Flavonoid compounds and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel flavonoid compounds of formula 1 where R1-R5 assume values given in the description. The invention also relates to a pharmaceutical composition based on said compounds and a treatment and prevention method. Such compounds and corresponding pharmaceutically acceptable derivatives and/or salts are used in pharmaceutical, veterinary and nutraceutical fields.

EFFECT: compounds and compositions have antioxidant properties and are especially effective in treating ischemic and reperfusion injury.

39 cl, 19 dwg

 

Cross-reference to related applications

This application claims priority under provisional patent application Australia No. 2005901214 filed March 11, 2005, the contents of which are introduced in this description by reference in its entirety.

The technical field to which the invention relates.

The present invention relates to new compounds, to compositions containing these compounds, methods for their preparation and application of these compounds. In particular, the present invention relates to compounds of flavonoids, methods of producing compounds of flavonoids, the compositions containing compounds of flavonoids, and methods of use thereof.

Prior art

Immediate reperfusion of ischemic tissue is especially important to restore normal functioning. But the restoration of blood flow can paradoxically cause progressive destruction of reversibly damaged cells, thus leading to tissue dysfunction and heart attack. This "reperfusion injury" has multifactorial causes of disease, but, probably, it is largely associated with the inflammatory response; restoration of blood flow may occur with certain inflammatory processes that enhance ischemic damage, VK is UCA adhesion and infiltration of leukocytes, and the release of reactive oxidative residues (ROS), such as representatives of oxygen free radicals and peroxides, such as H2O2.

Probably a significant part of this inflammatory response is mediated by interleukins (IL), multifunctional subclass of cytokines. Leukocytes (white blood cells), probably also play an important role in reperfusion injury. In addition to damage to the endothelium and neurons, leukocytes can directly impede microcirculation. The blockage of capillaries by leukocytes may also be the main mechanism of the phenomenon of unrestored flow". Thus, in the areas of parenchyma, which are still viable when restoring blood flow is not adequate reperfusion, and eventually they die. In particular, extensive blockage of capillaries causes myocardial ischemia.

Ischemia, and particularly reperfusion, have the ability to contribute to increased ROS release from leukocytes, which leads to further tissue damage. One of the most damaging types of free radicals are superoxide anions, which act, disrupting endothelial function and activity of nitric oxide (NO). This further impairs the process of blockage of capillaries, since it was shown that NO inhibits the aggregation of t is ambiatol and prevents the adhesion of leukocytes to the endothelium.

The degree of repair tissue formed after ischemia and reperfusion, depends on the nature of the tissue and the severity of the damage.

Ischemia can be caused by many conditions. For example, the ischemia can cause acute cases, such as stroke, myocardial infarction or mechanical injury, and chronic conditions such as atherosclerosis, peripheral vascular disease and diabetes. Another form of the disease, leading to ischemia, is hypertension.

After an acute event, such as myocardial infarction, due to blockage of a coronary artery affected by myocardial infarction individual intravenously injecting various drugs to help eliminate any clogging of the blood vessels, thereby restoring blood flow, which leads to reperfusion of the tissue. However, this treatment option is not directed at preventing or weakening associated with reperfusion tissue injury. Creating environmental conditions for reperfusion for the emergence and restore the supply of oxygen to tissues may lead to increased tissue damage due to increased production of free radicals.

In this respect, the conventional methods for the treatment of individuals with ischemia or at risk of developing ischemia, do not meet the requirements.

It was hypothesized that different substances, the improvement which indicate the status and functioning of vessels and that populations with a diet, rich in fruits and vegetables have a lower incidence of coronary arterial disease. This effect was associated with favorable effects of flavonoids, which represents the polyphenolic compounds, which are found in fruits and vegetables.

Flavonoids represent a very large and widespread group derived from plant compounds, which are believed to have many biological effects, including lowering levels of low-density lipoprotein in plasma, inhibition of platelet aggregation, removing free radicals and decrease cell proliferation, and modulation of vascular tone.

It was revealed a large number of flavonoids, and they differ from each other by the orientation of hydroxylation or methylation, regulation bentinho Deputy, degree of unsaturation and types of attached substituents. General tricolia structure (rings A, B and C) many of flavonoids based on the structure of 2-phenyl-4H-1-benzopyran-4-it.

the basic structure of flavonoid

For example, a synthetic flavonoid 3',4'-dihydroxyflavone (DiOHF)has a hydroxyl group in the provisions of the 3,3' and 4', and for him during surveysin vitroit was shown weakening of heart attack and damage associated with myocardial ischemia by reperfuse (Shen Wang, Gregory Dusting, May Give and Owen Woodman, British Journal of Pharmacology (2004) 142, 443-452).

However, the pharmacokinetics of many flavonoids were largely limited their therapeutic effectiveness. For synthetic flavonoids are characterized by a high solubility of the molecules in lipids and, therefore, inherent lack of solubility, which leads to problems when introduced as a therapeutic agent. These characteristics limit the applicability of flavonoids in the treatment, in which it is desirable term parenteral administration, for example, when vasodilator treatment.

Considering the problems described above, there remains a need in the development of synthetic derivatives of flavonoids with improved solubility and pharmacokinetics in comparison with the known flavonoids.

The invention

In accordance with the first aspect of the present invention relates to pharmaceutical and/or veterinary composition containing a pharmaceutically and/or veterinary acceptable carrier or diluent together with at least one compound of General formulaI

where

denotes a single or double bond; and

R1, R2, R3, R4, R5independently selected from H, OH, or a group of formula (Ia)

where

O represents oxygen;

L represents a linker group that is covalently linked to the oxygen and D, if present, or covalently linked to the oxygen and E, or is absent;

D represents a spacer elements group with a chain length equivalent to approximately from 1 to 20 carbon atoms, or is absent; and

E represents solubilizing group;

provided that at least one of R1, R2, R3, R4, R5is not H or OH.

Preferably, E is chosen from a complex ester, carboxylic acid, sulfonic acid, phosphonic acid, a complex phosphate ester, sulpham, complex sulfonic ester, phosphonate, complex phosphonate ester, sulfonate, zwitter-ion residue, amino acids, aminophosphonate, acyclic amine, cyclic amine, Quaternary ammonium cation, polyethylene glycol, oligosaccharide or dendrimers.

In one of the preferred embodiments E is chosen from a complex ester, carboxylic acid, sulfonic acid, phosphonic acid, a complex phosphate ester, polyethylene glycol, oligosaccharide or dendrimers.

Preferably, E is chosen from a complex ester, carboxylic acid, or a complex phosphate ester.

In a particularly preferred embodiment, E, not only is no a group of the formula (Ib)

where

W represents O, NH, S, O, NH-or S-; and

X represents H, a mono - or divalent cationic salt, or a cationic ammonium salt.

Preferably, W represents O and/or X represents H.

In another embodiment, E is an ester of the formula (Ic)

where

Q represents a substituted or unsubstituted alkylene, albaniles, akinyan, optionally interrupted by one or more heteroatoms;

W represents O, NH, S, O-, NH-or S-; and

X represents H, substituted or unsubstituted alkyl, alkylbenzene, mono - or divalent cationic salt, or a cationic ammonium salt.

Preferably, Q represents a substituted or unsubstituted lower alkylene.

In another embodiment, E is a complex phosphate ester of the formula (Id)

where

Y represents O, NH, S, O-, NH-or S-;

Z represents O or S; and

R6and R7independently selected from H, substituted or unsubstituted alkyl, mono - or divalent cationic salt, or cationic ammonium salts.

Preferably, Y and Z are O.

In one embodiment, the implementation of measures at the one of R 1, R2, R3, R4and R5is a complex phosphate ester of the formula (Ie)

where R6and R7independently selected from H, a mono - or divalent cationic salt, or cationic ammonium salts.

In one of embodiments L is present and is selected from-CO-, complex, ester, phenol, complex phosphonate ester, carbamate, carbonate or Mannich bases. In a more preferred embodiment L represents-CO-.

In another embodiment, D is selected from substituted or unsubstituted alkylene, Alcanena, akinlana, optionally interrupted by one or more heteroatoms, aryl, heteroaryl, cycloalkyl or geterotsiklicheskie.

In a preferred embodiment, D is a substituted or unsubstituted alkylene, optionally interrupted by one or more heteroatoms, preferably, the lower alkylene.

In another aspect, the present invention relates to pharmaceutical and/or veterinary composition containing a pharmaceutically and/or veterinary acceptable carrier or diluent together with at least one compound of General formula II

where

---denotes a single or double bond; and

R1, R2and R 3are as described above.

In another aspect the present invention relates to pharmaceutical and/or veterinary composition containing a pharmaceutically and/or veterinary acceptable carrier or diluent together with at least one compound of General formulaIII

where R3is the same as above.

In another aspect, the present invention relates to pharmaceutical and/or veterinary composition containing a pharmaceutically and/or veterinary acceptable carrier or diluent together with at least one compound of General formulaIV

where

Q represents a substituted or unsubstituted alkylene, optionally interrupted by one or more heteroatoms;

X represents H, a mono - or divalent cationic salt, or a cationic ammonium salt.

Preferably, Q represents a substituted or unsubstituted lower alkylene, optionally interrupted by one or more heteroatoms.

In another aspect, the present invention relates to a compound selected from the group

3-(benzyloxycarbonylamino)flavone;

3-hydroxyflavone-3-gemadept;

4'-(benzyloxy)-3-(benzyloxycarbonylamino)flavone; 4'-hydroxyflavone-3-g is mediate;

3',4'-dimensions-3-(benzyloxycarbonylamino)flavone;

3',4'-dihydroxyflavone-3-gemadept;

3,4'-di(benzyloxycarbonylamino)flavone;

Flavon-3,4'-bis(remediate);

3,7-di(benzyloxycarbonylamino)flavone;

3,7-dihydroxyflavone-3,7-bis(remediate);

4'-hydroxy-3-hydroxyflavone-3-Quaternary ammonium complex ether;

4'-(benzyloxy)-3-(dibenzalacetone)flavone and disodium salt 3-hydroxyflavone-3-phosphate.

In another aspect, the present invention relates to pharmaceutical and/or veterinary composition containing a pharmaceutically and/or veterinary acceptable carrier or diluent together with at least one compound selected from the group consisting of

3-(benzyloxycarbonylamino)flavone;

3-hydroxyflavone-3-gemadept;

4'-(benzyloxy)-3-(benzyloxycarbonylamino)flavone; 4'-hydroxyflavone-3-gemadept;

3',4'-dimensions-3-(benzyloxycarbonylamino)flavone;

3',4'-dihydroxyflavone-3-gemadept;

3,4'-di(benzyloxycarbonylamino)flavone;

Flavon-3,4'-bis(gemadept);

3,7-di(benzyloxycarbonylamino)flavone;

3-(dibenzalacetone)flavone;

3,7-dihydroxyflavone-3,7-bis(gemadept);

4'-hydroxy-3-hydroxyflavone-3-Quaternary am viewy ester;

the disodium salt of the flavone-3-phosphate;

4'-(benzyloxy)-3-(dibenzalacetone)flavone or

the disodium salt of 3-hydroxyflavone-3-phosphate.

In another aspect the present invention relates to a method for prevention and/or treatment of individual diseases(nd), bound(s) with the presence of reactive oxidative residues (ROS), where the method includes:

the introduction of an effective amount of at least one of the above compounds.

Preferably, the individual in need of such treatment has a risk of developing ischemia. More preferably, the individual suffers from ischemia and/or reperfusion injury, as the result of acute or chronic conditions.

In a specific embodiment, a chronic condition selected from cancer, cerebrovascular disease, vascular lung disease, atherosclerosis, diseases of the arteries, congestive heart failure, coronary heart disease, peripheral vascular disease, diabetes, hypertension, migraines, burns, chronic obstructive pulmonary diseases and vascular diseases of the retina.

In another embodiment, the acute condition selected from stroke, myocardial infarction, damage due to mechanical trauma or surgery. Preferably, the surgical VM is shatelstve is a vascular surgical intervention. More preferably, vascular surgery is a heart bypass surgery and/or transplant surgery.

In a specific embodiment, the compound is administered to the individual before and/or during surgery.

In another aspect, the present invention relates to a method of prevention, delay of development and/or slow the development of atherosclerosis and/or coronary heart disease in an individual, where the method includes:

the introduction of an effective amount of at least one of the above compounds.

In another aspect the present invention relates to therapeutic and/or prophylactic method of prevention and/or treatment of individual disease(s)associated with the presence of reactive oxidative residues (ROS), where the method includes:

the introduction of an effective amount of at least one of the above compounds.

In another aspect the present invention relates to a method for prevention and/or at least weakening the individual violations caused by ischemia and/or reperfusion injury, where the method includes:

the introduction of an effective amount of at least one of the above compounds.

In another aspect, the present invention relates to a method of prophylact the key and/or at least weakening the individual violations caused by the introduction of a therapeutic agent, where the method includes a joint introduction to the individual:

i) a therapeutic agent and

ii) introducing an effective amount of at least one of the above compounds.

Preferably, therapeutic agent is an oxidative therapeutic agent.

In a specific embodiment, therapeutic agent is an anticancer agent. Preferably, an anti-cancer agent is anthracyclin and its derivatives.

In specific embodiments, the implementation of the compound is administered orally, topically, subcutaneously, parenterally, intramuscularly, intraarterially and/or intravenously.

In another aspect, the present invention relates to the use of compounds as described above with obtaining the drug.

In another aspect the present invention relates to a compound of General formula I

where

denotes a single or double bond; and

R1, R2, R3, R4, R5independently selected from H, OH, or a group of formula (Ia)

where

O represents oxygen;

L represents a linker group that is covalently linked to the oxygen and D, if PR is no, or covalently linked to the oxygen and E, or is absent;

D represents a spacer elements group with a chain length equivalent to approximately from 1 to 20 carbon atoms, or is absent; and

E represents solubilizing group;

provided that at least one of R1, R2, R3, R4, R5is not H or OH,

provided that the compound is not a

Flavon-3'-hydroxyacetate; flavone-4'-hydroxyacetate;

Flavon-3-hydroxyacetate; (±)4,1-acetoxylation;

flavanol-3,4',7-trihydroxy-3-acetate;

3,7-bis(atomic charges)-2,3-dihydro-2-phenyl-(2R-TRANS)-4H-1-benzopyran-4-one;

(±)-7-(atomic charges)-2-[4-(atomic charges)phenyl]-2,3-dihydro-4H-1-benzopyran-4-one; (+)4',7-diacetoxynaphthalene;

(2S,3S)was 3.7-dihydroxybutanedioate;

flavone-3,4'-dihydroxyvitamin;

flavanone-3',4'-dihydroxyvitamin;

flavanol-3,7-dihydroxyvitamin;

3,7-bis(atomic charges)-2-(3,4-dihydroxyphenyl)-2,3-dihydro-(2R-TRANS)-4H-1-benzopyran-4-one;

Flavon-3,3'-dihydroxyvitamin; flavone-4',7-dihydroxyvitamin;

Flavon-3,7-dihydroxyvitamin;

Flavon-3,3',7-trihydroxystearin;

Flavon-3,3',4'-trihydroxystearin;

7-(atomic charges)-2-[3,4-bis(atomic charges)phenyl]-4H-1-benzopyran-4-one; flavone-3,4',7-trihydroxystearin;

flavanone-3',4',7-trihydroxystearin;

7-(atomic charges)-2-[3,4-bis(atomic charges)phenyl]-2,3-dig the draw(S)-4H-1-benzopyran-4-one; flavone-3,4',7-trihydroxystearin;

TRANS(t)-flavanone-3,4',7-trihydroxystearin;

3,7-bis(atomic charges)-2-[3-4-bis(atomic charges)phenyl]-4H-1-benzopyran-4-one; fastinternet;

3,7-bis(atomic charges)-2-[3,4-bis(atomic charges)phenyl]-2,3-dihydro-(2R-TRANS)-4H-1-benzopyran-4-one;

3,7-bis(atomic charges)-2-[3,4-bis(atomic charges)phenyl]-2,3-dihydro-TRANS-4H-1-benzopyran-4-one;

flavanol-3,3',4',7-tetrahydrocarbazole;

3-(1-oxopropoxy)-2-phenyl-4H-1-benzopyran-4-one;

2-methyl-4-oxo-2-phenyl-4H-1-benzopyran-3-silt ester propanoic acid;

2,2-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran-3-silt ester propanoic acid;

4-oxo-2-phenyl-4H-1-benzopyran-3-silt ether benzooxazol acids;

4-oxo-2-phenyl-4H-1-benzopyran-3-silt ether of benzoylpropionic acids;

a-phenyl-4-oxo-2-phenyl-4H-1-benzopyran-3-silt ether benzooxazol acids;

o-[4-[3-[(diethoxyphosphoryl)oxy]-4-oxo-4H-1-benzopyran-2-yl]phenyl]-o,o-diethyl ether tiofosfornoy acid;

o-[3-[3-[(diethoxyphosphoryl)oxy]-4-oxo-4H-1-benzopyran-2-yl]phenyl]-o,o-diethyl ether tiofosfornoy acid;

diethyl-4-(4-oxo-4H-1-benzopyran-2-yl)phenyl phosphoric acid;

2-phenyl-3-(phosphonooxy)-4H-1-benzopyran-4-one;

diammonium salt Flavon-3-hydroxydehydrogenase;

pentahydrate magnesium salts of 2-phenyl-3-(phosphonooxy)-4H-1-benzopyran-4-it (1:1);

2-[3-hydroxy-4-(phosphonooxy)phenyl]-4H-1-benzopyran-4-one

3',4'-dihydroxyflavone-4'-phosphate;

sodium salt of 3',4'-dihydroxyflavone-4'-β-D-glucopyranoside;

sodium salt of 3',4'-dihydroxyflavone-4'-β-D-ribofuranoside;

and their pharmaceutically and/or veterinary acceptable salt and solvate.

