Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 12  |  Issue : 1  |  Page : 20-27

Synthesis and antihypertensive activity of certain substituted dihydropyridines and pyrimidinones


1 Department of Chemistry of Natural and Microbial Products, National Research Centre, Giza, Egypt
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Giza, Egypt

Date of Submission17-Jul-2012
Date of Acceptance10-Oct-2012
Date of Web Publication18-Jul-2014

Correspondence Address:
Hanaa A. Tawfik
PhD, Department of Chemistry of Natural and Microbial Products, National Research Centre, Dokki, Giza 12311
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EPJ.0000426587.41764.d4

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  Abstract 

Background and objective

Some bulky substituted aromatic aldehydes reacted with urea and ethyl acetoacetate in the presence of acetic acid as a catalyst to yield solely substituted dihydropyridines (Hantzsch-type molecule). In the presence of p-toluene sulfonic acid as a catalyst, the products were only dihydropyrimidines (Biginelli compounds). The same aldehydes yielded dihydropyrimidinones on using acetyl acetone instead of ethyl acetoacetate whatever the catalyst used. These two classes of molecules represent a heterocyclic system of a remarkable antihypertensive effect. The aim of this study was to synthesize certain dihydropyridine and pyrimidinone derivatives with aromatic moiety with bulky substituents to be evaluated for their antihypertensive effect.

Methods

The aldehydes 3-(substituted-phenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 35, 4-oxo-4H-chromene-3-carbaldehyde (6), and substituted phenylazo-benzaldehyde 79 reacted with ethyl acetoacetate and urea in ethanol in the presence of acetic acid to yield dihydropyridines 1015. Aldehydes 39 reacted with ethyl acetoacetate and urea in the presence of p-toluene sulfonic acid to yield dihydropyrimidinones 1622. Furthermore, the reaction of the aldehydes 39 with ethyl acetoacetate and urea in the presence of either acetic acid or p-toluene sulfonic acid yielded the corresponding dihydropyrimidinones 2329.

Results and conclusion

The hypotensive activity of compounds 1014 and 1620 indicated that the 4-aryl-dihydropyridine derivatives 1014 showed higher activity than the pyrimidinones 1620. The most active compound was 4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (10) at dose levels of 0.6, 1.2, and 2.4 mg/kg. It showed more or less similar hypotensive activity as the reference drug nifedipene at doses of 1.2 and 2.4 mg/kg. Its LD50=298 mg/kg body weight.

Keywords: antihypertensive activity, bulky substituted aldehydes, dihydropyridines, dihydropyrimidinones


How to cite this article:
El-Hamouly WS, Amine KM, Tawfik HA, Dawood DH. Synthesis and antihypertensive activity of certain substituted dihydropyridines and pyrimidinones. Egypt Pharmaceut J 2013;12:20-7

How to cite this URL:
El-Hamouly WS, Amine KM, Tawfik HA, Dawood DH. Synthesis and antihypertensive activity of certain substituted dihydropyridines and pyrimidinones. Egypt Pharmaceut J [serial online] 2013 [cited 2020 Aug 5];12:20-7. Available from: http://www.epj.eg.net/text.asp?2013/12/1/20/136940


  Introduction Top


The one-pot acid-catalyzed Biginelli 1,2 condensation is the most commonly used reaction to produce dihydropyrimidines (DHPMs, 1). This very simple reaction involves three component cyclocondensation of urea, an aldehyde and a β-oxoester or 1,3-dicarbonyl compound using ethanol as a solvent and catalytic amounts of HCl, AcOH, or H2SO4 among other acids 3–7. In contrast, in the Hantzsch reaction discussed, more than a century ago 8, the main way to obtain dihydropyridines (DHPs, 2) and is commonly carried out as a one-pot condensation of a β-dicarbonyl compound with an aldehyde but with ammonia instead of urea using ethanol as a solvent.



