Derivatives of aminothiols

FIELD: organic chemistry, medicine, physiology.

SUBSTANCE: invention relates to agents for regulation (maintaining or suppression) of physical working ability and/or adaptation to different variants represented by solvated complex compounds of the general formula (I): Katm+[L1qEL2]Ann- x p.Solv (I) wherein L1 means aminothiols of the formula: R1NHCH(R2)(CH2)1-2SR3 wherein R1 means hydrogen atom (H), (C1-C20)-alkyl or RCO; R means (C1-C19)-alkyl; R2 means H or carboxyl; R3 means H, (C1-C20)-alkyl, (C2-C20)-alkenyl or benzyl; q = 1, 2 or 3; L2 means halogen atom, water and/or organic ligand. For example, bis-(N-acetyl-L-cysteinato)aquozinc (II) diheptahydrate suppresses physical working ability and in the dose 50 mg/kg increases reviving time of mice by 6 times and cats - by 2.8fold under conditions of acute hypoxia with hypercapnia, and increases reviving time of mice by 4 times under conditions of acute hypobaric hypoxia. Under the same conditions the known antihypoxic agents amtizol, acizol or mexidol are inactive or less active significantly by their activity. Bis-(N-acetyl-L-cysteinato)-ferrous (II) pentahydrate is more active as compared with the known antihypoxic agents and protects experimental animals in 4 variants of hypoxia. Bis-(N-acetyl-L-cysteinato)zinc (II) sulfate octahydrate is similar to enumerated compounds by its antihypoxic activity.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 dwg, 11 tbl, 33 ex

 

The invention relates to new compounds of the number of complex compounds of bimetallic with, in particular, biological activity and which may find use as pharmaceuticals.

It is well known that the high biological activity of trace elements is determined by their biochemical function in the structure of enzymes and enzyme systems as working tools last. Some contribution to their biological activity have also been low-molecular-weight metabolites. Efficiency coming from outside in the animal organism of trace elements is largely determined by the presence in the digestive tract of suitable ligands necessary for their biological transport. Low molecular weight metabolites of trace elements, which is equal to the right can be considered as metabolites of organic ligands, can simultaneously perform the function of protecting the body from exposure to a variety of alien factors physical, chemical or biological nature. These facts collectively formed the basis of the scientific basis for the development of complex compounds of Bioelements multi-purpose [1-3].

One of the most suitable ligands for the complex compounds of Bioelements for medical purposes can be considered natural aminothio the s. These compounds find property good chelators and play a very important role to control the thiol-disulfide equilibrium in biological systems. Therefore, complex compounds of Bioelements with aminosilane can be considered as prodrugs in relation not only to bioelement, but also to the ligand, and the most durable of them as self-medication purposes. This idea has not yet been expressed in the form of a systematic experimental study, however, you can specify on a separate development of this plan. Thus, in the patent [4] described a group of precursors of glutathione, including the form of complex compounds with some Bioelements, based on ideas about the important role of glutathione in the regulation of biochemical thiol-disulfide balance.

However, the cited work does not exhaust the possible choices as ligands, and the bio-elements and methods for their inclusion in the design of complex compounds. In addition, in this paper when discussing the possible beneficial role of compounds aminothiols lists only some pathological situation and says nothing about their useful manifestations in extreme situations and in normal physiology.

The task of this invention are new chemical compounds having, in particular, biological engineering is th activity.

