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Definitions

• the invention relates to new biologically active compounds, derivatives of dicarboxylic acid bisamides or their pharmaceutically acceptable salts, having the ability to complexation or chelation of metal ions, as well as their use as a means for the prevention and / or treatment of cardiovascular, viral, oncological, neurodegenerative, inflammatory diseases diabetes, gerontological diseases, diseases caused by toxins of microorganisms, as well as alcoholism, alcoholic cirrhosis audio, anemia, porphyria later, poisoning transition metal salts.
• Metal ions play an important role both in the normal functioning of cells and the whole organism, and in the development of pathologies.
• complexing agents are derivatives of polyaminocarboxylic acids (for example, EDTA), D-penicillamine, polycyclic cryptands, which are successfully used in cases of heavy metal poisoning.
• Deferroxamine is used as an iron chelator in some iron-rich conditions and hematochromatosis.
• chelation therapy prevents the deposition of cholesterol and restores its level in the blood, lowers blood pressure, avoids angioplasty, suppresses undesirable side effects of certain heart medications, removes calcium from cholesterol plaques, dissolves blood clots and restores the elasticity of blood vessels, normalizes arrhythmia, and prevents aging , restores the strength of the heart muscle and improves heart function, increases the intracellular potassium content, regulates the mineral metabolism, useful in the treatment of Alzheimer's disease, prevents the onset of cancer, improves memory and exhibits many other positive effects.
• strong chelators currently used in chelation therapy, as a rule, have a toxic effect, which is manifested mainly in damage to the mucous membrane of the small intestine and impaired renal function. In some cases, with the rapid introduction of large quantities of known chelators, a violation of muscle excitability and blood coagulation is possible.
• strong chelators can interact with useful bioelements (Na, K, Ca, Mg, Ca), and can also change the activity of vital metal enzymes [Zelenin K.N. "Complexons in medicine", Soros Educational Journal, 2001, v.7, N ° 1, p. 45-50].
• hepatotherapy in case of viral diseases such as HIV, human papilloma, herpes, hepatitis C and others is especially relevant.
• Rice WG Schaeffer S.A., Harten B., Nature, 1993, v.4, p. 473-475, discloses 3-nitrosobenzamide, which removes zinc from NCp7 of an HIV protein, inhibiting HIV replication and its pathogenicity in vitro and in vivo.
• a zinc finger type site of the human papillomavirus E6 protein was also selected. This virus is a possible mediator in the etiology of cervical carcinoma.
• Hepatitis C virus is one of the most widespread human pathogens. Modern hepatitis C therapy is based almost exclusively on the use of interferon, as well as its combination with a nucleoside analogue, ribavirin [Kozlov MV, Polyakov KM, Ivanov AV, Biochemistry, 2006, vol. 71, N ° 9 , p. 1253-12594]. It should be noted the low effectiveness of such therapy.
• NS3-cepHHOBan proteinase in which the zinc region plays an important role in maintaining the stability of the structure
• Inhibition or alteration of its activity by the use of compounds capable of extracting zinc has been evaluated in some literature as a promising strategy for managing the disease caused by the hepatitis C virus.
• RNA-dependent RNA polymerase of hepatitis C virus (viral protein NS5B), which has a zinc-binding site in its structure [Timothy L. Tellinghuisen, Matthew S. Paulson, Charles M. Rice, J. Virology, 2006, v. 80, W ° 1, p. 7450-7458].
• RNA-dependent RNA polymerase of hepatitis C virus can be divided into two main classes: derivatives of nucleosides and non-nucleoside inhibitors of various nature [Maria Bretner, Acta biochemica polonica, 2005, v.52, N ° 1, p. 57-70].
• inhibition of the activity of this enzyme by pyrogallol derivatives was found. It is noteworthy that the mechanism of inhibition by pyrogallol derivatives is believed to be the chelation of magnesium cations involved in the catalytic act at the phosphoryl transfer stage the remainder [Kozlov M.V., Polyakov K.M., Ivanov A.V., Biochemistry, 2006, vol. 71, JSfa 9, p. 1253-12594].