These two classes of molecules (1 and 2) represent a heterocyclic system with remarkable pharmacological properties that include antiviral 9, 10, antitumor 11, 12, antibacterial 13, 14, and anti-inflammatory 15–18 activities. In addition, a number of these heterocyclic systems have emerged as exerting orally active antihypertensive effects or to act as α-1A-adrenoceptor-selective antagonists 19, 20, for example nifedipene and amludepine. It is worth mentioning that several examples of highly substituted DHPMs and DHPs are reported to show high antihypertensive activity, for example doxazosin 20 and nicardipine 21,22.



The aim of this work was to synthesize some DHPs and pyrimidinones with the aromatic moiety bearing bulky substituents to be evaluated for their antihypertensive activity.


  Experimental Top


Chemistry

All melting points were determined in open capillary tubes using silicon oil on a Gallen Kamp Apparatus (Finsbury, London, England) and were uncorrected. 1H-NMR spectra were determined using a JEOL EX-270 NMR spectrometer (Musashino 3-chome, Akishima, Tokyo, Japan) with tetramethylsilane as an internal standard. Mass spectra were performed using a GC-MS-QP 1000EX Schimadzu Gas Chromatography MS Spectrometer (Columbia, Maryland, USA). The infrared spectra were recorded on an FT/IR330E infrared spectrophotometer using KBr discs. Elemental analyses were carried out at the Micro analytical Laboratory of the National Research Center, Dokki, Cairo, Egypt. The reactions were followed up by thin layer chromatography (TLC) using chloroform/methanol (9 : 1) as an eluent and detected using a UV lamp.

General procedure for the preparation of substituted dihydropyridine compounds (10–15)

A mixture of the appropriate aldehydes 3–9 (6 mmol), urea (0.9 g, 15 mmol), ethyl acetoacetate (1.17 ml, 9 mmol), and glacial acetic acid (2 ml) in absolute ethanol (50 ml) was heated under reflux for several hours (12–18 h) (monitored by TLC). After the completion of the reaction, the solvent was removed under vacuum and the precipitated product was treated with water, filtered off, washed with water, dried, and crystallized from methanol.

4-(1,3-Diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (10)

Yield 72%, m.p. 154–156°C, IR (KBr, cm−1): 3343 (NH), 1682 (CO); 1H-NMR (d6-DMSO, δ, ppm): 0.91 (t, 6H, 2CH3), 2.22 (s, 6H, 2CH3), 3.84 (q, 4H, 2CH2), 5.16 (s, 1H, C4-H), 7.26–7.88 (m, 10H, Ar-Hs), 8.00 (s, 1H, pyrazole), 8.78 (s, 1H, NH, D2O exchangeable); Ms: m/z (%): 469 [(M+-2, (62)], 441 (100%), 397 (83), 326 (71), 251 (93), 220 (90), 206 (22), 179 (32), 77 (99). Analysis: for C28H29N3O4 (471.55), calcd: C, 71.32; H, 6.20; N, 8.91%. Found: C, 71.45; H, 6.30; N, 8.71%.

2,6-Dimethyl-4-[3-(4-nitrophenyl)-1-phenyl-1-H-pyrazole-4-yl]-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (11)

Yield 75%, m.p. 110–113°C, IR (KBr, cm−1): 3369 (NH), 1683 (CO); 1H-NMR (d6-DMSO, δ, ppm) 0.87 (t, 6H, 2CH3), 2.24 (s, 6H, 2CH3), 3.87 (q, 4H, 2CH2), 5.18 (s, 1H, C4-H), 7.31–8.36 (m, 10H, 9Ar-Hs and 1H pyrazole), 8.81 (s, 1H, NH); Ms: m/z (%): 514 [M+-2, (22)], 486 (70), 442 (100), 251 (52). Analysis: for C28H28N4O6 (516.55), calcd: C, 65.11; H, 5.46; N, 10.85%. Found: C, 65.33; H: 5.19; N, 10.67%.