This problem is solved derived aminothiols General formula I

Katm+[L1qL2]Ann.p.Solv,

where L1- aminothiol R1NHCH(R2)(CH2)1-2SR3and where R1is hydrogen, alkyl (C1-20or the group RCO, R is alkyl (C1-19; R2is hydrogen or carboxyl, R3is hydrogen, alkyl With1-20alkenyl2-20or benzyl, and q can take values 1, 2 or 3;

L2- halogen, water and/or organic ligand from among substituted by one or two alkilani1-20one or two hydroxy or oxymethylene groups, pyridine, hydroxy coumarin derivatives, nicotinic, p-aminobenzoic, phenylacetic acid, or ascorbic acid, or arginine;,

E-Cu(I), CA(II), Co (II), Cu (II), Fe(II), Mn(II), Ni (II), Zn(II)

Co (III), Cr (III), Ge(IV), Ti (IV), V(IV);

Kat is absent or represented by a cation 2-ethyl-6-methyl-3-hydroxypyridine or inorganic cation of an alkaline or alkaline-earth metal;

An absent or represented by the anion of p-toluenesulfonic acid or sulfate;

Solv - water, and R can take values from 0 to 8.5;

m can take values from 0 (with the exception of compound I, where R1- CH3CO, R2- COO, L2- no, n - 0, p - 0) to 2;

n can take values from 0 to 3.

Preferred are compounds I, where

L1- N-acetyl-L-sistei is; L2- water, e - Zn(II), q - 2; R - 2,5; m=n=0,

or the compounds I, where L1- N-acetyl-L-cysteine; L2no, e - Fe(II); q - 2; p - 5; m=n=0,

or the compounds I, where L1- N-acetyl-L-cysteine; L otsutstvuet, e - Zn (II), q - 2; An - sulfate; p - 8; m is 0; n is 2.

The synthesis of compounds of General formula (I) can be any of the known literature methods. In this patent the development of these selected only those that are either not accompanied by the formation of by-products, or may result in the formation of volatile products that are easy to catch. The General method consists of mixing calculated amounts of reactants in water or in aqueous alcohol at a temperature of 20-80°until the reaction is completed. Then the solvent and volatile products of the reaction is distilled off in vacuum and bring the residue to constant weight.

The following examples illustrate the synthesis of compounds according to the invention and their biological activity.

Example 1. N-Acetyl-L-cysteinato(akvo)zinc (II) disabilitati.

Mixed 3.00 g of N-acetyl-L-cysteine and a 4.03 g of the acetate of zinc (II) dihydrate in 15 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 1.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr) and bring the residue to constant weight. Exit 5, 27, Trasl. 252°C. Found, %: C 20,47; H5,09; N 4,62. C5H9NO4SZn. 2,5 H2O. Calculated, %: C 20,74; N To 4.87; N 4,84.

Example 2. N-Acetyl-L-cysteinato(akvo)cobalt(II)]tetracampidae.

Mixed 3.00 g of N-acetyl-L-cysteine and 4,58 g of cobalt acetate(II) tetrahydrate in 15 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 1.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 6.52, So different. 64-66°C. Found, %: C 18,56; N. Of 5.81; N 4,18. C5H9NO4S2Co.4,5 H2O. Calculated, %: C 18,81; N. Of 5.68; N 4,39.

Example 3. N-Acetyl-L-systemnational(III).

Mix of 5.00 g of N-acetyl-L-cysteine and 8,19 g to Balt(III)examineralfred in 70 ml of water at 60°and incubated for 3.5 hours at 18-20°C. Then evaporated to about 50 ml of aqueous ammonia under vacuum (10-15 Torr), separating the precipitated product by filtration, washed his 15-20 ml of water and brought to a constant weight. The yield of 6.71, So different. 227°C. Found, %: C 27,12; N 2,79; N 6,52. With5H6NO3SCo. Calculated, %: 27,41; N Was 2.76; N 6,39.

Example 4. N-Acetyl-L-cysteinato (akvo) copper (I) semihydrate.

Mix is 4.21 g of N-acetyl-L-cysteine and 1.84 g of copper oxide (I) in 8 ml of water and stirred for 1.5-2 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 6.52, Trasl. 136°C. Found, %: C 23,47; N 4,51; N 5,38. C5H10NO4 SCu. 0,5H2O. Calculated, %: C 23,76; N. Of 4.66; N Of 5.05.