Preferably, R1, R2, R3, R4and R5are as described above.

In another aspect, the present invention relates to a compound of General formula (II)

where

---denotes a single or double bond; and

R1, R2and R3are as described above.

In another aspect the present invention relates to a compound of General formula (III)

where R3is the same as above.

In another aspect, the present invention relates to a compound of General formula (IV)

where

Q represents a substituted or unsubstituted alkylene, optionally interrupted by one or more heteroatoms;

X represents H, a mono - or divalent cationic salt, or a cationic ammonium salt.

Preferably, Q represents a substituted or unsubstituted lower alkylene, optionally interrupted by one or more heteroatoms.

In another aspect the present invention relates to soy is inniu General formula V

where R3and R5are as described above.

In another aspect, the present invention relates to a method for producing compounds as described above.

In accordance with another aspect of the present invention relates to compounds of General formula

where

denotes a single or double bond; and

R1, R2, R3, R4, R5independently selected from H, OH, substituted or unsubstituted alkoxygroup, aryloxy, esters, complex carbonate esters, ethers, complex phosphate esters and simple α-aryloxyalkyl esters, provided that at least one of R1, R2, R3, R4, R5is not H or OH;

and their pharmaceutically acceptable salts or solvate.

Preferably, at least R3selected from substituted or unsubstituted esters, complex carbonate esters, ethers, complex phosphate esters and simple α-aryloxyalkyl esters.

Preferably, at least one of R1, R2, R3, R4, R5choose from:

i) phosphate of General formula

where Y represents O, NH, S, O-, NH-or S-;

Z represents O or S; is

each of R6and R7independently selected from substituted or unsubstituted alkyl, H, a mono - or divalent cationic salt, or a cationic ammonium salt;

ii) complex ester of General formula

where R8represents a substituted or unsubstituted lower alkyl, lower alkylalkoxy;

iii) a complex ester of General formula

where Q represents a substituted or unsubstituted lower alkylene, lower alkenyl and quinil;

W represents O, NH, S, O-, NH-or S-; and

X represents H, substituted or unsubstituted alkyl, alkylbenzene, mono - or divalent cationic salt, or a cationic ammonium salt,

and their pharmaceutically acceptable salts or solvate.

In specific embodiments of the invention Y and Z both represent O.

In one of the embodiments the present invention relates to a compound of General formula

where

---denotes a single or double bond; and

R1, R2or R3independently selected from H, OH, substituted or unsubstituted alkoxygroup, aryloxy, esters, complex carbonate esters, ethers, complex phosphate esters and simple α-aryloxyalkyl esters, provided that n is at least one of R 1, R2or R3is not H or OH;

and their pharmaceutically acceptable salts or solvate.

Preferably, at least one of R1, R2or R3choose from:

i) phosphate of General formula

where Y represents O, NH, S, O-, NH-or S-;

Z represents O or S; and

each of R6and R7independently selected from substituted or unsubstituted alkyl, H, a mono - or divalent cationic salt, or a cationic ammonium salt;

ii) complex ester of General formula

where R8represents a substituted or unsubstituted lower alkyl, lower alkylalkoxy;

iii) a complex ester of General formula

where Q represents a substituted or unsubstituted lower alkylene, lower albaniles, akinyan, optionally interrupted by one or more heteroatoms;

W represents O, NH, S, O-, NH-or S-; and

X represents H, substituted or unsubstituted alkyl, alkylbenzene, mono - or divalent cationic salt, or a cationic ammonium salt;

and their pharmaceutically acceptable salts or solvate.

Preferably

R1represents H or OH;

R2represents H or OH; and

R3ybiraut from

In another embodiment, the present invention relates to a compound of General formula

where

R9represents a substituted or unsubstituted alkoxygroup, alloctype, ester, complex carbonate ester, a simple ester or a group of the formulawhere U represents a substituted or unsubstituted alkylene, optionally interrupted by one or more heteroatoms.

In another embodiment, the present invention relates to a compound of General formula

where n is an integer from 2 to 6, preferably n is 4.

Imply that specified in this formula include all possible geometrical and optical isomers and racemic mixtures.

In another aspect, the present invention relates to methods for producing compounds of formula I, formula II, formula III or formula IV, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as above, or its pharmaceutically acceptable salt or solvate.

In another aspect, the present invention relates to pharmaceutical and/or veterinary composition containing a pharmaceutically and/or veterinary acceptable the initial carrier or diluent together with at least one compound of formula I, formula II, formula III or formula IV, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as above, or its pharmaceutically acceptable salt or solvate.

In accordance with another aspect of the present invention relates to a method for prevention and/or at least weakening the individual violations, due to the introduction of a therapeutic agent, where the method includes a joint introduction to the individual:

i) a therapeutic agent; and

ii) an effective amount of at least one of the compounds of formula I, formula II, formula III, formula IV or formula V, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as above, or its pharmaceutically acceptable salt or solvate.

In another aspect the present invention relates to a method for prevention and/or treatment of disease(s)associated(s) with the presence of reactive oxidative residues (ROS), where the method includes introducing an effective amount of at least one of the compounds of formula I, formula II, formula III, formula IV or formula V, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as described in the above, or its pharmaceutically acceptable salt or solvate.

In another embodiment, the present invention relates to a method for prevention and/or treatment of disease(s)associated with the presence of reactive oxidative residues (ROS), where the method includes introducing an effective amount of at least one of the compounds of formula I, formula II, formula III or formula IV, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as above, or its pharmaceutically acceptable salt or solvate.

Typically, an individual in need of such treatment is the individual at risk of developing ischemia. Alternatively, the individual may be the individual who currently suffers from ischemia and/or reperfusion as a result of acute or chronic conditions.

In another additional aspect, the present invention relates to a method for prevention and/or at least weakening the individual violations caused by ischemia and/or reperfusion, where the method includes introducing an effective amount of at least one of the compounds of formula I, formula II, formula III or formula IV, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as is defined above, or its pharmaceutically acceptable salt or solvate.

Preferably, solubilizers group attached to the compound of at least partial solubility, and more preferably, complete solubility in aqueous solution, preferably water.

Preferably, the compounds according to the invention have at least one Deputy, split by the enzymein vivo.

Preferably cleaved by the enzymein vivothe Deputy is a group, an ionisable at physiological pH.

Brief description of drawings

Figure 1 presents the scheme of the synthesis of disodium salt of 3-hydroxyflavone-3-phosphate (5).

Figure 2 presents the scheme of the synthesis of 3',4'-dihydroxyflavone-3-phosphate (10).

Figure 3 presents a scheme of the synthesis of 3-hydroxyflavone-3-hemisuccinate (15) through monobenzoyl ester of succinic acid.

4 shows the scheme for synthesis of 3-hydroxyflavone-3-gemadept (19) through monobenzoyl ester of adipic acid.

Figure 5 presents the scheme of the synthesis of 3',4'-dihydroxyflavone-3-gemadept (21).

Figure 6 presents the effects of media (dH2O), Flavon-3-gemadept (19) (F3HA), in the presence and absence butyrylcholinesterase (BuCHE, 1000 units/l) and DiOHF (10-4M), the level of superoxide anions generated in the rat aorta in the presence of NADPH, expressed in percentage of the control.

7 performance is established with representation from the effects of the media (dH 2O), 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-6M-10-4M), in the presence and absence butyrylcholinesterase (BuCHE, 1000 units/l) and DiOHF (10-4M), the level of superoxide anions generated in the rat aorta in the presence of NADPH, expressed in percentage of the control.

On Fig presents the curves of the concentration-response on the Ca2+in the presence of media or 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-4M), in the presence and absence of BuCHE in comparison with DiOHF in endothelium intact aortic rings isolated from rats. The magnitude of reduction is expressed as a percentage of the initial reactions to the Ca2+(3×10-3M)observed before treatment DiOHF3HA.

Figure 9 presents the effects of media (dH2O), flavone-3-phosphate (F3P, 10-8M-10-4M) in the presence of phosphatase (1000 units/l) and DiOHF (10-4M) on the level of superoxide anions generated in the rat aorta in the presence of NADPH, expressed in percentage of the control.

Figure 10 presents the curves of the concentration-response for Ca2+in the presence of the media or the flavone-3-phosphate (F3P, 10-8M-10-4M), in the presence and absence of phosphatase (P, 1000 units/l)in endothelium intact aortic rings isolated from rats. The magnitude of reduction is expressed as a percentage of the initial reactions to the Ca2+(3×10-3M)observed before treatment flavone-3-phosphate.

Figure 11 presents a direct relax the rd effect media 1000 units/l BuCHE, DiOHF3HA (10-4M), DiOHF3HA (10-4M) plus 1000 units/l BuCHE. In vessels pre-constricted PE, medium, 1000/l BuCHE and DiOHF3HA (10-4M) had no effect. DiOHF3HA (10-4M) plus 1000 units/l BuCHE had a significant effect on the vascular tone of the aorta of rats previously narrowed PE.

On Fig(a) presents a dose-dependent decrease in MAP (mm Hg), which indicates the expansion of blood vessels in response to DiOHF3HA the shot rats.

On Fig(b) presents a dose-dependent decrease in HR (beats/min) in response to DiOHF3HA.

On Fig presents the decrease in MAP (mm Hg), indicating the vasodilation in response to ACh in shot rats, where expanding the response to ACh was reinforced pre-treatment for 30 minutes using 3 mg/kg DiOHF3HA. The increase in MAP (mm Hg) indicates vasoconstriction in response to PE in shot rats, where the convergent responses to PE were reduced pre-treatment for 30 minutes using 3 mg/kg DiOHF3HA.

On Fig presents the curves of the concentration-response for PE obtained in the presence of control, DiOHF3HA in the presence and absence of BuCHE and DiOHF in aortic rings of rats. For DiOHF3HA in the presence of BuCHE and DiOHF observed inhibition of response to PE dependent on concentration.

The maximum contraction
(percentage of 3 mm Ca2+)
control101±1
DiOHF3HA 10-4M101±1
DiOHF3HA 10-4M+BuCHE35±6
DiOHF 10-4M18±2

On Fig presents the effect phosphatase (1000 units/l) and flavone-3-phosphate (F3P) (10-5M-10-4M) plus phosphatase curves on the concentration-response to ACh in endothelium intact aortic rings of rats (n=5). It was obvious that separately phosphatase had no effect on the relaxation response to ACh, however, in comparison with the control rings relaxation response to ACh were amplified in the presence F3P plus phosphatase at both tested concentrations.

pEC50Rmax
control7,31±0,03100±3
phosphatase 10-4M (P)7,30±0,04100±1
F3P 10-5The+P 7,80±0,06100±1
F3P 10-4M+P7,70±0,07100±1

On figa presents a dose-dependent decrease in MAP (mm Hg) in response to F3P and DiOHF the shot rats.

On fig.16b presents a dose-dependent decrease in HR (beats/min) in response to F3P and DiOHF the shot rats.

On Fig exposed region of the myocardium associated with risk (left panel)and the size of myocardial infarction (right panel) for the control samples (n=4)treated with DiOHF (2 mg/kg, n=2 and 5 mg/kg, n=3) and DiOHF3HA (2-7 mg/kg, n=3 and 6.6 mg/kg, n=4) group shot of sheep. AR/LV%=related risk area, which is expressed as a percentage of the total volume of the left ventricle. IS/AR%=of infarct size, expressed as a percentage of the area of infarction-related risk.*indicates a significant difference in infarct size between control animals and animals treated with diatom (6.6 mg/kg).

On Fig presents the time delay in filing (A and C) and termination (B and D) stimulation on the contralateral front leg compared to the ipsilateral anterior extremity, which is evaluated after 24, 48 and 72 hours after induced ET-1 shock and treatment with vehicle (A and B) or DiOHF3HA (15 mg/kg/day) (C and D) in rats with stroke, not the one to moderate severity.

On Fig presents the effect of delayed introduction of DiOHF3HA (15 mg/kg/day) or media on the area of infarction in the cerebral cortex (A) and striatum (B) in rats with a blow from minor to moderate severity.

Definition

As used in the present description, the term "alkyl" includes branched or unbranched hydrocarbon chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, octadecyl and 2-methylpentyl. These groups can be unsubstituted or unsubstituted by one or more functional groups commonly attached to such chains, such as hydroxyl, bromine, fluorine, chlorine, iodine, mercapto or thio, cyano, alkylthio, heterocyclyl, carboxyl, carbachol, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like, with the formation of such alkyl groups as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-foretel, carboxymethyl, cyanomethyl etc.

As used in the present description, the term "lower" includes linear or branched chain with 1-6 carbon atoms.

The term "alkylene" refers to a bivalent alkyl, as defined above, such as methylene (-CH2-), propylene (-CH2CH2CH2-), chlorethylene (-CHClCH2-), 2-Tibetan (-CH2CH(SH)CH2CH2-), 1-bromo-3-hydroxyl-4-methylpentan (-CHBrCH2CH(OH)CH(CH3)CH2-), ethylethylene, trimethylene, propylene-1, propylene-2, tetramethylene, 1-metallisation, 2-metallisation, 3-metallisation, 1-ethylethylene, 2-ethylethylene, pentamethylene, 1-methyltyramine, 2-methyltyramine, 3-methyltyramine, 4-methyltyramine and hexamethylene etc.

The term "alkenyl" includes branched or unbranched hydrocarbon chain containing one or more double carbon-carbon bonds.

The term "quinil" includes branched or unbranched hydrocarbon chain containing one or more triple carbon-carbon bonds.

"Aryl" means an aromatic carbocyclic group with a single ring (e.g. phenyl), multiple rings (e.g., biphenyl) or multiple condensed rings, from which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which are not necessarily mono-, di - or tizamidine. As used in the present description, the aryl groups are unsubstituted or, as specified, substituted by various groups in one or more capable replacement provisions.

As used in the present description, the term "cycloalkyl" refers to saturated carbocyclic radicals containing from three to twelve carbon atoms. Cycloalkyl may be monocyclic or may present polizeiliches the combined system. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As used in this description, cycloalkyl groups are unsubstituted or, as specified, substituted by various groups in one or more capable replacement provisions. For example, such cycloalkyl groups can be optionally substituted C1-C6the alkyl, C1-C6alkoxygroup, halogen, hydroxy-, cyano-, nitro-, amino-, mono(C1-C6)alkylamino-, di(C1-C6)alkylaminocarbonyl, C1-C6alkenyl, C1-C6the quinil, C1-C6halogenation, C1-C6halogenlampe, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-C6)alkyl.

The term "acyl" includes a group-C(O)R, where R represents alkyl or aryl, as described above, for example formyl, acetyl, propionyl or butyryl.

The term "alkoxy" includes-OR-, where R represents alkyl. The term "lower alkoxyalkyl" can mean linear and branched alkoxygroup with 1-6 carbon atoms, such as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy-, pentyloxy, isopentylamine, hexyloxy and isohexadecane.

the Ermin "amido" includes amide bond,- C(O)NR- (where R represents hydrogen or alkyl).

The term "amino" means an amino link: NR-, where R represents hydrogen or alkyl.

The term "carboxyl" means-C(O)O-, and the term "carbonyl" means-C(O)-.

The term "carbonate" means-OC(O)O-.

The term "sulfonate" means-S(O)2O-.

The term "carboxylic acid" means-C(O)OH.

The term "sulfonic acid" means-S(O)2OH.

The term "phosphonic acid" means-P(O)(OH)2.

The term "postamat" means-Ar-NHPO4-.

The term "complex phosphate ester" means-O-P(O)(OR)2.

The term "sulpham" means-Ar-NHSO3-.

The term "complex sulfonic esters" means-S(O)2-OR.

The term "sulfonate" means-S(O)2O-.

The term "complex phosphonate ester" means R-P(O)(OR)2.

The term "carboxylic acid" means-C(O)OH.

The term "sulfonic acid" means-S(O)2OH

The term "phosphonic acid" means-P(O)(OH)2.

The term "postamat" means-Ar-NHPO4-.

The term "carbamate" means-NHC(O)O-.

The hydrocarbon chain may be optionally interrupted by one or more heteroatoms.

When present, the linker group may be any of those known in the field of molecules, which are described in the present description.

As is clear from the above description, the spacer elements group D can no what to. Also from the above description it is clear that may be missing linker group.