4-[3-(2-Hydroxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester (12)

Yield 68%, m.p. 98–100°C, IR (KBr, cm−1): 3357 (OH), 3249 (NH) and 1693 (CO); 1H-NMR (d6-DMSO, δ, ppm), 0.98 (t, 6H, 2CH3), 2.13 (s, 6H, 2CH3), 3.87 (q, 4H, 2CH2), 5.10 (s, 1H, C4-H), 6.91–7.77 (m, 9H, Ar-Hs), 8.12 (s, 1H, pyrazole-H), 8.54 (s, 1H, NH) and 9.59 (s, 1H, OH); Ms: m/z (%): 485 [(M+-2, (94%)], 457 (24), 438 (100), 413 (43), 394 (20), 252 (16), 236 (27). Analysis: for C28H29N3O5 (487.55), calcd: C, 68.98; H, 6.00; N, 8.62%. Found: C, 68.86; H, 5.79; N, 8.52%.

2,6-Dimethyl-4-(4-oxo-4H-chromen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (13)

Yield 65%, m.p. 213–215°C; 1H-NMR (d6-DMSO, δ, ppm) 1.10 (t, 6H, 2CH3), 1.12 (t, 6H, 2CH3), 2.22 (s, 6H, 2CH3), 2.25 (s, 6H, 2CH3), 3.96 (q, 4H, 2CH2), 4.02 (q, 4H, 2CH2), 4.82 (s, 1H, C4-H), 5.24 (s, 1H, C4-H), 7.43 (t, 1H, H-6), 7.50 (t, 1H, H-6), 7.55 (d, 1H, H-8), 7.57 (d, 1H, H-8), 7.64 (t, 1H, H-7), 7.73 (t, 1H, H-7), 7.93 (s, 1H, H-2), 8.14 (s, 1H, H-2), 8.00 (d, 1H, H-5), 8.02 (d, 1H, H-5), 8.82 (s, 1H, NH), 9.18 (s, 1H, NH); Ms m/z (%) 397 (M+, 12%), 352 (7), 324 (100), 294 (10), 252 (32), 223 (17). Analysis: for C22H23NO6 (397.42), calcd: C, 66.49; H, 5.83; N, 3.52%. Found: C, 66.80; H, 5.70; N, 3.41%.

2,6-Dimethyl-4-(2-hydroxy-3-methoxy-5-phenylazo-phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (14)

Yield 75%, m.p. 124–126°C; IR (KBr, cm−1): 3448 (OH), 3344 (NH), 1693 (CO); 1H-NMR (d6-DMSO, δ, ppm): 1.10 (t, 3H, CH3), 2.28 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.00 (q, 2H, CH2), 5.17 (s, 1H, C4-H), 7.03 (s, 1H, Ar-H), 7.22 (s, 1H, Ar-H), 7.56 (t, 3H, Ar-Hs), 7.80 (s, 1H, N3H, D2O exchangeable), 7.98 (d, 2H, Ar-Hs), 9.26 (s, 1H, N1H, D2O exchangeable), 10.99 (s, 1H, OH); Ms: m/z (%): 477 [M+-2, (34)], 431 (12), 372 (38), 354 (32), 252 (81), 238 (41), 105 (55), 93 (86) and 77 (100). Analysis: for C26H29N3O6 (479.52), calcd: C, 65.12; H, 6.10; N, 8.76%. Found: C, 65.29; H, 6.12; N, 8.95%.

2,4-Dimethyl-5-oxo-9-phenylazo-5H-chromeno [3,4-c]pyridine-1-carboxylic acid ethyl ester (15)

Yield 66%, m.p. 203–206°C; IR (KBr, cm−1): 1730 (CO), 1684 (CO); 1H-NMR (d6-DMSO, δ, ppm): 1.33 (t, 3H, CH3), 2.69 (s, 3H, CH3), 2.93 (s, 3H, CH3), 4.58 (q, 2H, CH2), 7.61 (t, 3H, Ar-Hs), 7.64 (d, 1H, Ar-H), 7.88 (d, 1H, Ar-H), 8.22 (d, 2H, Ar-Hs), 8.31 (s, 1H, Ar-H); Ms: m/z (%), 400 [M+-1, (27)], 356 (10), 329 (17), 268 (37), 250 (60), 224 (24), 169 (91), 105 (55), 77 (100). Analysis: for C23H19N3O4 (401.41), calcd: C, 68.82; H, 4.78; N, 10.47%. Found: C, 68.63; H, 4.91; N, 10.60%.