Example 5. Bis(N-acetyl-L-cysteinato)equating(II) disabilitati.

Mix of 5.00 g of N-acetyl-L-cysteine and to 3.36 g of the acetate of zinc(II) dihydrate in 20 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 0.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr) and bring the residue to constant weight. Exit 7, 33, So different. 112-118°C. Found, %: C 26,22; N 5,44; N 6,37. C10H16N2O6S2Zn. 2,5 H2O. Calculated, %: C 26,53; N 5,12; N Is 6.19.

Example 6. Bis(N-acetyl-L-cysteinato) cobalt (II) tricameral.

Mix of 5.00 g of N-acetyl-L-cysteine and 3,82 g of cobalt acetate (II) tetrahydrate in 20 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 1.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr). Output for 6.81, Trasl. 56°C. Found, %: C 26,42; N 5,42, N 5,93. With10H16H2O6S2With. 3,5H2O. Calculated, %: C 26,91; N 5,19; N 6,28.

Example 7. Bis (N-acetyl-L-cysteinato) cobalt (III) trihydrate.

Mix of 6.00 g of N-acetyl-L-cysteine and to 4.92 g of cobalt(III)examineralfred in 30 ml of water at 50°and incubated for 3.5 hours at 18-20°C. and Then distilled water ammonia under vacuum (10-15 Torr), separating the precipitated product by filtration and washed it 10-15 ml of water and bring the OS is atok until constant weight. Output 10,89, Trasl. 111°C. Found, %: C 27,22; N 5,23; N OF 6.31 .C10H15N2O6S2Co.3 H2O. Calculated, %: C 27,53; N Is 4.85; N, 6.42 Per.

Example 8. Bis(N-acetyl-L-cysteinato)manganese(II) pentahydrate.

Mix of 5.00 g of N-acetyl-L-cysteine and 3.75 g of manganese acetate(II) tetrahydrate in 20 ml of water at 18-20°With, bring bring the temperature of the reaction medium up to 60°C and stirred at this temperature for 1.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr) and bring the residue to constant weight. The output of 7.25, Trasl. 76°C. Found, %: C 25,42; N 5,70; N 6,11. C10H16N2O6S2Mn. 5H20. Calculated, %: C 25,59; N To 5.58; N 5,97.

Example 9. Bis (N-acetyl-L-cysteinato) iron (II) pentahydrate.

Mix of 5.00 g of N-acetyl-L-cysteine and 3.77 g of the acetate of iron (II) tetrahydrate in 20 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 1.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr) and bring the residue to constant weight. Output 7,16, So different. 113°C. Found, %: C 25,07; N 5,42; N 5,61. C10H16N2O6S2Fe. 5H2O. Calculated, %: C 25,54; N 5,69; N 5,96.

Example 10. Bis (2-methyl-5-ethyl-3-hydroxypyridine) bis (N-acetyl-L-cysteinato)-acculturation (IV) tetracampidae.

Mix of 5.00 g of N-acetyl-L-cysteine, 2,73 g esculetin and 4,20 g 2-methyl-5-ethyl-3-is hydroxypyridine with 15,32 millimole hydrated Titanic acid in 30 ml of water at 18-20° With increase of the temperature of the reaction medium up to 60°C and stirred at this temperature for 2.5 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 13,81, So different. 124°C. Found, %: C 46,25; N 6,01; N 6,18. C35H42N4O12S2Ti. 4,5H2O. Calculated, %: C 46,51; N 5,69; N 6,20.

Example 11. Bis(N-acetyl-L-cysteinato) acculturation (IV).

Mix 5.0 g of N-acetyl-L-cysteine, 2,73 g esculetin and 15,32 millimole hydrated Titanic acid in 30 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 2.5 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 8,46 was So different. 112°C. Found, %: C 41,32; N 4,01; N 4,86. C19H20N2O10S2Ti. Calculated, %: C 41,61; N 3,68; N 5,11.