• Herpesvirus diseases are widespread. So, several human herpes viruses are known - herpes simplex virus 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), chickenpox virus, Epstein-Barr virus. Destructive actions, which at the same time turn out to be on the central nervous system, cause diseases such as encephalitis and meningitis. Interest can be noted in studies of the effect of zinc chelating compounds, for example, diethylenetriaminepentaacetic acid, on inhibition of in vitro replication of human cytomegalovirus [Kanekiyo M., Itoh N., Mano M., Antiviral Res., 2000, v. 47, p. 207-214].
• herpes viruses like the above viruses, have proteins containing a zinc finger motif. Chemical changes in the zinc finger can lead to zinc release and changes in the functioning of viral proteins [Yan Chen, Christine M. Livingston, Stacy D. Carrington-Lawrence, J. of Virology, 2007, v.81, tfs 16, p . 8742-8751].
• Zinc fingers can serve as a target for a new generation of antiviral drugs. Several such compounds have already been identified. However, at present, their effectiveness can only be judged based on in vitro studies.
• Zinc chelator - clioquinol, binding Zn 2+ ions induces apoptosis of human cancer cells [Haijun Yu, Yunfeng Zhou, Stuart E. Lind, "Clioquinol targets zinc to lysosomes in human cancer cells", Biochem. J., 2009, v. 417, p. 133-139].
• Chelators are used as aldehyde dehydrogenase inhibitors to treat alcoholism [Shian S.G., Kao Y.R., Wu F.Y., Wu C.W., "Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram", Mol. Pharmacol., 2003, v. 64 (5), p.
• the activity of some antioxidants is due to the chelation of transition metal ions (Fe, Cu), which is accompanied by a decrease in metal-dependent lipid peroxidation [Babizhayev MA, Seguin Marie-C, Gueynej J., Evstigneev RP, Ageyeva EA, Zheltuchina GA, "L-Carnosine (-alanyl-L-histidine) and carcinme f-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities ", Biochem. J., 1994, v. 304, p. 509-516].
• antioxidants can help resolve cataracts, eliminate retinal diseases and reduce the need for insulin in diabetics, eliminate skin pigmentation, and also help eliminate the effects of stroke. Chelation is also useful in the treatment of inflammatory diseases such as osteoarthritis, rheumatoid arthritis. [Zelenin KN, "Complexons in medicine", Soros Educational Journal, 2001, v. 7, jYsl, pp. 45-50].
• Chelators can be used in medicine as complexones for transporting and easy excretion of arsenic, mercury, antimony, cobalt, zinc, chromium, nickel [Zholnin A.V., “Complex compounds”, Chelyabinsk: ChGMA, 2000, p. 28 ].
• Chelation therapy is useful in the treatment of neurodegenerative diseases, in particular Alzheimer's disease, contributing to improved memory [Bossy-Wetzel E., Schwarzenbacher R., Lipton S.A., "Molecular pathways to neurodegeneration", Nat. Med, 2004, v. 10, p. 2-9]; Parkinson's disease [Kevin J. Barnham, Colin L. Masters, Ashley I. Bush, "Neurodegenerative diseases and oxidative stress, Nature Reviews Drug Discovery, 2004, v. 3, p. 205-214]; Wilson’s disease [Yu Yu, Jacky Wong, David B. Lovejoy, "Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond", Clin. Cancer Res.? 2006, v. 12, p.
• Derivatives occupy a significant place among the known chelators heterocyclic compounds, for example, imidazole containing imido and amido groups.
• N, ⁇ -glutarylbis (histamine) including the interaction of histamine dihydrochloride and glutaric acid dichloride in dimethylformamide in the presence of a 4-fold excess of triethylamine, is described in Elfriede Schuhmann et al., "Bis [platinum (II)] and Bis [Pall [II] )] complexes of ⁇ , ⁇ -Dicarboxylic Acid Bis (l, 2,4-triaminobutane-N 4 ) -Amides ", Inorg. Chem., 1995, v. 34, p. 2316-2322.
• the inventors of the present invention first discovered that a bishistamine derivative of glutaric acid, namely, N ⁇ N'-nryTapmi bis (histamine), is capable of forming complexes with metal ions.
• an object of the present invention is to provide biocompatible heterocyclic chelators of metal ions and their use as a medicine for the treatment and / or prevention of various diseases, using the ability of the claimed compounds to chelate metal ions.
• the objective of the invention is also the development of simple, using available reagents, methods for producing such compounds.
