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Heterocyclic Communications

Editor-in-Chief: Strekowski, Lucjan

Ed. by Baumstark, Alfons L. / Saczewski, Jaroslaw / Stephens, Chad / Yamada, Hidetoshi


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Volume 24, Issue 4

Issues

Synthesis of benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-ones, derivatives of a novel heterocyclic system

Marta S. Yahodkina-Yakovenko
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  • Institute of Organic Chemistry, National Academy of Science of ukraine, 5 Murmanska str., Kyiv 02660, Ukraine
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/ Andriy V. Bol’but
  • Corresponding author
  • Institute of Organic Chemistry, National Academy of Science of ukraine, 5 Murmanska str., Kyiv 02660, Ukraine
  • RPA “Enamine”, 78 Chervonotkatska str., Kyiv 02660, Ukraine
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/ Mykhailo V. Vovk
  • Institute of Organic Chemistry, National Academy of Science of ukraine, 5 Murmanska str., Kyiv 02660, Ukraine
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Published Online: 2018-07-19 | DOI: https://doi.org/10.1515/hc-2017-0143

Abstract

Methyl 2-[(cyanophenoxy)methyl]-3-furoates obtained from methyl 2-(chloromethyl)-3-furoate and salicylonitriles undergo tandem cyclization in the presence of excess t-BuOK in N,N-dimethylformamide (DMF) solution at 65°C to give substituted benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-ones, derivatives of a novel heterocyclic system.

Keywords: alkylation; benzofuro[3,2-b]furo[2,3-d]pyridines; methyl 2-(chloromethyl)-3-furoates; salicylonitriles; tandem cyclization

Introduction

Benzofuro[3,2-b]pyridines are biomedically attractive compounds. For instance, some 2-oxo-3-carboxylic acids derived from them act as endothelin receptor antagonists [1], [2], and the esters are Р2Х4 receptor modulators [3]. A number of analogous heterocyclic systems with the benzo[d]-annelated pyridine ring, such as benzofuro[3,2-c]isoquinolines [4], [5], [6], inhibit hepatitis C viral infection [7] and are used to treat erectile dysfunction [8], inflammation and cardiovascular diseases [9]. At the same time, heteroannelated benzofuropyridines are much less studied and the reported compounds are restricted to a few quinolino [10], [11] and coumarino derivatives [12], [13] with anti-inflammatory and antimicrobial activities. Their analogues with a fused furan ring are hitherto unknown. These structures can be regarded as polycyclic systems originated from superposition of benzofuro[3,2-b]pyridine and furo[3,2-c]pyridine moieties. It is worth noting, that among furo[3,2-c]pyridine derivatives used for reversible control of protein transport [14], melanin-concentrating hormone receptor 1 antagonists [15] and protein kinase inhibitors [16] have been found.

Most of the benzo and heteroannelated benzofuropyridines described in the literature have been synthesized starting with salicylonitriles [4], [5], [6], [11], [12], [13] under the conditions of the Pictet-Spengler reaction. One approach used in this paper, provides a convenient way to obtain benzofuro[3,2-b]furo[2,3-d]pyridine, a novel heterocyclic system. More specifically, easily accessible methyl 2-(chloromethyl)-3-furoate [17] has been used as a bis-electrophilic component in the condensation with a salicylonitrile.

Results and discussion

Methyl 2-(chloromethyl)-3-furoate (1) is an effective reagent for the alkylation of salicylonitriles 2a–i. The reaction conducted in the presence of K2CO3 in DMF solution at 60°C produces methyl 2-[(cyanophenoxy)methyl]-3-furoates 3a–i in 69–80% yields (Scheme 1). When heated with t-BuOK in DMF solution at 65°C, compounds 3a–i are converted in 67–83% yields to derivatives 5а–h of benzofuro[3,2-b]furo[2,3-d]pyridine, a hitherto unknown heterocyclic system (Scheme 1). This reaction is a variation of tandem cyclization, with its first step proceeding by the Thorpe-Ziegler scheme and leading to intermediate aminobenzofurans 4 that undergo intramolecular condensation between the amino and methoxycarbonyl groups to form the pyridone ring.