Example 12. Magnesium bis(N-acetyl-L-cysteinato) acculturation(IV) trihydrate

Mix 3.25 g of N-acetyl-L-cysteine, 1,77 g esculetin and 0.40 g of magnesium oxide from 9.46 to millimole hydrated Titanic acid in a mixture of 15 ml of water and 5 ml of alcohol at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 2 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 6,21 was So different. 94°C. Found, %: C 36,22; N. Of 3.25; N 4,62. C19H18N2O10S22O. Calculated, %: C 36,53; H 2,90; N 4,48.

Example 13. Magnesium bis (N-acetyl-L-cysteinato)bis (esculenta)titanium(IV) pentahydrate.

Mix of 5.00 g of N-acetyl-L-cysteine, 5,46 g esculetin and 0.62 g of magnesium oxide with 15,32 millimole hydrated Titanic acid in a mixture of 25 ml of water and 5 ml of alcohol at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 2.5 hours. Then distilled water alcohol under vacuum (10-15 Torr) and bring the residue to constant weight. Output 12,88 was So different. 108°C. Found, %: C 39,69; N 3,12; N 3,11. C28H24N2O14S2MgTi. 5H2O. Calculated, %: 40,09; N 2,88; 3,34 N.

Example 14. Bis(N-acetyl-L-cysteinato)germanium(IV) trihydrate.

Mix 5.0 g of N-acetyl-L-cysteine with 15,32 millimole hydrated germanium acid in 15 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°C and stirred at this temperature for 2.5 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 6,87, Trasl. 152°C. Found, %: C 26,82; N To 4.62; N 6,02. C10H14N2O6S2Ge. 3H2O. Calculated, %: C 26,75; N. Of 4.49; N 6,24.

Example 15. Bis(S-allyl-L-homocysteine)calcium(II) trihydrate.

Mix 4,48 g S-allyl-L-homocysteine from 0.72 g of calcium oxide in 15 ml of water at 18-20°To increase the temperature of the reaction medium up to 60°and With mix PR is this temperature for 1 hour. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 5.68, So different. Number 109-121°C. Found, %: C 37,64; N 7,02; N of 5.83. C14N24N2O4S2Ca. 3H2O. Calculated, %: C 37,99; N 6,83; N 6,33.

Example 16. Bis(S-benzyl-L-homocysteine)manganese(II) tetrahydrate.

Mix of 4.46 g of S-benzyl-L-homocysteine 2.43 g of manganese acetate (II) tetrahydrate in 15 ml of water at 18-20°With, bring the temperature of the reaction medium up to 60°C and stirred at this temperature for 2 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 5,70, So different. 96-117°Found, %: C 45,69, N 6,55; N of 4.83. C22H28N2O4S2Mn. 4H2O. Calculated, %: C 45,91; N 6,30; N 4,87.

Example 17. Sodium [N-acetyl-L-cysteinato(nicotinate)zinc (II) sulfate tetrahydrate.

Mix 1.73 g of N-acetyl-L-cysteine and 1.31 g of nicotinate and 3.06 g of zinc sulfate (II) heptahydrate in 15 ml of water at 18-20°With, then gradually added with stirring 0.56 g sodium, increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 6.52, So different. 179°C. Found, %: C 23,96; N. Of 4.35; N 4,86. C11H13N2O9S2NaZn. 4H20. Calculated, %: 24,38; N 3,91; N 5,17.

Example 18. Bis(L-cysteinato)zinc(II) sulfate(that is ilat) octanamide.

Mix of 1.61 g of L-cysteine, 2,53 g of the monohydrate of p-toluenesulfonic acid, 1, 46 g of dihydrate zinc acetate(II) and of 2.27 ml, 24.4% of sulfuric acid in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours. Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 6,00 was So different. 74°C. Found, %: 26,34; N 5,43, N 6,17. C20H28N2O14S3Zn.8,5H2O. Calculated, %: 26,71; N 5,04; N 5,96.

