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Medication, inhibiting na+/h+-exchange, and halogenides of 1-dialkylaminoethyl-3-[substituted(disubstituted)phenacyl]-2-aminobenzimidazolium

IPC classes for russian patent Medication, inhibiting na+/h+-exchange, and halogenides of 1-dialkylaminoethyl-3-[substituted(disubstituted)phenacyl]-2-aminobenzimidazolium (RU 2518741):

A61P43/00 - Drugs for specific purposes, not provided for in groups ; A61P0001000000-A61P0041000000

A61K31/4164 -

A61K31/14 - Quaternary ammonium compounds, e.g. edrophonium, choline (betaines A61K0031205000)

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FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to field of pharmacology and medicine and deals with application of halogenides of 1,3-disubstituted 2-aminobenzimidazolium, of general formula I as inhibitors of Na+/H+-exchange, as well as novel 1,3-disubstituted halogenides of 2- aminobenzimidazolium.

EFFECT: increased efficiency of inhibitors.

3 cl, 1 tbl, 2 ex

The invention relates to possessing the ability to inhibit Na⁺/H⁺exchange (NHE inhibitors).

Na⁺/H⁺exchangers (NHE) are a group of integral membrane proteins expressed in all tissues of the body, which carry the transmembrane exchange of Na⁺ions H⁺. Currently, nine different types of Na⁺/H⁺protein-exchangers have been cloned from mammalian tissue, and these isoforms are usually referred to as NHE-1,2,3,4,5,6,7,8,9, respectively. They vary in amino acid composition, tissue specificity, mechanisms of intracellular regulation. NHE-exchangers involved in many complex physiological and pathological processes, including regulation of cellular pH, cell migration, apoptosis, hypertrophy damage associated with ischemia and reperfusion, protection of cells from acidification of the cytoplasm, regulation of cell volume [Malo ME, Fliegel L Physiological role and regulation of the Na⁺/H⁺exchanger./ Can. J. Physiol. Pharmacol. - 2006. No. 84 (11). - p.1081-1095.], endothelial dysfunction, as well as diseases such as diabetes and its complications, heart failure, cerebrovascular disease, the development of malignant tumors [Fliegel L. Regulation of the Na(⁺)/H(⁺) exchanger in the healthy and diseased myocardium. / Expert. Opin. Ther. Targets. - 2009. No. 13 (1). - p.55-68.; Karmazyn M, Kilic A., Javadov s The roleof NHE-1 in myocardial hypertrophy and remodeling. / J. Mol. Cell Cardiol. - 2008. No. 44. - p.647-653.; Provost JJ, Wallert MA. Inside Out: Targeting NHE1 as an Intracellular and increasing interest among Regulator of Cancer Progression. // Chem Biol Drug Des. - 2013. No. 81(1). - p.85-101.].

There are various groups of NHE inhibitors: amiloride and its derivatives (DMA, EIPA, MIBA and intangible assets), benzylguanine derivatives, such as NOAH-642 (cariporide), its derivative NOAH-694 and eniporide (EMD-85131), cariporide (BIIB-722), bicyclic guanidine derivatives containing quinoline (MS 31038), indole (SM-20220, SM 20550, SMP-300), benzoxazine (KB-R9032), dihydrobenzofuran (BMS 284640), tetrahydronaphthalene (T-162559), cycloheptatrien (TY-12533) and others [Masereel Century, L. Pochet, Laeckmann D. An overview of inhibitors of Na+/H+ exchanger. // Eur. J. Med. Chem. - 2003. No. 38. - P.547-554].

Known derivatives of benzimidazole containing acyclic guanidine group (benzimidazole-2-yl and benzimidazole-2-altimeter benzylguanine), able to inhibit Na⁺/H⁺currency [Zhang R et al. Benzimidazol-2-yl or benzimidazol-2-ylthiomethyl benzoylguanidines as novel Na⁺/H⁺exchanger inhibitors, synthesis and protection against ischemic-reperfusion injury. / Bioorg. Med. Chem. Lett. - 2007. - No. 17. - p.2430-2433.].

The closest to the achieved result is Zoniporide (CF-597396)-[1-(quinoline-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine hydrochloride monohydrate [A Guzman-Perez et al. Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. / Bioorganic & Medicinal Chemistry Letters. - 2001. No. 11(6). - p.803-807]. In vitro studies on rabbit platelets was shown that the p, the drug inhibits NHE-1 - dependent swelling of platelets (EC₅₀=56 nm) [Tracey WR et al. Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1) // Cardiovasc Drug Rev. - 2003. - No. 21. - p.17-32].