For compound 3i containing a fluorine atom at position 3 of the benzene ring, it was found using liquid chromatography-mass spectrometry (LC-MS) analysis that the reaction mixture after 3 h at 65°C contained not only 54% of 6-fluorinated product 5i but also 40% of 6-methoxy derivative 5j. Heating of 3i at 90°C led to the formation of the product 5j exclusively, which was isolated in 68% yield. This transformation is caused by a nucleophilic substitution of compound 5i with MeOK which is generated under the reaction conditions as a side product of the cyclocondensation (Scheme 2).

The possibility of the synthesis of compound 5a without isolation of the intermediate product 3a was studied using salicylonitrile 2a. It was found that the addition of t-BuOK after the first step and heating of the reaction mixture at 65°C also leads to the formation of 5a, albeit in a low yield of 24%.

Structural determination of the synthesized compounds was performed using analytical and spectral methods. In particular, the infrared (IR) spectra of compounds 5а–j feature characteristic N-H (νmax 3154–5170 cm−1) and C=O (νmax 1665–1671 cm−1) absorption peaks. Typical downfield signals of the C=O carbon of the pyridone moiety (δ 158–164) are observed in carbon-13 nuclear magnetic resonance ( 13C NMR) spectra.

Conclusion

An efficient construction of the previously unknown benzofuro[3,2-b]furo[2,3-d]pyridine system based on tandem heterocyclization of 2-[(2-cyanophenoxy) methyl]- 3-furoates was developed. The products, due to the presence of a lactam fragment can be considered as promising scaffolds for further modifications aiming at the identification of bioactive derivatives.

Experimental

All commercially available chemicals were purchased from Sigma-Aldrich Chemicals (Steinheim, Germany). Methyl 2-(chloromethyl)-3-furoate 1 and salicylic nitriles 2a–i were purchased from Enamine Ltd (Kyiv, Ukraine). The reactions were monitored by thin-layer chromatography (TLC) using commercial silica gel plates Silufol UV-254. Melting points were taken on a hot-stage apparatus. IR spectra were obtained on a Bruker Vertex 70 spectrometer in KBr pellets. Proton nuclear magnetic resonance (1H NMR) (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Varian VXR-400 spectrometer using deuterated dimethyl sulfoxide-d6 (DMSO-d6) as a solvent. Elemental analyses were conducted at the Laboratory of Organic Analysis, Institute of Organic Chemistry, National Academy of Science of Ukraine. Electrospray ionization mass spectra (ESI-MS) were recorded on an Agilent 1100/DAD/HSD/VLG119562 instrument.

General procedure for preparation of compounds 3a–i

To a solution of methyl 2-(chloromethyl)-3-furoate (1, 0.52 g, 3 mmol) in dry DMF (10 mL) was added salicylic nitrile 2a–i (3 mmol) and anhydrous K2CO3 (0.83 g, 6 mmol). The mixture was stirred for 2 h at 60°C. After removal of the solvent under reduced pressure, the residue was washed with water (10 mL) and crystallized from ethanol.

Methyl 2-[(2-cyanophenoxy)methyl]-3-furoate (3a)

Brown solid; yield 80%; mp 73–74°C; IR: νmax 2231 (CN), 1721 cm−1 (C=O); 1H NMR: δ 3.79 (s, 3H, CH3), 5.54 (s, 2H, CH2), 6.83 (s, 1H, CH), 7.15 (t, 1H, J=7.6 Hz, CH), 7.40 (d, 1H, J=8.4 Hz, CH), 7.71 (m, 2H), 7.88 (s, 1H, CH); 13C NMR: δ 52.3, 62.0, 101.4, 111.2, 113.9, 116.6, 117.3, 122.3, 134.3, 135.6, 144.9, 154.35, 159.8, 163.2; ESI-MS: m/z 258 (M+H)+. Anal. Calcd for C14H11NO4: C, 65.37; H, 4.31; N, 5.44. Found: C, 65.30; H, 4.38; N, 5.39.