Example 19. Cysteamine(pyridoxine)chlorotic(II) the uranyl.

Mix 1.20 g group probably facilitates hydrochloride, 1,79 g of pyridoxine hydrochloride and 2, 32 g of dihydrate zinc acetate(II) in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 2 hours. Distilled water mixed with volatile acids in vacuum (10-15 Torr) and bring the residue to constant weight. The output of 4.77, So different. 166°C. Found, %: C 25,98; N 6,63; N by 5.87. C15H27N5O5S2Ni.7,5H2O. Calculated, %: 26,44; N To 6.43; N 6,17.

Example 20. Sodium D,L-methionate(p-aminobenzoate)copper(II) heptahydrate.

Mix 1.22 g of D,L-methionine, 1.12 g of p-aminobenzoic acid and 2.03 g of copper acetate(II) tetrahydrate in 15 ml of water at 18-20°With, then gradually added with stirring to 0.44 g of sodium, increase the temperature of the reaction mixture to 60°and mix With p and this temperature for 1.5 hours. Then distilled water acetic acid under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 6.52, Trasl. above 210°C. Found, %: C Of 28.72; N 3,12; N 5,86. C12H16N2O4SCuNa. 7H2O. Calculated, %: C 29,00; N 3,24; N 5,64.

Example 21. Bis [(D,L-methionate(L-cysteinato)chromium(III)] trisulfate octahedral.

Mix of 1.32 g of D,L-methionine, 1.07 g of L-cysteine and 3,17 g of sulfate of chromium(III) octadecahydrate in 15 ml of water at a temperature of 18-20°To increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1 hour. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The output value of 4.76, So different. 221°C. Found, %: C 17,36; N 3,18; N is 5.06. C16H36N4O20S7Cr2. 8H2O. Calculated, %: C 17,84; N 3,37; N 5,20.

Example 22. Cysteamine(L-arginine)Nickel (II) toilet heptageniidae.

Mix 1.18 g group probably facilitates hydrochloride, of 1.80 g of L-arginine, 1.97 g of the monohydrate of p-toluenesulfonic acid and 2.58 g of leads to compounds, which Nickel(II) tetrahydrate in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 2 hours. Distilled water hydrogen chloride in vacuum (10-15 Torr) and bring the residue to constant weight. Output 6,38 was So different. 64°C. Found, %: C 29,12; N. Of 6.75; N 11,18. C15H27N5O5S2Ni. 7,5H2O. Calculated, %: 29,37; N 6,41; 11,42.

Example 23. L-Cysteinato (phenylacetate)vanadyl acidic uranyl sulfate.

Mix 1.44 g of L-cysteine, of 1.62 g of phenylacetate and 2, 58 g of the three-hydrate sulphate vanadyl in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours. Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The output of 6.25 was So different. 71°C. Found, %: C 24,59; N the ceiling of 5.60; N 2,31. C11H16NO9S2V.6H2O. Calculated, %: C 24,96; N 5,33; N 2,64.

Example 24. Bis(N-acetyl-L-cysteinato)zinc(II) sulfate octahydrate.

Mix at 3.35 g of N-acetyl-L-cysteine from 2.95 g of zinc sulfate(II) heptahydrate in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 2 hours. Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 6,46 was So different. 163°C. Found, %: From 18.76; H 3,02; N 4,56. C10H18N2O10S3Zn.8H2O. Calculated, %: From 19.00; N 2,87; N 4,43.

Example 25. Disodium bis(N-acetyl-L-cysteinato)zinc(II) tetrahydrate.