Description of embodiments

The present invention relates to the derivatives of flavonoids and to compositions containing the derivatives of flavonoids, as well as to methods of their use.

It was shown that the presence of reactive oxidative residues (ROS) in living tissue is associated with many diseases in animals. Reactive oxidative substances may contain nitrogen and oxygen or oxygen atoms. Some examples of molecules of ROS include singlet O2H2O2free radicals such as OH·O2NO·and ROO·. Many of these residues are formed during normal metabolic activity, but the magnitude of their concentrations can be increased under conditions of oxidative stress associated with chronic inflammation, infections and other diseases.

Many of ROS molecules formed as a result of natural processes, such as oxygen metabolism and inflammatory processes. For example, if the cells use oxygen to obtain energy, free radicals are formed as a consequence of ATP production by the mitochondria. Exercise can increase levels of free radicals as well as environmental effects such as ionizing radiation (caused by industry, the influence of solar radiation, cosmic radiation and medical x-rays), environmental toxins, modified atmospheric conditions (e.g., hypoxia and hyperoxia), ozone, and nitrogen oxides (mainly from exhaust gases of automobiles, medical devices). It is also known that the levels of free radicals affect such stress lifestyle factors as cigarette Smoking and excessive alcohol consumption. Radicals may be joined to form other, causing more damage or more toxic substances, such as peroxynitrite ONOO-the reaction product of superoxide-radical and radical nitric oxide.

Another source of ROS are some therapeutic agents, such as anticancer drugs. Derivative anthracycline are highly effective anticancer drug for treatment of neoplastic diseases, such as acute leukemia, malignant lymphoma, etc. However, an undesirable feature of their application may be oxidative tissue damage that can lead to cardiomyopathy and possible heart failure. Thus, the presence of a therapeutic agent can cause the development of congestive heart failure (CHF). This feature of some therapeutic agents may limit the effectiveness and it is advisable to design an appropriate scheme of joint injection.

Thus, in one aspect the present invention relates to a method for prevention and/or at least weakening the individual violations, due to the introduction of a therapeutic agent, where the method includes a joint introduction to the individual:

i) a therapeutic agent; and

ii) an effective amount of at least one of the compounds of formula I, formula II, formula III or formula IV, where R1, R2, R3, R4, R5, R6, R7, R8, R9, U, Q, W, X, Y, Z and n have the same meaning as above, or its pharmaceutically acceptable salt or solvate.

In another aspect, the present invention relates to a method for prevention and/or at least mitigate the damage to the skin of the individual as a result of UV-irradiation, where the method includes the introduction of a therapeutically effective amount of the composition according to the invention. Preferably, in this aspect the composition is in the form of a sunscreen agent. The composition can be topically applied to the skin. The composition may contain emollients and moisturizers.

In another aspect, the present invention relates to a method of prophylaxis and/or prevention of the effects of aging, reduce the pronounced wrinkles and the treatment and or prevention of dry skin.

In another aspect, the present invention relates to a method of treatment of an individual with a disease or disorder, including oxidative damage, where the method involves the introduction of a therapeutically effective amount of the composition according to the invention.

Preferably, the disease or disorder, including oxidative damage, which are selected from the group consisting of cancer, heart disease, neurological diseases, autoimmune diseases, damage caused by ischemia and reperfusion, complications of diabetes, septic shock, hepatitis, atherosclerosis, Alzheimer's disease and complications arising from HIV or hepatitis, including hepatitis B.

In a specific embodiment, the individual is an animal. The animal can be selected from the group consisting of human, non-human primates, cattle, horses, pigs, sheep, goats, dogs, cats, birds, chickens or other poultry, ducks, geese, pheasants, turkeys, quail, Guinea pigs, rabbits, hamsters, rats and mice.

In some aspects of the invention, one or more derivatives of flavonoids administered simultaneously, separately or sequentially with one or more therapeutic agents.

When used in this combination one or more therapeutic substances and one or more derivatives of flavonoids according to the present invention can be entered as separate funds in the same or different times or they can be in the form of a single composition, containing both compounds.

Free radicals react with key organic substrates in cells, for example, lipids, proteins and DNA. The oxidation of such biomolecules can damage them, disrupting the normal functions, and can contribute to many illnesses. It was noted that certain organ systems are prone to higher levels of oxidative stress or nitrotyrosine stress. These are the most sensitive to damage to the organ systems represent the pulmonary system (exposed to high levels of oxygen), brain (manifesting intense metabolic activity, but with lower levels of endogenous antioxidants), eyes (constantly exposed to the damaging effects of UV-irradiation), cardiovascular system (suffering from changes in the levels of oxygen and nitrous oxide) and reproductive system (at risk as a result of intensive metabolic activity of spermatozoa).

Examples of relevant acute disturbance caused by the production of ROS include ischemic reperfusion, stroke, myocardial infarction or damage due to mechanical trauma or surgery. Some of the types of surgery, such as heart bypass surgery or transplant x is rorge, inevitably cause ischemia and reperfusion of the tissue. Typically, the individual before and/or during surgical intervention is administered one or more derivatives of flavonoids according to the present invention.

Chronic diseases can be selected from the group comprising cancer, cerebrovascular disease, atherosclerosis, a disease of the arteries, including coronary heart disease, peripheral vascular disease (including damage due to diseases such as diabetes), hypertension, pulmonary hypertension, chronic airway obstruction, emphysema, neurological diseases, autoimmune diseases, diabetic complications, septic and hypovolemic shock, burns, hepatitis and complications resulting from hepatitis and HIV. Another chronic disease may be selected from complications arising from the use of hyperbaric oxygen atmosphere or an atmosphere with a high oxygen pressure, which is often used to facilitate breathing, especially in a premature baby, including damage to the retina or other eye damage. Individuals with a relevant risk of chronic diseases can be diagnosed by analyzing the symptoms, diagnostic testing, enzyme markers or by genetic testing revealed what I genetic predisposition. Predisposition to certain acute diseases, such as myocardial infarction or stroke, can also be identified by genetic testing and may be an indication for prophylactic use of one or more derivatives of flavonoids for the exposed individual. Induced drug diseases that are caused ROS represent, for example, induced drug congestive heart disease.

If the disease or disorder is an impact or risk of impact, then the above-described composition is preferably introduced before the development impact as prophylaxis to reduce the risk of shock or within twelve hours (preferably within four hours) after the onset of shock.

An example of a pathological condition involving ROS ischemia, where the lack of blood flow to a certain area of the body leads to inadequate perfusion of tissues with oxygen. Ischemia causes damage to the tissue, where the severity of the damage depends on the period of time during which the tissue is deprived of oxygen, and, if appropriate reperfusion with oxygen after the ischemic event.

At least one compound of the present invention can be entered in many different ways, for example the local er, orally, subcutaneously, intramuscularly, intraarterially and/or intravenously.

The synthesis of compounds

The present invention relates to compounds of flavonoids formula I, II, III or IV, V, and to methods of synthesis of such compounds.

Derivatives of flavonoids

Phosphate derivatives of flavonoids receive a selective way to protect/unprotect.

The disodium salt of 3-hydroxyflavone-3-phosphate (5)

Synthesis of disodium salt of 3-hydroxyflavone-3-phosphate are presented with reference to figure 1. 3-hydroxyflavone (1) was subjected to fosfaurilirovania, then worked dibenzyl-N,N-diisopropylphosphoramidite and intermediate phosphate directly oxidized with m-chloroperbenzoic acid (mCPBA) to its corresponding protected phosphate. Complex phosphate ester was purified flash chromatography followed by recrystallization to yield 45%.

Complex phosphate ester was subjected to hydrogenolysis in ethanol with palladium hydroxide with the formation of phosphate, which is immediately converted to its disodium salt by adding a slight excess of 0.1 m solution of sodium hydroxide. Removing protection by hydrogenolysis provided a pure sample of the disodium salt of 3-hydroxyflavone-3-phosphate with the release of 73%.

Appropriate diammonium salt was obtained by ion-exchange chromatography using diethylaminoethyl the new column (DEAE) connection (5).

3',4'-dihydroxyflavone-3-phosphate (as disodium salt) (10)

A similar technique was used for the synthesis of analog trihydroxyflavone, as shown in figure 2.

Thus, 3',4'-dimensions-3-hydroxyflavone (6) were subjected to fosforilirovanii aminobutiramida-N,N-dibenzyldithiocarbamate in the presence of 1H-tetrazole with the formation of a complex of 3',4'-dibenzylidene-3-fanfictionjennifer (7), which was oxidized mCPBA to secure complex phosphate ester, a complex of 3',4'-dibenzylidene-3-phosphatidylinositide (8). As a result of these two steps was obtained the desired compound with a yield of 40% after recrystallization.

Then a complex phosphate ester was subjected to hydrogenolysis in ethanol with palladium with the formation of the desired 3',3'-dihydroxyflavone-3-phosphate (9), which was transformed by the addition of NaOH to the corresponding disodium salt, the disodium salt of 3',4'-dihydroxyflavone-3-phosphate (10).

Ester derivatives of flavonoids

3-hydroxyflavone-3-hemisuccinate (15)

3-hydroxyflavone-3-hemisuccinate (15) was obtained by reaction presented in figure 3. As a result of interaction of succinic anhydride (11) and benzyl alcohol (12) in the presence of 4-dimethylaminopyridine (DMAP) and pyridine in dichloromethane received monobenzoyl ester of succinic acid (13) as white crystalline flake is in with the release of 77%. Received protected derivative of succinic acid were subjected to the combination with 3-hydroxyflavone (1) in the presence of DCC and DMAP, forming a complex monumentally ether Flavon-3-hemisuccinate in the form of yellow or brown oil that solidified upon standing, with the yield up to 96%.

To give the desired 3-hydroxyflavone-3-hemisuccinate (15) carried out the reaction on a larger scale, removing protection from complex monobenzyl ether with the formation of the corresponding hemisuccinate using Pd(OAc)2in the system of solvents THF:EtOH:acetic acid.

3-hydroxyflavone-3-gemadept (19)

3-hydroxyflavone-3-gemadept (19) was synthesized in accordance with methods similar to those described above for hemisuccinate, as shown in figure 4.

Monobenzoyl ester of adipic acid (17) was obtained from adipic acid and benzyl alcohol in the presence of p-TsOH, obtaining the desired product as colourless oil with a yield of 34%.

Then secure adipic acid were subjected to binding of DCC with 3-hydroxyflavone (1) with the formation of complex monobenzyl ether Flavon-3-gemadept in the form of a yellow/brown resin with a yield of 59%. Hydrogenation of the compounds obtained in the presence of a catalyst Pd(OH)2using system-based solvents THF (9:1 THF:EtOH+0,05% acetic acid) drive the lo to the hydrogenolysis complex monobenzyl ether with the formation of Flavon-3-gemadept in the form of a yellow solid with a yield of 89%.

3',4'-dihydroxyflavone-3-gemadept (21)

The scheme for synthesis of 3',4'-dihydroxyflavone-3-gemadept (21) is shown in figure 5. In accordance with the above method 3',4'-dimensions-3-hydroxyflavone (6) and monobenzoyl ester of adipic acid (17) was subjected to the binding of the DCC to obtain complex monobenzyl ether of gemadept in the form of a brown resin with a yield of 59%.

Removing protection by hydrogenolysis on a small scale (100-500 mg) was performed gradually to complete within 3-5 hours, getting the 3',4'-dihydroxyflavone-3-gemadept (21) with the release of 33%.

Compositions and methods

Compounds of the present invention can be in the composition in a variety of media and delivery systems. The amount subject to the introduction of therapeutic compounds and the concentration of the compounds depend on the selected media or device, the clinical condition of the patient, side effects and stability of the compounds in the product. Thus, the physician uses the appropriate drug that contains therapeutic compound at the appropriate concentration, and selects the amount of preparation depending on the clinical experience in the concerned patient or in respect of similar patients.

In addition, the drug can be included excipients. Examples include supporting races is Writely, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. You can use any pharmacologically acceptable buffer, such as Tris buffer or phosphate buffer. Effective amounts of diluents, additives and excipients are those amounts that are effective with obtaining the drug, pharmaceutically acceptable in respect of solubility, biological activity, etc.

Thus, the composition according to the invention includes a therapeutic compound that can be joined together with conventional pharmaceutically acceptable carriers for local, oral or parenteral administration. The preparations can contain small amounts of adjuvants such as buffers and preservatives to maintain isotonicity, physiological stability and pH stability.

Introduction

Compounds according to the invention it is possible to enter both people and animals.

Compounds of the present invention can be introduced in the composition where the active compound is thoroughly mixed with one or more inert ingredients, also optionally including one or more additional active ingredients. The compounds can be used in any composition known to specialists in this field for vodenicharov and animals.

The composition according to the invention it is possible to introduce an appropriate way in accordance with the dosage form. For example, the injection can be performed intravenous, intraarterial, subcutaneous, intramuscular, etc.

For oral administration can be obtained solid or liquid unit dosage forms. Water-soluble forms can be dissolved in an aqueous medium together with sugar, flavorings and preservatives to form a syrup. Elixir is obtained using aqueous-alcoholic medium (e.g., ethanol) with an acceptable sweeteners, such as sugar and saccharin, together with flavoring. Suspension can be obtained together with the aqueous media using suspendisse tool, such as gum, tragakant, methylcellulose, etc. Also synthetic compounds flavonoids according to the present invention can be joined together with stabilizers, such as chelating metal restore means, such as ethylenediaminetetraacetic acid (EDTA), or regenerating agent such as sodium metabisulfite.

Appropriate compositions for parenteral administration are obvious to practitioners in this field.

Typically, therapeutic compound obtained as an aqueous solution with a concentration of from about 1 to about 100 mg/ml is Usually oncentrate is approximately from 10 to 60 mg/ml or about 20 mg/ml In some cases it may be necessary concentration below 1 mg/ml depending on the solubility and activity of the compounds selected for use. A sterile composition suitable for different methods of parenteral administration, including intradermal, intraarticular, intramuscular, intravenous, inhalation, and subcutaneous injection.

The compositions of the present invention can be in the form of sunscreen compositions for skin care, softening means for humidifiers.

To ensure a continuous or long-standing source of therapeutic compounds together with described in the present description, the compositions can be used delivery systems with delayed or prolonged release, including any of a number of biopolymers (biological basis), systems using liposomes and polymeric delivery systems, such as dendrimers. Such systems with a slow release suitable for preparations for local ophthalmic, oral and parenteral use.

Also a synthetic compound(I) of flavonoids according to the present invention can be in the form of nutriformance or nutraceutical means. For example, a synthetic compound(I) of flavonoids can be in the form of food, such as cereal porridge, written in the Cove, such as fruit juice, alcoholic beverages, bread, etc. for oral administration.

Vasodilator and antioxidant activity of derivatives of flavonoids

The effects of media, Flavon-3-gemadept (10-8-10-4M) and DiOHF (10-4M) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH was determined and expressed as a percentage of control. Obviously, the presence of the flavone-3-gemadept in any concentration has no effect on the production of superoxide.

The effects of media, Flavon-3-gemadept (F3HA) in the presence and absence butyrylcholinesterase (BuCHE, 1000 units/l) and DiOHF (10-4M) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH, expressed as a percentage of control, is illustrated with reference to Fig.6. In the absence of esterase see the lack of effect on the production of superoxide. In the presence of cholinesterase observed depending on the concentration of the inhibiting effect of flavone-3-remediate. This corresponds to removing emediately groupin vitrowith the formation of free hydroxyl derivative, 3-hydroxyflavone. Suppression of superoxide production by incorporating as Flavon-3-gemadept (19)and esterase differs from the activity of DiOHF (3',4'-dihydroxyflavone). The decrease in the concentration of superoxide and other ROS was associated with a possible is the reduction of myocardial damage, induced by the presence of these radicals.

Determined curves of the concentration-response on the Ca2+in the presence of media or increasing concentrations of flavone-3-gemadept (15) (F3HA, 10-8M-10-4M) in endothelium intact aortic rings isolated from rats. At lower concentrations (10-8M-10-5M) Flavon-3-gemadept had no effect on the contraction of aortic rings due to the Ca2+. At higher test level of 10-4M, Flavon-3-gemadept has a certain inhibitory effect is most likely due to the presence of esterase in the tissue of the aorta of the rat.

The effects of media (dH2O), 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-8M-10-4M) and DiOHF (10-4M) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH, expressed as a percentage of control. The concentration of superoxide remained constant throughout the investigated range of concentration DiOHF3HA, therefore, DiOHF3HA not have had on the formation of superoxide.

The effects of media, 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-6M-10-4M) in the presence and absence butyrylcholinesterase (BuCHE, 1000 units/l) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH, expressed as a percentage of the control, is illustrated with reference to Fig.7. For comparison also the presents expressed as a percentage of control the results of the use of DiOHF (10 -4M) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH. Concerning the presence of cholinesterase was found dependent inhibition concentration levels of superoxide.

