RU2725770C2 - Bicamides derivative of dicarboxylic acids, use thereof, a pharmaceutical composition based thereon, methods for production thereof - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention relates to a dicarboxylic acid bisamide derivative of formula 1 below, which is capable of complexing or chelating metal ions. Invention also relates to medicinal agents, pharmaceutical compositions and application of said compound of formula 1 for prevention and/or treatment of viral diseases, atherosclerosis and inflammatory diseases, methods of preventing and/or treating the listed diseases and methods of producing the compound of formula 1.

EFFECT: disclosed is a bicamides derivative of dicarboxylic acids, use thereof, a pharmaceutical composition based thereon, methods for production thereof.

21 cl, 5 tbl, 9 ex

Description

The invention relates to new biologically active compounds, derivatives of dicarboxylic acid bisamides or their pharmaceutically acceptable salts, which are capable of complexing or chelating metal ions, as well as their use as an antioxidant agent, agents 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.

Known drugs 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 effective and selective chelation of metal ions and suitable for biomedical use.

Compounds with chelating ability were found among various classes of compounds of mono- and dithiols, disulfides, azo compounds, nitroaromatic compounds, derivatives of polyaminocarboxylic acids, thiosemicarbazone, pyridoxal isonicotinoylhydrazone, quinoline, adamantane, pyrogallolum, phenanthroline phosphate, thianthroline phosphate. In addition, they are noted among other natural compounds, such as, for example, carnosine, phytin, pectin. Of the greatest interest are compounds having several functional groups capable of acting as electron donors in complex formation. In this regard, such compounds can be ligands that specifically interact with metal ions or metal groups.

Currently widely known complexing agents are derivatives of polyaminocarboxylic acids (for example, EDTA), D-penicillamine, polycyclic cryptands, which are successfully used in case of 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, with arthrosis, atherosclerosis, and kidney stone disease. 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 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 mineral metabolism, is useful in the treatment of Alzheimer's disease, prevents the onset of cancer, improves memory and exhibits many other positive effects. However, the strong chelators currently used in chelotherapy, 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. In addition, 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, No. 1, pp. 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 hepatotherapy in case of viral diseases such as HIV, human papilloma, herpes, hepatitis C and others is especially relevant.

A promising target for this is zinc-binding sites in the structure of viral proteins - the so-called “zinc fingers”.

Currently, several compounds have been identified that act on the “zinc fingers” of important proteins of these viruses.

An article by Andreas J.K., Boorganic & Medicinal chemistry, 2003, v.11, p. 4599-4613, describes an adamantane derivative having the trivial name bananin, which is a chelator of zinc ions. It is believed to be chemically suitable for removing zinc from the HIV NCp7 protein. Having the aforementioned mechanism of action, the azo derivative, azadicarbonamide, is in the I / II stage of clinical trials against progressive AIDS.

Rice WG, Schaeffer CA, Harten B., Nature, 1993, v.4, p.473-475, discloses 3-nitrosobenzamide, which removes zinc from the NCp7 HIV protein, inhibiting HIV replication and its pathogenicity in vitro and in vivo .

As a target of drugs, 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.

Beerheide W., Bernard H.-U., Tan Y.-J., Ganesan AJ, National Cancer Institute, 1999, v. 91, No. 14, 1211-1220, describe in vitro tests of azo 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 genital papillomavirus infections. Hepatitis C virus is one of the most widespread human pathogens. Modern therapy for hepatitis C 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, No. 9, p. 1253-12594]. It should be noted the low effectiveness of such therapy.

Regarding the development of therapeutic agents against hepatitis C virus, one of the targets is NS3-serine proteinase, in which the zinc region plays an important role in maintaining the stability of the structure [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 through 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.

Timothy L. Tellinghuisen, Matthew S. Paulson, Charles M. Rice, J. Virology, 2006, v. 80, No. 15, p. 7450-7458, it is described that metal chelators (EDTA and 1,10-phenanthroline) were effective protease inhibitors evaluated against NS2 / 3 auto-cleavage. There is also evidence that 1,10-phenanthroline acted in this case precisely through chelation of zinc.

In an article by Sperandio D., Gangloff AR, Litvak J. Goldsmith R., Bioorg. Med. Chem. Lett., 2002, v.12, No. 21, 3129-3133, describes a screening of a group of bisbenzimidazoles to search for serum protease inhibitors NS3 / NS4A of hepatitis C virus, 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 hepatitis C virus (viral protein NS5B), which has a zinc-binding region in its structure [Timothy L. Tellinghuisen, Matthew S. Paulson, Charles M. Rice, J. Virology, 2006, v. 80, No. 15, p. 7450-7458].

Normally, the liver cell does not contain proteins with similar activity [Kozlov MV, Polyakov KM, Ivanov AV, Biochemistry, 2006, vol. 71, No. 9, pp. 1253-12594].

Currently known inhibitors of the 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, 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 participating in the catalytic act at the stage of phosphoryl residue transfer [Kozlov MV, Polyakov KM, Ivanov AV, Biochemistry, 2006, t. 71, No. 9, pp. 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 thus 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].