Methyl 2-[(4-bromo-2-cyanophenoxy)methyl]-3-furoate (3b)

Brown solid; yield 78%; mp 142–143°C; IR: νmax 2230 (CN), 1714 cm−1 (C=O); 1H NMR: δ 3.79 (s, 3H, CH3), 5.54 (s, 2H, CH2), 6.82 (s, 1H, CH), 7.38 (d, 1H, J=9.6 Hz, CH), 7.88 (m, 2H), 8.02 (s, 1H, CH); 13C NMR: δ 52.2, 62.4, 103.5, 111.1, 113.1, 115.2, 116.1, 117.4, 136.2, 138.3, 145.0, 154.0, 159.3, 163.2; ESI-MS: m/z 336 and 338 (M+H)+. Anal. Calcd for C14H10BrNO4: C, 50.03; H, 3.00; N, 4.17. Found: C, 50.20; H, 3.08; N, 4.05.

Methyl 2-[(5-chloro-2-cyanophenoxy)methyl]-3-furoate (3c)

Brown solid; yield 75%; mp 138–139°C; IR: νmax 2233 (CN), 1718 cm−1 (C=O); 1H NMR: δ 3.80 (s, 3H, CH3), 5.57 (s, 2H, CH2), 6.83 (s, 1H, CH), 7.22 (d, 1H, J=8.4 Hz, CH), 7.59 (s, 1H, CH), 7.79 (d, 1H, J=8.4 Hz, CH), 7.89 (s, 1H, CH); 13C NMR: δ 52.4, 62.4, 100.4, 111.3, 114.7, 115.9, 117.6, 122.6, 135.6, 140.6, 145.2, 153.7, 160.5, 163.2; ESI-MS: m/z 292 and 294 (M+H)+. Anal. Calcd for C14H10ClNO4: C, 57.65; H, 3.46; N, 4.80. Found: C, 57.88; H, 3.32; N, 4.64.

Methyl 2-[(5-bromo-2-cyanophenoxy)methyl]-3-furoate (3d)

Brown solid; yield 74%; mp 147–148°C; IR: νmax 2234 (CN), 1715 cm−1 (C=O); 1H NMR: δ 3.80 (s, 3H, CH3), 5.57 (s, 2H, CH2), 6.83 (s, 1H, CH), 7.36 (d, 1H, J=8.4 Hz, CH), 7.69–7.72 (m, 2H), 7.88 (s, 1H, CH); 13C NMR: δ 52.4, 62.4, 100.8, 111.3, 116.0, 117.5, 117.6, 125.5, 129.0, 135.6, 145.1, 153.8, 160.2, 163.2; ESI-MS: m/z 336 and 338 (M+H)+. Anal. Calcd for C14H10BrNO4: C, 50.03; H, 3.00; N, 4.17. Found: C, 50.23; H, 3.10; N, 4.02.

Methyl 2-[(2-cyano-4-(trifluoromethyl)phenoxy)methyl]-3-furoate (3e)

Beige solid; yield 69%; mp 102–104°C; IR: νmax 2231 (CN), 1720 cm−1 (C=O); 1H NMR: δ 3.80 (s, 3H, CH3), 5.65 (s, 2H, CH2), 6.84 (s, 1H, CH), 7.62 (d, 1H, J=8.8 Hz, CH), 7.90 (s, 1H, CH), 8.08 (d, 1H, J=8.8 Hz, CH), 8.25 (s, 1H, CH); 13C NMR: δ 52.4, 62.6, 102.2, 111.3, 114.7, 115.3, 117.6, 122.9 (q, J=33.5 Hz), 123.8 (q, J=271.5 Hz), 132.0, 132.7, 145.1, 153.7, 162.4, 163.2; ESI-MS: m/z 326 (M+H)+. Anal. Calcd for C15H10F3NO4: C, 55.39; H, 3.10; N, 4.31. Found: C, 55.58; H, 3.07; N, 4.22.

