EA043024B1 - A DERIVATIVE OF BISAMIDES OF DICARBOXIC ACIDS AND METHODS FOR ITS OBTAINING - Google Patents

Description

The invention relates to a new biologically active compound, a derivative of dicarboxylic acid bisamides or its pharmaceutically acceptable salts, having the ability to complex or chelate 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 of the liver, anemia, late porphyria, poisoning with transition metal salts.

State of the art

Metal ions play an important role both in the normal functioning of cells and the whole organism, and in the development of pathologies.

Drugs are known that carry out their action due to the ability to chelate metal ions. In this regard, a search is currently underway for non-toxic compounds capable of highly efficient and selective chelation of metal ions and suitable for biomedical applications.

Compounds with chelating ability were found among various classes of compounds of mono- and ditols, disulfides, azo compounds, nitrosoaromatic compounds, derivatives of polyaminocarboxylic acids, thiosemicarbazone, pyridoxal isonicotinoylhydrazone, quinoline, adamantane, pyrogallol, phenanthroline, thiopyrophosphates and others. In addition, they are noted among other natural compounds, such as, for example, carnosine, phytin, pectin. Of greatest interest are compounds with several functional groups capable of acting as electron donors during complex formation. In this regard, such compounds can be ligands specifically interacting with metal ions or groups of metals.

Currently widely known complexing agents are derivatives of polyaminocarboxylic acids (for example, EDTA), D-penicillamine, polycyclic cryptands, which are successfully used in heavy metal poisoning. Deferroxamine is used as an iron chelator in some iron-rich conditions and hematochromatosis. In addition, it is possible to use chelators in pathologies associated with Ca-excess conditions, for example, in arthrosis, atherosclerosis, and nephrolithiasis. It is also known that chelation therapy prevents the deposition of cholesterol and restores its level in the blood, lowers blood pressure, avoids angioplasty, suppresses unwanted side effects of certain heart drugs, 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 intracellular potassium, regulates mineral metabolism, is useful in the treatment of Alzheimer's disease, prevents cancer, improves memory and has many other positive effects. However, strong chelators currently used in chelation therapy, as a rule, have a toxic effect, which manifests itself mainly in damage to the mucous membrane of the small intestine and impaired renal function. In some cases, with the rapid introduction of large amounts of known chelators, muscle excitability and blood clotting may be impaired. In addition, strong chelators can interact with useful bioelements (Na, K, Ca, Mg, Ca), and can also change the activity of vital metalloenzymes [Zelenin K.N. Complexons in medicine, Soros Educational Journal, 2001, v.7, no. 1, p. 45-50].

In this regard, an active search is underway for new highly effective chelators with a chelating ability sufficient to achieve a biological effect in vivo, devoid of side effects.

The idea of using chelation therapy in case of viral diseases such as HIV, human papilloma, herpes, hepatitis C and others is especially relevant.

A promising target for this seems to be zinc-binding sites in the structure of viral proteins - the so-called zinc fingers.

Several compounds have now been identified that act on the zinc fingers of important proteins of these viruses.

In Andreas J.K., Boorganic & Medicinal chemistry, 2003, v. 11, p. 4599-4613, an adamantane derivative, trivially named banananin, is described as a zinc ion chelator. It is believed to be chemically suitable for removing zinc from the HIV NCp7 protein. Having the above mechanism of action azaderivative - azadicarbonamide is in I/II stage of clinical trials against progressive AIDS.

Rice W.G., Schaeffer C.A., Harten B., Nature, 1993, v. 4, p. 473-475, 3-nitrosobenzamide is disclosed, which removes zinc from the HIV NCp7 protein, inhibiting HIV replication and pathogenicity in vitro and in vivo.

The zinc finger region of the E6 protein of the human papillomavirus was also chosen as a drug target. This virus is a possible mediator in the etiology of cervical carcinoma.

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Beerheide W., Bernard H.-U., Tan Y.-J., Ganesan A.J., National Cancer Institute, 1999, v. 91, No. 14, 1211-1220 describes in vitro testing of aza compounds, disulfide and nitrosoaromatic derivatives. It has been shown that compounds of the 4,4'-dithiodimorpholine type provoke the release of zinc ions. As a result, a change in the structure of the viral protein and a violation of its functions associated with the biology and pathology of the human papillomavirus were observed. However, clinical trials of these compounds in this regard are not yet completed, and their effectiveness can only be judged on the basis of in vitro studies.

The above compounds are considered as promising for the development of drugs against cervical cancer, genital warts and latent papillomavirus infections of the genital organs. The 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 M.V., Polyakov K.M., Ivanov A.V., Biochemistry, 2006, v. 71, No. 9, With. 1253-12594]. The low efficiency of such therapy should be noted.

With regard to the development of therapeutic agents against the hepatitis C virus, one of the targets is NS3-serine proteinase, in maintaining the stability of the structure of which the zinc site plays an important role [Andrea Urbani, Renzo Bazzo, Maria Chiara Nardi, Daniel Oscar Cicero, Raffaele De Francesco, J Biol. Chem, 1998, v. 273, no. 30, p. 18760-18769]. Inhibition or alteration of its activity by the use of compounds capable of extracting zinc has been evaluated in some literature sources as a promising strategy for the management of hepatitis C virus disease.

Timothy L. Tellinghuisen, Matthew S. Paulson, Charles M. Rice, J. Virology, 2006, v. 80, no. 15, p. 7450-7458, the metal chelators (EDTA and 1,10-phenanthroline) were reported to be effective protease inhibitors assessed for NS2/3 autocleavage. There is also evidence that 1,10-phenanthroline acted in this case precisely through zinc chelation.

Sperandio D., Gangloff AR, Litvak J. Goldsmith R., Bioorg. Med. Chem. Lett., 2002, v. 12, No. 21, 3129-3133, a screening of a group of bisbenzimidazoles for inhibitors of the NS3/NS4A serine protease of hepatitis C virus is described, which also led to the identification of a corresponding potent Zn ²⁺ -dependent inhibitor.

When developing new approaches to the treatment of hepatitis C, another attractive target is the RNA-dependent RNA polymerase of the 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, no. 15, p. 7450-7458].

Currently known inhibitors of hepatitis C RNA-dependent RNA polymerase can be divided into two main classes: nucleoside derivatives and non-nucleoside inhibitors of various nature [Maria Bretner, Acta biochemica polonica, 2005, v. 52, no. 1, p. 57-70]. In addition, 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 stage of transfer of the phosphoryl residue [Kozlov M.V., Polyakov K.M., Ivanov A.V., Biochemistry, 2006, vol. 71, no. 9, p. 1253-12594].

Diseases caused by herpes viruses are widespread. So, several human herpesviruses are known - herpes simplex virus 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), varicella-zoster virus, Epstein-Barr virus. The destructive actions that are thus exerted 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 the inhibition of human cytomegalovirus replication in vitro [Kanekiyo M., Itoh N., Mano M., Antiviral Res., 2000, v. 47, p. 207-214].