However, it should be noted that 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, 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 argue about the important role of metal ions 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 the creation of drugs capable of treating a variety of diseases, in particular, viral ones.

In the article by 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, effective iron chelators are disclosed that exhibit high antiproliferative and antitumor activity comparable to that of known cytostatics and are promising for clinical studies.

In 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 indicated that some iron chelators can be used as "helpers" 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, 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. 1076-84], as well as alcoholic cirrhosis of the liver, iron-rich anemia, late 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 antracyclin as antibiotics: studies in vitro ”, Physiol Res., 2004, v. 53 (6), p. 683-691].

The activity of some antioxidants is due to the chelation of transition metal ions (Fe, Cu), which is accompanied by a decrease in the metal-dependent lipid peroxidation [Babizhayev MA, Seguin Marie-C., Gueynej J., Evstigneev RP, Ageyeva EA, Zheltuchina GA, “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 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, No. 1, pp. 45-50].

Chelators can be used in medicine as complexones for the transportation and easy excretion of arsenic, mercury, antimony, cobalt, zinc, chromium, nickel [Zholnin A.V., “Complex compounds”, Chelyabinsk: ChGMA, 2000, p. 28 ].

Inhibition of botulinum toxin by chelating zinc ions is known [Anne C., Blommaert A., “Thio-derivvede 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 with gas gangrene [Zelenin KN, "Complexons in medicine", Soros Educational Journal, 2001, v. 7, No. 1, pp. 45-50].

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. 6876-6883]; Huntington's disease [Whitnall M., Richardson D.R., “Iron: a new target for pharmacological interention 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, L11-L13]. 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].

Derivatives of heterocyclic compounds, for example, imidazole, containing imido and amido groups, occupy a significant place among the known chelators.

In an 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, pp. 5950-5956, describes a bishistamine derivative of glutaric acid, which can serve as a model of the active center of nucleases and exhibits weak activity in the cleavage of RNA molecules.

In an article by Elfriede Schuhmann et al., “Bis [platinum (II)] and Bis [Palladium (II)] complexes of α, ώ-Dicarboxylic Acid Bis (1,2,4-triaminobutane-N ⁴ ) -Amides”, Inorg . Chem., 1995, v. 34, p. 2316-2322, described are bishistamines derivatives of glutaric and adipic acids, which are intermediate compounds for the synthesis of complexes with platinum and palladium:

n = 3-6.8

M = Pt, Pd

A method for the synthesis of N ¹ , N ¹ -glutarylbis (histamine), comprising 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 [platinum (II)] and Bis [platinum (II)] and Bis Palladium (II)] complexes of α, ώ-Dicarboxylic Acid Bis (1,2,4-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 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 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.

SUMMARY OF THE INVENTION

The present invention relates to dicarboxylic acid bisamide derivatives of the general formula I

wherein

R ₁ 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 (O) —R ₃ —C (O) -, where R ₃ represents a group - (CH ₂ ) _n - optionally substituted with one or two C ₁ -C ₆ alkyls, or phenyl,

n is an integer from 0 to 4;

or their pharmaceutically acceptable salts.

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.

The present invention also relates to methods for producing compounds of General formula I, including:

the interaction of the 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

the interaction of the dicarboxylic acid diester with hydrazine hydrate, processing the obtained dihydrazide with sodium nitrite to obtain the corresponding azide, which is condensed with an amine; or

heating an imide solution formed from 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 the general formula I are simple to implement, proceed under fairly mild conditions, without formation of by-products, are technologically advanced, and they allow to obtain target products with a good yield (up to 82%) and a high degree of purity.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of the present invention are compounds of the general formula I:

,

,

where R ₁ represents a group selected from:

R ₂ represents a group selected from: —C (O) - (CH ₂ ) ₀ —C (O) -, —C (O) - (CH ₂ ) ₁ —C (O) -, —C (O) - (CH ₂ ) ₂ -C (O) -, -C (O) - (CH ₂ ) ₃ -C (O) -, -C (O) - (CH ₂ ) ₄ -C (O) -, - C (O) —CH ₂ —CH (CH ₃ ) —CH ₂ —C (O) -, —C (O) —CH ₂ —C (CH ₃ ) ₂ —CH ₂ —C (O) -, or a group

The most preferred compounds of the present invention are the compounds shown in table 1.

