Low molecular weight pharmacological activity modulators
Claimed are a compound of the general formula (I) and pharmaceutically acceptable salts thereof, where M signifies metal atoms selected independently from the group comprising Pd, Fe, Mn, Co, Ni, Cu, Zn and Mo; R 1 and R 2 , independently of each other, signify hydrogen, amino, hydroxy, oxy, carboxy, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylamino, C 1-12 alkoxycarbonyl, C 1-12 alkylamido, arylamido, wherein the alkylene groupings in the given substituents can in turn be substituted by one or more of the following groups: hydroxy, oxy, carboxy, amino or amido; R 3 -R 10 , independently of each other, signify hydrogen; or NHR 3 R 4 and NHR 5 R 6 , taken together, and/or NHR 7 R 8 and NHR 9 R 10 , taken together, are a ligand (or ligands) containing one or several donor aliphatic or aromatic atoms of nitrogen and being in cis position on the metal atoms (M). The claimed compound can be used in a preparation containing a coordination compound and free molecules of an aliphatic thiol (or derivatives thereof), which are not bound to the coordination compound. The coordination compound and the free molecules of an aliphatic thiol (or derivatives thereof) in the preparation can be in either cationic or anionic form or in the form of neutral particles. The proposed substances are capable of making the action of drugs more effective by increasing the affinity of the target to the drug and/or providing for therapeutically optimal concentrations of the drug in the microenvironment of the target and/or reducing the toxicity of drugs.
1. A compound of the general formula
or a pharmaceutically acceptable salts thereof,
where M signifies metal atoms selected independently from the group consisting of Pd, Fe, Mn, Co, Ni, Cu, Zn and Mo,
R 1 and R 2 , independently of each other, signify hydrogen, amino, hydroxy, carboxy, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, C 1-12 alkylamino, C 1-12 alkoxycarbonyl, C 1-12 alkylamido, arylamido, wherein the alkyl groupings included in said substituents may, in their turn, be substituted by one or more than one of the following groups: hydroxy, oxy, carboxy, amino, or amido, or R 1 and R 2 , taken together, are oxo;
R 3 -R 10 , independently of each other, signify hydrogen, or
NHR 3 R 4 and NHR 5 R 6 , taken together, and/or NHR 7 R 8 and NHR 9 R 10 , taken together, are a ligand (or ligands), containing one or several donor aliphatic or aromatic atoms of nitrogen and occupying the cis-position on the metal atoms (M).
2. The compound as claimed in claim 1 , where NHR 3 R 4 and NHR 5 R 6 , taken together, and/or NHR 7 R 8 and NHR 9 R 10 , taken together, are a diamino compound or an aryl with two aromatic nitrogen atoms.
3. The compound as claimed in claim 2 , where the diamino compound is a C 2- C 6 diaminoalkylene, and the aryl contains two pyridyl rings.
4. The compound as claimed in claim 3 , where NHR 3 R 4 and NHR 5 R 6 , taken together, and/or NHR 7 R 8 and NHR 9 R 10 , taken together, are ethylenediamine, 2,2′-bidipyridyl (2,2′-bipy), 1,10-phenanthroline (1,10-phen), or derivatives thereof.
5. The compound as claimed in claim 3 , where R 1 R 2 CH—CH 2 —SH is 2-aminoethanethiol (aet, cysteamine), 2-acetamidoethanethiol, cysteine (Cys), cysteine methyl ester, cysteine ethyl ester, acetylcysteine (Accys), acetylcysteine methyl ester, acetylcysteine ethyl ester, acetylcysteine nitrile, 3-mercaptopropionic acid, γ-glutamine-cysteine-glycine, homocysteine, thioglycolic acid or derivatives thereof.