However, it should also be noted that herpesviruses, 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 how viral proteins function [Yan Chen, Christine M. Livingston, Stacy D. Carrington-Lawrence, J. of Virology, 2007, v. 81, no. 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.

The above information allows us to assert the important role of metal ions both in the normal functioning of cells and the whole organism, and in the development of pathologies. The ability of some compounds to chelate metal ions can serve as the basis for creating drugs capable of treating various diseases, in particular, viral ones.

In Megan Whitnall, Jonathan Howard, Prem Ponka, A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics, PNAS, 2006, v. 103, no. 40, p. 14901-14906 disclose effective iron chelators that exhibit high antiproliferative and antitumor activity comparable to that of known cytostatics and are promising for clinical research.

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Kik K., Szmigiero L., Dexrazoxane (ICRF-187)- a cardioprotectant and modulator of some anticancer drugs, Postepy Hig Med Dosw Online, 2006, v. 60, p. 584-590, it is stated that some iron chelators can be used as adjuncts in anti-cancer therapy, as they have a cardioprotective effect.

Chelation of copper ions inhibits angiogenesis and reduces tumor growth [Yu Yu, Jacky Wong, David B. Loveioy, Chelatorsat the cancer coalface: Desferrioxamine to Triapine and Beyond, Clin. Cancer Res., 2006, v. 12, p. 6876-6883].

Zinc chelator - clioquinol, by binding Zn ²⁺ ions, causes 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].

As aldehyde dehydrogenase inhibitors, chelators are used 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. 1076-84], as well as in alcoholic cirrhosis of the liver, iron deficiency anemia, tardive skin porphyria [Schroterova L., Kaiserova H., Baliharova V., The effect of new lipophilic chelators on the activities of cytosolic reductases and P450 cytochromes involved in the metabolism of anticracyclin as antibiotics: studies in vitro, Physiol Res., 2004, v. 53(6), p. 683-691].

The activity of some antioxidants is due to chelation of transition metal ions (Fe, Cu), which is accompanied by a decrease in metal-dependent lipid peroxidation [Babizhayev M.A., Seguin Marie-C, Gueynej J., Evstigneev R.P., Ageyeva E.A., Zheltuchina G.A., L-Carnosine(alanyl-L -histidine) and carcinine f-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities, Biochem. J., 1994, v. 304, p. 509-516].

The use of antioxidants can promote the resolution of cataracts, eliminate retinal diseases and lower the need for insulin in diabetics, eliminate skin pigmentation, and also help eliminate the effects of a stroke. Chelation is also useful in the treatment of inflammatory diseases such as osteoarthritis, rheumatoid arthritis. [Zelenin K.N., Complexons in medicine, Soros Educational Journal, 2001, v. 7, No. 1, p. 45-50].

Chelators can be used in medicine as chelators for transporting and easily removing arsenic, mercury, antimony, cobalt, zinc, chromium, nickel from the body [Zholnin A.V., Complex compounds, Chelyabinsk: ChGMA, 2000, p. 28].

Known inhibition of botulinum toxin by chelation of zinc ions [Anne C., Blommaert A., Thio-derivede disulfides as potent inhibitors of botulinum neurotoxin B: implications of zinc interaction, Bioorg. Med. Chem., 2003, v. 11(21), p. 4655-60], in addition, chelation protects against gas gangrene [Zelenin K.N., Complexons in medicine, Soros Educational Journal, 2001, vol. 7, No. 1, p. 45-50].

Chelation therapy is useful in the treatment of neurodegenerative diseases, in particular Alzheimer's disease, by improving 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. 6876-6883]; Huntington's disease [Whitnall M., Richardson D.R., Iron: a new target for pharmacological intervention in neurodegenerative diseases, Semin Pediatr Neurol, 2006, v. 13, p. 186-197]; amyotrophic lateral sclerosis [Kevin J. Bernham, Colin L. Masters, Ashley I. Bush, Neurodegenerative diseases and oxidative stress, Nature Reviews Drug Discovery, 2004, v. 4] and prion diseases [Daniel L. Cox, Jianping Pan, Rajiv R.P. Singh, A Mechanism for Copper Inhibition of Infection Prion Conversion, Biophysical Journal, 2006, v. 91, L11L13]. Chelators prevent cancer [Megan Whitnall, with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics, PNAS, 2006, v. 103, no. 40, p. 14901-14906].

A significant place among the known chelators is occupied by derivatives of heterocyclic compounds, for example, imidazole, containing imido and amido groups in their composition.

In the article by M.A. Podyminogin, V.V. Vlassov, Synthesis RNA-cleaving molecules mimicking ribonuclease A active center. Design and cleavage of tRNA transcrints, Nucleic Acids Research, 1993, v. 21, no. 25, p. 59505956 describes a bishistamine derivative of glutaric acid, which can serve as a model for the active site of nucleases and exhibits weak activity in cleaving RNA molecules.

Elfriede Schuhmann et al., Bis[platinum(II)] and Bis[Palladium(II)] complexes of α,ώDicarboxylic Acid Bis(1,2,4-triaminobutane-N ⁴ )-Amides, Inorg. Chem., 1995, v. 34, p. 2316-2322, describes bishistamine derivatives of glutaric and adipic acids, which are intermediates for the synthesis of complexes with platinum and palladium:

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A method for the synthesis of N ¹ ,N ¹ -glutaryl-bis-(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 the article by Elfriede Schuhmann et al., Bis[platinum(II)] and Bis[Palladium(II)] complexes of α,ώ-Dicarboxylic Acid Bis(1,2,4-triammobutane-N ⁴ )-Amides, Inorg. Chem., 1995, v. 34, p. 2316-2322.

The present inventors have discovered for the first time that a bishistamine derivative of glutaric acid, namely N ¹ ,N ¹ -glutaryl-bis-(histamine), is capable of forming complexes with

metal ions.

Thus, the aim of the present invention is to obtain biocompatible heterocyclic chelators of metal ions and their use as a drug for the treatment and/or prevention of various diseases, using the ability of the claimed compounds to chelate metal ions.

It is also an object of the invention to develop simple, using available reagents, methods for the preparation of such compounds.

Brief description of the invention

The present invention relates to a dicarboxylic acid bisamide derivative of formula 6

n or a pharmaceutically acceptable salt thereof.

The present invention also relates to processes for the preparation of a compound of formula 6, comprising:

the interaction of dicarboxylic acid and the corresponding amine when heated; or reacting a dicarboxylic acid with N-hydroxysuccinimide in the presence of N,N'-dicyclohexylcarbodiimide to give the corresponding bis-N-oxysuccinimide ester which is condensed with an amine; or reacting a dicarboxylic acid diester with hydrazine hydrate, treating the obtained dihydrazide with sodium nitrite to give the corresponding azide, which is condensed with an amine; or heating a solution of an imide formed from a dicarboxylic acid and the corresponding amine in an organic solvent; or the interaction of the corresponding amine and dicarboxylic acid in molar ratios of 2:1 in the presence of a condensing agent.