Table 1 Connection number Structure 1

2

3

4

five

6

7

8

nine

ten

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

The most preferred known compounds that can be used in the pharmaceutical composition and method of treatment of the present invention are the glutarimide derivatives shown in table 2.

table 2 Connection number Structure eleven

12

The compounds of the present invention can be obtained by a method comprising condensation of a dicarboxylic acid of the general formula II:

R ₄ OC (O) -R ₃ -C (O) -OR ₄ ,

where R ₃ represents a group - (CH ₂ ) _n - optionally substituted with one or two C ₁ -C ₆ alkyls, or phenyl,

n is an integer from 0 to 4,

R ₄ represents hydrogen, C ₁ -C ₆ alkyl,

and an amine of the general formula III:

NH ₂ - (CH ₂ ) ₂ -R ₁ ,

where R ₁ 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;

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, 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 method comprising reacting a dicarboxylic acid of the general formula II:

R ₄ OC (O) -R ₃ -C (O) -OR ₄ ,

where R ₃ represents a group - (CH ₂ ) _n - optionally substituted with one or two C ₁ -C ₆ alkyls, or phenyl,

n is an integer from 0 to 4,

R ₄ represents hydrogen,

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

,

,

which is condensed with an amine of the general formula III:

NH ₂ - (CH ₂ ) ₂ -R ₁ ,

where R ₁ 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 II:

R ₄ OC (O) -R ₃ -C (O) -OR ₄ ,

where R ₃ represents a group - (CH ₂ ) _n - optionally substituted with one or two C ₁ -C ₆ alkyls, or phenyl,

n is an integer from 0 to 4,

R ₄ represents C ₁ -C ₆ alkyl,

with hydrazine hydrate in an organic solvent to obtain bishydrazide of the general formula V:

H ₂ N-NH-C (O) -R ₃ -C (O) -NH-NH ₂ ,

treatment of bishydrazide with sodium nitrite in an acidic medium at a temperature of about 0 ° C to obtain a bisazide of the general formula VI:

N ^- -N ⁺ = NC (O) -R ₃ -C (O) -N = N ⁺ -N ^- ,

condensation of bisazide with an amine of the general formula III:

NH ₂ - (CH ₂ ) ₂ -R ₁ ,

where R ₁ 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.

Preferably, 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:

,

,

where R3 represents a group - (CH2) n- 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 the general formula III:

NH ₂ - (CH ₂ ) ₂ -R ₁ ,

where R ₁ 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 when heated.

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 ₄ OC (O) -R ₃ -C (O) -OR ₄ ,

where R ₃ represents a group - (CH ₂ ) _n - optionally substituted with one or two C ₁ -C ₆ alkyls, or phenyl,

n is an integer from 0 to 4,

R ₄ represents hydrogen,

and an amine of the general formula III:

NH ₂ - (CH ₂ ) ₂ -R ₁ ,

where R ₁ 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 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 medicament, pharmaceutical composition containing 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;

diabetes and its vascular complications; 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;

alcoholism and alcoholic cirrhosis of the liver; iron-rich anemia, late porphyria; poisoning with salts of transition metals.

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, inhaled 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 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.

It should be noted that 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, and speed of its elimination from an organism, the combination of drugs specifically used, and the severity of the disease in the individual being treated.

The 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 an active ingredient in a mixture with 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, components such as starch paste, for example, corn, wheat, rice, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone. If necessary, 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 may be used.

The core of the dragee 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.

As additives, stabilizers, thickeners, colorants and perfumes may also be used.

As an ointment base, 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 for giving denser consistency - such as paraffin wax 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.

As the basis for the gels, methyl cellulose, sodium salt of carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol or polyethylene oxide, carbopol can be used.

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

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

So, 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% by weight. As diluents, 0.9% sodium chloride solution, distilled water, novocaine solution for injection, Ringer's solution, glucose solution, specific additives for dissolution can be used. When introduced into 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 obtained according to standard methods, such as, for example, mixing, granulating, dragee formation, dissolution and lyophilization.

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

Examples of the synthesis of glutarimide derivatives of the general formula I

Means and methods

The individuality of the compounds obtained is checked by TLC on Kieselgel 60 F254 plates (Merck, Germany) in a 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 Kondopoga Pulp and Paper Mill, 120 × 320 mm) is carried out in a buffer with a pH of 5.1 of pyridine-acetic acid-water 12: 10: 1000 in a chamber (150 × 320 × 150 mm) with a gradient of 15 V / cm for 1.5 hours.

Chromatograms and electrophoregrams exhibit chloro-tetramethylbenzidine reagent and Pauli reagent.

The melting temperature is determined on a PTP device (laboratory of laboratory devices, Russia, Klin).

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

Spectra ¹ H-NMR recorded on the device AMX-400 (Germany), Bruker DPX-400 (Germany).

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

Shimadzu Analytical HPLC SCL10Avp multicomponent mixtures LC / MS analysis system, PE SCIEX API 165 (150) mass spectrometer, (Canada).

Analytical reverse phase HPLC was performed on an instrument: Shimadzu HPLC chromatograph under conditions: Luna C18 (2) 100 A column, 250 × 4.6 mm (ser. 599779-23), elution gradient in a phosphate buffer solution pH 3.0: methanol (conditions A). On a Beskman (USA) System Gold chromatograph with a UV detector (λ = 220 nm), a C-18 Gemini column, 150 × 2.0 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 μl (conditions B).