Determined curves of the concentration-response for Ca2+in the presence of media or increasing concentrations of 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-6M-10-4M) in endothelium intact aortic rings isolated from rats. The magnitude of the contraction is expressed as a percentage of the initial reactions to the Ca2+(3×10-3M)observed before treatment DiOHF3HA. For DiOHF3HA at 10-4M observed a slightly inhibitory effect on Ca2+. Perhaps this effect is caused by the presence of a certain amount of esterase in the tissue of the aorta of the rat.

With reference to Fig illustrated by comparison of the curves of the concentration-response for Ca2+in the presence of media or 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-4M), in the presence and absence of BuCHE, with DiOHF in endothelium intact aortic rings isolated from rats. The magnitude of the contraction is expressed as a percentage of the initial reactions to the Ca2+(3×10-3M)observed before treatment DiOHF3HA. The presence of cholinesterase was significantly enhanced the inhibitory effect DiOHF3HA.

Figure 9 presents expressed as a percentage of the control effects of the media, the flavone-3-phosphate (F3P, 10-8M-10 -4M), in the presence of phosphatase (1000 units/l) and DiOHF (10-4M) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH. The presence of the flavone-3-phosphate caused depending on the concentration of reduced levels of superoxide. This effect is contrary to previous studies where it was shown that the presence of 3',4'-dihydroxyl group in ring B is crucial in reducing the levels of superoxide.

Determined curves of the concentration-response for Ca2+in the presence of media or increasing concentrations of flavone-3-phosphate (F3P, 10-6M-10-4M) in endothelium intact aortic rings isolated from rats. When higher concentrations of flavone-3-phosphate caused a partial inhibition of the contraction induced by calcium.

With reference to figure 10 presents the curves of the concentration-response on the Ca2+in the presence of the media or the flavone-3-phosphate (F3P, 10-8M-10-4M) in the presence and absence of phosphatase (P, 1000 units/l) in endothelium intact aortic rings isolated from rats. The magnitude of the contraction is expressed as a percentage of the initial reactions to the Ca2+(3×10-3M)observed prior to processing the flavone-3-phosphate. The presence of phosphatase was significantly increased inhibiting effects of flavone-3-phosphate.

The invention is illustrated in the following non-limiting examples.

Synthesis of derivatives of flavonoids

3-(benzyloxycarbonylamino)flavone

To a solution of monobenzyl ester of adipic acid (has 0.168 g, 0,754 mmol) in dichloromethane (10 ml) was added 3-hydroxyflavone (0,105 g, 0,442 mmol), dicyclohexylcarbodiimide (0,193 g, 0,933 mmol) and 4-dimethylaminopyridine (9,80 mg, 0,0802 mmol) and the mixture was stirred for 19 hours at room temperature in an atmosphere of N2. Was added water (50 μl), the mixture was stirred for 10 minutes and then added a simple diethyl ether (10 ml). The mixture was filtered, the filtrate was concentrated and purified flash chromatography (15-40% EtOAc in toluene) to obtain the complex monobenzyl ester as a yellow resin (0.16 g, 80%). A small portion was recrystallized from a mixture of EtOAc/petroleum spirit to obtain colorless powder; TPL=74-76ºC;1H NMR (399,7 MHz, CDCl3) δ 1,60-1,75 m, 4H, CO2CH2CH2); 2,31 (t, J=6,8 Hz, 2H, CO2CH2); to 2.55 (t, J=6,8 Hz, 2H, CO2CH2); 5,02 (s, 2H, CH2Ph); 7,20-7,28, 7,39-7,45 (2m, H, PhCH2, H3', 4', 5'); 7,34 (DD, 1H, J5,6=8.0 Hz, J6,7=7,6 Hz, H6); 7,46 (d, 1H, J7,8=8,0 Hz, H8); a 7.62 (DDD, 1H, J5,7=1,6 Hz, J6,7=7,6 Hz, J7,8=8,0 Hz, H7); 7,73-to 7.77 (m, 2H, H2', 6'); is 8.16 (DD, 1H, J5,7=1,6 Hz, H5).13C NMR (100,5 MHz, CDCl3) δ 25,29 (2C, CO2CH2CH2); 34,62, 34,91 (2C, CO2CH2); 67,30 (1C, CH2Ph); 119,21, 124,68, 126-29, 127,17, 129,29, 129,40, 129,63, 129,75, 13105, 132,36, 134,72, 135,06, 137,03, 156,7I, 157,45 (20C, Ar); 171,54, 173,27, 174,16 (3C, C=O). Elemental analysis: C, 73,54; H, 5,27; C42H36O8calculated C, 73,67; H, and 5.30%HRMS (ESI+) m/z 479,1469, C28H24NaO6[M+Na]+calculated 479,1471.

3-hydroxyflavone-3-gemadept

A mixture of 3-(benzyloxycarbonylamino)flavone (312 mg, 0.7 mmol) and Pd(OH)2(49,4 mg) in a mixture of 9:1 THF:EtOH+0,05% acetic acid (15 ml) was treated with H2within 5 hours. The crude product was filtered (celite), the filtrate was concentrated and the residue was purified flash chromatography (10-25% EtOAc in toluene+1% acetic acid) to obtain remediate as a pale yellow solid (0,211 g, 89%). A small portion was recrystallized from a mixture of EtOAc/white alcohol to obtain a colorless powder; TPL=118-121ºC;1H NMR (399,7 MHz, CDCl3) δ 1,66 of-1.83 (m, 4H, CH2CH2CO2); of 2.38 (t, J=6,8 Hz, 2H, CH2CO2); 2,63 (t, J=6,8 Hz, 2H, CO2CH2); 7,42 (DD, 1H, J5,6=8.0 Hz, J6,7=8.0 Hz, H6); 7,47-7,53 (m, 3H, H3', 4', 5'); 7,54 (d, 1H, J7,8=8,4 Hz, H8); of 7.70 (DDD, 1H, J5,7=1,6 Hz, J6,7=8.0 Hz, J7,8=8,4 Hz, H7); 7,81-7,86 (m, 2H, H2', 6'); 8,24 (DD, 1H, J5,6=8.0 Hz, J5,7=1,6 Hz, H5).13C NMR (100,5 MHz, CDCl3) δ 25,01, 25,20 (2C, CO2CH2CH2); 34,57 (2C, CO2CH2); 119,20, 124,66, 126,33, 127,21, 129,41, 129,76, 131-04, 132,40, 134,70, 135,10, 156,74, 157,60 (14C, Ar); 171,52, 173,38, 179,36 (3C, C=O). Elemental anal is C: C, 68,89; H, 4,91; C21H18O6calculated C, 68,85; H, 4.95%of, HRMS (ESI+) m/z 389,1000, C21H18NaO6[M+Na]+calculated 389,1001).

4'-(benzyloxy)-3-(benzyloxycarbonylamino)flavone

To a solution of 4'-benzyloxy-3-hydroxyflavone (1,00 g, 2,90 mmol), monobenzyl ester of adipic acid (1.30 grams, of 5.50 mmol) and DMAP (354 mg, 2.89 mmol) in dichloromethane (110 ml) was added dichloroethane (EDC) (843 mg, 4.40 mmol) and stirred the mixture overnight at room temperature. Then the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (×3), 1M HCl (×3), saturated NaHCO3(×3), saturated salt solution (×3), dried (MgSO4) and concentrated. The residue was purified flash chromatography (50% EtOAc/petrol) to give the complex benzyl ester as a brown oil, which was led from a mixture of EtOAc/petroleum spirit to obtain a colorless solid (900 mg, 55%); TPL 93ºC;1H NMR (500 MHz, CDCl3) δ 1,77 of-1.83 (m, 4H, CH2CH2), 2,42 (t, 2H, J=7.5 Hz, CH2CO)to 2.67 (t, 2H, J=6.5 Hz, CH2CO)to 5.13 (s, 2H, CH2Ph)of 5.15 (s, 2H, CH2Ph), to 7.09 (d, 1H, J7,8=8.5 Hz, H8), 7,35 (apparent d, 2H, J=8,5 Hz, H2',6'), 7,40-7,46 (m, 11H, 2×Ph-H6), of 7.69 (DDD, 1H, J5,7=1,5, J6,7=7,0, J7,8=8,5 Hz, H7), 7,85 (apparent d, 2H, J=8.5 Hz, H3',5'), 8,25 (4 1H, J=8 Hz, H5);13C NMR (125 MHz, CDCl3) δ 24,2 (×2), 33,6, 33,8 (4, CH2), 66,2, 70,1 (2C, CH2Ph), 115,0, 117,9, 122,4, 123,5, 125,0, 126,0, 127,4, 128,1, 128,2, 128,5, 128,7, 130,0, 133,0, 133,7, 135,9, 136,2, 155,5, 156,1, 161,1 (AT), 170,4, 172,0, 173, 0mm (3C, C=O); IR (thin film) 2937, 1760, 1730, 1646, 1602, 1507, 1468, 899 cm-1; Elemental analysis: C, 74,67; H, from 5.29, C35H30O7calculated C, 74,72; H, 5.37 percent.

4'-hydroxyflavone-3-gemadept

A mixture of 4'-(benzyloxy)-3-(benzyloxycarbonylamino)flavone (400 mg, 0,711 mmol) and Pd(OH)2(56 mg) in THF (10 ml), ethanol (1.2 ml) and AcOH (100 ml) was treated with hydrogen (50 psi) for 18 hours. Then the reaction mixture was filtered (layer Celica) and layer washed with THF. The filtrate was concentrated, the solid residue was purified flash chromatography (70% THF/toluene+1% AcOH) and the obtained solid substance was recrystallized from a mixture of THF/petroleum spirit to obtain the acid as a colourless solid (150 mg, 55%); TPL 177-180ºC;1H NMR (500 MHz, d6-DMSO) δ 1.56 to of 1.66 (m, 4H, CH2CH2in ), 2.25 (t, 2H, J=7,0 Hz, CH2CO)of 2.64 (t, 2H, J=7,0 Hz, CH2CO), of 6.96 (apparent d, 2H, J=8,5 Hz, H2',6'), 7,52 (t, 1H, J6,7=J7,8=7.5 Hz, H7), 7,80 (apparent d, 2H, J=7.5 Hz, H3',5'), 7,78 (m, 1H, H8), the 7.85 (t, 1H, J5,6=J6,7=7.5 Hz, H6), of 8.06 (d, 1H, J5,6=8.0 Hz, H5);13C NMR (125 MHz, d6-DMSO) δ 23,8, 23,9, 32,9, 33,3 (4C, CH2), 115,9, 118,5, 119,7, 122,7, 125,0, 125,6, 130,1, 131,9, 134,5, 154,9, 155,8 160,6 (Ar), 170,4 to 170.9, 174,3 (3C, C=O); IR 3257, 2944, 2869, 1765, 1706, 1595, 854 cm-1; HRMS (ESI+m/z 383,1123, C21H19O7(M+H]+calculated 383,1131.

3',4'-dimensions-3-(benzyloxycarbonylamino)flavone

To a stirred solution of 3',4'-dibenzalacetone (1,21 g, 2.68 mmol) in dry dichloromethane (100 ml) was added monobenzoyl ester of adipic acid (1,91 g 5,04 mmol)and then EDC hydrochloride (0,764 g, 3,98 mmol) and DMAP (0,324 g, to 2.65 mmol) and the resulting mixture was stirred for 3 hours at room temperature in an atmosphere of N2. The reaction mixture was concentrated under reduced pressure and resuspendable in ethyl acetate (100 ml). Then the suspension was washed with water (3×50 ml), 1M HCl (3×50 ml), saturated NaHCO3(3×50 ml) and saturated salt solution (3×50 ml). The organic extract was dried (MgSO4), filtered, concentrated under reduced pressure and was led yellow precipitate from a mixture of EtOAc/petroleum spirit with getting complicated benzyl ester in the form of friable yellow solid (1,58 g, 88%); TPL=84-85ºC;1H NMR (399,8 MHz, CDCl3) δ 1,70-1,80 (m, 4H, CH2CH2); of 2.38 (t, 2H, J=6,8 Hz, CH2CO)to 2.55 (m, 2H, CH2CO)to 5.10 (s, 2H, CH2Ph); 5,20 (s, 2H, CH2Ph); of 5.24 (s, 2H, CH2Ph); 7,01 (d, 1H, J7,8=8,4 Hz, H8); 7,26-7,49 (m, 19H, Ar, H6, 2', 5 6'); 7,62 (DDD, 1H, J5,7=1.2 Hz, J6,7=7,2 Hz, J7,8=8,4 Hz, H7); by 8.22 (DD, 1H, J5,5=7,6 Hz, J5,7=1.2 Hz, H5).13C NMR (100,5 MHz, CDCl3) δ 25,33 (2C, CH 2CH2CO2); 34,59, 34,93 (2C, CH2CO2); 67,30, 71,91, 72,59 (2C, CH2Ph); 114,77, 115,84, 119,06, 123,76, 123,84, 124,60, 126,19, 127,12, 128,25, 128,36, 129,15, 129,29, 129-64, 129,73, 130,12, 134,23, 134,89, 137,05, 137,54, 137,85, 149,61, 152,64, 156,53, 157,00 (32C, Ar); 171,49, 173,12, 174,18 3C, C=O). Elemental analysis: C, 75,39; H, 5,47; C42H36O8calculated C, 75,43; H, 5,43%, HRMS (ESI+) m/z 691,2303, C42H36NaO8[M+Na]+calculated 691,2308.

3',4'-dihydroxyflavone-3-gemadept

A mixture of 3',4'-dimensions-3-(benzyloxycarbonylamino)flavone (2,12 g, and 3.16 mmol) and Pd(OH)2(107 mg) in a mixture of 9:1 THF:EtOH containing 0.05% acetic acid (50,0 ml), treated for 5 hours H2at high pressure. The reaction mixture was filtered (celite) and concentrated to obtain a dark green solid. The green residue was purified flash chromatography (30 to 90% THF/toluene+1% acetic acid) followed by crystallization from a mixture of THF/white spirit with getting clean remediate in the form of a light brown solid (0,70 g, 56%); TPL=194-197ºC;1H NMR (399,8 MHz, CDCl3) δ 1,44-of 1.62 (m, 4H, CH2CH2); 2,10 (t, 2H, J=6,8 Hz, CH2CO)is 2.44 (t, 2H, J=6,8 Hz, CH2CO)of 6.73 (d, 1H, J5',6'=8,4 Hz, H5'); to 7.09 (DD, 1H, J2',6'=2.0 Hz, J5',6'=8,4 Hz, H6'); 7,16-7,22 (m, 2H, H6, 2'); 732 (d, 1H, J7,8=8,0 Hz, H8); of 7.48 (DDD, 1H, J5,7=1,6 Hz, J6,7=6,8 Hz, J7,8=8,0 Hz, H7); 7,94 (DD, 1H, J5,6=8,4 G is, J5,7=1,6 Hz, H5).13C NMR (100,5 MHz d6-DMSO) δ 25,30, 25,62 (2C, CH2CH2CO2); 34,43, 34,81 (2C, CH2CO2); 116,59, 117,42, 119,98, 121,41, 122,06, 124,13, 126,51, 127,07, 133,32, 136,04, 146,97, 150,65, 156,35, 157,27 (14C, Ar); 171,97, 173,46, 179,95 (3C, C=O). Elemental analysis: C, 68,89; H, 4,91; C21H18O6calculated C, 68,85; H, 4.95 %of, HRMS (ESI+) m/z 389,1000, C21H18NaO6[M+Na]+calculated 389,1001.

3,4'-di(benzyloxycarbonylamino)flavone

To a solution of 3,4'-dihydroxyflavone (500 mg, 1.97 mmol), monobenzyl ester of adipic acid (1.86 g, 7,88 mmol) and DMAP (481 mg, of 3.94 mmol) in dichloromethane (30 ml) was added dichloroethane (1.13 g, 5,91 mmol) and the mixture was stirred for 50 minutes at room temperature. Then the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (×3), 1M HCl (×3), saturated NaHCO3(×3), saturated salt solution (×3), dried (MgSO4) and concentrated. The residue was purified flash chromatography (50% EtOAc/petrol) to give the complex diapir in the form of a colorless oil, which was led from EtOAc/petroleum spirit to obtain a colorless solid (850 mg, 62%); TPL 79ºC;1H NMR (500 MHz, CDCl3) δ 1,76-to 1.82 (m, 8H, 2×CH2CH2), 2,42 (t, 2H, J=7,0 Hz, CH2CO), a 2.45 (t, 2H, J=7,0 Hz, CH2CO), 2,62 (t, 2H, J=7,0 Hz, CH2CO)to 2.65 (t, 2H, J=7,0 Hz, CH2CO), 5,12 (C, H, CH2Ph), 5,14 (s, 2H, CH2Ph), 7,25 (d, 2H, J=8,5 Hz, H2',6'), 7,31-7,37 (m, 10H, 2×Ph), 7,44 (t, 1H, J5,6=J6,7=8,5 Hz, H6), at 7.55 (d, 1H, J7,8=8,5 Hz, H8), 7,72 (TD, 1H, J6,7=J7,8=8,5, Jthe 7.5=1.5 Hz, H7), 7,89 (d, 2H, J=8.5 Hz, H3',5'), of 8.25 (DD, 1H, J5,6=8,5, J5,7=1.5 Hz, H8);13C NMR (125 MHz, CDCl3) δ 24,16, 24,17, 24,21, 33,5, 33,8, 33,9, 66,1, 66,3 (CH2), 118,0, 121,9, 123,5, 125,2, 126,1, 127,4, 128,1, 128,18, 128,22, 128,49, 128,53, 129,7, 133,7, 134,0, 135,9, 136,0, 152,8, 155,4, 155,5 (Ar), 170,3, 171,2, 172,1, 173,97, 173,0 (5C, C=O); IR 2943, 1765, 1732, 1652, 1501, 1465, 902 cm-1; Elemental analysis: C, 71,30; H, 5.56mm, C41H38O10calculated C, 71,29; H, 5,55%.