• the present invention relates to derivatives of dicarboxylic acid bisamides of the general formulas
• R] represents a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and / or S, optionally fused to a 6-membered unsaturated cyclic group;
• R 2 represents a group —C (0) —R 3 —C (0) -, where R 3 represents a group - (CH 2 ) P - optionally substituted with one or two Ci-C 6 alkyls, or phenyl,
• n is an integer from 0 to 4.
• the present invention also relates to derivatives of dicarboxylic acid bisamides of the general formula I having the ability to chelate metal ions (Zn, Cu, Fe, Mg, Ca, etc.); as well as their use as a means for the prevention and / or treatment of cardiovascular, viral, oncological, neurodegenerative, inflammatory diseases, diabetes, gerontological diseases, as well as diseases caused by toxins of microorganisms, as well as alcoholism, alcoholic cirrhosis of the liver, anemia, late porphyria, poisoning with salts of transition metals.
• metal ions Zn, Cu, Fe, Mg, Ca, etc.
• the present invention also relates to methods for producing compounds of General formula I, including:
• Preferred compounds of the present invention are compounds of the general formula I:
• Ri represents a group selected from:
• R 2 represents a group selected from: —C (O) - (CH2) 0 —C (O) -, —C (O) - (CH 2 ), —C (0) -, —C (0) - (CH 2 ) 2 -C (0) -, -C (0) - (CH 2 ) 3 -C (0) -, -C (0) - (CH 2 ) 4 -C (0) -, -C (0) —CH 2 —CH (CH 3 ) —CH 2 —C (0) -, —C (0) —CH 2 —C (CH 3 ) 2 —CH 2 —C (0) -, or a group
• the most preferred compounds of the present invention are the compounds shown in table 1.
• organic acid addition salts e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
• inorganic acid addition salts e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
• salts with amino acids e.g., aspartic acid salt, glutamic acid salt, etc.
• hydrochlorides and acetates e.g., aspartic acid salt, glutamic acid salt, etc.
• R 3 represents a group - (CH 2 ) P - optionally substituted with one or two Ci-C 6 alkyls, or phenyl,
• n is an integer from 0 to 4,
• R4 represents hydrogen, Ci-C 6 alkyl
• Ri represents a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and / or S, optionally fused to a 6-membered unsaturated cyclic group;
• dimethyl ether it is preferable to use dimethyl ether, and heating to a temperature of 150-170 ° C, it is even more preferable to conduct condensation at boiling.
• Diglyme or alcohols most preferably isoamyl alcohol, can be used as solvents.
• Another method for producing dicarboxylic acid bisamide derivatives of the general formula I is a process comprising reacting dicarboxylic acid of General formula II:
• R 3 represents a group - (CH 2 ) P - optionally substituted with one or two Ci-C b alkyls, or phenyl,
• n is an integer from 0 to 4,
• R4 is hydrogen
• Ri represents a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and / or S, optionally fused to a 6-membered unsaturated cyclic group.
• Preferred is cooling to a temperature of 0-5 ° C.
• Another method for producing dicarboxylic acid bisamide derivatives of the general formula I is a method comprising reacting a dicarboxylic acid ester of the general formula I:
• R 3 represents a group - (CIS),! - optionally substituted with one or two Ci-C b alkyls, or phenyl,
• n is an integer from 0 to 4,
• R4 is Ci-C 6 alkyl
• R] represents a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and / or S, optionally fused to a 6-membered unsaturated cyclic group, in an organic solvent.
• alcohols most preferably isopropanol, are used as the organic solvent.
• the method is simple, but applicable if the number of methylene units in the initial dicarboxylic acid is greater than or equal to three, since the bisazides obtained in the synthesis process for acids with fewer methylene groups are unstable.
• Derivatives of dicarboxylic acid bisamides of the general formula I can also be prepared by a process comprising condensation of an imide of the general formula VII:
• R 3 represents a group - (CH 2 ) P - optionally substituted with one or two Ci-C 6 alkyls
• n is an integer from 0 to 4,
• Ri represents a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and / or S, optionally fused to a 6-membered unsaturated cyclic group,
• Alcohols are preferably used as the organic solvent, most preferably isopropanol and condensation is carried out by boiling.