Example 1

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

To 5 g (0.031 mol) of glutaric acid dimethyl ester, 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 monitored by TLC or electrophoresis. Then the reaction mass is suspended in isopropyl alcohol and left for 24 hours at + 4 ° C. The product is separated, washed with isopropyl alcohol, dried. Yield 6.8 g (69%). R_f 0.42 (1). E⁺49 mm. Mp 166-168ºС. LC / MS, individual peak, retention time 0.3 min [M + H]⁺= 319. HPLC under conditions A, individual peak, retention time 5.58 min. Range¹H-NMR (400.13 MHz, DMSO-d₆, δ, ppm, J / Hz): 1.70 (pent., 2H, CH₂C H ₂ CH₂, J = 7.3 Hz), 2.03 (t, 4H, C H ₂CH ₂ C H ₂, J = 7.3 Hz), 2.61 (t, 4H, CC H ₂ CH₂N, J = 7.5 Hz), 3.26 (q, 4H, CCH ₂ C H ₂N, J = 7.5 Hz), 6.76 (br s, 2H, CC H ), 7.50 (s, 2H, NC H N ), 7.94 (br t, 2H, N H ) IR-Fourier spectrum (in the table KBr, ν, cm^-1): 1651 (ν C = O amide I), 1580 (δ NH amide II), 1425 (-CH ₂ -CO-). Found,%: C 56.40, H 6.86, N 26.31. FROM₁₅N₂₂N₆O₂. Calculated,%: C 56.59, H 6.96, N 26.40.

Example 2

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

12.5 g (0.11 mol) of histamine are added to 5.5 g (0.046 mol) of succinic acid and heated at 170 ° C for 3.5-4 hours until the evolution of water vapor ceases. The completeness of the reaction is monitored by TLC or electrophoresis. Then the reaction mass is suspended in 50 ml of water and left for 24 hours at + 4 ° C. The product is separated, washed with water, dried. Yield 10.7 g (76%). R _f 0.51 (1). E ⁺ 51 mm. Mp 230-231ºС. [M + H] ⁺ 304.95. Spectrum ¹ H-NMR (D ₂ O): δ, ppm: 2.48 (s, 4H, CH ₂ -Suc), 2.80-2.84 (t, 4H, β-CH ₂ -HA ), 3.44-3.48 (t, 4H, α-CH ₂ -HA), 6.97 (s, 2H, 5-CH-Im), 7.78 (s, 2H, 2-CH-Im ) IR-Fourier spectrum (in the table KBr, ν, cm ^-1 ): 1634 (ν C = O amide I), 1583 (δ NH amide II), 1429 (- СН ₂ -СО-). 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 -histaminyl) 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, 9.0 g (0.081 mol) of histamine is added and heated at 170 ° C for 2.5-3 hours until the evolution of ethyl alcohol vapor ceases. The completeness of the reaction is monitored 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, dried. Yield 5.0 g (44%). R _f 0.41 (1). E ⁺ 57 mm. Mp 187-188ºС. Spectrum ¹ H-NMR (D ₂ O): δ, ppm: 2.74-2.78 (t, 4H, β-CH ₂ -HA), 3.15 (s, 2H, CH ₂ -Mal ), 3.41-3.44 (t, 4H, α-CH ₂ -HA), 6.78 (s, 2H, 5-CH-Im), 7.66 (s, 2H, 2-CH-Im ) IR-Fourier spectrum (in the table KBr, ν, cm ^-1 ): 1643 (ν C = O amide I), 1574 (δ NH amide II), 1426 (- СН ₂ -СО-). Found,%: C 53.24, H 6.51, N 28.56. C ₁₃ H ₁₈ N ₆ O ₂ . Calculated,%: C 53.78, H 6.25, N 28.95.

Example 4

Bis-1,2- (N ^β -histaminyl) 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 ether in 35 ml of isoamyl alcohol, 12.2 g (0.11 mol) of histamine is added and boiled for 4 hours. The reaction is complete by TLC or electrophoresis. The reaction mixture is left for 16 hours at + 4 ° C. The precipitate was separated, washed with isopropyl alcohol, and dried. Yield 10 g (72%). R _f 0.55 (1). E ⁺ 55 mm. Mp 235-236ºС. Spectrum ¹ H-NMR (DMSO): δ, ppm: 2.66-2.72 (t, 4H, β-CH ₂ -HA), 3.33-3.41 (m, 4H, α- CH ₂ -HA), 6.81 (s, 2H, 5-CH-Im), 7.54 (s, 2H, 2-CH-Im), 8.78-8.84 (t, 2H, NH - CO). IR-Fourier spectrum (in the table KBr, ν, cm ^-1 ): 1651 (ν C = O amide I), 1566 (δ NH amide II), 1425 (- СН ₂ -СО-). 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- (N ^β -histaminyl) isophthalic acid (compound 6)