Flavon-3,4'-bis(gemadept)

A mixture of 3,4'-di(benzyloxycarbonylamino)flavone (435 mg, 0,629 mmol) and Pd(OH)2(50 mg) in EtOAc (5 ml) were treated for 2 hours with hydrogen, getting a grey precipitate. To dissolve the precipitate was added THF and the mixture was filtered (layer Celica). Layer washed with THF and the filtrate was concentrated. The solid residue was recrystallized from a mixture of THF/white spirit with obtaining bis(remediate) as a colourless solid (183 mg, 50%); TPL 133ºC;1H NMR (500 MHz, d6-DMSO) δ 1,55-1,70 (m, 8H, CH2CH2), 2,24 (t, 2H, J=7,0 Hz, CH2CO), and 2.27 (t, 2H, J=7,0 Hz, CH2CO), 2,63 (t, 2H, J=7,0 Hz, CH2CO)of 2.64 (t, 2H, J=7,0 Hz, CH2CO), 7,37 (apparent d, 2H, J=9,0 Hz, H3',5'), 7-55 (DD, 1H, J5,6=8,5, J6,7=7,5 Hz, H6), 7,80 (d, 1H, J7,8=8,5 Hz, H8), 7,88 (DDD, 1H, J6,7 =7,5, J7,8=8,5, J5,7=1.5 Hz, H7), of 7.96 (apparent d, 2H, J=9,0 Hz, H2',6'), 8,08 (DD, 1H, J5,6=8,5, J5,7=1.5 Hz, H5);13C NMR (125 MHz, d6-DMSO) δ 23,77, 23,82, 32,6, 33,2, 33,3; 44,3 (CH2), 118,7, 122,5, 122,6, 122,7, 125,1, 126,8, 129,7, 132,9, 134,8, 152,7, 154,9, 155,1 (Ar), 170,4, 171,1, 171,4, 174,3, 174,3 (5C, C=O); IR 3059, 2940, 2873, 1768, 1706, 1504, 759 cm-1; HRMS (ESI-) m/z 509,1441, C27H25O10[M-H]-calculated 509,1442.

3,7-di(benzyloxycarbonylamino)flavone

To a solution of 3,7-dihydroxyflavone (250 mg, 0,983 mmol), monobenzyl ester of adipic acid (921 mg, 3.90 mmol) and DMAP (220 mg, of 1.80 mmol) in dichloromethane (25 ml) was added dichloroethane (EDC) (517 mg, 2.7 mmol) and the mixture was stirred for 1 hour at room temperature. Then the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (×2), 1M HCl (×2), saturated NaHCO3(×2), saturated salt solution (×2), dried (MgSO4) and concentrated. The precipitate was filtered through a layer of silicon oxide, elwira a mixture of 50% EtOAc/petroleum spirit, getting a solid, which was recrystallized from a mixture of EtOAc/petroleum spirit to obtain complex diapir in the form of a colorless solid (565 mg, 91%); TPL 58ºC;1H NMR (500 MHz, CDCl3) δ 1,74-to 1.82 (m, 8H, CH2CH2×2), 2,39 (t, 2H, J=7,0 Hz, CH2CO), a 2.45 (t, 2H, J=7,0 Hz, CH2CO), 2,62-of 2.64 (m, 4H, CH2CO×2), 7,5-7,17 (m, 2H, H2', 6'), 7,30-7,36 (m, 10H, 2×Ph), 7,39 (d, 1H, J6,8=1,6 Hz, H8), of 7.48-7,51 (m, 2H, H3', 5'), 7,81-7,83 (m, 2H, 4' H6) of 8.25 (d, 1H, J5,6=9, H5);13C NMR (125 MHz, CDCl3) δ 24,1, 24,20, 24,21, 33,5, 33,80, 33,82, 34,0, 44,7, 66,2, 66,3, (CH2), 111,0, 119,5, 121,5, 172,5, 128,19, 128,22, 128,3, 128,5, 128,6, 128,7, 129,8, 131,3, 133,7, 135,9, 136,0, 154,8, 156,1, 156,6 (Ar), 170,3, 170,8, 171,5, 172,96, 173,0 (5C, C=O); IR 3071, 3035, 2944, 2876, 1760, 1726, 1615, 848 cm-1; Elemental analysis: C, 71,34; H, the ceiling of 5.60%, C41H38O10calculated C, 71,29; H, 5,55%.

3,7-dihydroxyflavone-3,7-bis(gemadept)

A mixture of 3,7-di(benzyloxycarbonylamino)flavone (565 mg, 0,818 mmol) and Pd(OH)2(65 mg) in EtOAc (10 ml) was treated with hydrogen for 3 hours. Formed a grey precipitate, and THF was added to until the precipitate has dissolved. The mixture was filtered (layer celite), the layer is washed with THF and the filtrate was concentrated. The solid residue was recrystallized from a mixture of THF/white spirit with getting dibasic acid as a colourless solid (311 mg, 76%); TPL 128ºC;1H NMR (400 MHz, d6-DMSO) δ 1,55-of 1.74 (m, 8H, CH2CH2×2), of 2.23 (t, 2H, J=7,0 Hz, CH2CO), 2,28 (t, 2H, J=7,0 Hz, CH2CO), 2,61 of 2.68 (m, 4H, CH2CO×2), 734 (m, 1H, H4'), 7,58-to 7.61 (m, 3H, H6, H2', 6'), to 7.68 (d, 1H, J6,8=1,6 Hz, H8), 7,87-7,89 (m, 2H, H3', 5'), to 8.12 (d, 1H, J5,6=8,8, H5);13C NMR (100 MHz, d6-DMSO) δ 23,7, 23,76, 23,78, 23,9, 32,9, 33,19, 33,24, 33,28 (CH2), 111,9, 120,5, 120,6, 126,6, 128,1, 129,0, 129,2, 131,7, 133,0, 154,9, 155,6, 155,9 (Ar), 170,4, 170,6, 171,1, 174,2, 14,3 (5C, C=O); IR 3035, 2952, 2920, 1762, 1708, 1112 cm-1; Elemental analysis: C, 63,64; H, 5,14%, C27H26O10calculated C, 63,53; H, 5,13%.

Obtaining phosphates flavonol

3-(dibenzalacetone)flavone

To a solution of 3-hydroxyflavone (3.00 g, 12.6 mmol) in dry dichloromethane (150 ml) was added dibenzyldithiocarbamate (12.5 ml, 38,0 mmol) and 1H-tetrazole (74,0 ml, and 31.7 mmol). The reaction mixture was stirred for 2 hours at room temperature in an atmosphere of N2. Then the mixture was cooled to -78°C was added m-CPBA (8,72 g, and 50.6 mmol). The mixture was allowed to return to room temperature and was stirred for an additional 45 minutes. The reaction mixture was washed 0,25M Na2S2O4(3×100 ml), saturated NaHCO3(3×100 ml) and water (2100 ml). The organic extract was dried (MgSO4), filtered and concentrated under reduced pressure to get crude white solid. The crude substance was purified flash chromatography (20-50% EtOAc in toluene) followed by crystallization from a mixture of EtOAc/petroleum spirit to receive the protected phosphate in the form of a white friable solid (5,28 g, 84 %); TPL=85-88ºC;1H NMR (399,7 MHz, CDCl3) δ 5,09-5,17 (m, 4H, CH2Ph); 7,22-7,30, 7,38-7,47 (2×m, 14H, Ar, H3', 4', 5',6'); 7,51 (d, J7,8=8,5 Hz, H8); of 7.69 (DDD, J5,7=1.5 Hz, J6,7=7,2 Hz, J7,8=8,5 Hz, 1H, H7); 7,93-of 7.96 (m, 2, H2',6'); 8,29 (DD, J5,6=7.5 Hz, J5,7=1.5 Hz, 1H, H5).13C NMR (100,5 MHz, CDCl3) δ 78,13 (2C, CH2Ph); 119,13, 124,86, 126,23, 127,22, 128,90, 129,36, 129,48, 129,62, 130,06, 131,03, 132,29, 135,06, 157,03, 157,10 (25C, Ar); 136,89 (1C, JC P=8.0 Hz, C-O-phosphate); 173,87 (1C, C=O),31P NMR (161,8 MHz, CDCl3) δ -7,45 (s, P=O). Elemental analysis: C, 69,81; H, 4,60; C29H23O6P calculated C, 69,88; H, 4.65%, the HRMS (ESI+) m/z 521,1126, C29H23NaO6P [M+Na]+calculated 521,1130].

The disodium salt of 3-hydroxyflavone-3-phosphate

A solution of 3-(dibenzalacetone)flavone (2,05 g, 4.09 to mmol) and palladium on carbon (10%, 0.25 g) in a mixture of EtOH:water (4:1, 250 ml) were treated for 3.5 hours H2at atmospheric pressure. The reaction mixture was filtered (celite) and the filtrate was treated with NaOH (0.50 g in 100 ml water). Water the mixture was concentrated under reduced pressure and then was led from a mixture of water/acetone to obtain phosphate in the form of light yellow crystals (of 1.03 g, yield 87%).1H NMR (499,7 MHz, D2O) δ 7,33 (DD, 1H, J5,6=8.0 Hz, J5,7=1.2 Hz, H6); 7,40-7,46 (m, 3H, H3', 4', 5'); 7,52 (d, 1H, J7,8=8,5 Hz, H8); to 7.64 (DDD, 1H, J5,7=1.2 Hz, J6,7=7.5 Hz, J7,8=8,5 Hz, H7); of 7.97 (DD, 1H, J5,6=8.0 Hz, J5,7=1.2 Hz, H5); 8,10 (m, 2H, H2', 6').13C NMR (100,5 MHz, D2O) δ 118,29, 122,92, 124,97, 125,06, 128,50, 129,15, 130,92, 131,33, 134,22, 155,06, 156,68 (13C, Ar); 136,11 (1C, JC, P=6,8 Hz, C-O-P); 177,15 (1C, C=O),31P NMR (161,8 MHz, D2O) δ of 2.9 (s, P), Elemental analysis: C, 49,68; H, of 2.51; C15H11Na2O6P calculated C, 49,74; H 2,50%.

4'-(benzyloxy)-3-(dibenzalacetone)flavone

To a mixture of 4'-benzyloxy-3-hydroxyflavone (1,00 g of 2.72 mmol), dibenzyl-N,N-diisopropylphosphoramidite (1.5 ml, 1.6 g, 4.4 mmol) in dichloromethane (30 ml) was added 1H-tetrazole (483 mg, 6,89 mmol) and the reaction mixture was stirred for 2 hours at room temperature. Added additional dibenzyl-N,N-diisopropylphosphoramidite (1.0 ml, 1.1 g, 1.5 mmol) and the reaction mixture was additionally stirred for 1 hour. Then the reaction mixture was cooled to -78°C was added m-CPBA (3.00 g, 12.1 mmol, 70% wt./mass.). Then the reaction mixture was heated to room temperature and was stirred for 45 minutes. The organic layer was washed 0,25M Na2S2O3(×3), saturated NaHCO3(×3), saturated salt solution (×3), dried (MgSO4) and concentrated. The residue was purified flash chromatography (50% EtOAc/petrol) to give a yellow solid, which was recrystallized from a mixture of EtOAc/petroleum spirit to obtain phosphate as a colorless solid (1.01 g, 58%); TPL 101ºC;1H NMR (500 MHz, CDCl3) δ 5,02 (s, 2H, CH2Ph), 5,16 (s, 2H, CH2Ph)to 5.17 (s, 2H, CH2Ph), 6,97 (apparent d, 2H, J=8,8 Hz, H3',5'), 7,29-7-36 (m, 15H, 3×Ph), 7,41 (t, 1H, J5,6=J6,7=8.0 Hz, H), 7,51 (l, J7,8=8,5 Hz, H8), to 7.68 (DD, 1H, J6,7=8,0, J7,8=8,5 Hz, H7), of 7.96 (apparent d, 2H, J=8,8, H2',6'), 8,30 (DD, 1H, J7,8=8,5, J6,8=1.5 Hz, H8);13C NMR (100 MHz, CDCl3) δ 69,9, 70,0 (CH2), 144,7, 117,9, 122,3, 123,7, 125,0, 126,1, 127,4, 127,8, 128,2, 128,4, 128,7, 130,7, 133,8, 135,8, 135,9, 136,1, 155,2, 155,7, 161,0 (Ar), 172,6 (1C, C=O);31P NMR (162 MHz, CDCl3) δ -5,3 (s, P); IR 3063, 3031, 1647, 1601, 1506, 983 cm-1; Elemental analysis: C, 72,60; H, of 5.05%, C35H29O7P calculated C, 71,52; H, a 4.83%.

The disodium salt of the flavone-3-phosphate

A mixture of 4'-(benzyloxy)-3-(dibenzalacetone)flavone (1,00 g of 1.65 mmol) and Pd(OH)2(120 mg) in THF (10 ml) and water (15 ml) was treated with hydrogen for 3 days. The mixture was filtered (layer celite), the layer is washed with THF and water, and the filtrate was concentrated. The solid residue was dissolved in THF (20 ml), was added water (10 ml) and triethylamine (600 μl, 4.3 mmol) and stirred at room temperature for 30 minutes. The mixture was concentrated and the residue was dissolved in water. The insoluble substance was removed by filtration and the solution was passed through the ion exchange column. Eluent was concentrated to obtain solid, which was recrystallized from a mixture of acetone/water to obtain phosphate in the form of a brown solid (226 mg, 36%); TPL 182-184ºC;1H NMR (500 MHz, D2O) δ 7,07 (apparent d, 2H, J=8.5 Hz, H3', 5'), a 7.62 (t, 1H, J5,6=J6,7 =7.5 Hz, H6), 7,72 (l, J7,8=8,5 Hz, H8), 7,92 (t, 1H, J6,7=J7,8=7.5 Hz, H7), 8,18 (d, 1H, J5,6=7.5 Hz, H5) 8,19 (apparent d, 2H, J=8,5, H2',6');13C NMR (100 MHz, D2O) δ 118,4, 122,5, 122,6, 124,9, 125,3, 131,2, 134,4, 155,0, 157,1, 157,2, 15S,5 (Ar), 176,3 (1C, C=O);31P NMR (162 MHz, CDCl3) δ 0,60 (s, P); IR 3281, 1597, 1579, 1542, 1393, 903 cm-1; HRMS (ESI-) m/z 333,0160, C15H10O7P [M+H]-calculated 333,0159.

Chloride 4'-(benzyloxy)-3-(trimethylammoniumchloride)flavone

A mixture of carboxypropylbetaine (0.5 g, 2.7 mmol) and thionyl chloride (2 ml), 3,26 g, 27 mmol) was stirred over night at room temperature. The solvent is evaporated, the residue was dissolved in nitrobenzene (2 ml) was added 4'-benzyloxyphenol (344 mg, 1.00 mmol). The solution was stirred for 30 minutes at room temperature and then for 5 hours at 65°C. was Removed under reduced pressure nitrobenzene (water bath to 80°C) and the residue was purified by filtration through a layer of silicon oxide (7:2:1 EtOAc:MeOH:H2O). The precipitate washed with THF and recrystallized from a mixture of ethanol/white spirit with a yellow powder (30 mg);1H NMR (399,7 MHz, CDCl3) δ 2,01 and 2.13 (2H, m, CH2), 2,78 (2H, d, J=6,8 Hz, CH2), 3,09 (9H, s, NMe3), of 3.25 to 3.35 (2H, m, CH2N), a total of 5.21 (2H, m, CH2Pb), 7,24 (2H, apparent d, J=9,2 Hz, H2',6'), 7,33-7,49 (m, 5H, Ph), 7,54 (1H, DD, J=8,0, 8.0 Hz, H6), 7,81 (1H, d, J7,88,4 Hz, H8), 7,88 (1H, is, J=8,0, 8,4 Hz, H7), 7,92 (2H, apparent d, J=9,2 Hz, H3',5'), 8,07 (1H, d, J5,6=8.0 Hz, H5).

Chloride 4'-(hydroxy)-3-(trimethylammoniumchloride)flavone

A mixture of flavone (30 mg) and Pd/C (5%, 5 mg) in EtOH (5 ml) was stirred for 2 hours in hydrogen atmosphere. The mixture was filtered and the solvent evaporated to obtain a yellow solid.