Mix of 3.73 g of N-acetyl-L-cysteine and 2.51 g of the acetate of zinc(II) dihydrate in 15 ml of water at 18-20°With, then gradually added with stirring to 1.21 g soda, raise the temperature of the reaction mixture to 60°C and stirred at this temperature for 2 hours. Distilled water under vacuum (10-15 Torr) and bring the STATCOM to constant weight. Output 5,79 was So different. 166°C. Found, %: C 23,56; N To 2.57; N 5,31. C10H14N2O6S2Na2Zn.42O. Calculated, %: C 23,75; N To 2.79; N, 5,54.

Example 26. Sodium bis(N-acetyl-L-cysteinato)zinc(II) dihydrate.

Mix 3,93 g N-acetyl-L-cysteine and 2.64 g of the acetate of zinc(II) dihydrate in 15 ml of water at 18-20°With, then gradually added with stirring 0.64 g of soda, raise the temperature of the reaction mixture to 60°C and stirred at this temperature for 2 hours. Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 5,42 was So different. 163°C. Found, %: C 27,12; N 3,16; N 5,94. C10H15N2O6S2NaZn.2H2O. Calculated, %:C 26,82; N 3,38; N 6,26.

Example 27. N-Acetyl-L-cysteinato(nicotinate)zinc(II) disabilitati.

Mix 2,32 g N-acetyl-L-cysteine, 1,75 g nicotinate and 3.12 g of the acetate of zinc(II) dihydrate in 25 ml of water and stirred at a temperature of 60°1.5-2 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output, 5,65 So different. 195°C. Found, %: C 32,96; N Is 3.21; N 7,21. C11H13N2O5S2Zn.2,5H2O. Calculated, %: C Represented 33.47 Per; N. Of 3.06; N 7,10.

Example 28. Sodium N-Acetyl-L-cysteinato(nicotinate)zinc(II) tetrahydrate.

Mix 2.17 g of N-acetyl-L-cysteine, 1.64 g of nicotinate and of 2.92 g of the acetate of zinc(II) dihydrate in 20 ml of water at 18-20°With, then gradually under stirring to relax the Ute 0.71 g sodium, raise the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 5,88 was So different. 82°C. Found, %: C 29,49; N Is 2.74; N 6,18. C11H11N2O5SNaZn.4H2O. Calculated, %: C 29,78; H 2,50; N Of 6.31.

Example 29. Sodium N-acetyl-L-cysteinato (nicotinate)the chlor-zinc(II) tetracampidae.

Mix 1.88 g of N-acetyl-L-cysteine, 1.42 g of nicotinate, of 0.68 g of sodium chloride and of 2.53 g of the acetate of zinc(II) dihydrate in 15 ml of water at 18-20°With, then gradually added with stirring and 0.61 g of sodium, increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 5.68, So different. 163°C. Found, %: C 26,87; N 2,85; Cl 7,16; N 5,47. C11H12N2O5SNaZn. 4,5H2O. Calculated, %: 27,01; N 2,47; Cl 7,25; N5,73.

Example 30. Disodium nicotinate(N-acetyl-L-cysteinato)zinc(II) pentahydrate.

Mix of 2.05 g of N-acetyl-L-cysteine, 1.55 g of nicotinate and 2.76 g of the acetate of zinc(II) dihydrate in 15 ml of water at 18-20°With, then gradually added with stirring to 1.33 g of sodium, increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 2 hours. Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output between 6.08, Try the L. 230°C. Found, %: C 26,95; N 2,41; N 5,64. C11H11N2O5SNa2Zn. 5H2O. Calculated, %: C 27,26; N To 2.29; N 5,78.

Example 31. N-Acetyl-L-cysteinato(nicotinate)zinc(II) sulfate octahydrate.

Mix 1,82 g N-acetyl-L-cysteine, 1,38 g nicotinate and 3.21 g of zinc sulfate(II) katakata in 15 ml of water and stirred at a temperature of 60°1.5-2 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 6,57, So different. 132°C. Found, %: C 22,51; N 1,96; N to 4.52. C11H14N2O9S2Zn.8H2O. Calculated, %: 22,32; N. Of 2.38; N 4,73.