4-(Aryl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylicacid ethyl ester (16–22)

General procedure

A mixture of the appropriate aldehydes 39 (10 mmol), urea (1.5 g, 25 mmol), ethyl acetoacetate (1.95 ml, 15 mmol), and p-toluene sulfonic acid (1.72 g, 10 mmol) in absolute ethanol (35 ml) was heated under reflux for 6–8 h (monitored by TLC). After completion of the reaction, the solvent was removed under vacuum and the precipitated product was treated with water, filtered, washed with water, and dried. Crystallization from the appropriate solvent yielded the desired compounds 1622.

4- [1,3-Diphenyl-1H-pyrazole-4-yl]-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (16)

Yield 74%, m.p. 178–180°C (methanol); IR (KBr, cm−1): 3349 (NH), 3222 (NH), 1693 (CO), 1642 (CO); 1H-NMR (d6-DMSO, δ, ppm): 0.82 (t, 3H, CH3), 2.23 (s, 3H, CH3), 3.80 (q, 2H, CH2), 5.38 (s, 1H, C4-H), 7.27–7.90 (m, 11H, 10Ar-Hs and 1H pyrazole), 8.35 (s, 1H, N3H) and 9.16 (s, 1H, N1H). Analysis: for C23H22N4O3 (402.45), calcd: C, 68.64; H, 5.51; N, 13.92%. Found: C, 68.80; H, 5.34; N, 13.71%.

6-Methyl-4-[3-(4-nitro-phenyl)-1-phenyl-1H-pyrazol-4-yl]-2-oxo-1, 2, 3, 4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (17)

Yield 83%, m.p. 190–193°C; IR (KBr, cm−1): 3439 (OH), 3210 (NH), 3122 (NH), 1713 (CO), 1657 (CO); 1H-NMR (d6-DMSO, δ, ppm): 0.87 (t, 3H, CH3), 2.25 (s, 3H, CH3), 3.82 (q, 2H, CH2), 5.44 (s, 1H, C4-H), 6.87–7.89 (m, 10H, 9Ar-Hs and 1H pyrazole), 8.34 (s, 1H, N3H), 9.20 (s, 1H, N1H). Analysis: for C23H21N5O5 (447.44), calcd: C, 61.74; H, 4.73; N, 15.65%. Found: C, 61.96; H, 4.53; N, 15.85%.

4-[3-(2-Hydroxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (18)

Yield 79%, m.p. 201–204°C; IR (KBr, cm−1): 3223 (NH), 3109 (NH), 1698 (CO), 1649 (CO); 1H-NMR (d6-DMSO, δ, ppm): 0.83 (t, 3H, CH3), 2.26 (s, 3H, CH3), 3.82 (q, 2H, CH2), 5.44 (s, 1H, C4-H), 7.13–8.50 (m, 10H, 9Ar-Hs and 1H pyrazole), 7.85 (s, 1H, N3H, D2O exchangeable), 9.23 (s, 1H, N1H, D2O exchangeable). Analysis: for C23H22N4O4 (418.45), calcd: C, 66.02; H, 5.30; N, 13.39%. Found: C, 66.37; H, 5.49; N, 13.21%.