Vasodilator and antioxidant activity of derivatives of flavonoids

The effect of derivatives of flavonoids to reduce induced Ca2+

To determine the effect of flavonoids in response to receipt of extracellular Ca2+investigated the contractile response to exogenous introduction of Ca2+in the presence of flavonoids in a solution with a high content of K+(60 mm, KPSS), not containing Ca2+. First, the aortic rings within 45 minutes was balanced when the voltage of rest amount of 1 g in normal PSS, not containing Ca2+. Then the liquid medium for 45 minutes was replaced KPSS, not containing Ca2+to determine the control value reduction in response to Ca2+(3×10-3M). After 30-minute period of re-equilibration with PSS, not containing Ca2+determined the total contractile response to Ca2+(10-5-3×10-3M) KPSS in the presence of carrier, 3',4'-dihydroxyflavone, 3-hydroxyflavone-3-gamedip is the 3',4'-dihydroxy-3-gemadept, 3-hydroxyflavone-3-phosphate in the concentration range (10-8-10-4M). Before the study of reactions on Ca2+flavonoids kept within a 20-minute incubation period.

Relaxation due to derivatives of flavonoids

After testing the integrity of the endothelium rings repeatedly washed and re-balanced for 30 minutes before adding PE (10-8-2×10-7M) and 9,11-dideoxy-9α,11α-epoxytetradecane F(U46619, 10-9-10-8M) obtaining the current strength in the range of 40-60% of the value of reducing induced KPSS. The degree of pre-reduction for different groups coordinated by the reduction of the concentrations of PE and U46619. Received total curves of the concentration-response in the range of 10-8-10-4M 3',4'-dihydroxyflavone, 3-hydroxyflavone-3-gemadept, 3',4'-dihydroxy-3-gemadept, 3-hydroxyflavone-3-phosphate.

The experiments were conducted in the presence of esterase butyrylcholinesterase (BuCHE, 1000 units/l) in the case of derivatives of gemadept and phosphatase (1000 units/l) in the case of phosphate derivatives.

The effects of derivatives of flavonoids on the levels of superoxide in the analysis of in vitro

Production of superoxide anions in aorta isolated from rats, was determined using chemiluminescent the AI of lucigenin. The aortic rings were obtained as described above and then placed in chilled on ice Krebs-N-[2-hydroxyethyl]piperazine-N'-[2-econsultancy acid] (HEPES buffer) (composition (mm); NaCl 99,0, of 4.7 KCl, KH2PO41,0, MgSO4·7H2O 1,2, D-glucose 11,0, NaHCO325,0, CaCl2·2H2O 2.5, Na-HEPES 20,0). The aortic rings pre-incubated for 45 minutes at 37°C and pH 7.4 buffer Krebs-HEPES containing diethylthiocarbamoyl acid (DETCA, 10-3M) for inactivation of superoxide dismutase and β-nicotinamide-adenine-dinucleotide (NADPH, 10-4M) as a substrate for NADPH-oxidase, and 3',4'-dihydroxyflavone (10-4M) as a positive control, the media, 3-hydroxyflavone-3-gemadept, 3',4'-dihydroxy-3-gemadept, 3-hydroxyflavone-3-phosphate (10-8-10-4M). The background emission of photons was measured during 12 cycles of 96-hole tablet Optiplate, containing in each well of 0.3 ml buffer Krebs-HEPES plus lucigenin (5×10-5M) and a carrier or a flavonoid (10-8-10-4M). Each cycle was calculated every minute. After reading the background value of inkubirovanie rings of aorta transferred into the appropriate wells and re-calculated the emission of photons, as described above. Then the fabric was placed for 48 hours in a drying Cabinet at 65°C to allow normalization of superoxide production in the accordance with the dry mass of tissue.

The effects of derivatives of flavonoids on the levels of superoxide in the in vitro assays in the presence or absence of esterase

The effects of media, 3',4'-dihydroxyflavone-3-gemadept (21) (DiOHF3HA, 10-8-10-4M) and DiOHF (10-4M) in the presence and absence butyrylcholinesterase (BuCHE, 100, 300 and 1000 units/l) on the level of superoxide anions generated in isolated from rat aorta in the presence of NADPH, expressed as a percentage of control. The method used was as described above except adding butyrylcholinesterase.

The effects of derivatives of flavonoids on the levels of superoxide in the in vitro assays in the presence or absence of phosphatase

Expressed as a percentage of the control effect of the media, 3-hydroxyflavone-3-phosphate (10-8-10-4M), in the presence or absence of phosphatase (1000 units/l) on the level of superoxide anions generated in the aorta of rats in the presence of NADPH was determined as described above for the 3',4'-dihydroxyflavone-3-remediate. Measurable effect on the formation of superoxide anions was observed when using 3-hydroxyflavone-3-phosphate in the absence of phosphatase. Assumed that this is due to the presence of natural phosphatases in isolated from rat tissue.

Analysis of the effects of derivatives of flavonoids on the functioning of the blood vessels of the rat in vivo

The ane group is tsirovannykh male rats Sprague Dawley was intravenously injected unit dosage form of an aqueous solution of 3-hydroxyflavone-3-gemadept (15) and within a certain period of time, estimated blood pressure.

In rats revealed a significant decrease in blood pressure, which means the expansion vesselin vivodue to the derivatives of flavonoids. With the introduction of the second group of rats aqueous solution effect is not observed.

The experiment was repeated with aqueous solutions of other synthesized derivatives of flavonoids, which also led to various lower blood pressure in rats.

Screening for activity and pharmacokinetic parameters

Getting aorta of rats

Quickly dissected rats descending section of the thoracic aorta and placed in Krebs-bicarbonate solution. Removed the superficial connective tissue and adipose tissue surrounding the aorta, and the aorta was dissected into sections with a length of 2-3 mm and placed in containers for bodies.

The effect of flavonoids on the relaxation of ACh and SNP

After washing and re-equilibration for 30 minutes of aortic rings then pre-reduced to a submaximal degree through PE and U46619, which are used to obtain the current voltage value of 45-60% of the maximum contraction induced KPSS. In the study of the effects of flavonoids, flavonol, Flavon-3-gemadept (F3HA), 3',4'-dihydroxyflavone, 3',4'-dihydroxyflavone, 3',4-dihydroxyflavone-3-gemadept (DiOHF3HA) and flavone-3-phosphate (F3P) vasodilator re the work rings were incubated with one of the compounds for 20 minutes before their preliminary reduction to submaximal degree, receiving then the total curve of the concentration-response to ACh (100 nm-10 μm) or SNP (10 PM-1 μm). In the case of experiments using F3P in some experiments for cleavage of the phosphate used phosphatase 1000 units/L. Some experiments were performed in the presence and absence butyrylcholinesterase (BuCHE, 1000 units/l) for splitting adipate in DiOHF3HA and F3HA.

The effect of flavonols and flavones on contraction induced by PE

Ring for 20 minutes, incubated with DiOHF3HA in the concentration range (10-7-10-4M) or vehicle (0.1% dimethyl sulfoxide, DMSO). Then got the curve of the concentration-response (10-9-10-5M) in aortic rings with intact endothelium (EI). The experiments were performed in the presence and absence of BuCHE (1000 units/l) for splitting adipate in DiOHF3HA.

The effect of flavonols on the contraction induced Ca2+

To determine the effect of flavonoids in response to receipt of extracellular Ca2+investigated the contractile response to exogenous introduction of Ca2+in the presence of flavonoids in a solution with a high content of K+(60 mm, K+-PSS), not containing Ca2+. First, the aortic rings within 45 minutes was balanced in PSS containing no Ca2+when the off-load voltage value 1, Then the liquid medium for 45 minutes replaced the K+-PSS, not containing Ca2+, to determine the control value reduction in response to added Ca2+(3 mm). After 30 minutes period of re-equilibration PSS, not containing Ca2+determined the total contractile response to Ca2+(10-5-3×10-3M) in the K+PSS in the presence of vehicle (0.1% DMSO) or 3-hydroxyflavone, F3HA, DiOHF3HA or F3P in the concentration range (10-7-10-4M). Before the study of reactions on Ca2+flavonoids kept within a 20-minute incubation period. The experiments were performed in the presence and absence of BuCHE (1000 units/l) for splitting adipate in F3HA and DiOHF3HA. In the case of experiments using F3P in some experiments for cleavage of the phosphate used phosphatase (1000 units/l).

Relaxation caused by flavonoids

After testing the integrity of the endothelium rings repeatedly washed and re-balanced for 30 minutes before adding PE (10-8-2×10-7M) and 9,11-dideoxy-9α,11α-epoxytetradecane F2α(U46619, 10-9-10-8M) obtaining the current strength in the range of 40-60% of the value of reducing induced KPSS. Received cumulative curves of the concentration-response in the range of 10-7-10-4M for medium, 3'-hydroxyflavanone, F3HA, DiOHF3HA, F3P. The experiments were performed in the presence and absence of 1000 units/l BuCHE is La splitting adipate in F3HA and DiOHF3HA. In the case of experiments using F3P in some experiments for cleavage of the phosphate used phosphatase 1000/HP

The effect of flavonols and flavones in the vasodilation in response to ACh in the presence of oxidative stress

Control value total enhancing the response to ACh were compared with values obtained for aortic rings with intact endothelium, which were treated with pyragollole (2×10-5M). Also determined the effects of vehicle (0.1% DMSO), phosphatase (1000 units/l) or F3P (10-6-10-4M) in response to ACh in isolated from rat aortic rings, which was affected by pyragollole (2×10-5M). When the rings of aorta reached a stable value reduction with PE and U44619 level from 50 to 70% of the value of the voltage induced KPSS, added pyragollole and kept for 10 minutes prior to determination of the total concentration curves response to ACh. In some experiments using F3P for cleavage of the phosphate used phosphatase 1000/HP

The effect DiOHF3HA and F3P the shot rats

Male rats Sprague-Dawley (250-350 g) were anestesiologi pentobarbitone sodium (60 mg kg-1, intraperitoneally). Was isolated trachea and Coulibaly plastic tracheal tube (2.0 mm I.D.) and the rat was given the opportunity of spontaneous breathing.

Measurement of blood on the effect and heart rate

Was Coulibaly right carotid artery and connected to a cannula filled with heparinised saline solution (of 0.75 O.D., I.D. 0.58 mm), and was attached to the pressure sensor. Average and phase blood pressure was continuously measured and recorded on a multichannel recorder. The value of heart rate was obtained from the magnitude and phase of blood pressure using a tachometer.

Antioxidant and vascular effects of flavonol and dihydroxyflavone

Flavonol and dihydroxyflavone (DiOHFne) caused depending on the concentration of reduced levels of superoxide generated in the aortic rings of rats. At the highest tested concentration (0.1 mm) and flavonol, and DiOHFne reduced levels of superoxide to 36±3% of control. Flavonol had no effect on the relaxing effects of ACh or SNP. DiOHFne caused depending on the concentration of the relaxation in the aorta of rats, which was weaker than the effect of DiOHF. Flavonol caused depending on the concentration reduction reduction of aortic rings of rats induced by calcium, which was relatively weaker in comparison with the previous observations for DiOHF.

Antioxidant and vascular effects of flavone-3-gemadept (F3HA)

F3HA (10-7-10-4M) had no inhibitory effect on the formation of superoxide in the aorta of rats, however, the presence of butyrylcholinesterase (BuCHE, 100-1000 e is./ml) determined depending on the concentration increased inhibition effect F3HA (6). F3HA only at the higher concentration (0.1 mm) inhibited the contractile response to increasing concentrations of extracellular calcium.

Antioxidant and vascular effects dihydroxyflavone-3-gemadept (DiOHF3HA)

DiOHF3HA (10-7-10-4M) had no inhibitory effect on the formation of superoxide in the aorta of rats, however, the presence of butyrylcholinesterase (BuCHE, 1000 units/ml) led to depend on the concentration of the inhibitory effect. DiOHF3HA separately had no effect on the relaxation response to ACh or SNP. In contrast, in the presence of BuCHE (1000 units/ml) DiOHF3HA significantly increased the susceptibility relaxation response to SNP. Similarly, DiOHF3HA individually had little effect on induced by calcium reduction of the aorta in rats, however, in the presence of BuCHE (1000 units/ml) DiOHF3HA (0.1 mm) had an inhibitory effect equivalent DiOHF. This suggests that when adipate was removed by esterase, gemadept was active to the same extent as the original DiOHF. It was also revealed that DiOHF3HA causes direct relaxation of pre-reduced aortic rings of rats only in the presence of esterase (11).

DiOHF3HA (0,1, 0,3, 1, 3 mg/kg) was administered by intravenous infusion, providing at least a 30 minute break between injections, and was determined to change the maximum values cf the last blood pressure and heart rate. DiOHF3HA caused a dose-dependent decrease in blood pressure (figa) and heart rate (fig.12b). In a separate group of experiments ACh (0.3 mg/kg intravenously) and phenylephrine (PE, 30 mg/kg intravenously) was administered by injection before and 30 minutes after DiOHF3HA (3 mg/kg intravenously), the time during which blood pressure and heart rate returned to control level. DiOHF3HA was greatly enhanced depressor response to ACh and weakened induced PE increased blood pressure (Fig).

In aortic rings of rats in the absence or presence of cholinesterase, DiOHF3HA (0.1 mm)had no effect on endothelium-dependent relaxation in response to calcium ionophor A23187 or izoprenalin. Entered separately DiOHF3HA (0.1 mm) had no effect on the contraction induced by PE, but caused a significant inhibition in the presence of esterase. The degree of inhibition was similar to the level observed in response to the presence of DiOHF in the same concentration (0.1 mm).

Antioxidant and vascular effects of flavone-3-phosphate (F3P)

F3P or phosphatase (1000 units/l) had no effect on the formation of superoxide in the aorta of rats, however, in the presence of phosphatase F3P caused dependent inhibition concentration levels of superoxide. F3P in the presence of phosphatase increased susceptibility of aortic rings of rats to Russ is ablany, due to ACh, but not SNP. Oxidative stress, caused by the presence pyragollole (2×10-5M), significantly reduced the maximum response to ACh, but the reaction was recovered in the presence F3P with phosphatase. In response to SNP was not affected by any of these treatment options. F3P caused a slight inhibition of the contraction induced by calcium, however, the presence of phosphatase was greatly enhanced the effect.

F3P(0,1, 0,3, 1, 3, 10 mg/kg) was administered by intravenous infusion, providing at least a 30 minute period between injections, and was determined to change the maximum values of mean arterial pressure and heart rate (figa). DiOHF3HA caused a dose-dependent decrease in blood pressure and heart rate (figa and 12b), however, the depressor response in comparison with DiOHF (1 mg/kg intravenously) was negligible.

The summarized results

Data of the study was to assess vascular and antioxidant activity of flavonols, 3',4'-dihydroxyflavone (DiOHFne), 3',4'-dihydroxyflavone (DiOHF), Flavon-3-gemadept (F3HA), 3',4'-dihydroxyflavone-3-gemadept (DiOHF3HA) and flavone-3-phosphate.

The Flavon-3-gemadept (F3HA) had no antioxidant or vascular activity when used alone, however, in the presence of cholinesterase, Rasse is looking adept in the case of substitution, watched ability F3HA inhibition induced by calcium reduction.

Dihydroxyflavone-3-gemadept (DiOHF3HA) when used alone had no antioxidant or vascular activity, however, in the presence of cholinesterase splitting adept in the case of replacement, watched ability DiOHF3HA to inhibit the levels of superoxide generated in the aorta of rats, inhibition induced by calcium reduction and cause direct relaxation of aortic rings of rats. In the presence of esterase activity level DiOHF3HA was similar DiOHF. The shot rats DiOHF3HA caused depending on the concentration of lowering blood pressure and frequency of the heart beat.

The flavone-3-phosphate (F3P) one had no antioxidant or vascular activity, however, in the presence of phosphatase that cleave phosphate in the case of replacement, watched ability F3P to inhibit the levels of superoxide generated in the aorta of rats, inhibition induced by calcium reduction and enhance endothelium-dependent relaxation in the presence of oxidative stress. In the presence of phosphatase activity level F3P was similar DiOHF. The shot rats F3P caused only a slight decrease in blood pressure and heart frequency reduction, depending on the concentration. The effects were much weaker than observed what passed for DiOHF.

Cardiotoxin step 3',4'-dihydroxybutanedioate (DiOHF3HA) after ischemia-reperfusion

Evaluated the ability of synthetic flavonol, 3',4'-dihydroxybutanedioate (DiOHF3HA), to prevent myocardial ischemia and reperfusion injury have shot the sheep. Unlike the parent compound DiOHF adipate derivative was soluble in aqueous solution, especially in the water.

DiOHF3HA entered in aqueous solution, caused a dose-dependent decrease in the size of lesion of heart attack, similar to the reduction, due to the same molar dose of DiOHF when dissolved in DMSO.

Intravenous infusion DiOHF3HA did not modify the hemodynamic parameters (blood pressure, heart rate, end-diastolic pressure in the left ventricle (LV-EDP)).