The proposed methods for the preparation of heterocyclic bis-derivatives of dicarboxylic acids of general formula I are easy to implement, proceed under fairly mild conditions, without the formation of by-products, are technologically advanced, and make it possible to obtain target products in good yield (up to 82%) and a high degree of purity.

Detailed description of the invention

The present invention relates to a dicarboxylic acid bisamide derivative of formula 6

or a pharmaceutically acceptable salt thereof.

Table 1

As pharmaceutically acceptable salts of the compounds of the present invention, addition salts of organic acids (for example, formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), addition salts of inorganic acids (for example, hydrochloride, hydrobromide, sulfate, phosphate, etc.), amino acid salts (eg, aspartic acid salt, glutamic acid salt, etc.), preferably hydrochlorides and acetates.

The compounds of the present invention may be prepared by a process comprising the condensation of a dicarboxylic acid of general formula II

R ₄ OC(O)-R ₃ -C(O)-OR4,

- 4 043024 where R ₃ is a -(CH ₂ ) _p - group, optionally substituted with one or two C1-C6 alkyls, or phenyl, n is an integer from 0 to 4,

R4 represents hydrogen, C ₁ -C ₆ -alkyl, and an amine of general formula III

NH ₂ -(CH ₂ ) ₂ -R _b where R1 is a 5-membered unsaturated heterocyclic group containing 1 to 2 heteroatoms selected from N and/or S, optionally fused to a 6-membered unsaturated cyclic group;

when heated, optionally in the presence of a solvent.

It is preferable to use dimethyl ether, and heating to a temperature of 150-170°C, even more preferably to carry out boiling condensation.

As solvents, diglyme or alcohols can be used, most preferably isoamyl alcohol.

Another method for obtaining derivatives of bisamides of dicarboxylic acids of general formula I is a method involving the interaction of a dicarboxylic acid of general formula II

R ₄ OC(O)-R ₃ -C(O)-OR4, where R ₃ is -(CH ₂ ) _p - optionally substituted with one or two C1-C6 alkyls, or phenyl, n is an integer from 0 up to 4,

R4 is hydrogen, with N-hydroxysuccinimide in the presence of N,N'-dicyclohexylcarbodiimide in N,N-dimethylformamide to give the corresponding bis-N-oxysuccinimide ester of general formula IV

which is condensed with an amine of general formula III

NH ₂ -(CH ₂ ) ₂ -R _b where R1 is a 5-membered unsaturated heterocyclic group containing 1 to 2 heteroatoms selected from N and/or S, optionally fused to a 6-membered unsaturated cyclic group.

Cooling to a temperature of 0-5°C is preferred.

Another method for obtaining dicarboxylic acid bisamide derivatives of general formula I is a method involving the interaction of a dicarboxylic acid ester of general formula II

R ₄ OC(O)-R ₃ -C(O)-OR4, where R ₃ is -(CH ₂ ) _p - optionally substituted with one or two C1-C6 alkyls, or phenyl, n is an integer from 0 up to 4,

R ₄ is C ₁ -C ₆ -alkyl, with hydrazine hydrate in an organic solvent to give a bishydrazide of general formula V

H ₂ N-NH-C(O)-R ₃ -C(O)-NH-NH ₂ , treatment of bishydrazide with sodium nitrite in an acid medium at a temperature of about 0°C to obtain bisazide of general formula VI

N--N ⁺ =NC(O)-R ₃ -C(O)-N=N ⁺ -N·, condensation of bisazide with an amine of general formula III

NH ₂ -(CH ₂ ) ₂ -R _b where R ₁ is a 5-membered unsaturated heterocyclic group containing 1 to 2 heteroatoms selected from N and/or S, optionally fused to a 6-membered unsaturated cyclic group, in an organic solvent.

Preferably, alcohols are used as the organic solvent, most preferably isopropanol. The method is simple, but applicable if the number of methylene units in the original dicarboxylic acid is greater than or equal to three, since the bisazides obtained during the synthesis for acids with a smaller number of methylene groups are unstable.

Bisamide derivatives of dicarboxylic acids of general formula I can also be obtained by a method comprising condensation of an imide of general formula VII

- 5 043024 where R3 is a -(CH ₂ ) _P - group, optionally substituted with one or two C1-C6 alkyls, n is an integer from 0 to 4, with an equimolar amount of an amine of general formula III

NH ₂ -(CH ₂ ) ₂ -R _b where R1 is a 5-membered unsaturated heterocyclic group containing from 1 to 2 heteroatoms selected from N and/or S, optionally fused with a 6-membered unsaturated cyclic group, in an organic solvent when heated.

Preferably, alcohols are used as the organic solvent, most preferably isopropanol, and the condensation is carried out at reflux.

Another method of the present invention is a method for preparing dicarboxylic acid bisamide derivatives of general formula I, including the interaction of a dicarboxylic acid of general formula II

R ₄ OC(O)-R ₃ -C(O)-OR4, where R3 is -(CH ₂ ) _p - optionally substituted with one or two C1-C6 alkyls, or phenyl, n is an integer from 0 to 4,

R ₄ is hydrogen and an amine of general formula III

NH ₂ -(CH ₂ ) ₂ -R _b where R1 is a 5-membered unsaturated heterocyclic group containing 1 to 2 heteroatoms selected from N and/or S, optionally fused to a 6-membered unsaturated cyclic group;

at a molar ratio of 1:2-2.5 in a solution of tetrahydrofuran in the presence of a condensing agent, preferably carbonyldiimidazole.

The present invention also relates to a medicinal product, a pharmaceutical composition containing dicarboxylic acid bisamide derivatives of general formula I, and a method comprising the administration of dicarboxylic acid bisamide derivatives of general formula I, for the prevention and/or treatment of viral diseases in humans and animals, 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, cholesterol deposition, high blood pressure; diseases associated with metal-dependent reactions of free radical oxidation, including gerontological diseases such as cataracts, retinal diseases, skin pigmentation; consequences of a stroke; atherosclerosis; inflammatory diseases such as osteoarthritis, rheumatoid arthritis;

diabetes and its vascular complications; neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Wilson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases;

oncological diseases; diseases caused by toxins of microorganisms, in particular, botulism or gas gangrene;

alcoholism and alcoholic cirrhosis of the liver; iron deficiency anemia, late porphyria; transition metal salt poisoning.

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, inhaledly and rectally in unit dosage forms containing non-toxic pharmaceutically acceptable carriers. Used in the present description, the term parenteral administration means subcutaneous, intravenous, intramuscular or intrathoracic injection or infusion.