• Another method of the present invention is a method for producing dicarboxylic acid bisamide derivatives of the general formula I, comprising reacting a dicarboxylic acid of the general formula II:
• R 3 represents a group - (CH 2 ) P - optionally substituted with one or two C [-C 6 alkyl, or phenyl,
• n is an integer from 0 to 4,
• R4 is hydrogen
• Ri represents a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and / or S, optionally fused to a 6-membered unsaturated cyclic group;
• the present invention also relates to a medicament, a pharmaceutical composition comprising dicarboxylic acid bisamide derivatives of the general formula I, and a method comprising administering dicarboxylic acid bisamide derivatives of the general formula I for the prevention and / or treatment of human and animal viral diseases, including diseases caused by hepatitis C virus, human papillomavirus, HIV or oncogenic RNA viruses, such as leukemia virus; cardiovascular diseases, including diseases caused by cardiotoxicity of cytostatics, deposition of cholesterol, high blood pressure; diseases associated with metal-dependent free radical oxidation reactions, including gerontological diseases such as cataracts, retinal diseases, skin pigmentation; consequences of a stroke; atherosclerosis; inflammatory diseases such as osteoarthritis, rheumatoid arthritis;
• neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Wilson. Huntington amyotrophic lateral sclerosis, prion diseases;
• oncological diseases diseases caused by toxins of microorganisms, in particular botulism or gas gangrene;
• the compounds of the present invention are administered in an effective amount that provides the desired therapeutic result.
• the compounds of general formula (I) can be administered orally, topically, parenterally, intranasally, inhalation and rectally in unit dosage forms containing non-toxic pharmaceutically acceptable carriers.
• parenteral administration means subcutaneous, intravenous, intramuscular or intrathoracic injection or infusion.
• the compounds of the present invention can be administered to a patient in doses of 0.1 to 100 mg / kg body weight per day, preferably in doses of 0.25 to 25 mg / kg one or more times per day.
• the specific dose for each particular patient will depend on many factors, including the activity of the compound used, age, body weight, gender, general health status and diet of the patient, time and method of administering the drug, speed of its removal from an organism, the combination of drugs used specifically, and the severity of the disease in the individual being treated.
• compositions of the present invention contain a compound of the general formula (I) in an amount effective to achieve the desired result, and can be administered in unit dosage forms (for example, in solid, semi-solid or liquid form) containing the compounds of the present invention as an active ingredient in a mixture with a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration.
• a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration.
• the active ingredient may be included in the composition along with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, dragees, emulsions, suspensions, ointments, gels and any other dosage forms.
• Various substances such as saccharides, for example, glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphates, for example tricalcium phosphate or calcium acid phosphate, can be used as fillers, such as starch paste, for example, corn, wheat, rice, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone.
• disintegrating agents such as the aforementioned starches and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, can be used.
• Optional additives such as flow control agents and lubricants such as silica, talc, stearic acid and its salts such as magnesium stearate or calcium stearate, and / or propylene glycol can be used.
• the core of the dragee is usually coated with a layer that is resistant to the action of gastric juice.
• concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, and suitable organic solvents or mixtures thereof.
• additives As additives, stabilizers, thickeners, colorants and perfumes can also be used.
• hydrocarbon ointment bases such as white and yellow petroleum jelly (Vaselinum album, Vaselinum flavum), liquid paraffin (Oleum Vaselini), white and liquid ointment (Unguentum album, Unguentum flavum), and as additives to give more dense consistency - such as paraffin wax and wax; absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases, washed off with water, such as hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases, such as polyethylene glycol ointment (Unguentum Glycolis Polyaethyleni), bentonite bases and others.
• absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum),
• methyl cellulose sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol or polyethylene oxide, carbopol can be used.
• water-insoluble bases such as cocoa butter can be used; bases soluble in water or miscible with water, such as gelatin-glycerol or polyethylene oxide; combined bases - soap-glycerin.
• the amount of active ingredient used in combination with a carrier may vary depending on the recipient being treated, on the particular route of administration of the drug.
• the content of the active agent in them is up to 5% by weight.
• diluents 0.9% sodium chloride solution, distilled water, novocaine solution for injection, Ringer's solution, glucose solution, specific additives for dissolution can be used.
• their amount is up to 200 mg per unit dosage form.
• Dosage forms of the present invention are obtained according to standard methods, such as, for example, mixing, granulating, dragee formation, dissolution and lyophilization.