Methyl 2-[(4-chloro-2-cyano-6-methylphenoxy)methyl]-3-furoate (3f)

Brown solid; yield 73%; mp 141–144°C; IR: νmax 2233 (CN), 1722 cm−1 (C=O); 1H NMR: δ 2.14 (s, 3H, CH3), 3.65 (s, 3H, CH3), 5.39 (s, 2H, CH2), 6.78 (s, 1H, CH), 7.67 (s, 1H, CH), 7.78 (s, 1H, CH), 7.89 (s, 1H, CH); 13C NMR: δ 15.2, 51.6, 65.4, 108.3, 111.0, 114.8, 117.4, 128.6, 130.3, 135.1, 135.9, 144.6, 153.4, 156.8, 162.4; ESI-MS: m/z 306 and 308 (M+H)+. Anal. Calcd for C15H12ClNO4: C, 58.93; H, 3.96; Cl, 11.60; N, 4.58. Found: C, 58.99; H, 3.90; Cl, 11.54; N, 4.51.

Methyl 2-[(2,4-dibromo-6-cyanophenoxy)methyl]-3-furoate (3g)

Beige solid, yield 70%; mp 163–165°C; IR: νmax 2231 (CN), 1720 cm−1 (C=O); 1H NMR: δ 3.62 (s, 3H, CH3), 5.50 (s, 2H, CH2), 6.77 (s, 1H, CH), 7.86 (s, 1H, CH), 8.10 (s, 1H, CH), 8.27 (s, 1H, CH); 13C NMR: δ 51.7, 65.8, 110.4, 111.1, 113.5, 117.4, 118.0, 119.1, 135.2, 140.4, 144.8, 152.5, 155.8, 162.4; ESI-MS: m/z 414, 416 and 418 (M+H)+. Anal. Calcd for C14H9Br2NO4: C, 40.52; H, 2.19; Br, 38.50; N 3.37. Found: C, 40.59; H, 2.25; Br, 38.59; N, 3.31.

Methyl 2-[(2-acetyl-6-cyanophenoxy)methyl]-3-furoate (3h)

Brown solid; yield 69%; mp 103–104°C; IR: νmax 2233 (CN), 1721 cm−1 (C=O); 1H NMR: δ 2.50 (s, 3H, CH3), 3.59 (s, 3H, CH3), 5.45 (s, 2H, CH2), 6.75 (s, 1H, CH), 7.41 (t, 1H, J=7.8 Hz, CH), 7.87 (m, 2H), 7.99 (d, 1H, J=7.8 Hz, CH); 13C NMR: δ 30.1, 51.6, 67.3, 108.0, 111.0, 115.4, 117.7, 125.2, 134.1, 134.6, 137.1, 144.6, 152.8, 158.0, 162.3, 197.8; ESI-MS: m/z 300 (M+H)+. Anal. Calcd for C16H13NO5: C, 64.21; H, 4.38; N, 4.68. Found: C, 64.29; H, 4.44; N, 4.59.

Methyl 2-[(2-cyano-3-fluorophenoxy)methyl]-3-furoate (3i)

Brown solid; yield 69%; mp 103–104°C; IR: νmax 2232 (CN), 1721 cm−1 (C=O); 1H NMR: δ 3.80 (s, 3H, CH3), 5.57 (s, 2H, CH2), 6.83 (s, 1H, CH), 7.10 (m, 1H, CH), 7.27 (m, 1H, CH), 7.75 (q, 1H, J=7.2 Hz, CH), 7.88 (s, 1H, CH); 13C NMR: δ 52.4, 62.6, 91.1 (d, J2=19 Hz), 109.3 (d, J2=19 Hz), 110.0, 111.3, 111.9, 117.5, 137.0 (d, J2=11 Hz), 145.1, 153.9, 160.9 (d, J3=4 Hz), 163.2, 164.7 (d, J1=255 Hz); ESI-MS: m/z 276 (M+H)+. Anal. Calcd for C14H10FNO4: C, 61.09; H, 3.66; N, 5.09. Found: C, 61.31; H, 3.54; N, 5.01.

General procedure for the preparation of compounds 5а–h

To a solution of methyl 2-[(cyanophenyl)methyl]-3-furoate 3а–h (3 mmol) in dry DMF (10 mL) was added t-BuOK (0.34 g, 3 mmol). The mixture was stirred for 3 h at 65°C. After removal of the solvent under reduced pressure, water (5 mL) was added to the residue followed by acidification with hydrochloric acid to pH 6. The resulting precipitate was filtered off and crystallized from DMF.

Benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5a)

Yellow solid; yield 83%; mp>250°C; IR: νmax 3154 (NH), 1670 cm−1 (C=O); 1H NMR: δ 7.12 (s, 1H, CH), 7.42 (t, 1H, J=7.2 Hz, CH), 7.51 (t, 1H, J=7.2 Hz, CH), 7.75 (d, 1H, J=8 Hz, CH), 8.09 (m, 2H), 12.65 (s, 1H, NH); 13C NMR: δ 109.2, 112.4, 115.3, 121.0, 123.1, 123.3, 126.6, 128.9, 133.4, 143.3, 146.4, 155.5, 164.1; ESI-MS: m/z 226 (M+H)+. Anal. Calcd for C13H7NO3: C, 69.33; H, 3.13; N, 6.22. Found: C, 69.49; H, 3.01; N, 6.09.

7-Bromobenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5b)

Yellow solid; yield 69%; mp>250°C; IR: νmax 3162 (NH), 1665 cm−1 (C=O); 1H NMR: δ 7.13 (s, 1H, CH), 7.64 (d, 1H, J=8.4 Hz, CH), 7.74 (d, 1H, J=8.4 Hz, CH), 8.08 (s, 1H, CH), 8.24 (s, 1H, CH), 12.53 (s, 1H, NH); 13C NMR: δ 108.5, 116.1, 116.4, 120.4, 120.7, 124.7, 128.5, 134.9, 135.1, 150.0, 152.1, 157.8, 158.3; ESI-MS: m/z 304 and 306 (M+H)+. Anal. Calcd for C13H6BrNO3: C, 51.35; H, 1.99; N, 4.61. Found: C, 51.59; H, 1.85; N, 4.68.

8-Chlorobenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5c)

Beige solid; yield 70%; mp>250°C; IR: νmax 3168 (NH), 1669 cm−1 (C=O); 1H NMR: δ 7.09 (s, 1H, CH), 7.43 (d, 1H, J=8 Hz, CH), 7.85 (s, 1H, CH), 7.96 (m, 2H), 12.61 (s, 1H, NH); 13C NMR: δ 108.7, 112.4, 115.5, 120.9, 121.4, 123.6, 129.2, 130.2, 130.4, 143.6, 146.2, 155.1, 162.0; ESI-MS: m/z 260 and 262 (M+H)+. Anal. Calcd for C13H6ClNO3: C, 60.14; H, 2.33; N, 5.39. Found: C, 60.36; H, 2.21; N, 5.50.

8-Bromobenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5d)

Yellow solid; yield 68%; mp>250°C; IR: νmax 3170 (NH), 1671 cm−1 (C=O); 1H NMR: δ 7.09 (s, 1H, CH), 7.59 (d, 1H, J=8.4 Hz, CH), 7.91 (m, 3H), 12.61 (s, 1H, NH); 13C NMR: δ 108.1, 115.5, 117.8, 118.3, 122.5, 126.3, 129.1, 130.8, 134.1, 149.6, 151.8, 157.9, 158.8; ESI-MS: m/z 304 and 306 (M+H)+. Anal. Calcd for C13H6BrNO3: C, 51.35; H, 1.99; N, 4.61. Found: C, 51.17; H, 2.08; N, 4.75.

8-(Trifluoromethyl)benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5e)

Beige solid; yield 68%; mp>250°C; IR: νmax 3165 (NH), 1669 cm−1 (C=O); 1H NMR: δ 7.17 (s, 1H, CH), 7.85 (d, 1H, J=8.4 Hz, CH), 8.02 (d, J=8.4 Hz, CH), 8.12 (s, 1H, CH), 8.53 (s, 1H, CH), 12.64 (s, 1H, NH); 13C NMR: δ 108.5, 115.7, 116.5, 122.5, 120.2, 125.8 (q, J1=270 Hz), 129.1, 129.2, 130.9 (q, J2=34 Hz), 135.3, 150.3, 152.1, 158.7, 160.2; ESI-MS: m/z 294 (M+H)+. Anal. Calcd for C14H6F3NO3: C, 57.35; H, 2.06; N, 4.78. Found: C, 57.47; H, 1.98; N, 4.69.