Because after ischemia-reperfusion damage of the heart in shot sheep DiOHF3HA had cardiotoxicity effect to the extent equivalent to the original connection, these data support the hypothesis that this new derivative compound effectively convertsin vivoin the original connection.

Surgical treatment

Researched five shot groups adult Merino (castrated rams, 35-45 kg):

(1) Control (n=5)

(2) DiOHF (2 mg/kg, n=2)

(3) DiOHF3HA (2.7 mg/kg, n=3)

(4) DiOHF (5 mg/kg, n=3)

(5) DiOHF3HA(6.6 mg/kg, n=4)

Anesthesia was caused by the intravenous injection of thiopentone sodium (15 mg/kg) and maintained subsequent tracheal intubation using izoflurana (1,5-2%). For a sample of arterial blood and check blood pressure injected with a catheter in the right facial artery. Intravenous infusion was performed through a catheter inserted in the jugular vein. Effects on the heart was carried out by opening the left side of the chest, performed in the fourth intercostal space. To measure the pressure in the left ventricle (LVP) in the left ventricle via the left atrium is injected with a pressure gauge with a tip-catheter 4F. Additional slastikov cannula was inserted in the eyelet of the left atrium for injection of lignocaine and for infusion of blue dye Evans. From epicardium was dissected left anterior descending coronary artery (LAD) directly distal in relation to the second diagonal branch, and around it were placed time sensor pass 2 mm, the registration thread for observation of blood flow in LAD. On LAD, proximally relative to the sensor, put silk suture, and both ends of the silk thread threaded through a plastic tube for the formation of a vascular loop.

Scheme of the experiment

The animal was allowed to stabilize for 10-15 minutes after completion of the surgical procedure. Then on the EC was randomly divided into different groups of treatment. For all sheep were check the source level for 30 minutes with subsequent ischemia for 1 h and reperfusion for 3 hours.

In the experiment, measurements of hemodynamics were recorded in 5-minute intervals and blood samples were collected at predefined points in time. After 30 minutes of ischemia were processed by flavonols. DiOHF was dissolved in 2 ml of DMSO plus 14 ml of a mixture of polyethylene glycol:water (1:1). DiOHF3HA was dissolved in 20 ml of 0.1 m Na2CO3. Drugs were injected intravenously at 1 ml/min. Chose two doses DiOHF3HA (2.7 mg/kg and 6.6 mg/kg) to achieve a molar doses, equivalent to the original connection DiOHF (2 mg/kg and 5 mg/kg, respectively). Control animals received no intravenous solutions have not entered. As necessary to mitigate arrhythmias were used lignocain.

The definition of the exposed region and size of lesion of heart attack

The boundaries of the exposed region of the myocardium and the focus size of infarction was determined by staining blue dye Evans and triphenyltetrazolium (TTC). After reperfusion for 3 hours re-corked LAD in the plot of the original blockage. Immediately after intravenous injection pentobarbitone (100 mg kg-1), stopping the contraction of the heart, the left atrium was entered by injection of blue dye e is the ANS (1,5%, 40 ml) to determine at risk of infarction. The heart was quickly removed and the left ventricle was dissected on transverse slices with a thickness of about 1 cm On the same drugs were outlined unpainted area at risk. Then the slices for 20 minutes (37°C, pH of 7.4) were incubated with 1% TTC in 0.1m phosphate buffer sodium. The sections were outlined area stricken by a heart attack. Exposed region of the myocardium and the focus size of infarction was measured by computerized layout. Exposed region of the myocardium was expressed as a percentage of the final volume of the left ventricle (AR/LV%), and the focus size of the infarct was expressed as a percentage of the exposed area of the myocardium (IS/AR%).

Markers of myocardial infarction in plasma

Were collected in chilled heparinized tubes samples of arterial blood (5 ml) in the initial time moment during ischemia and at three time point during the reperfusion period (1 hour, 2 hours and 3 hours). After centrifugation at 4°C. plasma samples were stored at -20°C before measurement, determining the levels of lactate dehydrogenase and creatinekinase.

Results

In the following description of the final results of the dimensions of the hearth of myocardial infarction for 5 groups with different treatment options. Given the efficacy of higher doses DiOHF3HA, changes in all other parameters, the cauldrons only in relation to the comparison of the control group animals and groups of animals DiOHF3HA (6.6 mg/kg).

In the control group one of the sheep died due to ventricular fibrillation in the first 10 minutes of reperfusion. Therefore, the control data based on the number of sheep n=4.

The size of the focus of myocardial infarction

In this study, 5 groups of sheep with different processing region of the left ventricle, subjected to ischemia (AR), was similar (11%-20%, Fig, left panel). In contrast, normalized to AR the focus size of infarction in the groups treated with DiOHF and DiOHF3HA was less compared with the control animals (Fig, right panel). Specifically, the focus size of the infarct, normalized with respect to the exposed area (IS/AR), was reduced to a value of from 83±4% in controls to 49±8% for DiOHF3HA (6,7 mg/kg) and up to 47±8% for DiOHF (5 mg/kg). At lower doses DiOHF3HA (2.7 mg/kg) and DiOHF (2 mg/kg) IS/AR was 64% and 73%, respectively.

The flow in LAD

The initial value of the flow in the LAD (7-9 ml/min) was similar in the control group of sheep in the group DiOHF3HA (6.6 mg/kg). During ischemia in all animals the flow in the LAD fell to zero. During the early stage of reperfusion in all sheep arose coronary hyperaesthesia. Usually this is a temporary increase in the flow in the LAD returned to the original levels within 30-60 minutes of reperfusion. The return flow to a former condition was faster in the group DiOHF3HA./p>

Hemodynamic response to ischemia/reperfusion

Initial blood pressure in two groups of sheep did not differ (average within 30 minutes ~80 mm Hg). In contrast, HR rest of the control sheep (90±4 BPM) was lower (P<0.05) in comparison with sheep, processed DiOHF3HA (105±3 beats per minute). This difference remained throughout the course of the experiment. As MAP and HR were unchanged during the 20-minute infusion in the introduction DiOHF3HA. In addition, in any of the groups of sheep were not observed significant changes in blood pressure or HR during myocardial ischemia and reperfusion.

LV-EDP in two groups of sheep did not differ (~11 mm Hg), however, the maximum positive value of the first derivative of LVP (dP/dtmax) the control sheep (1454±62 mm Hg/second) was less (P<0.05) in comparison with sheep, processed DiOHF3HA (1967±103 mm Hg/second). This difference remained throughout the course of the experiment. As LV-EDP and dP/dtmaxwere unchanged during the 20-minute infusion in the introduction DiOHF3HA. In addition, in any of the groups of sheep were not observed significant changes in LV-EDP and dP/dtmaxduring ischemia-reperfusion. The beneficial effects of the medicinal product on the hemodynamics and more clearly manifested after 24 hours of reperfusion.

The shot of the sheep through 1 cheesepie and 3 hours of reperfusion the content of lactate dehydrogenase in plasma increased to 227±141 units/l in the control group (n=3) and 67±32 units/l in the group, processed DiOHF3HA (n=4). These sheep the content of creatine kinase in plasma increased to 2411±958 units/l in the control group and in 1579±936 units/l in the group treated DiOHF3HA.

Recovery after ischemic stroke in rats, due to the synthetic flavonoids

Markers of myocardial infarction in plasma

Ischemic stroke was investigated in in the minds of rats, with daily monitoring of neurological function and post-mortem morphological assessment of brain infarction within 72 hours after impact. Unilateral transient ischemia and reperfusion brain of conscious rats induced by injection of active vasoconstrictor substances, endothelin-1, from the outside, but near the right middle cerebral artery MCA, (through pre-implantirovannoi the guide tube). The resulting kick was classified according to a scale from 0 to 5 in accordance with the directly resulting behavioral response, and 3 hours after stroke and in the future at time intervals of 24 hours was administered by intravenous infusion putative neuroprotective compounds.

Surgical treatment

Male Hooded rats Wistar (280-340 g) was anestesiologi pentobarbitone sodium in a volume of 0.6 ml (60 mg/kg intraperitoneally) for injection intravenously (i.v.) catheter in the yoke is left Vienna for the urgent introduction of a medicinal product. Then the guide cannula caliber 23 stainless steel stereotaxically implanted in pear-shaped gyrus of the cerebral cortex, 2 mm dorsalgia right MCA (0-2 mm front, -5,2 mm on the side and -5,9 mm ventral). The cannula was fixed dental acrylic cement and the skull was inserted two small screws. The skin on the skull was closed by sutures. The rats were kept separately during the day/night cycle of 12 hours at a temperature of 18-22°C and allowed to recover for 5 days before induction of shock.

Induction stroke

We are in conscious rats induced narrowing of the right middle cerebral artery (MCA) by introducing the active vasoconstrictor tools, endothelin-1 (ET-1), (60 pmol in 3 μl of saline for 10 minutes) through the device for injection 30 caliber, which was performed at 2 mm above the end of the previously implanted stereotactic guide cannula. Device for injection is kept in place by a sleeve of polymeric tubing, and the rat was placed in a transparent Plexiglas chamber for observation during the injection of ET-1. During the induction stroke watched counterclockwise rotation, compression and drawing contralateral front paw, which confirmed the correct positioning of the cannula. These behavior changes occurred within 2-10 minutes after the start of inyecci the ET-1, when using this model, other researchers have described similar behavior. Was used to scale the severity of impact, based on these changes in behavior during the strike, and it was shown that the treated carrier rats, which were determined by a higher estimate of the impact, had higher amounts of hearth infarction and neurological disorders. It was hypothesized that rats not showing any behaviour change had no impact, and they were excluded from the study. Rats who were given a placebo, were subjected to the implantation of the cannula, but they have not performed any injection of ET-1. Rectal temperature was determined using sensor thermistor to development impact and in 30 - or 60-minute intervals for 3 hours after a stroke.

Assessment of functional outcome

All behavioral tests were performed before any procedures to surgery, day 1), immediately before induced ET-1 MCA occlusion (before ischemia, day 6) and after 24, 48 and 72 hours after induced ET-1 MCA occlusion. The behavior of each rat was compared with the behavior before the impact, thus, each rat served as its own control. All rats were identified by the cipher so that the researcher had no information about the treatment conditions. Neuro is logicheskie pathology was evaluated using a scoring scale of neurological disorders, based on registration of pathological postures and hemiplegia. Pathological posture was assessed by hanging rats by the tail and calculation of bending of the thoracic and vytjagivanii front legs. Hemiplegia was evaluated by placing rats on a raised platform. Thought disorder was present, if the rear limb, contralateral relatively affected by infarction of the cerebral hemispheres, slid off the edge of the platform and/or if the contralateral anterior limb slipped in the absence of contact of the muzzle and whiskers with the surface. Each behavior was rated on the following scale: 0 = no disorder; 1 = slight; 2 = moderate and 3 = severe. Thus, the sum of the estimates of the maximum score for neurological disorders was 12. A score of 0 was considered normal.

Unilateral absence of sensitivity was assessed using a dough consisting of areas of adhesive tapes (adhesive label Avery, diameter 100 mm) at the distal-radial region of each wrist. The location of the first tape was chosen randomly between contralateral and ipsilateral limbs. The tape was applied simultaneously on both front legs before placing the animal in a Plexiglas cage and measurement using a stopwatch, record the time the backside of the LCD to touch and delay time to address each of the stimulus to the contralateral and ipsilateral forelimb. The test was completed after 180 seconds, if the tapes have not yet been removed.

Treatment drug

All compounds were administered single intravenous loading dose bolus over 3 hours after stroke in concentration, reaching 37 µmol/kg Also used control the media, and they were specific for each connection. After the first dose 3 hours after hitting an animal once a day, after 24 and 48 hours was administered by injection drug or the media. Total input injection volume of each compound was approximately 300 ál in the case of rats with a weight of 300 g with immediate washing, 200 μl of saline to ensure the full implementation of the drug.

Quantitative assessment of ischemic damage

At 72 hours after ischemia, rats were decapitated, the brain was removed and frozen in liquid nitrogen and kept at -80°C. Front cryostate sections (16 μm) were cut in eight pre-defined frontal planes during brain from -3,2 to 6.8 mm on bregma. The focus of myocardial infarction was assessed in three series of uncolored sections based on the observation that the damaged area in unpainted microscopic preparations of brain slices visible to the naked eye as clearly delineated opaque or dark areas, then the AK normal tissue is mostly transparent. Due to the application of the principle of ballistic light propagation and the use of simple devices, combined with computerized image analysis, unpainted sections for microscopic preparations, which watched the affected area were clearly visible on the monitor. Light emission was held in camera directly through the transparent unaffected tissue, while the damaged tissue rays of light dissipated. Then the damaged area, you can easily outline, choose and register using image analysis. The total focus of infarction was calculated by integrating the cross-sectional area in the damaged area on each stereotactic level during the intervals between levels. A correction for the influence of swelling on the area of infarction was introduced using the following formula:

(the area of the normal hemisphere/area affected by the infarct hemisphere)×area of infarction.

Microscopic preparations were also identified by the cipher so that the researcher did not have information about the treatment conditions.

Assessment of impact

Rats were observed characteristic stroke neurological behavioral disorder within 2-10 minutes of injection of ET-1, but not after the introduction of separate equal volume of saline. These disorders include specific is such behavioral responses, such as compression and inability to pull the contralateral front leg and contralateral rotation in the direction to the blockage. The rotation was preceded by cleaning, and it was observed almost in all rats. Cleaning was a stereotypical way, where for cleaning the muzzle was followed by a cleansing of the body in a continuous movement. Other behavioral responses, such as knocking teeth, biting cells and the occurrence or protrusion of the tongue were observed less frequently. Such behavioral responses observed during impact, can be classified based on their severity and gravity. It was also shown that the treated carrier rats (n=40) there is a positive relationship between impact assessment and grading the assessment of neurological disorders, as well as assessment of the impact and displacement of the center of a heart attack. After evaluation of rats with stroke were combined into pairs based on the same estimates of the impact so that the magnitude of the impact assessment were evenly distributed between groups treated with media and medicine. Then these rats were identified by the cipher so that the rest of the evaluation can be performed without information about option processing.

Stratified treatment drug

To predict functional outcome and survival of Uluda with a punch, to facilitate clinical care for patients with stroke and to properly stratify the processing group in clinical trials using predictive models. The use of such models in animals with experimental stroke has not previously been undertaken. In the case of the model ET-1 MCA occlusion, there is the opportunity to observe behavioral responses during the induction stroke and apply point scale assessing the severity of impact, based on these reactions. Therefore, it is possible to predict which animals will be a severe blow, and which animals will blow from mild to moderate severity. This method also gives the opportunity to predict areas at risk, which is theoretically possible to recover after hitting a neuroprotective agents. When severe blow for the neuroprotective action remains small exposed area as a hotbed of heart attack is more than 70% of the total volume of the hemisphere. However, when the shock from mild to moderate severity see more extensive exposed area for recovery, and therefore there is greater opportunity for neuroprotective actions. Indeed, at present, clinical studies of patients by MRI similarly used to stratify patients, Thu is to determine one subsequent treatment drug most likely to be favorable. For this reason, animals that at the end of the analysis processing of the medicinal product had 4 or 5 corresponding to severe shock, removed and re-analyzed the data in groups with a blow from mild to moderate severity (rating 1-3) for all subsequent test compounds.

3',4'-dihydroxyflavone (DiOHF)

In the initial experiments conducted in the laboratory of the authors of the invention was evaluated delayed neuroprotective ability DiOHF (10 mg/kg)was administered intravenously over 3 hours after stroke. Each rat was injected 3 loading dose DiOHF, dissolved in 20% DMSO, 40% polyethylene glycol and 40% of sterile water for injection. Introduction 3',4'-dihydroxyflavone (DiOHF) rats with stroke of moderate severity (estimate 2-3, n=6 and 5, the connection and the carrier, respectively) weakened neurological disorders after 48 and 72 hours and eliminated the increase in the assessment of unilateral absence of sensory information ("test tape") after hitting observed in the control rats, which were administered endothelin only together with the carrier medicines. It is important to note that DiOHF reduced the volume of the hearth of a heart attack, resulting in the cerebral cortex, and fully before the rotated development of a heart attack in the striatum of the brain.

Treatment of rats with a blow from mild to moderate severity DiOHF (10 mg/kg) significantly reduced the area of infarction within the cerebral cortex and striatum in comparison with treatment by the media. Treatment of rats with a blow from mild to moderate severity by DiOHF significantly improved neurological outcome in comparison with rats treated with media.

3',4'-dihydroxyflavone-3-gemadept (DiOHF3HA) for the treatment of stroke

Each rat was injected 3 loading dose DiOHF3HA (15 mg/kg/day intravenously), dissolved in buffered Na2CO3physiological solution (0.1 M, pH 7.8) for injection.

MediaDiOHF3HA
category No. 2 (n=3)No. 2 (n=1)
category No. 3 (n=4)No. 3 (n=4)
category No. 4 (n=7)No. 4 (n=6)

After a hit in any of the treatment groups were not observed significant weight loss. The internal temperature to hit for both treatment groups were within the physiological norm. After 30 minutes of kick observed a significant increase in temperature in both treatment groups, but after this the time the temperature had returned to normal levels. After intravenous injection of the carrier or DiOHF3HA in both treatment groups were observed temperature increase, but it is not significantly different from the temperature to strike.