5 g (30 mmol) of isophthalic acid and 7.93 g (69 mmol) of N-hydroxysuccinimide are dissolved in 30 ml of dimethylformamide. To the resulting solution, cooled to 5 ° C, a cooled solution of 14.24 g (69 mmol) of N, N'-dicyclohexylcarbodiimide in 10 ml of dimethyl foramide was added, the reaction mixture was 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 reaction yield is considered equal to 80%. The solution of N-hydroxysuccinimide isophthalic acid diester is cooled to 5 ° C, after which a melt of 6.84 g (61.6 mmol) of histamine is added in portions. The reaction mixture was left for 2 hours. The solvent was removed in vacuo. The yellow oil residue was dissolved in 120 ml of water and passed through an Amberlite IRA-96 column (27 × 115). The fractions containing the product are combined. 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 crystals of the product are filtered, washed with water (3 × 30 ml) and isopropanol (2 × 13 ml), dried. Get the target product in the form of white crystals. Yield 1.55 g (18%, based on histamine, or 14% - on isophthalic acid). R _f 0.42 (1). Mp 218-219ºС. E ⁺ 40 mm. Macc spectrum: [M + 1] ⁺ 353 _. ¹ H-NMR spectrum: (300 MHz, DMSO-d ₆ ): δ, ppm: 2.74-2.79 (t, 4H, β-CH ₂ -Ha), 3.46-3.52 (t 4H, α-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, ArH), 8.28 (s, 1H, ArH), 8.65 (br s, 2H, -C (O) -NH-), 11.80 (br s , 2H, -NH-). HPLC under conditions B, individual peak, exit time 12.5 min.

Example 6

Bis-1,5- (N ^β -histaminyl) 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 were} added in portions while cooling and stirring. The solvent from the reaction mixture was removed in vacuo. The resulting residue was distilled in vacuo. Obtain 14.7 g (92%) of glutaric acid dimethyl ester with boiling point. 110-112ºС.

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 ether are added dropwise, the reaction mixture is left at + 20 ° С for 16 hours. The precipitated product is separated off, washed with isopropyl alcohol. They are drying. 7.3 g (91%) of glutaric acid dihydrazide are obtained with a melting point of 210-212ºС.

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-chilled chloroform, 1.45 g (0.021 mol) of sodium nitrite are added portionwise. The chloroform layer is separated, washed with 10 ml of water cooled to + 4 ° C and added to a cooled solution of 2.6 g (0.023 mol) of histamine in 5 ml of isopropanol. The reaction mixture was left at + 20 ° C for 2 hours, then the solvent was removed in vacuo. The resulting residue was dissolved in 20 ml of water and passed through a column of 50 ml of KU-2-20 ion-exchange resin in H ⁺ form. The resin is washed with a 0.5% ammonia solution, collecting fractions of a histamine-free product. The eluates are combined, the solvent is removed in vacuo, the obtained residue is recrystallized from 2 ml of isopropanol, dried. 1.8 g (55%) are obtained. R _f 0.42 (1). E ⁺ 49 mm. Mp 166-168ºС. Spectrum ¹ H-NMR (D ₂ O): δ, ppm: 1.73-1.78 (m, 2H, β-CH ₂ -Glt), 2.10-2.15 (t, 4H, α-CH ₂ -Glt), 2.78-2.82 (t, 4H, β-CH ₂ -HA), 3.43-3.48 (t, 4H, α-CH ₂ -HA), 6, 94 (s, 2H, 5-CH-Im); 7.69 (s, 2H, 2-CH-Im). IR-Fourier spectrum (in the table KBr, ν, cm ^-1 ): 1651 (ν C = O amide I), 1580 (δ NH amide II), 1425 (- СН ₂ -СО-). Found,%: C 56.40, H 6.86, N 26.31. C ₁₅ H ₂₂ N ₆ O ₂ . Calculated,%: C 56.59, H 6.96, N 26.40.

Example 7

Bis-1,5- (N ^β -histaminyl) 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 was removed in vacuo, the resulting residue was distilled in vacuo. Obtain 7.5 g (86%) of adipic acid dimethyl ester, b.p. 115-117ºС.

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 + 20º for 16 hours. The precipitated product is separated off, washed isopropyl alcohol, dried. 6.2 g (83%) of adipic acid dihydrazide are obtained with a melting point of 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 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 3 g (0.027 mol) of histamine in 8 ml of isopropanol. The completeness of the reaction is monitored by TLC or electrophoresis. The reaction mixture is left for 24 hours at + 4 ° C, the precipitate is separated, washed with isopropyl alcohol, recrystallized from water, dried. 2.8 g (65%) are obtained. R _f 0.48 (1). E ⁺ 45 mm. Mp 184-186ºС. [M + H] ⁺ 332.92. ¹ H-NMR spectrum (D ₂ O): δ, ppm: 1.37-1.41 (m, 4H, β-CH ₂ -Adip), 2.11-2.15 (m, 4H, α-CH ₂ -Adip), 2.74-2.78 (t, 4H, β-CH ₂ -HA), 3.40-3.44 (t, 4H, α-CH ₂ -HA), 6, 88 (s, 2H, 5-CH-Im); 7.63 (s, 2H, 2-CH-Im). IR-Fourier spectrum (in the table KBr, ν, cm ^-1 ): 1646 (ν C = O amide I), 1581 (δ NH amide II), 1425 (- СН ₂ -СО-). Found,%: C 57.45, H 7.15, N 24.97. C ₁₆ H ₂₄ N ₆ O ₂ . Calculated,%: C 57.81, H 7.28, N 25.28.