7-Chloro-9-methylbenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5f)

Beige solid; yield 68%; mp>250°C; IR: νmax 3169 (NH), 1663 cm−1 (C=O); 1H NMR: δ 2.68 (s, 1H, CH3), 7.47 (s, 1H, CH), 7.51 (s, 1H, CH), 7.88 (s, 1H, CH), 8.04 (s, 1H, CH); 13C NMR: δ 14.9, 108.2, 118.9, 119.4, 127.1, 128.0, 129.2, 133.3, 133.6, 134.8, 150.1, 152.1, 156.4, 157.2; ESI-MS: m/z 274 and 276 (M+H)+. Anal. Calcd for C14H8ClNO3: C, 61.44; H, 2.95; Cl, 12.95; N, 5.12. Found: C, 61.49; H, 2.97; Cl, 12.90; N, 5.17.

7,9-Dibromobenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5g)

Beige solid; yield 71%; mp>250°C; IR: νmax 3166 (NH), 1670 cm−1 (C=O); 1H NMR: δ 7.12 (s, 1H, CH), 7.88 (s, 1H, CH), 8.07 (s, 1H, CH), 8.29 (s, 1H, CH), 12.33 (s, 1H, NH); 13C NMR: δ 105.4, 108.6, 116.1, 117.0, 120.2, 121.5, 122.2, 129.6, 131.3, 134.5, 145.8, 150.5, 158.2; ESI-MS: m/z 382, 384 and 386 (M+H)+. Anal. Calcd for C13H5Br2NO3: C, 40.77; H, 1.32; Br, 41.73; N, 3.66. Found: C, 40.71; H, 1.37; Br, 41.64; N, 3.62.

9-Acetylbenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5h)

Brown solid, yield 68%; mp>250°C; IR: νmax 3167 (NH), 1668 cm-1 (C=O); 1H NMR: δ 2.88 (s, 1H, CH3), 7.11 (s, 1H, CH), 7.48 (m, 1H, CH), 7.93 (m, 1H, CH), 8.05 (s, 1H, CH), 8.32 (m, 1H, CH), 12.44 (s, 1H, NH); 13C NMR: δ 30.38, 108.6, 116.1, 120.3, 123.8, 125.0, 125.4, 127.6, 145.3, 146.5, 152.6, 158.4, 162.3, 194.9; ESI-MS: m/z 268 (M+H)+. Anal. Calcd for C14H9NO4: C, 67.42; H, 3.39; N, 5.24. Found: C, 67.47; H, 3.30; N, 5.28.

Preparation of 6-methoxybenzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-one (5j)

To a solution of methyl 2-[(cyano-3-fluorophenoxy)methyl]-3-furoate (3i, 0.3 g, 1.1 mmol) in dry DMF (7 mL) was added t-BuOK (0.25 g, 2.2 mmol). The mixture was stirred for 4 h at 90°C. Then the solvent was removed under reduced pressure, water (5 mL) was added to the residue, and the mixture was acidified with hydrochloric acid to pH 6. The resulting precipitate was filtered off and crystallized from DMF: yield 68% of a brown solid; mp>250°C; IR: νmax 3167 (NH), 1674 cm−1 (C=O); 1H NMR: δ 3.96 (s, 3H, CH3), 6.91 (d, 1H, J=8 Hz, CH), 7.12 (s, 1H, CH), 7.32 (d, 1H, J=8, CH), 7.43 (m, 1H, CH), 8.04 (s, 1H, CH), 11.59 (s, 1H, NH); 13C NMR: δ 56.1, 105.2, 105.3, 108.9, 110.2, 114.6, 127.8, 128.7, 144.1, 144.6, 146.7, 154.5, 156.1, 160.0; ESI-MS: m/z 256 (M+H)+. Anal. Calcd for C14H9NO4: C, 65.88; H, 3.55; N, 5.49. Found: C, 65.74; H, 3.59; N, 5.52.

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About the article

Received: 2017-08-01

Accepted: 2018-04-02

Published Online: 2018-07-19

Published in Print: 2018-08-28


Citation Information: Heterocyclic Communications, Volume 24, Issue 4, Pages 177–181, ISSN (Online) 2191-0197, ISSN (Print) 0793-0283, DOI: https://doi.org/10.1515/hc-2017-0143.

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