However, its properties as an inhibitor of NHE are not sufficiently effective.

The technical result is to increase the efficiency of inhibitors of Na⁺/H⁺-exchange (NHE inhibitors).

The technical result is achieved by using as inhibitors of Na⁺/H⁺-exchange of halides of 1,3-disubstituted 2-amino-benzimidazole, the General formula I:

Ar=C₆H₄F-4, C₆H₃(O₂CH₂)-3,4

NR₂=N(C₂H₅)₂N(CH₂)₅N(CH₂CH₂)₂O

X=Cl, Br

including,

Ia Ar=C₆H₄F-4; NR₂=N(CH₂)₅X=Br

Ib Ar=C₆H₄F-4; NR₂=N(CH₂CH₂)₂O, X=Br

Ic Ar=C₆H₄F-4; NR₂=N(CH₂CH₂)₂O, X=Cl

Id Ar=C₆H₃(O₂CH₂)-3,4; NR₂=N(C₂H₅)₂X=Br

Connections may be used including for the manufacture of tools, with the ability to inhibit Na⁺/H⁺-currency, as well as for inhibition of Na⁺/H⁺-exchange in living organisms.

Compound Ia is known as having gematologicheskimi properties (patent RF №2290404, IPC C07D 487/04, 2006).

Obedinenie Ib is known as an intermediate product in the synthesis of compounds exhibiting analgesic effect (patent RF №2412187, IPC C07D 487/04, 2011).

Compounds Ic and Id are not described.

The technical result is also new connections among the halides of 1,3-disubstituted 2-aminobenzimidazole that has the property to inhibit Na⁺/H⁺-currency.

The technical result is achieved halides 1-dialkylaminomethyl-3-[substituted(disubstituted) phenacyl]-2-aminobenzo-imidazole General formula Ic, d:

Ar=C₆H₄F-4, C₆H₃(O₂CH₂)-3,

NR₂=N(C₂H₅)₂N(CH₂CH₂)₂O

X=Cl, Br, including

Ic Ar=C₆H₄F-4; NR₂=N(CH₂CH₂)₂O, X=Cl

Id Ar=C₆H₃(O₂CH₂)-3,4; NR₂=N(C₂H₅)₂X=Br

Below are examples of the preparation of compounds Ic and Id.

Example 1. Synthesis of chloride 1-morpholinomethyl-3-(4-florfenicol)-2-aminobenzimidazole (Ic).

A mixture of 1.23 g (5 mmol) 1-morpholinoethyl-2-aminobenzimidazole, 0.87 g (5 mmol) of ω-chloro-4-fortetienne and 15 ml of dry acetonitrile is boiled until complete reaction of quaternization (~8-10 hours, control - TLC). Then, the acetonitrile evaporated to small volume, the residue of which represents the desired chloride, filtered and washed with acetone. The yield of 92.5%. TPL 198-199°C.

Found, %: C 60,15; N 5,68; Cl 8,54; F 4,60;N 13,45. C₂₁H₂₄ClFN₄O₂.

Calculated, %: C 60,21; N 5,77; Cl 8,46; F Of 4.54; N 13,37.

IR spectrum, ν, cm^-1: 3206, 3168, 3022 (N⁺H₂), 1693 (C=O), 1663 (C=N), 1599 (C=C), 1226 (C-N), 1118 (C-O).

An NMR spectrum¹H (DMSO-d₆), δ, ppm (J, Hz): 2.40-2.60 m [4H, N(CH₂)₂], 2.67 t (2N, J=5.7 Hz, NCH₂), 3.48 t [4H, J=3.9 Hz, O(CH₂)₂], 4.39 t (2N, J=5.7 Hz, NCH₂), equal to 6.05 (2H, CH₂), 7.24-7.62 m (6N, H_Ar), 8.14-8.21 (m 2N, H_Ar), 9.22 USS (2N, N⁺H₂).

Example 2. Bromide 1-diethylaminoethyl-2-amino-3-(3,4-methylenedi-oxybenzyl)benzimidazole (Id).