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

Connection number Structural formula Physicochemical data Compound 8

Macc spectrum: [M + 1] ⁺ = 353. HPLC: under conditions B, individual peak, exit time 16.1 minutes. Spectrum ¹ H-NMR (400 MHz, DMSO-d 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, J1 = 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). Compound 10

LC / MS, individual peak, retention time 0.3 min [M + H]⁺= 319. HPLC under conditions A, individual peak, retention time 4.12 min. Range¹H-NMR (400.13 MHz, DMSO-d₆, δ, ppm, J / Hz): 1.69 (pent., 2H, CH₂C H ₂ CH₂, J = 7.3 Hz), 2.01 (t, 4H, C H ₂ CH ₂ C H ₂, J = 7.3 Hz), 2.73 (t, 4H, CC H ₂ CH₂N, J = 7.5 Hz), 3.31 (q, 4H, CCH ₂ C H ₂ N, J = 7.5 Hz), 6.87 (s, 4H, C H N ), 8.00 (br t, 2H, N H )

Example 8

Bis-1,4- (N ^β -histaminyl) 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 reaction progress is monitored by TLC or electrophoresis. Then the reaction mass is cooled to room temperature and left for 26 hours at + 4 ° C. The product is separated, washed with isopropyl alcohol, dried. Yield 0.20 g (81%). R _f 0.44 (1). E ⁺ 51 mm. Mp 231ºС. [M] ⁺ 304.12. Spectrum ¹ H-NMR (D ₂ O): δ, ppm: 2.48 (s, 4H, CH ₂ -Suc), 2.80-2.84 (t, 4H, β-CH ₂ -HA ), 3.44-3.48 (t, 4H, α-CH ₂ -HA), 6.97 (s, 2H, 5-CH-Im), 7.78 (s, 2H, 2-CH-Im ) IR-Fourier spectrum (in the table KBr, ν, cm ^-1 ): 1634 (ν C = O amide I), 1583 (δ NH amide II), 1429 (- СН ₂ -СО-). Found,%: C 6.57, N 27.18. C ₁₄ H ₂₀ N ₆ O ₂ . Calculated,%: C 55.25, H 6.62, N 27.61.

Example 9

Bis-1,5- (N-ethylamino-2-benzimidazolyl) glutaric acid; (N, N'-bis- [2- (1H-benzimidazol-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 and 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 hours and left at room temperature. The precipitate of the product is separated, washed with water, dried. Obtain 21 g (82.9%). R _f 0.21 (2). Mp 170-170.5ºС. [M + 1] ⁺ 419. Spectrum ¹ H-NMR (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, 2CH ₂ ), 3.45-3.55 (q, 4H, 2CH ₂ ), 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.

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

Connection number Structural formula Physicochemical data Compound 9

Macc spectrum: [M + 1] ⁺ = 453. ¹ H-NMR spectrum: (400 MHz, DMSO-d 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, J1 = 6, 48, J2 = 5.87, 2CH ₂ ), 7.35-7.44 (1H, m, Ar), 7.44-7.52 (1H, m, Ar), 7.9-7.96 ( 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, exit time 18.7 min.

The 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 complexation or chelation of metal ions. They have several functional groups that can act as electron donors in 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, magnesium ions.

An important characteristic of the complexing ability of the ligand is the dissociation constants (pk _n ) of the studied compounds in aqueous solution. Pk _n values are determined using potentiometric titration. The calculation of dissociation constants is carried out according to the Schwarzenbach method [A. Greenberg, “Introduction to the chemistry of complex compounds”, ed. 4th, rev., L., Chemistry, 1971].

PH potentiometric titration methods

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 (Zn (NO ₃ ) ₂ · 6H ₂ O), 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). Stock solutions of M ^{z +} salts were standardized 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 method for determining stepwise acid dissociation constants (k ₁ , ..., k _n ) 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 a 0.5 M aqueous solution of KNO₃. The resulting 0.02 M solution with vigorous stirring was titrated with a 0.05 M aqueous solution of NaOH or HCl. The quantity (V, ml) of the spent 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 a pH of 11.0-11.5. The pH value of the solution corresponding to a = 0.5 and / or a = 1.5 was determined from the titration curve pH = f (a), and a is 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 [pk _n ] by the Schwarzenbach method of the studied compounds are presented in table 3.