The compounds of the present invention may be administered to the patient at doses ranging from 0.1 to 100 mg/kg of body weight per day, preferably at doses of 0.25 to 25 mg/kg one or more times a day.

It should be noted, however, that the specific dose for any given patient will depend on many factors, including the potency of the compound used, age, body weight, gender, general health and diet of the patient, time and route of drug administration, and rate of elimination. organism, the specific combination of drugs used, as well as the severity of the disease in the individual being treated.

Pharmaceutical compositions of the present invention contain a compound of 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 the active ingredient in admixture with a carrier or vehicle suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration. The active ingredient may be included in the composition along with conventional non-toxic pharmaceutically acceptable carriers,

- 6 043024 suitable for the manufacture of solutions, tablets, pills, capsules, dragees, emulsions, suspensions, ointments, gels and any other dosage forms.

Various substances can be used as fillers, such as saccharides, for example glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as a binder can be used, such as starch paste, eg corn, wheat, rice, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone. If necessary, disintegrating agents such as the aforementioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate can be used.

Optional additives such as flow control agents and lubricating agents such as silica, talc, stearic acid and its salts such as magnesium stearate or calcium stearate and/or propylene glycol may be used.

The dragee core is usually coated with a layer that is resistant to the action of gastric juice. For this purpose, 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.

Stabilizers, thickeners, colorants and perfumes can also be used as additives.

As an ointment base, hydrocarbon ointment bases can be used, such as white and yellow vaseline (Vaselinum. album, Vaselinum flavum), vaseline oil (Oleum. Vaselini), white and liquid ointment (Unguentum album, Unguentum flavum), and as additives to give a denser consistency - such as hard paraffin and wax; absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases, washable with water, such as hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases such as polyethylene glycol ointment (Unguentum Glycolis Polyaethyleni), bentonite bases and others.

Methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyethylene glycol or polyethylene oxide, carbopol can be used as the basis for gels.

As a suppository base, water-insoluble bases such as cocoa butter can be used; water-soluble or water-miscible bases such as gelatin-glycerol or polyethylene oxide; combined bases - soap-glycerin.

When preparing a standard dosage form, the amount of the active ingredient used in combination with the carrier may vary depending on the recipient being treated, on the specific route of administration of the drug.

For example, when using the compounds of the present invention in the form of solutions for injection, the content of the active agent in them is up to 5 wt.%. As diluents, 0.9% sodium chloride solution, distilled water, novocaine solution for injection, Ringer's solution, glucose solution, specific dissolution additives can be used. When administered to the body of the compounds of the present invention in the form of tablets and suppositories, their amount is up to 200 mg per unit dosage form.

Dosage forms of the present invention are prepared by standard procedures such as, for example, mixing, granulating, drageeing, dissolving and lyophilizing processes.

A detailed description of the compounds of the present invention, their preparation and activity studies are presented in the following examples, intended to illustrate the preferred embodiments of the invention, and not limiting its scope.

Examples of the synthesis of glutarimide derivatives of general formula I

Means and methods.

The individuality of the obtained compounds is checked by TLC on Kieselgel 60 F254 plates (Merck, Germany) in the solvent system: pyridine-acetic acid-water (20:6:11) system A, A: ethyl acetate 3:1 (1), chloroform-methanol 9:1(2).

Electrophoresis on paper (electrophoresis paper of the Kondopoga Pulp and Paper Mill, 120x320 mm) is carried out in a buffer with pH 5.1 of the composition pyridine-acetic acid-water 12:10:1000 in a chamber (150x320x150 mm) with a gradient of 15 V/cm for 1.5 h.

Chromatograms and electrophoregrams are shown with chlor-tetramethylbenzidine reagent and Pauli's reagent.

The melting point is determined on the device PTP (factory of laboratory instruments, Russia, Klin).

Fourier IR spectra were recorded in KBr tablets on a Magna 750 instrument (Nicolet (USA)).

1H-NMR spectra were recorded on an AMX-400 instrument (Germany), Bruker DPX-400 (Germany).

High-resolution mass spectra are obtained on a time-of-flight mass spectrometer by matrix laser desorption ionization using 2,5-dihydroxybenzoic acid as a matrix, on an Ultraflex instrument (Bruker, Germany).

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Shimadzu Analytical HPLC SCLIOAvp LC/MS system for analysis of multicomponent mixtures, PE mass spectrometer SCIEX API 165 (150), (Canada).

Analytical reverse-phase HPLC was carried out on the instrument: Shimadzu HPLC chromatograph under the conditions: Luna C18 (2) 100 A, 250x4.6 mm column (ser. conditions a). On the instrument, a Beckman (USA) System Gold chromatograph with a UV detector (λ=220 nm), Gemini C-18 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, 10 μl injection (conditions B).

Example 1 bis-1,5-(N ^β -Histaminel)glutaric acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide (compound 11).

To 5 g (0.031 mol) of dimethyl ester of glutaric acid, 8 g (0.072 mol) of histamine are added and heated at 170°C for 3.5-4 hours until the evolution of methyl alcohol vapor ceases. The completeness of the reaction is controlled by TLC or electrophoresis. Then the reaction mass is suspended in isopropyl alcohol and left for 24 h at +4°C. The product is separated, washed with isopropyl alcohol and dried. Yield 6.8 g (69%). R f 0.42 (1). E ⁺ 49 mm. So pl. 166-168°C. LC/MS, individual peak, retention time 0.3 min [M+H]+=319. HPLC under Condition A, individual peak, retention time 5.58 min. 1H-NMR spectrum (400.13 MHz, DMSO-d6, δ, ppm, J/Hz): 1.70 (pent., 2H, CH2CH2CH2, J=7.3 Hz), 2.03 (t , 4H, CH2CH2CH2, J=7.3 Hz), 2.61 (t, 4H, CCH2CH2N, J=7.5 Hz), 3.26 (sq., 4H, CCH2CH2N, J=7.5 Hz), 6.76 (br s, 2H, CCH), 7.50 (s, 2H, NCHN), 7.94 (br t, 2H, NH). FT-IR spectrum (in table KBr, ν, cm ^-1 ): 1651 (ν C=O amide I), 1580 (δ NH amide II), 1425 (-CH2-CO-). Found, %: C 56.40, H 6.86, N 26.31. _{C15H22N6O2 . _} Calculated, %: C 56.59, H 6.96, N 26.40.

Example 2 bis-1,4-(N ^β -Histaminel)succinic acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]butanediamide) (compound 3).