6-Methyl-2-oxo-4-(4-oxo-4H-chromen-3-yl)-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (19)

Yield 78%, m.p. 287–290°C, IR (KBr, cm−1): 3386 (NH), 3281 (NH), 1710 (CO), 1669 (CO), 1638 (CO); 1H-NMR (d6-DMSO, δ, ppm): 1.00 (t, 3H, CH3), 2.23 (s, 3H, CH3), 3.98 (q, 2H, CH2), 5.23 (s, 1H, C4-H), 7.24 (s, 1H, H-2), 7.45 (t, 1H, H-6), 7.63 (d, 1H, H-8), 7.78 (t, 1H, H-7), 8.12 (d, 1H, H-5), 8.23 (s, 1H, N3H), 9.31 (s, 1H, N1H); Ms: m/z (%): 328 (M+, 12), 269 (17%), 255 (100%), 169 (18%); Analysis: for C17H16N2O5 (328.32), calcd: C, 62.19; H, 4.91; N, 8.53%. Found: C, 62.37; H, 4.79; N, 8.37%.

4-(2-Hydroxy-3-methoxy-5-phenylazo-phenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (20)

Yield 74%, m.p. 210–212°C, IR (KBr, cm−1): 3357 (OH), 3214 (NH), 3198 (NH), 1689 (CO), 1640 (CO); 1H-NMR (d6-DMSO δ, ppm): 1.10 (t, 3H, CH3,), 2.28 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.00 (q, 2H, CH2), 5.17 (s, 1H, C4-H), 7.03 (s, 1H, Ar-H), 7.22 (s, 1H, Ar-H), 7.56 (t, 3H, Ar-Hs), 7.80 (s, 1H, N3H, D2O exchangeable), 7.98 (d, 2H, Ar-Hs), 9.26 (s, 1H, N1H, D2O exchangeable), 10.99 (s, 1H, OH, D2O exchangeable); Ms: m/z (%), 410 [M+ (12)], 302 (44), 210 (32), 105 (42), 93 (52), 77 (100). Analysis: for C21H22N4O5 (410.43), calcd: C, 61.46; H, 5.40; N, 13.65%. Found: C, 61.35; H, 5.35; N, 13.68%.

4-(2-Hydroxy-5-phenylazo-phenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (21)

m.p. 167–170°C, IR (KBr, cm−1): 3455 (OH), 3220 (NH), 3210 (NH), 1690 (CO), 1662 (CO); 1H-NMR (d6-DMSO, δ, ppm) 1.05 (t, 3H, CH3), 2.24 (s, 3H, CH3), 3.98 (q, 2H, CH2), 5.52 (s, 1H, C4-H), 6.93 (d, 1H, Ar-H), 7.37 (s, 1H, N3H, D2O exchangeable), 7.51 (t, 3H, Ar-Hs), 7.63 (s, 1H, Ar-H), 7.75 (d, 1H, Ar-H), 7.84 (d, 2H, Ar-Hs), 9.23 (s, 1H, N1H, D2O exchangeable), 10.61 (s, 1H, OH, D2O exchangeable); Ms: m/z (%), 380 (M+, 20), 183 (22), 105 (21), 93 (28), 77 (100). Analysis: for C20H20N4O4 (380.40), calcd: C, 63.15; H, 5.30; N, 14.73%. Found: C, 63.38; H, 5.40; N, 14.87%.

4-[2-Hydroxy-5-(4-nitrophenylazo)phenyl]-6-methyl-2-oxo-1, 2, 3, 4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (22)

Yield 74%, m.p. 158–161°C, IR (KBr, cm−1): 3356 (OH), 3234 (NH), 3114 (NH), 1687 (CO), 1651 (CO); 1H-NMR (d6-DMSO, δ, ppm): 1.07 (t, 3H, CH3), 2.30 (s, 3H, CH3), 3.97 (q, 2H, CH2), 5.50 (s, 1H,C4-H), 7.00 (d, 1H, Ar-H), 7.38 (s, 1H, N3H), 7.69 (s, 1H, Ar-H), 7.72–8.07 (m, 5H, Ar-Hs), 9.21 (s, 1H, N1H), 10.90 (s, 1H, OH). Analysis: for C20H19N5O6 (425.39), calcd: C, 56.47; H, 4.50; N, 16.46%. Found: C, 56.66; H, 4.23; N, 16.64%.