Table 3
The pk values of the test compounds in aqueous solution calculated by the Schwarzenbach method (C 0.02 M, the ionic strength of the solution is 0.5 (KNO ₃ ), 22ºС) Connection number pk ₁ pk ₂ 2 7.11 ⁽¹⁾ 11.27 ⁽²⁾ 3 6.88 ⁽¹⁾ 11.27 ⁽²⁾ eleven 7.16 ⁽¹⁾ 11.89 ⁽²⁾ 12 7.13 ⁽¹⁾ 11.95 ^{(2) (1)} titration with an 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 procedure for its conduct and calculation of constants, the Bierrum method [Galaktionov, MA, is the most suitable, informative and simple Chistyakov, V.G. Sevastyanov et al., "Step stability constants of complexes of group III B elements and lanthanides with acetylacetone in an aqueous solution and solubility products of their triacetylacetonates", J. Phys. Chem., 2004, v. 78, No. 9, p. 1596-1604].

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. Schematically, the complexation process can be described as follows:

M + L↔ML K ₁ = [ML] / [M] [L]

ML _n-1 + L↔ML _n K _n = [ML _n ] / [ML _n-1 ] [L]

According to the Bierrum method, the test compound is titrated twice with a NaOH solution: in the absence and 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. The concentration stepwise stability constants (K _n ) are experimentally found. In addition, it is possible to obtain information on the composition of the resulting complexes, namely, the maximum possible number of attached ligands (n).

Typical method for determining stepwise stability constants of complexes by pH-metric titration according to the Bierrum method

=f(pA) при каждом полу-целочисленном значении функции образования

=n-0,5 определяли lgK_n.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, 1.0 ml (5 × 10^-4 mol) 0.05 M aqueous solution of salt M^{z +}. Investigated systems with 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 11.0-11.5). The amount of titrant consumed (V_NaOH, ml) and the pH of the solution. At the time of the formation of a precipitate, turbidity of the solution, or a change in its color, the pH value, the nature of the change, and the volume of the NaOH solution that went into titration were recorded. The titration step is 0.25 ml. According to the Bierrum curve

= f (pA) for each semi-integer value of the education function

= n-0.5 determined logK_n.

, представляющей собой среднее число лигандов, входящих в комплекс. Так, в любой момент титрования, используя экспериментальные данные, можно рассчитать [L^-] (а именно, -lg[L^-]=рА) и по уравнению (1) -

. Когда лиганд имеет несколько диссоциирующих групп, то в уравнении (1) K_L соответствует значению константы диссоциации, имеющей наибольшее значение рk.Currently, the Bierrum method is often used to study complexation. This method involves the determination of two parameters - the concentration of free ligand in equilibrium conditions - [L ^- ] and the formation function

, which is the average number of ligands in the complex. So, at any moment of titration, using experimental data, it is possible to calculate [L ^- ] (namely, -lg [L ^- ] = рА) and according to equation (1) -

. When a ligand has several dissociating groups, then in equation (1) K _L corresponds to the value of the dissociation constant having the highest pk value.

=f(pA) по уравнению (2) при каждом полу-целочисленном значении функции образования

=n-0,5 находят K_n. Таким образом, ступенчатая константа устойчивости будет равна обратной концентрации свободного лиганда в точке

=n-0,5. Соответственно, чем больше значение K_n, тем более устойчивым является комплексное соединение (хелат).From the constructed Bierrum curve (education curve)

= f (pA) according to equation (2) for each half-integer value of the education function

= n-0.5 find K _n . Thus, the stepwise stability constant will be equal to the inverse concentration of the free ligand at the point

= n-0.5. Accordingly, the higher the K _n value, the more stable is the complex compound (chelate).

и

- общие концентрации присутствующих в растворе лиганда и металла, моль/л;Where

and

- total concentration of the ligand and metal present in the solution, mol / l;

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

K _L is the acid dissociation constant of the ligand;

- объем раствора NaOH (

, моль/л) в любой момент титрования, добавленный к титруемой смеси M^z+ и L, л;

- volume of NaOH solution (

, mol / l) at any moment of titration added to the titratable mixture M ^{z +} and L, l;

- количество вещества лиганда и соли M^z+ в титруемом растворе, моль.n _L ,

- the amount of ligand substance and salt M ^{z +} in the titrated solution, mol.

The logK ₁ values found by the Bierrum method for complexes of the studied compounds with divalent metal ions are presented in Tables 4, 5. The choice of the ratio M ^{z +} to L equal to 1: 6 is due to the availability 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].

Table 4
The first stability constant for complexes of 1: 1 composition of the studied compounds with divalent metal ions is logK ₁ found by the Bierrum method (aqueous solution, C _L = 0.02 M, the ratio of M ^{z +} to L 1: 6, ionic strength 0.5 (KNO ₃ ), 22ºС) Connection number The first stability constant for complexes of 1: 1 composition of the studied compounds with divalent metal ions is logK ₁ Zn (II) Cu (II) 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

<0,5

<0.5 12 5.46 4.62 6.40 6.10 3.72 3.60

Table 5
Stepwise stability constants of complexes of 1: 1 composition of the studied compounds with zinc ions, found by the Bierrum method (aqueous solution, C _L = 0.02 M, the ratio of M ^{z +} to L 1: 6, the ionic strength of the solution is 0.5 (KNO ₃ ), 22ºС) Connection number Stepwise stability constants of complexes of 1: 1 composition of the studied compounds with zinc ions The first stability constant, logK ₁ The second stability constant, logK ₂ Third stability constant, logK ₃ 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 ten 5.50 5.24 4.48 eleven 5.05 4.70 2.87 12 5.46 5.03 3.38

Thus, the studies showed that the tested compounds, derivatives of dicarboxylic acid bisamides, are effective complexing agents, for most of which high values _of logK ₁ ≥5 with respect to transition metal ions were found. In this case, a slightly increased complexing ability of the proposed compounds of general formula I with respect to iron ions is observed.