To 5.5 g (0.046 mol) of succinic acid is added 12.2 g (0.11 mol) of histamine and heated at 170°C for 3.5-4 hours until the release of water vapor ceases. The completeness of the reaction is controlled by TLC or electrophoresis. Then the reaction mass is suspended in 50 ml of water and left for 24 h at +4°C. The product is separated, washed with water and dried. Yield 10.7 g (76%). Rf 0.51 (1). E ⁺ 51 mm. So pl. 230-231°C. [M+H]+=304.95. ¹ H-NMR spectrum (D2O): δ, ppm: 2.48 (s, 4H, CH2-Suc), 2.80-2.84 (t, 4H, s-CH2-HA), 3, 44-3.48 (t, 4H, a-CH2-HA), 6.97 (s, 2H, 5-CH-Im), 7.78 (s, 2H, 2-CH-Im). IR Fourier spectrum (in table KBr, ν, cm ^-1 ): 1634 (ν C=O amide I), 1583 (δ NH amide II), 1429 (-CH ₂ -CO-). Found, %: C 55.40, H 6.66, N 27.31. C ₁₄ H ₂₀ N ₆ O ₂ . Calculated, %: C 55.25, H 6.62, N 27.61.

Example 3 bis-1,3-(N ^β -Histaminel)malonic acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide) (compound 2).

To 6.4 g (0.039 mol) of malonic acid diethyl ester is added 9.0 g (0.081 mol) of histamine and heated at 170°C for 2.5-3 hours until the evolution of ethyl alcohol vapor ceases. The completeness of the reaction is controlled by TLC or electrophoresis. Then the reaction mass is suspended in 20 ml of water and left for 72 hours at +4°C. The product is separated, washed with isopropyl alcohol and dried. Yield 5.0 g (44%). Rf 0.41 (1). E ⁺ 57 mm. So pl. 187-188°C. ¹ H-NMR spectrum (D2O): δ, ppm: 2.74-2.78 (t, 4H, s-CH2-HA), 3.15 (s, 2H, CH2-Mal), 3, 41-3.44 (t, 4H, a-CH2-HA), 6.78 (s, 2H, 5-CH-Im), 7.66 (s, 2H, 2-CH-Im). FT-IR spectrum (in table KBr, ν, cm ^-1 ): 1643 (ν C=O amide I), 1574 (δ NH amide II), 1426 (-CH2-CO-). Found, %: C 53.24, H 6.51, N 28.56. C13H18N6O2. Calculated, %: C 53.78, H 6.25, N28.95.

Example 4 bis-1,2-(H ⁱⁿ -Histaminel)oxalic acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]ethanediamide) (compound 1).

To a solution of 7.3 g (0.05 mol) of oxalic acid diethyl ester in 35 ml of isoamyl alcohol is added 12.2 g (0.11 mol) of histamine and boiled for 4 hours. The completeness of the reaction is monitored by TLC or electrophoresis. The reaction mixture is left for 16 hours at +4°C. The precipitate is separated, washed with isopropyl alcohol, and dried. Yield 10 g (72%). Rf 0.55 (1). E ⁺ 55 mm. So pl. 235236°C. ¹ H-NMR spectrum (DMSO): δ, ppm: 2.66-2.72 (t, 4H, s-CH2-HA), 3.33-3.41 (m, 4H, a-CH2 -HA), 6.81 (s, 2H, 5-CH-Im), 7.54 (s, 2H, 2-CH-Im), 8.78-8.84 (t, 2H, NH-CO) . FT-IR spectrum (table KBr, ν, cm ^-1 ): 1651 (ν C=O amide I), 1566 (δ NH amide II), 1425 (-CH2-CO-). Found, %: C 52.24, H 5.51, N 29.97. C ₁₂ H ₁₆ N ₆ O ₂ . Calculated, %: C 52.17, H 5.84, N 30.42.

Example 5 bis-1,3-(H ⁱⁿ -Histaminel)isophthalic acid (compound 6).

5 g (30 mmol) of isophthalic acid and 7.93 g (69 mmol) of Nhydroxysuccinimide are dissolved in 30 ml of dimethylformamide. To the resulting solution, cooled to 5°C, add a cooled solution of 14.24 g (69 mmol) of N,N'-dicyclohexylcarbodiimide in 10 ml of dimethylformamide, the reaction mixture is left overnight at 5°C. The urea is separated, washed with 15 ml of dimethylformamide and dried. Based on the mass of the obtained urea, the yield of the reaction is considered equal to 80%. A solution of N-hydroxysuccinimide diester of isophthalic acid is cooled to 5°C, after which a melt of 6.84 g (61.6 mmol) of histamine is poured into it in portions. The reaction mixture is left for 2 hours.

- 8 043024 brew in vacuum. The residue, which is a yellow oil, is dissolved in 120 ml of water and passed through a column of Amberlite IRA-96 (27x115). Fractions containing product are pooled. The precipitated crystals of the target product are separated. The resulting technical product is recrystallized from a mixture of 35 ml of isopropanol with 10 ml of water. The product crystals are filtered, washed with water (3x30 ml) and isopropanol (2x13 ml), dried. The target product is obtained in the form of white crystals. Yield 1.55 g (18% for histamine or 14% for isophthalic acid). R f 0.42 (1). So pl. 218-219°C. E ⁺ 40 mm. Mass spectrum: [M+1] ⁺ =353. Spectrum ¹ H-NMR: (300 MHz, DMSO-d ₆ ): δ, ppm: 2.74-2.79 (t, 4H, in-CH ₂ -Ha), 3.46-3.52 (t , 4H, a-CH ₂ -Ha), 6.81 (s, 2H, 5-CH-Im), 7.52-7.56 (m, 3H, ArH+2-CH-Im), 7.92 -7.95 (d, 2H, ArN), 8.28 (s, 1H, ArN), 8.65 (br s, 2H, -C(O)-NH-), 11.80 (br s , 2H, -NH-). HPLC under conditions B, individual peak, recovery time 12.5 min.

Example 6 bis-1,5-( ^N.beta. -Histaminel)glutaric acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide) (compound 11).

To a solution of 13.2 g (0.10 mol) of glutaric acid in 50 ml of methanol, 8 ml of PCl ₃ are added in portions with cooling and stirring. The solvent from the reaction mixture is removed in vacuo. The resulting residue is distilled in vacuo. 14.7 g (92%) of dimethyl ester of glutaric acid with bp 110-112°C are obtained.

7.5 ml of hydrazine hydrate is added to 20 ml of isopropyl alcohol, heated to boiling, and 8 g (0.05 mol) of glutaric acid dimethyl ester are added dropwise, the reaction mixture is left at +20°C for 16 hours. The precipitated product is separated, washed with isopropyl alcohol. Dry. 7.3 g (91%) of glutaric acid dihydrazide, m.p. 210-212°C.

