounds.

13. The compound according to any one of claims 1 to 11, affect the biological activity of the cells through the modulation of the activity of the extracellular surface of the cell and intracellular receptors, enzymes, ion channels, proteins of the cytoplasmic transporters and intracellular membranes, extracellular regulatory and transport molecules peptide.

14. The compound according to any one of claims 1 to 11, which have specific cellular trapnest and/or organotropism and/or system-specific effect and at least one pharmacological activity, selected from the group including antiviral, antibacterial, antiproliferative, proapoptotic, cytoprotective, direct and indirect antioxidant, gemostimuliruyuschee, antihypoxant together with immunomodulating, toxicologically, antifibrotic, anti-inflammatory activity, as well as the ability to suppress the reaction of multidrug resistance of various origins, to modulate regulatory, metabolic, immune dysfunction and imbalances that can be used to obtain medications external, inhalation, enteral and parenteral use.

15. Pharmaceutical composition having the property of increasing therapeutic activity of the pharmacologically active is soedineniya, comprising at least one compound according to claims 1 to 11 in effective amounts with pharmaceutically acceptable excipients.

16. The pharmaceutical composition according to item 15, optionally containing free molecules R1R2CH-CH2-SH, where R1and R2have the meanings indicated in claim 1.

17. The pharmaceutical composition according PP and 16, optionally containing thioctic acid.

18. The pharmaceutical composition according PP and 16, optionally containing lithium ions.

19. The pharmaceutical composition according PP and 16, optionally containing adenosine.

20. The use of compounds according to claims 1 to 11 for the manufacture of medicines that increase the affinity of EGFR to its substrates and ligands.

21. The use of compounds according to claims 1 to 11 for the manufacture of a medicinal product, which is the inhibitor of Pgp.

22. The way a therapeutic effect on the patient's body to enhance therapeutic activity of pharmacologically active compounds, in which the needy in this patient is administered an effective amount of a compound according to claims 1-11.

23. The method according to item 22, wherein the number of input patient coordination compounds of d-metals is 10-3-10-15mol/kg body weight.

24. The method according to item 22, wherein the number of input d-metal in the composition of the coordination compounds of n is greater than physiologically acceptable values for this metal.

25. The method according to item 22, wherein the needy in this patient an effective amount is administered inhalation, enterline, parenteral or applied externally.



 

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