• Electrophoresis on paper is carried out in a buffer with a pH of 5.1 with a composition of pyridine-acetic acid-water 12: 10: 1000 in a chamber (150x320x 150 mm) with a gradient of 15 V / cm for 1, 5 hours
• Chromatograms and electrophoregrams exhibit chlorotetramethylbenzidine reagent and Pauli reagent.
• the melting temperature is determined on a PTP device (laboratory of laboratory devices, Russia, Klin).
• Analytical reverse phase HPLC was performed on an instrument: Shimadzu HPLC chromatograph under conditions: Luna C18 (2) column 100 A, 250x4.6 mm (ser. 599779-23), elution gradient in the system phosphate buffer solution pH 3.0: methanol ( conditions A).
• a Beckman (USA) System Gold chromatograph with a UV detector ( ⁇ 220 nm), a C-18 Gemini column, 150x2.0 mm Phenomenex, mobile phase gradient in 0.05 M phosphate buffer (pH 3, 0) 90% MeCN in water, elution rate 0.25 ml / min, injection of 10 ⁇ l (conditions B).
• adipic acid dimethyl ether To a mixture of 20 ml of isopropyl alcohol and 5 ml of hydrazine hydrate, heated to boiling, 7.5 g (0.04 mol) of adipic acid dimethyl ether are added dropwise, the reaction mixture is left at + 20 ° for 16 hours. The precipitated product is separated off, washed with isopropyl alcohol, dried. 6.2 g (83%) of adipic acid dihydrazide are obtained with a melting point of 182-182.5 ° C.
• the proposed compounds of general formula I have the ability to complexation or chelation of metal ions. They have several functional groups that can act as electron donors during complex formation, for example, a carboxyl group, imido, amido groups, and are ligands that specifically interact with metal ions, for example, zinc, copper, iron, calcium, and magnesium ions.
• dissociation constants (pk n ) of the studied compounds in aqueous solution. Pk values are determined using potentiometric titration. The calculation of dissociation constants is carried out according to the Schwarzenbach method [Grinberg AA, "Introduction to the chemistry of complex compounds", ed.4-e, rev., L., Chemistry, 1971].
• Titration was carried out on a setup using a laboratory type ionomer I 120.1.
• the created galvanic cell consisted of two electrodes: an indicator glass and a silver chloride comparison electrode.
• the pH values were determined with an accuracy of ⁇ 0.2.
• the initial 0.05 M solutions of salts of metal ions M z + were prepared from zinc nitrates ( ⁇ ( ⁇ 0 3 ) 2 ⁇ 6 ⁇ 2 0), calcium (Ca (N0 3 ) 2 -4H 2 0), copper sulfate (CuS0 4 -5H 2 0), magnesium chloride (MgCl 2 -6H 2 0) and Mohr's salt ((NH 4 ) 2 Fe (S0 4 ) 2 '6H 2 0).
• test compound 3-U "4 mol
• the resulting 0.02 M solution was titrated with vigorous stirring with a 0.05 M aqueous solution of NaOH or HCl. Fixed in each the titration point the amount (V, ml) of the spent titrant and the pH of the solution. The titration step was 0.5 ml, near the point equivalence - 0.2 ml. Titration was carried out to a pH of the solution 11.0-1.5.
• the method is based on the idea of the stepwise process of complexation.
• the main assumption of the Bierrum method is the assumption that only mononuclear complexes are formed.
• the complexation process can be described as follows:
• the test compound is titrated twice with a NaOH solution: in the absence and presence of a metal ion. carried out at a high constant concentration of an indifferent electrolyte, providing a constant ionic strength of the solution.
• test compound 3-10 "4 mol
• 1.0 ml (5-10 " 4 mol) of a 0.05 M aqueous solution of salt M was added.
• z + a ratio of M z + to L 1: 6.
• the pH of the solution was fixed in the joint presence of the ligand and metal ions in the solution.
• the mixture was titrated with a 0.05 M aqueous NaOH solution over a wide pH range (up to pH 1 1.0–1.5).
• the amount of spent titrant (V aOH, ml) and the pH of the solution were recorded at each titration point.
• c L ⁇ and c m g + are the total concentrations of the ligand and metal present in the solution, mol / L;
• [L " ] is the concentration of free ligand ions, mol / l;
• KL is the ligand acid dissociation constant
• NaOH is the volume of NaOH solution (Chchaon, mol / L) at any moment of titration added to the titrated mixture M z + and L, L;

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