To a solution of 1.61 g (0.010 mol) of glutaric acid dihydrazide in a mixture of 20 g of ice with 2.5 ml of hydrochloric acid and 10 ml of pre-cooled chloroform, 1.45 g (0.021 mol) of sodium nitrite are added in portions with stirring. The chloroform layer is separated, washed with 10 ml of water cooled to +4°C and poured into a cooled solution of 2.6 g (0.023 mol) of histamine in 5 ml of isopropanol. The reaction mixture is left at +20°C for 2 h, then the solvent is removed in vacuo. The resulting residue is dissolved in 20 ml of water and passed through a column with 50 ml of ion-exchange resin KU-2-20 in H ⁺ -form. The resin is washed with 0.5% ammonia solution, collecting fractions of the product that does not contain histamine. The eluates are combined, the solvent is removed in vacuo, the resulting residue is recrystallized from 2 ml of isopropanol and dried. 1.8 g (55%) are obtained. R f 0.42 (1). E ⁺ 49 mm. So pl. 166-168°C. ¹ H-NMR spectrum (D2O): δ, ppm: 1.73-1.78 (m, 2H, e-CH ₂ -Glt), 2.10-2.15 (t, 4H, a- CH ₂ -Glt), 2.78-2.82 (t, 4H, s-CH ₂ -HA), 3.433.48 (t, 4H, a-CH ₂ -HA), 6.94 (s, 2H, 5-CH-Im), 7.69 (s, 2H, 2-CH-Im). FT-IR spectrum (table KBr, ν, cm ^-1 ): 1651 (ν C=O amide I), 1580 (δ NH amide II), 1425 (-CH2-CO-). Found, %: C 56.40, H 6.86, N 26.31. C15H22N6O2. Calculated, %: C 56.59, H 6.96, N 26.40.

Example 7 Bis-1,5-(N ^β -Histaminel)adipic acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]hexanediamide) (compound 12).

To a solution of 7.40 g (0.05 mol) of adipic acid in 25 ml of methanol, 4 ml of phosphorus trichloride are added dropwise with cooling. The solvent from the reaction mixture is removed in vacuo, the resulting residue is distilled in vacuo. 7.5 g (86%) of adipic acid dimethyl ester are obtained, bp 115-117°C.

To a mixture of 20 ml of isopropyl alcohol and 5 ml of hydrazine hydrate, heated to a boil, 7.5 g (0.04 mol) of adipic acid dimethyl ester are added dropwise, the reaction mixture is left at + 20 ° for 16 hours. The precipitated product is separated, washed with isopropyl alcohol, dried. 6.2 g (83%) of adipic acid dihydrazide, m.p. 182-182.5°C.

To a solution of 2.2 g (0.013 mol) of adipic acid dihydrazide in a mixture of 30 g of ice with 3 ml of hydrochloric acid and 15 ml of chilled chloroform, 1.8 g (0.026 mol) of sodium nitrite are gradually sprinkled in portions with stirring. The chloroform layer is separated, washed with 10 ml of water cooled to +4°C and poured into a cooled solution of 3 g (0.027 mol) of histamine in 8 ml of isopropanol. The completeness of the reaction is controlled by TLC or electrophoresis. The reaction mixture is left for 24 h at +4°C, the precipitate is separated, washed with isopropyl alcohol, recrystallized from water, and dried. 2.8 g (65%) are obtained. Rf 0.48 (1). E ⁺ 45 mm. So pl. 184-186°C. [M+H] ⁺ =332.92. 1H-NMR spectrum (D2O): δ, ppm: 1.37-1.41 (m, 4H, e-CH ₂ -Adip), 2.11-2.15 (m, 4H, a-CH ₂ -Adip), 2.74-2.78 (t, 4H, s-CH ₂ -HA), 3.403.44 (t, 4H, a-CH ₂ -HA), 6.88 (s, 2H, 5 -CH-Im), 7.63 (s, 2H, 2-CH-Im). FT-IR spectrum (in table KBr, ν, cm ^-1 ): 1646 (ν C=O amide I), 1581 (δ NH amide II), 1425 (-CH2-CO-). Found, %: C 57.45, H 7.15, N 24.97. C16H24N6O2. Calculated, %: C 57.81, H 7.28, N 25.28.

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In accordance with the above procedure, the following compounds were obtained.

Connection number Structural formula Physico-chemical data Connection 8 SG T Y Mass spectrum: [M+1] ⁺ =353. HPLC: under conditions B, individual peak, recovery time 16.1 min. ΉNMR spectrum (400 MHz, dmso-a ₆ ): δ, ppm: 1.63-1.75 (2H, m, CH ₂ ), 1.96-2.11 (4H, t, J=7 .46, 2CH ₂ ), 3.06-3.16 (4H, t, J=6.97, CH ₂ ), 3.35-3.46 (4H, dd, L=6.61, J2=6 .11, CH ₂ ), 7.66-7.74 (2H, d, J=3.18, Ar), 7.66-7.74 (2H, d, J=3.18, Ar), 7 .9-8.0 (2H, m, NH). Connection 10 Λ^ν^ ^ΝΗ ·^Ύ} LC/MS, individual peak, retention time 0.3 min [M+H] ⁺ =319. HPLC under Condition A, individual peak, retention time 4.12 min. W-NMR spectrum (400.13 MHz, DMSO-0 ₆ , δ, ppm, J/Hz): 1.69 (pent., 2H, CH ₂ CH ₂ CH ₂ , J=7.3 Hz) , 2.01 (t, 4H, CC/CHCHA, J=7.3 Hz), 2.73 (t, 4H, CC^CH ₂ N, J=7.5 Hz), 3.31 (square, 4H, SSCHCHNJ=7.5 Hz), 6.87 (s, 4H, CHNJ, 8.00 (br.t, 2H, RI).

Example 8 bis-1,4-(N ^β -Histaminel)succinic acid; (N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]butanediamide) (compound 3).

To a solution of 0.10 g (0.9 mmol) of histamine in 3 ml of isopropyl alcohol, 0.15 g (0.78 mmol) of succinimidohistamine is added and heated to boiling for 2.5-3 hours. The completeness of the reaction is monitored by TLC or electrophoresis. Then the reaction mass is cooled to room temperature and left for 26 h at +4°C. The product is separated, washed with isopropyl alcohol and dried. Yield 0.20 g (81%). R _f 0.44 (1). E ⁺ 51 mm. So pl. 231°C. [M] ⁺ 304.12. 1H-NMR spectrum (D ₂ O): δ, ppm: 2.48 (s, 4H, CH2-Suc), 2.80-2.84 (t, 4H, β-CH2-HA), 3 .44-3.48 (t, 4H, a-CH2-HA), 6.97 (s, 2H, 5-CH-Im), 7.78 (s, 2H, 2-CH-Im). FT-IR spectrum (in table KBr, ν, cm ^-1 ): 1634 (ν C=O amide I), 1583 (δ NH amide II), 1429 (-CH2-CO-). Found, %: C 6.57, N 27.18. C14H20N6O2. Calculated, %: C 55.25, H 6.62, N27.61.