Example 32. N-Acetyl-L-cysteinato(nicotinate)zinc(II) sulfate toilet octahedral.

Mix of 1.32 g of N-acetyl-L-cysteine, 0,99 g nicotinate, 1,53 g of the hydrate p-toluenesulfonic acid and 2,31 g of zinc sulfate(II) katakata in 15 ml of water and stirred at a temperature of 60°1.5-2 hours. Then distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. The yield of 6.02, So different. 179°C. Found, %: C 28,64; N 3,05; N 3,74. C18H22N2O12S3Zn.7H2O. Calculated, %: C 28,98; N 2,97; N 4,75.

Example 33. N-Acetyl-L-cysteine(L-ascorbate)vanadium(IV) sesquihydrate.

Mix of 1.39 g of N-acetyl-L-cysteine, 2,02 g of L-ascorbate and 0.95 g of vanadium oxide(IV) dihydrate in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 4.26 deaths, So different. above 146°C. Found, %: C 29,41; N 3,12; N 3,94. C9H11NO8SV.1,5H2O. Calculated, %: C 29,12; N 2,99; N Of 3.77.

Example 34. N-Acetyl-L-cysteine(L-ascorbate)chromium(III) tetracampidae.

Mix of 1.39 g of N-acetyl-L-cysteine, 2,02 g of L-ascorbate and of 1.65 g of chromium acetate(III) (chromium content 36,15%) in 15 ml of water at 18-20°With, then increase the temperature of the reaction mixture to 60°C and stirred at this temperature for 1.5 hours. Distilled water under vacuum (10-15 Torr) and bring the residue to constant weight. Output 4,88, Trasl. above 142°C. Found, %: C 24,99; N. Of 2.83; N 3,11. C9H12NO8SCr.4,5H2O. Calculated, %: 25,30; N. Of 2.83; N 3,28.

These compounds were subjected to biological tests on experimental models of stress reactions that occur in extreme situations. As such, were selected increased physical activity, which should be overcome by the person or in intense sports activities, either in an emergency or other dangerous situations. This option stress response was simulated on the model of running animals (mice) along the endless track (treadmill) or model in a swimming pool. The second variant of the stress response - the extreme situation caused by the lack of molecular oxygen at departure animal organism vital functions. Often, for various reasons (period rehabilit the tion after severe illness, the specifics of the performance of professional duties and the like) have to operate in conditions of physical inactivity. This type of stress response was also symitirovan on animal model. In addition, some compounds were tested on the model of the stress response, is complicated by additional factors (vibration, hypercapnia, and so on). The results of the tests are summarized in tables No. 1-11 and one drawing. As can be seen from the tables, the tested compounds have characteristic physiologically compatible compounds modulating (with the change of the sign of the effect) the nature of the manifestation of biological activity, as dependent on the structure of the compound and dose.

Sources of information

1. E.A.Parfenov, G.E.Zaikov. Biometals and Ligands for Anticancer Drug Design: Molecular Mechanisms of Superoxide Dismutase Models Antitumor Effects // Nova Science Publishers. - New York. - 1998. - P.380.

2. E.A.Parfenov, G.E.Zaikov. Biometals and Ligands for Anticancer Drug Design: Superoxide Dismutase Models for Combined Tumor Therapy // Nova Science Publishers. - New York. - 2001. - P.278.

3. E.A.Parfenov, G.E.Zaikov. Biotic Type Antioxidants: The Perspective of the Search Area of Novel Chemical Drugs // VSP. - Utrecht-Boston-Tokyo. - 2000. - P. 559.