In a hot solution of 1.16 g (5 mmol) 1-morpholinoethyl-2-aminobenzimidazole in acetone contribute 1.22 g (5 mmol) of 4-fortunaticlomid, the mixture is stirred and leave for 3-4 hours at 20-25°C. the precipitation bromide is separated and washed with acetone. The yield of 97.3%. TPL 235-236°C (decomposition).

IR spectrum (solid state), ν, cm^-1: 3310, 3236, 3090, 1681, 1652, 1449, 1255, 1033,751.

An NMR spectrum¹H (DMSO-d₆), δ, ppm: 0.81 t (6N, J 6.9 Hz, 2CH₃); 2.73 t (2N, J 6.2 Hz, CH₂); 4.29 t (2N, J 6.2 Hz, CH₂); 5.88 (2H, CH₂CO); 6.20 (2H, OCH₂O); 7.15-7.40 m (3H, H_Ar), 7.48-7.65 (m 3H, H_Ar), 7.75 (1H, J 8.1 Hz, H_Ar), N⁺H₂in the exchange.

Below are the results of testing properties of compounds I as inhibitors of Na⁺/H⁺exchange.

1. Materials and methods.

1.1. Research scheme.

stage 1 - study of the effect of compounds on the activity of Na ⁺/H⁺exchanger of rabbit platelets. The calculation of the IC₅₀.

stage 2 - study of acute toxicity.

1.2. Materials.

Compounds Ia-d, zoniporide (SIGMA, USA).

Reagents: sodium propionate (MP Biomedicals, Inc., France), HEPES (GERBU, Germany), calcium chloride-2-water (dihydrate) CaCI₂·2H₂O (LLC AGATE-MED, Russia), magnesium chloride 6-water "h" MgCI₂·6H₂O (CJSC UNICHEM", Russia), D-glucose (anhydrous) crystalline "h" C₆H₁₂O₆OJSC "AGAT-HONEY", Russia), sodium chloride "chemically pure" NaCl ("NPO ECROS", Russia), potassium chloride "analytical grade" KCl (LLC RAHIM", Russia), potassium phosphate one-deputizing KH₂PO₄"Analytical grade" (JSC "Petersburg Red chemist", Russia), magnesium sanitarily 7-water MgSO₄·7H₂O (000 "RAHIM", Russia), sodium bicarbonate NaHCO₃(LLC RAHIM", Russia), ethylenediaminetetraacetic acid (EDTA) (MP Biomedicals, Inc., France).

1.3. Animals.

In experiments were used rabbits-males, weighing 2.5-3.5 kg, which was kept in vivarium conditions with natural light regime on a standard diet of laboratory animals in accordance with GOST R 50258-92 [1993]. The study was performed in accordance with the applicable requirements of GOST ISO/IEC 17025-2009, GOST R ISO 5725-2002 and "good laboratory practice", approved by order of the health Ministry of the Russian Federation dated 23 August 2010 No. n, in compliance with the "European Convention for the protection of vertebrate animals used for experimental and other scientific purposes" [Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes Official Journal L 276, 20.10.2010 p.33-79 (revising Directive 86/609/EEC)].

Methods.

To study the effect of compounds on the activity of Na⁺/H⁺exchanger of rabbit platelets were conducted in vitro in rabbit platelets (method Rosskopf D. et. al. Rapid determination of the elevated Na⁺/H⁺exchanger in platelets of patients with essential hypertension using an optical swelling assay // Journal of Hypertension. - 1991. No. 9. - p.231-238; Kusumoto, K. et al.. In vitro and in vivo pharmacology of a structurally novel Na⁺/H⁺exchanger inhibitor, T-162559 // British Journal of Pharmacology. - 2002. No. 135. - p.1995-2003).

As research material selected rabbit platelets, on the membrane which actively Express NHE-1. The method is based on the approaches based on the change in light transmission when changing the form of the platelet.

Blood samples were taken from the marginal ear vein of the rabbit in a test tube containing 3.8% sodium citrate in a ratio of 1:10. To obtain platelet-rich plasma (PBGC) the blood was centrifuged at 1000 revolutions/minute for 12 minutes.

For calibration used PBGC with EDTA and the Krebs solution (NaCl 120 mm, KCl : 4.8 mm KN₂RHO₄- 1.2 mm MgSO₄2.5 mm NaHCO₃- 25 mm, CaCl₂- 2.6 mm, glucose - 5,4 mm, pH 7.4).