Example 9 bis-1,5-(N-ethylamino-2-benzimidazolyl)glutaric acid; (N,N'-bis-[2-(1Hbenzimidazol-2-yl)ethyl]pentanediamide) (compound 7).

To a solution of 8 g (0.06 mol) of glutaric acid in 500 ml of anhydrous tetrahydrofuran, 23.4 g (0.145 mol) of carbonyldiimidazole are added, stirred for 2 hours. Then 21.6 g (0.133 mol) of benzimidazolyl ethylamine are added to the reaction mixture. The resulting solution was stirred for 3 h and left at room temperature. The precipitate of the product is separated, washed with water and dried. 21 g (82.9%) are obtained. R _f 0.21 (2). So pl. 170-170.5°C. [M+1] ⁺ =419. 'H-NMR spectrum (DMSO): δ, ppm: 1.61-1.76 (m, 2H, CH ₂ ), 1.95-2.07 (t, 2H, CH 2 ), 2.9 -3.0 (t, 4H, 2CH2), 3.45-3.55 (q., 4H, 2CH2), 7.06-7.14 (m, 4H, Ar), 7.39-7.54 (m, 4H, Ar), 7.98-8.08 (t, 2H, Ar), 11.6-12.7 (s, 2H, NH). HPLC under conditions B, individual peak, exit time 26.6 min.

- 10 043024

In accordance with the above procedure, the following compounds were obtained.

Number connections Structural formula Physico-chemical data Connection 9 Mass spectrum: [M+1] ⁺ =453. ΉNMR spectrum: (400 MHz, DMSOd ₆ ): δ, ppm: 1.65-1.77 (2H, m, CH ₂ ), 2.0-2.1 (2H, t, J=7, 46, CH ₂ ), 3.16-3.26 (4H, t, J=6.97, 2CH ₂ ), 3.45-3.56 (4H, q., L=6.48, J2=5 .87, 2CH ₂ ), 7.35-7.44 (1H, m, Ar), 7.44-7.52 (1H, m, Ar), 7.97.96 (2H, d, Ar, J =7.82), 7.9 6-8.02 (2H, t, NH, J=5.5), 8.02-8.07 (2H, d, Ar, J=7.82). HPLC under conditions B, individual peak, recovery time 18.7 min.

Study of the chelating ability of the described compounds.

The proposed compounds of general formula I, as shown by further studies, have the ability to complex or chelate 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, with zinc, copper, iron, calcium, magnesium ions.

An important characteristic of the ability of a ligand to form complexes is the dissociation constants (pkn) of the compounds under study in an aqueous solution. The pkn values are determined using the potentiometric titration method. The calculation of dissociation constants is carried out according to the Schwarzenbach method [Grinberg A.A., Introduction to the chemistry of complex compounds, ed. 4th, corrected, L., Chemistry, 1971].

pH potentiometric titration methods

The titration was carried out on a setup using an I 120.1 laboratory type ion meter. The created galvanic cell consisted of two electrodes: an indicator glass electrode and a silver chloride reference electrode. The pH values were determined with an accuracy of ±0.2.

Initial 0.05 M solutions of salts of metal ions M ^{z +} were prepared from zinc nitrates (Ζπ (ΝΟ ₃ ) ₂ 6Η ₂ Ο), calcium (Ca (NO ₃ ) ₂ 4H ₂ O), copper sulfate (CuSO ₄ -5H ₂ O), magnesium chloride (MgCl ₂ 6H ₂ O) and Mohr's salt ((NH ₄ ) ₂ Fe(SO ₄ ) ₂ 6H ₂ O). Standardization of the initial solutions of M ^z+ salts was carried out by complexometric titration with Trilon B (M ^z+ =Zn ²⁺ , Cu ²⁺ , Mg ²⁺ , Ca ²⁺ ), spectrophotometrically at 490 nm using o-phenanthroline (M ^z+ = Fe ²⁺ ).

A typical procedure for determining stepwise acid dissociation constants (k1, ..., kn) by pH metric titration according to the Schwarzenbach method.

A portion of the test compound (3-10 ^-4 mol) was dissolved in 15.0 ml of 0.5 M aqueous solution of KNO3. The resulting 0.02 M solution was titrated with vigorous stirring with a 0.05 M aqueous solution of NaOH or HCl. The amount (V, ml) of the consumed titrant and the pH of the solution were recorded at each titration point. The titration step was 0.5 ml, near the equivalence point - 0.2 ml. Titration was carried out to pH values of the solution of 11.0-11.5. According to the pH=f(a) titration curve, the pH value of the solution corresponding to the value of a=0.5 and/or a=1.5 was determined, and the number of added g-equivalents of the titrant in terms of 1 mol of the titrated substance.

The results of determining the acid dissociation constants [pkn] according to the Schwarzenbach method of the studied compounds are presented in Table. 2.

table 2

pk values of test compounds in aqueous solution calculated by the Schwarzenbach method (C 0.02 M, solution ionic strength 0.5 (KNO3), 22°C)

Connection number pki pk ₂ 2 7.11( ¹ ) 11.27® 3 6.88( ¹ ) 11.27( ² ) AND 7.16W 11.89(2) 12 7.13 w 11.95(2)

⁽¹⁾ Titration with aqueous 0.05 M HCl solution.

⁽²⁾ Titration with an aqueous 0.05 M NaOH solution.

Taking into account such parameters as the amount of the test substance required for potentiometric titration, the method of its implementation and the calculation of constants, the Bjerrum method is the most suitable, informative and simple [Galaktionov, M.A. Chistyakov, V.G. Sevastyanov and others,

- 11 043024

Step stability constants of complexes of Group III B elements and lanthanides with acetylacetone in aqueous solution and solubility products of their triacetylacetonates, J. Fiz. Khim., 2004,

vol. 78, no. 9, p. 1596-1604].

The method is based on the idea of the stepwise process of complex formation. The main assumption of Bjerrum's method is the assumption that only mononuclear complexes are formed. Schematically, the complex formation process can be described as follows:

M+L^ML Kx=[ML]/[M][L]

ML^+L^MU K^MLJ/EML^HL]

According to the Bjerrum method, the test compound is titrated twice with NaOH solution: in the absence and in the presence of a metal ion. Titration is carried out at a high constant concentration of an indifferent electrolyte, providing a constant ionic strength of the solution.

For these purposes, highly soluble salts are used, for example, potassium nitrate. Concentration step stability constants (Kn) are experimentally found. In addition, it is possible to obtain information about the composition of the formed complexes, namely, the maximum possible number of attached ligands (n).

A typical procedure for determining the stepwise stability constants of complexes by pH-metric titration according to the Bjerrum method.