4. Patent USA No. 13947, class a 61 K 31/198, 2003.

Table 2

The effect of tested compounds on the duration of the voyage mice in standard the conditions
ExampleConnection nameDose, mg/kgThe duration of the voyage as a percent of control
0,5115±4
1120±4
1Bis(N-acetyl-L-cysteinato)cobalt(III)trihydrate5164±4
10154±4
25117±b
0,5125±3
1149±4
5155±2
2Bis(N-acetyl-L-cysteinato)iron(II)pentahydrate)10175±3
25163±3
50142±5
100122±6
Drugs comparisonThe bemythyl50124±2
100 134±3
Bromantan50128±3
100118±2

Table 4

Comparative effects of bis(N-acetyl-L-cysteinato)equating(II) disabilitato on the survival of different species of animals under conditions of acute hypoxia with hypercapnia intraperitoneal dose of 50 mg/kg
ExampleAnimalThe time of survival in the experiment, minutesThe time of survival of the control group, minutesThe increase in survival time
1Mouse21035×6
2Cats27598×2,8
Table 5

The effect of tested compounds on rectal temperature in mice
ExampleConnection nameRectal temperature (°)
1Bis(-acetyl-L-cysteinato)equating(II) dissemi-hydrate 31,02+0,66
Control37,06+0,11

Table 7.

Comparative effects of bis(N-acetyl-L-cysteinato)equating(II) disabilitato in comparison with known antihypoxants on the survival of mice in acute hypobaric hypoxia
SubstanceDose, mg/kgThe lifespan of mice (min); n=8P (compared with control)
Antizol257,1+0,9p<0,025
Azizol109,7+1,6p<0,025
Mexidol1004,6+0,05p>0,05
Bis(N-acetyl-L-cysteinato)equating(II) disabilitati5017,9+3,1p<0,005
Control-4,4+0,02-

Table 10

Anti-inflammatory activity of the compounds of aminothiols
Connection aminothiolCarrageenophyte swelling of the paws of rats (inhibition %)
Bis(N-acetyl-L-cysteinato)equating(II)disabilitati15,90
Bis(2-methyl-5-ethyl-3-hydroxypyridine) bis(N-acetyl-L-cysteinato)-acculturation(IV)tetracampidae28,40
Bis(N-acetyl-L-cysteinato)acculturation(IV)-56,10

1. Derivatives aminothiols General formula I

Katm+[L1qL2]Ann·p.Solv,

where L1- aminothiol R1NHCH(R2)(CH2)1-2SR3where R1is hydrogen, alkyl With1-20or the group RCO, R is alkyl (C1-19; R2is hydrogen or carboxyl, R3is hydrogen, alkyl With1-20alkenyl2-20or benzyl, and q can take values 1, 2 or 3;

L2- halogen, water and/or organic ligand from among substituted by one or two alkilani1-20; one or two hydroxy or oxymethylene groups, pyridine, hydroxy coumarin derivatives, nicotinic, p-aminobenzoic, phenylacetic acid, or ascorbic acid, or arginine, or missing;

E - Cu (I), CA (II), Co (II), Cu (II), Fe (II), Mn (II), Ni (II), Zn (II), Co (III), Cr (III), Ge (IV), Ti (IV), V (IV);

Kat is missing and who and presents a cation 2-ethyl-6-methyl-3-hydroxypyridine or inorganic cation of an alkaline or alkaline earth metal;

An - is absent or represented by the anion of p-toluenesulfonic acid or sulfate;

Solv - water;

R can take values from 0 to 8.5;

m can take values from 0 (with the exception of compound I, where R1- CH3CO., R2- COO, L2- no, n=0, p=0) to 2;

n can take values from 0 to 3.

2. Derived aminothiol General formula I according to claim 1, where L1- N-acetyl-L-cysteine; L2-water, e-Zn (II), q=2; p=2,5; m=n=0.

3. Derived aminothiol General formula I according to claim 1, where L1- N-acetyl-L-cysteine; L2- no, uh - Fe (II); q=2; p=5; m=n=0.

4. Derived aminothiol General formula I according to claim 1, where L1- N-acetyl-L-cysteine; L2- no, uh - Zn (II), q=2; An - sulfate; p=8; m=0; n=2.



 

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