In the control series of experiments to 200 ál of Pbgt to reduce intracellular pH was added 600 μl of a solution of sodium propionate (mmol/l: Na propionate 135, HEPES 20, CaCl₂1, MgCl₂1, glucose 10; pH 6.7; t=37°C). This was accompanied by activation of Na⁺/H⁺exchanger, the flow of sodium associated with the release of cytosolic H⁺leading to edema (ferulacea) the platelet as a result of water accumulation in the cytoplasm. It was observed facilitate light transmission. To control the changes of light transmission under conditions of physiological pH of the solution was used Krebs.

Changing the shape of the platelets was detected by changes in the level of light transmission using a laser aggregometry "BIOLA-220 LA", Russia.

In the study of new compounds and the comparison drug zoniporide (10 μl) of a substance added to a cuvette containing Pbgt (200 μl) for 3-5 minutes before adding a solution of sodium propionate, incubated at 37°C and constant stirring using a magnetic stirrer (1000 rpm).

The research was carried out in the concentration range 10^-10-10^-5M

Expected IC₅₀the concentration of compounds that block Na⁺/H⁺exchanger of rabbit platelets by 50%.

1.4. Study of acute toxicity

To calculate the latitude of therapeutic activity of a compound was determined acute toxicity of 50 mice male intraperitoneal injection. The calculation of LD₅₀performed graphically by Miller and Tataru [Belenky ML. Elements of quantitative evaluation of the pharmacological effect. - Leningrad, 1963. - 152 C.].

1.5. Methods of statistical processing

For the studied drug and drug compare experimentally determined values IC₅₀using the method of regression analysis of the relationship between lg concentration and the percentage inhibition activity of the exchanger in Microsoft Excel (Office XP, Microsoft, USA).

2. The results of the study

The study of the effects of new compounds and zoniporide on the activity of Na⁺/H⁺exchanger rabbit revealed a dose-dependent increase in the inhibitory effect. Calculated IC₅₀presented in table 1.

In the study of acute toxicity intraperitoneal injection to mice calculated LD₅₀. To assess the breadth of therapeutic action on the isolated organs intended therapeutic index (table 1).

It was demonstrated that NHE-inhibitory effect of the compounds Ic, Ia, Ib was more zoniporide and surpassed it as the largest IC₅₀50, 41, 6 times, and therapeutic index 52; 46; 10.5-fold, respectively. Connection ROUX-1183 was more zoniporide largest IC₅₀1.5 times for the same therapeutic indexes.

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Table 1
Calculate therapeutic index of the most active inhibitors of Na⁺/H⁺-sharing among 1,3-disubstituted 2-aminobenzimidazole
		Inhibition of NHE
Substance		ED₅₀mg/l (kg)	LD₅₀mg/kg	Therapeutic index
	IC₅₀M

	Ic	5,42×10^-10	is 0.0002	342,7	1509400,39
	Ia	6,56×10¹⁰	0,0003	401,8	1327769,35
	Ib	4,56×10^-9	0,002	643,3	304499,38
Id	of 1.76×10^-8	0,008	240,0	28690,01
	Zoniporide	2,7×l0^-8	0,009	250,0	28903,57

1. Use as inhibitors of Na⁺/H⁺-exchange of halides of 1,3-disubstituted 2-aminobenzimidazole, the General formula I:

where Ar=C₆H₄F-4, C₆H₃(O₂CH₂)-3,4
NR₂=N(C₂H₅)₂N(CH₂)₅N(CH₂CH₂)₂O
X=Cl, Br
including
Ia Ar=C₆H₄F-4; NR₂=N(CH₂)₅X=Br
Ib Ar=C₆H₄F-4; NR₂=N(CH₂CH₂)₂O, X=Br
Ic Ar=C₆H₄F-4; NR₂=N(CH₂CH₂)₂O, X=Cl
Id Ar=C₆H₃(O₂CH₂)-3,4; NR₂=N(C₂H₅)₂X=Br

2. The use according to claim 1 for the manufacture of tools, with the ability to inhibit Na⁺/H⁺-currency, as well as for inhibition of Na⁺/H⁺-exchange in living organisms.

3. Halides 1-dialkylaminomethyl-3-[substituted(disubstituted) phenacyl]-2-aminobenzimidazole, the General formula Ic, d:
< / br> Ic Ar=C₆H₄F-4; NR₂=N(CH₂CH₂)₂O, X=Cl
Id Ar=C₆H₃(O₂CH₂)-3,4; NR₂=N(C₂H₅)₂X=Br