A portion of the test compound (3·10 ^-4 mol) was dissolved in 14.0 ml of a 0.5 M aqueous solution of KNO3. With vigorous stirring was added 1.0 ml (5-10 ^-4 mol) of 0.05 M aqueous solution of salt M ^z+ . Systems with the ratio M ^z+ to L 1:6 were investigated. The pH values of the solution were recorded in the joint presence of the ligand and metal ions in the solution. The titration of the mixture was carried out with a 0.05 M aqueous NaOH solution in a wide pH range (up to pH 11.0-11.5). The amount of the consumed titrant (VNaOH, ml) and the pH of the solution were recorded at each titration point. At the time of the formation of a precipitate, cloudiness of the solution, or change in its color, the pH value, the nature of the change, and the volume of the NaOH solution used for titration were recorded. The titration step is 0.25 ml. From the Bjerrum curve n=f(pA) at each half-integer value of the formation function w=n-0.5 lgK _n was determined.

At present, the Bjerrum method is often used to study complex formation. This method involves the determination of two parameters - the concentration of free ligand in equilibrium conditions - [L^-] and the formation function A, which is the average number of ligands included in the complex. So, at any moment of the titration, using experimental data, one can calculate [L ] (namely, -lg[L^-]=pA) and according to equation (1) - p. When the ligand has several dissociating groups, then in equation (1) KL corresponds to the value of the dissociation constant having the largest value of pk. _

From the constructed Bjerrum curve (education curve) /?=f(pA) according to equation (2), for each half-integer value of the formation function w=n-0.5, K _n is found. Thus, the stepwise stability constant will be equal to the reciprocal concentration of the free ligand at the point d=n-0.5. Accordingly, the greater the value of K _n , the more stable is the complex compound (chelate).

_ _\u003d c _L - - [L-] SU-RY ₊ K _L ) C ° _a0H V ™ - K _L n _L ¹¹ with _{mg +} 10-PH. p _mg+ ^κ ^=ϋ?ϊ V where c _L - and c _M ^z+ are the total concentrations of the ligand and metal present in the solution, mol/l;

[L ^- ] - concentration of free ligand ions, mol/l;

KL is the acid dissociation constant of the ligand;

ttadded „ q ^v NaOH - the volume of NaOH solution (%% he, mol / l) at any moment of titration, added to the titrated mixture of M ^{z +} and L, l;

n _L , n _M ^z+ - the amount of the substance of the ligand and salt M ^z+ in the titrated solution, mol.

The lgK1 values found by the Bjerrum method for the complexes of the studied compounds with divalent metal ions are presented in Table 1. 3, 4. The choice of the ratio M ^z+ to L, equal to 1:6, is due to the presence of data on the maximum possible coordination number for Zn(II) and Fe(II), equal to six, and for Cu(II), equal to four [Claudia A Blindauer, M. Tahir Razi, Simon Parsons, Peter J. Sadler, Polyhedron, 2006, v. 25, p. 513-520].

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Table 3

The first stability constant of complexes of 1:1 composition of the studied compounds with divalent metal ions is lgK1, found by the Bjerrum method (aqueous solution, CL=0.02 M, ratio M ^z+ to L 1:6, ionic strength 0.5 (KNO ₃ ) , 22°C)

Connection number The first stability constant of complexes of 1:1 composition of the studied compounds with divalent metal ions is lgK ₃ Ζη(Π) Si(P) Fe(II) Fe(III) Mg(II) Ca(II) 2 4.84 4.17 5.08 5.29 2.59 2.06 3 5.40 5.32 5.95 6.59 4.36 4.57 eleven 5.05 4.39 6.27 6.60 2.82 ή <0.5 12 5.46 4.62 6.40 6.10 3.72 3.60

Table 4

Stepwise stability constants of 1:1 complexes of the studied compounds with zinc ions, found by the Bjerrum method (aqueous solution, CL=0.02 M, ratio M ^z+ to L 1:6, solution ionic strength 0.5 (KNO ₃ ), 22 °C)

Connection number Stepwise Stability Constants of 1:1 Complexes of Studied Compounds with Zinc Ions First stability constant, IgKx Second stability constant, lgK ₂ Third stability constant, lgK ₃ 1 4.52 4.21 3.75 2 4.84 4.50 2.60 3 5.40 5.05 3.80 6 5.62 5.15 4.04 8 6.25 5.80 5.05 10 5.50 5.24 4.48 eleven 5.05 4.70 2.87 12 5.46 5.03 3.38

Thus, the conducted studies have shown that the tested compounds - derivatives of dicarboxylic acid bisamides, are effective complexing agents, for most of which high values of lgK1>5 were found with respect to transition metal ions. In this case, there is a slightly increased complexing ability of the proposed compounds of general formula I in relation to iron ions.

Claims (11)

1. Bisamide dicarboxylic acid derivative of formula 6 or a pharmaceutically acceptable salt thereof. 2. Process for the preparation of a compound of formula 6 n including the interaction of isophthalic acid with N-hydroxysuccinimide in the presence of N,N'-dicyclohexylcarbodiimide in N,N-dimethylformamide to obtain the corresponding bis-Noxysuccinimide ester, which is condensed with an amine of the formula 3. The method according to claim 2, where the condensation is carried out while cooling to a temperature of 0-5°C. 4. Process for the preparation of a compound of formula 6 comprising a condensation of a dicarboxylic acid or ester of the formula R ₄ OC(O)-R ₃ -C(O)-OR4, - 13 043024 where R ₃ represents m-phenylene; R4 is hydrogen and C1- _C6 alkyl, and an amine of the formula when heated. 5. The method according to claim 4, wherein the condensation is carried out in the presence of a solvent. 6. The method according to claim 5, in which dimethyl ether, diglyme or alcohols are used as a solvent and heating is carried out to 150-170°C. 7. The method according to claim 5, in which the condensation is carried out in isoamyl alcohol at boiling. 8. Process for the preparation of a compound of formula 6 n including the interaction of a dicarboxylic acid ester of the general formula R ₄ OC(O)-R ₃ -C(O)-OR4, where R ₃ is m-phenylene; R4 is C1- _C6 alkyl, with hydrazine hydrate in an organic solvent to give a bishydrazide of general formula H ₂ N-NH-C(O)-R ₃ -C(O)-NH-NH ₂ treatment of bishydrazide with sodium nitrite in an acid medium at a temperature of about 0°C to obtain a bisazide of the general formula N'-N ⁺ =NC(O)-R ₃ -C(O)-N=N ⁺ -N', condensation of an azide with an amine of the formula n 9. Process according to claim 8, wherein alcohols, preferably isopropanol, are used as the organic solvent. 10. Process for the preparation of a compound of formula 6 n including the interaction of dicarboxylic acid of General formula R ₄ OC(O)-R ₃ -C(O)-OR4, where R ₃ represents m-phenylene; R4 is C1- _C6 alkyl, and an amine of the formula at a molar ratio of 1:2-2.5 in tetrahydrofuran in the presence of a condensing agent. 11. The method of claim 10 wherein carbonyldiimidazole is used as the condensing agent.