After a stroke in rats of both treatment groups was observed significantly higher estimates of neurological disorders after 24, 48 and 72 hours after impact, when compared with estimates of up to strike. Processing DiOHF3HA (15 mg/kg/day) significantly improved the assessment of neurological disorders after 24, 48 and 72 hours after impact, when compared with rats treated with media. The treated carrier rats affected by the impact of the contralateral front leg observed a delay of response to the removal of adhesive labels compared to the ipsilateral side (P<0,05, two-way RM-ANOVA with repetition 2 factors, hours after impact, and side). This effect continued after treatment DiOHF3HA (15 mg/kg/day).

The area of infarct cortex after treatment DiOHF3HA (15 mg/kg intravenously) was significantly decreased when compared with the media.

In General, processing DiOHF3HA (15 mg/kg) significantly improved neurological function in the test for unilateral absence of sensory information, as well as reduced the area of damage in the striatum after stroke in comparison with treatment by the media.

The effect DiOHF3HA impact from mild to moderate severity

Investigated in brannau group of rats with a blow from mild to moderate severity.

mediaDiOHF3HA
category No. 3 (n=4)No. 2 (n=1)
category No. 4 (n=3)No. 3 (n=4)

In each of the processing groups of rats after impact from mild to moderate severity did not lose weight. The internal temperature to strike in both treatment groups were within the physiological norm. After 30 minutes of kick from mild to moderate severity was observed a significant increase in temperature in both treatment groups, however, after this time the temperature had returned to normal levels.

In both groups, treatment of rats after blow from mild to moderate severity was observed significantly higher estimates of neurological disorders before impact and after 24, 48 and 72 hours after impact, when compared with estimates prior to surgical intervention. When compared with rats treated with media processing DiOHF3HA (15 mg/kg/day) had no effect on the evaluation of neurological disorders. The treated carrier rats with stroke from mild to moderate severity after 24 and 48 hours was observed increased latency of response to the application of adhesive labels for the affected UDA is the MD of the contralateral front leg compared to the ipsilateral side (P< of 0.05, two-way RM-ANOVA with repetition 2 factors, hours after impact, and side). The treated carrier rats was also observed increased latency of response to the removal of adhesive labels after 24 hours (P<0,05, two-way RM-ANOVA with repetition 2 factors, hours after impact, and side). These effects continued after treatment DiOHF3HA (15 mg/kg/day) (Fig).

In rats with stroke from mild to moderate severity of the infarction area of the cerebral cortex was significantly decreased after treatment DiOHF3HA (15 mg/kg per day, intravenously) in comparison with the carrier (Fig). Processing DiOHF3HA significantly reduced the area of infarct striatum.

In General, processing DiOHF3HA (15 mg/kg) rats with a blow from mild to moderate severity was significantly reduced infarction area of the cerebral cortex and striatum in comparison with treatment by the media. Processing DiOHF3HA was significantly restore neurological function in the test for unilateral absence of sensory information.

Unless otherwise noted, all values in the graphs represent mean values with standard error of the mean, represented by vertical lines.

Any discussion of documents, protocols, substances, devices, articles or the like, included in the present description is intended only to provide context of the present invention. It should not R is osmatrivat in recognition, that any or all of these matters form part of the basis of prior art, or that they were well-known knowledge in the field related to the present invention, as if it existed before the priority date of each item of the attached claims.

Throughout the present description, the word "include" or variations such as "comprises" or "comprising"should be understood as denoting the inclusion of the specified element, integer or step or group of elements, integers or steps, but not the exclusion of any other element, integer or step or group of elements, integers or steps.

Specialists in this field will be obvious that the invention can be implemented many changes and/or modifications, as shown in the specific embodiments, implementation, without departing from the spirits or scope of the invention as described in a broad sense. Thus, real options implementation in all respects should be considered as illustrative and not restrictive.

1. The compound of General formula I

wheredenotes a single or double bond, and
R1, R2, R3, R4, R5independently selected from H, HE, or a group of formula (Ia)

where O represents oxygen;
i) L is a group C=O, D represents alkylenes group with a chain length equivalent to approximately from 1 to 20 carbon atoms, and E represents a substituted or unsubstituted group of the carboxylic acid, or
ii) L and D are absent and E is an ester group of formula (Ic)

where Q represents a substituted or unsubstituted alkylene;
W represents O and
X represents H, substituted or unsubstituted alkyl, benzyl or mono - or divalent cationic salt, or a cationic ammonium salt; or
iii) L and D are absent and E is a complex phosphate ester of the formula (Ie)

where R6and R7independently selected from H, substituted or unsubstituted alkyl, mono - or divalent cationic salt, or cationic ammonium salts;
provided that at least one of R1, R2, R3, R4, R5different from H or HE.

2. The compound according to claim 1, where R4and R5both represent N.

3. The compound according to claim 1 or 2, where R1and R2both represent IT.

4. The compound according to claim 1, where L and D are absent and E is an ester group of formula (Ic)

where Q represents a substituted linesamsung alkylen;
W represents O and
X represents N; substituted or unsubstituted alkyl, benzyl or mono - or divalent cationic salt, or a cationic ammonium salt.

5. The compound according to claim 4, where Q is a substituted or unsubstituted C1-C6alkylen.

6. The compound according to claim 4, where X represents N and Q represents a butylene.

7. The compound according to claim 1, where L and D are absent and E is a complex phosphate ester of the formula (Ie)

where R6and R7independently selected from H, substituted or unsubstituted alkyl, mono - or divalent cationic salt, or cationic ammonium salts.

8. The connection according to claim 7, where R6and R7both represent N.

9. The compound according to claim 1, whererepresents a double bond.

10. The compound of General formula IV

where Q represents a substituted or unsubstituted alkylene, optionally interrupted by one or more heteroatoms,
X represents H, a mono - or divalent cationic salt, or a cationic ammonium salt.

11. The connection of claim 10, where Q is a substituted or unsubstituted lower alkylene, optionally interrupted by one or more heteroatoms.

12. The connection of claim 10, where Q is a substituted or nezame the military C 1-C6alkylen.

13. The connection of claim 10, where X represents N and Q represents a butylene.

14. The compound according to claim 1, which represents the

15. The compound according to claim 1, which represents the

16. The compound according to claim 1, which represents the

17. The compound according to claim 1, which represents the

18. A compound selected from the group including
3-(benzyloxycarbonylamino)flavone;
3-hydroxyflavone-3-gemadept;
4'-(benzyloxy)-3-(benzyloxycarbonylamino)flavone;
4'-hydroxyflavone-3-gemadept;
3',4'-dimensions-3-(benzyloxycarbonylamino)flavone;
3',4'-dihydroxyflavone-3-gemadept;
3,4'-di(benzyloxycarbonylamino)flavone;
Flavon-3,4'-bis(gemadept);
3,7-di(benzyloxycarbonylamino)flavone;
3-(dibenzalacetone)flavone;
3,7-dihydroxyflavone-3,7-bis(gemadept);
4'-hydroxy-3-hydroxyflavone-3-Quaternary ammonium ether;
the disodium salt of the flavone-3-phosphate;
4'-(benzyloxy)-3-(dibenzalacetone)flavone or the disodium salt of 3-hydroxyflavone-3-phosphate.

19. Pharmaceutical and/or veterinary composition having activity against the disease(s)associated with the presence of reactive is celitelnij residues (ROS), containing pharmaceutically and/or veterinary acceptable carrier or diluent together with the compound according to claim 1.

20. The method of prevention and/or treatment of individual disease(s)associated with the presence of reactive oxidative residues (ROS), where the method includes introducing an effective amount of at least one compound according to claim 1.

21. The method according to claim 20, where the individual in need of such treatment has a risk of developing ischemia.

22. The method according to claim 20, where the individual suffers from ischemia and/or reperfusion damage as the result of acute or chronic conditions.

23. The method according to item 22, where a chronic condition selected from cerebrovascular disease, vascular lung disease, atherosclerosis, diseases of the arteries, congestive heart failure, coronary heart disease, peripheral vascular disease, diabetes, hypertension, migraine, chronic obstructive pulmonary diseases and vascular diseases of the retina.

24. The method according to item 22, where acute condition selected from stroke, myocardial infarction, damage due to mechanical trauma or surgery.

25. The method according to paragraph 24, where surgical intervention is a vascular surgical intervention.

26. The method according A.25 vascular surgery p is ecstasy a heart bypass surgery and/or transplant surgery.

27. The method according to claim 20, where the compound is administered to the individual before and/or during surgery.

28. The method according to claim 20, where the compound is administered to an individual orally.

29. The method according to claim 20, where the connection is a

or its pharmaceutically acceptable salt.

30. The method according to claim 20, where the connection is a

or its pharmaceutically acceptable salt.

31. The method of prevention, delay of development and/or slow the development of atherosclerosis and/or coronary heart disease in an individual, where the method includes introducing an effective amount of at least one compound according to claim 1.

32. Therapeutic and/or prophylactic method of prevention and/or treatment of individual disease(s)associated with the presence of reactive oxidative residues (ROS), where the method includes introducing an effective amount of at least one compound according to claim 1.

33. The method of prevention and/or at least weakening the individual violations caused by ischemia and/or reperfusion injury, where the method includes introducing an effective amount of at least one compound according to claim 1.

34. The compound of General formula V

where R3and R5independently selected from H, HE, or group of formulas is (Ia)

where O represents oxygen;
i) L is a group C=O, D represents alkylenes group with a chain length equivalent to approximately from 1 to 20 carbon atoms, and E represents a substituted or unsubstituted group of the carboxylic acid, or
ii) L and D are absent and E is an ester group of formula (Ic)

where Q represents a substituted or unsubstituted alkylene;
W represents O and X represents H, substituted or unsubstituted alkyl, benzyl or mono - or divalent cationic salt, or a cationic ammonium salt; or
iii) L and D are absent and E is a complex phosphate ester of the formula (Ie)

where R6and R7independently selected from H, substituted or unsubstituted alkyl, mono - or divalent cationic salt, or cationic ammonium salts;
provided that at least one of R3and R5different from H or HE.

35. The connection 34, where L and D are absent and E is an ester group of formula (Ic)

where Q represents a substituted or unsubstituted alkylene;
W represents O and
X represents N; substituted or unsubstituted alkyl, benzyl or mono - or divalent, Katie the tin salt or a cationic ammonium salt.

36. Connection p, where Q is a substituted or unsubstituted C1-C6alkylen.

37. Connection p, where X represents N and Q represents a butylene.

38. The connection 34, where L and D are absent and E is a complex phosphate ester of the formula (Ie)

where R6and R7independently selected from H, substituted or unsubstituted alkyl, mono - or divalent cationic salt, or cationic ammonium salts.

39. Connection § 38, where R6and R7both are N.



 

Same patents:

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SUBSTANCE: invention relates to derivatives with anticancer activity of formulae:

, , , , ,

R2', R3', R4', R5' and R6' are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9; Y is selected from O and S; X is selected from F, Cl and Br; R8 and R9 are selected from (CH2)nCH3; R2, R3, R4 and R5 are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9, or R3 and R4 together form -Y(CH2)nY-; R1 and R1' are selected from H, Li+, Na+, K+, N+R8R9R10R11 or benzyl, where R10 and R11 are selected from H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, where n and m are integers from 0 to 4, q is an integer from 1 to 4.

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FIELD: chemistry.

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Ar-H--O-Ar< / BR>
(I) in which

Ar1the aromatic ring of the formula

_and Ar is an aromatic ring of the formula

in which p, n is 1 or 2;

Z is hydrogen, lower alkyl, lower alkoxyl, halogen atom, hydroxyl, lower acyloxy, lower alkenylacyl, phenoxy, phenyl or (lower alkyl) oxycarbonyl or chain(CH2)2Oh or CH CH-CH= CH, forming with the benzene ring more condensed cycle;

Y is H, lower alkyl, lower alkoxyl or lower acyloxy;

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r--CH2-O-A the latter being in engagement with the lower alkylhalogenide, then subjected to repair using a borohydride of an alkali metal to obtain diarylethene General formula

r-CHOH-CH2O-Ar< / BR>
(V) in which Ar, Ar' have the above meanings, X is hydroxyl, which is subjected to alkylation using an alkylating agent in a basic environment or subjected to acylation using a derivative of carboxylic or phosphonic, or sulfuric or sulfonic acid

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(RO)2(R O)P = O, where R is a C6H5-; R' - C6H5-, n-CH3C6H4-, n(CH3)3CC6H4-; R = R' - n-CH3C6H4-;

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9 cl, 2 dwg, 2 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate, which is non-hygroscopic product exhibiting protective activity relative to mucous membrane of gastrointestinal tract, including large intestine, as well as methods for preparation of this compound and pharmaceutical composition based thereon. Compound of invention has such advantages as mucosa-protection activity, handling easiness, and storage ability under humidity conditions because of lack of hygroscopicity, and constant activity allowing preparation of therapeutical composition in any moment when necessary. Preparation procedure is performed under mild conditions owing to elimination of methylation step under autoclave conditions.

EFFECT: enabled mass production of 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate without need in purification such as recrystallization or column chromatography.

15 cl, 5 dwg, 5 tbl, 3 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns an injection dosage form for treating an acute ischemic stroke and a craniocereberal injury characterised by the fact that as an active ingredient, it contains a therapeutically effective amount of heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, and at least one substance chosen from a group of antioxidants.

EFFECT: invention provides high neuroprotective effect in acute severe CNS affections associating various models of the stroke and the craniocereberal injury, as well as high stability and prolonged use.

12 cl, 13 ex, 2 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to aminophosphate derivatives of general formula (1a), pharmaceutically acceptable salts or hydrates thereof, which can be used in medicine as S1P (sphingosine-1-phosphate) receptor modulators,

where R3 is a straight alkyl group containing 1-3 carbon atoms; X is an oxygen or sulphur atom and n equals 2 or 3.

EFFECT: obtaining novel biologically active compounds with high S1P receptor modulating action.

9 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

, where R and R1 independently denote a link selected from: i) hydrogen; ii) substituted or unsubstituted phenyl and iii) substituted or unsubstituted 5- or 6-member heteroaryl in which heteroatoms are selected from nitrogen, oxygen, sulphur or combinations thereof; said substitutes are selected from: i) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkoxy; iii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic halogenalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) 5- or 6-member heteroaryl in which heteroatoms are selected from nitrogen, oxygen, sulphur or combinations thereof; or ix) two substitutes may be taken together to form a condensed ring containing 5-7 atoms; R4 is C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; R5a and R5b each independently denotes: 1) hydrogen; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring containing 3-7 atoms; R2 is selected from: i) -OR6; or ii) -NR7aR7b; R6 is hydrogen or C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; R7a and R7b each independently denotes: i) hydrogen; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; or iii) R7a and R7b may be taken together to form a ring containing 3-7 atoms; R3 is hydrogen, methyl or ethyl; L is a binding link of formula -[C(R8aR8b)]n -R8a and R8b each independently denotes hydrogen, methyl or ethyl; n ranges from 1 to 3; R9 is hydrogen or methyl; or pharmaceutically acceptable salt thereof; provided that R and R1 both denote hydrogen. The invention also relates to compositions based on the described compounds for treating anaemia or assisting wound healing and use of said compounds to prepare a composition for treating anaemia or wounds.

EFFECT: novel compounds which are HIF-16 prolyl hydroxylase inhibitors are obtained.

14 cl, 18 ex, 15 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: for treatment of patients with ischemic heart disease in addition to basic therapy introduced is cudesan in dose 25 drops simultaneously with preductal MB 35 mg 2 times per day during meal for 3 months, with further parenteral introduction of essentiale H in dose 0.5-1 g for 10 days, after that, enterally in dose 1 capsule 3 times per day for 20 days. Course of treatment is repeated 3 times per year.

EFFECT: expressed anti-ischemic effect and normalisation of processes of lipid peroxidation, including in patients with severe affection of coronary channel and expressed diastolic dysfunction of left ventricle.

2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: claimed are method of reducing in circulating blood of LDL-cholesterol, triglycerides, total cholesterol and their mixtures, including introduction of efficient amount of one or more phosphate derivatives of one or more electron-transfer agents, which represent monotocopheryl phosphate, dotocopheryl phosphate, monotocotrienyl phosphate, ditocotrienyl phosphate and their mixtures, their application for relief of symptoms, treatment and/or prevention of disease, selected from group which consists of chronic renal failure, primary and secondary hyperemias and dislipemia, retinopathy, enlargement of liver and spleen, xanthomas and their combinations by reduction of lipid content in circulating blood.

EFFECT: reduction under action of claimed tocopherylphosphates of levels of total cholesterol, LDL in mice and reduction in them of atherosclerotic lesions, in people - improvement of dislipidemia state and increase of HDL cholesterol in comparison with tocopherol acetate.

5 cl, 3 dwg, 5 tbl, 2 ex

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