6. The compound as claimed in claim 3 , where NHR 3 R 4 and NHR 5 R 6 , taken together, and/or NHR 7 R 8 and NHR 9 R 10 , taken together, are ethylenediamine, 2,2′-bidipyridyl (2,2′-bipy), 1,10-phenanthroline (1,10-phen), or derivatives thereof, and R 1 R 2 CH—CH 2 —SH is 2-aminoethanethiol (aet, cysteamine), 2-acetamidoethanethiol, cysteine (Cys), cysteine methyl ester, cysteine ethyl ester, acetylcysteine (Accys), acetylcysteine methyl ester, acetylcysteine ethyl ester, acetylcysteine nitrile, 3-mercaptopropionic acid, γ-glutamine-cysteine-glycine, homocysteine, thioglycolic acid or derivatives thereof.
7. The compound as claimed in claim 1 with the formula
where M, R 1 and R 2 are as defined in claim 1 .
8. The compound as claimed in claim 1 , which is a compound selected from the group which consisting of [Pd 2 (μ-S-L-Cys)(μ-S-L-CysH)(2,2′-dipy) 2 ](NO 3 ) 3 .4.5H 2 O, Pd 2 (aetH) 2 (phen) 2 ](NO 3 ) 4 . H 2 O 9 , [Pd 2 (μ-S-Accys) 2 (dipy) 2 ]Cl 2 .H 2 O, [Pd 2 (μ-S-Accys) 2 (NH 3 ) 4 ]Cl 2 , and [Cu 2 (μ-S-Cys) 2 (dipy) 2 ]Cl 2 .
9. The compound as claimed in claim 8 , which is [Pd 2 (μ-S-L-Cys)(μ-S-L-CysH)(2,2′-dipy) 2 ](NO 3 ) 3 .4.5H 2 O, which crystallizes in triclinic syngony with spatial group P-1, with elementary cell parameters (Å): a=13.86, b=13.82, c=12.17, α=122.13°, β=103.61°, γ=91.40°, V(Å 3 )=1887.0, Z=1, characterized by an IR spectrum (KBr pellets), ν max , cm −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.
10. The compound as claimed in claim 8 , which is Pd 2 (aetH) 2 (phen) 2 ](NO 3 ) 4 .H 2 O, which crystallizes in monoclinic syngony with spatial group Cc, elementary cell parameters, Å: a=24.53, b=13.10, c=22.65, β=104.26°, V(Å 3 )=7052.25, Z=4.
11. The compound as claimed in claim 8 , which is [Pd 2 (μ-S-Accys) 2 (dipy) 2 ]Cl 2 .H 2 O, characterized by an IR spectrum (KBr pellets), ν max , cm −1 : 507, 640, 692, 774, 815, 879, 946, 1058, 1094, 1212, 1229, 1343, 1381, 1404, 1427, 1573, 1723, 2655, 2820, 2971, 3377, 3406, 3480.
12. The compound as claimed in claim 8 , which is [Pd 2 (μ-S-Accys) 2 (NH 3 ) 4 ]Cl 2 , characterized by an IR spectrum (KBr pellets), ν max , cm −1 : 512, 597, 692, 773,839,879,946,1094,1212,1229,1254,1343,1403,1521,1572,1594,1723,2655,2925, 2971,3119,3460.
13. The compound as claimed in claim 8 , which is [Cu 2 (μ-S-Cys) 2 (dipy) 2 ]Cl 2 , characterized by an IR spectrum (KBr pellets), ν max , cm −1 : 520, 691, 815, 879, 1058, 1133, 1212, 1229, 1254, 1343, 1404, 1572, 1594, 1627, 2655, 2925, 2940, 2971, 3119, 3480.
14. A pharmaceutical composition which comprises at least one compound as claimed in claim 1 in an effective amount together with pharmaceutically acceptable excipients.
15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is formulated for external, inhalation, enteral and parenteral use.
16. The pharmaceutical composition as claimed in claim 14 , which additionally contains free CHR 1 R 2 —CH 2 SH, where R 1 and R 2 are as defined in claim 1 .
17. The pharmaceutical composition as claimed in claim 14 , which additionally contains thioctic acid.
18. The pharmaceutical composition as claimed in claim 14 , which additionally contains lithium ions.
19. The pharmaceutical composition as claimed in claim 14 , which additionally contains adenosine.