Claims (88)

1. Derived bisamide dicarboxylic acids of the formula 1

or a pharmaceutically acceptable salt thereof. 2. A drug for the prevention and / or treatment of viral diseases, which is a compound of formula 1

or a pharmaceutically acceptable salt thereof. 3. A medicament for the prevention and / or treatment of atherosclerosis, which is a compound of formula 1

or a pharmaceutically acceptable salt thereof. 4. A medicament for the prevention and / or treatment of inflammatory diseases, which is a compound of formula 1

or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition for the prevention and / or treatment of viral diseases, comprising an effective amount of a compound of formula 1

or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition for the prevention and / or treatment of atherosclerosis, comprising an effective amount of a compound of formula 1

or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition for the prevention and / or treatment of inflammatory diseases, comprising an effective amount of a compound of formula 1

or a pharmaceutically acceptable salt thereof. 8. The use of the compounds of formula 1

or its pharmaceutically acceptable salt for the prevention and / or treatment of viral diseases. 9. The use of the compounds of formula 1

or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of atherosclerosis. 10. The use of the compounds of formula 1

or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of inflammatory diseases. 11. A method of preventing and / or treating viral diseases, comprising administering an effective amount of a compound of formula 1

or a pharmaceutically acceptable salt thereof. 12. A method of preventing and / or treating atherosclerosis, comprising administering an effective amount of a compound of formula 1

or a pharmaceutically acceptable salt thereof. 13. A method for the prevention and / or treatment of inflammatory diseases, comprising administering an effective amount of a compound of formula 1

or a pharmaceutically acceptable salt thereof. 14. The method of obtaining the compounds of formula 1

, comprising condensation of a dicarboxylic acid ester of the formula R ₄ OC (O) -C (O) -OR ₄ , where R ₄ represents a C ₁ -C ₆ alkyl, and amine formulas NH ₂ - (CH ₂ ) ₂ -R ₁ , where R ₁ represents 2-imidazolyl, when heated in the presence of an organic solvent. 15. The method according to p. 14, in which dimethyl ether, diglyme and alcohols are used as a solvent, and heating is carried out to 150-170 ° C. 16. The method according to p. 15, in which the condensation is carried out in a solution of isoamyl alcohol by boiling. 17. A method of obtaining a compound of formula 1

, comprising the interaction of a dicarboxylic acid of the formula R ₄ OC (O) -R ₃ -C (O) -OR ₄ , where R ₃ represents a group - (CH ₂ ) _n -, n represents 0, R ₄ represents hydrogen, with N-hydroxysuccinimide in the presence of N, N'-dicyclohexylcarbodiimide in N, N-dimethylformamide to give the corresponding bis-N-oxysuccinimide ester of the formula

, which is condensed with an amine of the general formula III NH ₂ - (CH ₂ ) ₂ -R ₁ , where R ₁ represents imidazolyl. 18. The method according to p. 17, where the condensation is carried out while cooling to a temperature of 0-5 ° C. 19. The method of obtaining the compounds of formula 1

, comprising reacting a dicarboxylic acid ester of the formula R ₄ OC (O) -R ₃ -C (O) -OR ₄ , where R ₃ represents a group - (CH ₂ ) _n -, n represents 0, R ₄ represents C ₁ -C ₆ alkyl, with hydrazine hydrate in an organic solvent to obtain the bishydrazide of the general formula H ₂ N-NH-C (O) -R ₃ -C (O) -NH-NH _2, treatment of bishydrazide with sodium nitrite in an acidic medium at a temperature of about 0 ° C to obtain a bisazide of the formula N ^- -N ⁺ = NC (O) -R ₃ -C (O) -N = N ⁺ -N ^- , condensation of azide with an amine of the formula NH ₂ - (CH ₂ ) ₂ -R ₁ , where R ₁ represents 2-imidazolyl in an organic solvent. 20. The method of claim 19, wherein alcohols, preferably isopropanol, are used as the organic solvent. 21. The method of obtaining the compounds of formula 1

, comprising the interaction of a dicarboxylic acid of the formula R ₄ OC (O) -R ₃ -C (O) -OR ₄ , where R ₃ represents a group - (CH ₂ ) _n -, n represents 0, R ₄ represents hydrogen, and amine formulas NH ₂ - (CH ₂ ) ₂ -R ₁ , where R ₁ represents 2-imidazolyl, in the presence of a carbonyldiimidazole condensing agent.