Preparation of 5-acetyl-4-(3-aryl-1-phenyl-1H-pyrazole-4-yl)-6-methyl-3,4-dihydro-1H-pyrimidin-2-one (23–29)

General procedure

A mixture of the selected aldehyde, 39 (10 mmol), urea (1.5 g, 25 mmol) and acetylacetone (1.5 ml, 15 mmol) in ethanol (50 ml) acidified with glacial acetic acid (2 ml) or p-toluene sulfonic acid (1.72 g, 10 mmol) was heated under reflux for 5–6 h. The solvent was then evaporated under reduced pressure and the residue formed was treated with water, filtered off, washed with water, dried, and crystallized from methanol.

5-Acetyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-methyl-3,4-dihydro-1H-pyrimidin-2-one (23)

Yield 70%, m.p. 218–220°C, IR (KBr, cm−1): 3327 (NH), 3222 (NH), 1696 (CO), 1671 (CO); 1H-NMR (d6-DMSO, δ, ppm): 2.16 (s, 3H, CH3), 2.25 (s, 3H, COCH3), 5.43 (s, 1H, C4-H), 7.30–7.87 (m, 11H, 10Ar-Hs and 1H pyrazole), 8.28 (s, 1H, N3H), 9.12 (s, 1H, N1H); MS: m/z (%): 372 (M+, 93), 357 (38), 329 (36), 254 (8), 221 (100), and 153 (43). Analysis: for C22H20N4O2 (372.42), calcd: C, 70.95; H, 5.41; N, 15.04%. Found: C, 70.79; H, 5.51; N, 15.19%.

5-Acetyl-6-methyl-4-[3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-3,4-dihydro-1H-pyrimidin-2-one (24)

Yield 67%, m.p. 178–180°C, IR (KBr, cm−1): 3402 (OH), 3235 (NH), 3165 (NH), 1655 (CO), 1620 (CO); 1H-NMR (d6-DMSO, δ, ppm); MS: m/z (%): 386 (M+-2, 10), 345 (8), 235 (11), 221 (21), 154 (17) and 66 (100). Analysis: for C22H19N5O4 (417.42), calcd: C, 63.30; H, 4.59; N, 16.78%. Found: C, 63.47; H, 4.68; N, 16.92%.

5-Acetyl-4-[3-(2-hydroxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-3,4-dihydro-1H-pyrimidin-2-one (25)

Yield 82%, m.p. 193–196°C, IR (KBr, cm−1): 3227 (NH), 3114 (NH), 1656 (CO), 1619 (CO); 1H-NMR (d6-DMSO, δ, ppm): 2.07 (s, 3H, CH3), 2.33 (s, 3H, COCH3), 5.50 (s, 1H, C4-H), 7.12–8.36 (m, 10H, 9Ar-Hs and 1H pyrazole), 7.83 (s, 1H, N3H, D2O exchangeable), 9.20 (s, 1H, N1H, D2O exchangeable); MS, m/z (%): 416 (M+-1, 41), 373 (40), 326 (17), 266 (72), 235 (15), 153 (100) and 124 (50). Analysis: for C22H19N5O4 (417.42), calcd: C, 68.03; H, 5.19; N, 14.42%. Found: C, 68.23; H, 5.32; N, 14.61%.

5-Acetyl-6-methyl-4-(4-oxo-4H-chromen-3-yl)-3,4-dihydro-1H-pyrimidin-2-one (26)

Yield 75%, m.p. 218–220°C; IR (KBr, cm−1): 3340 (NH), 3273 (NH), 1703 (CO), 1671 (CO), 1645 (CO); 1H-NMR (d6-DMSO, δ, ppm): 2.15 (s, 3H, CH3), 2.31 (s, 3H, COCH3), 5.34 (s, 1H, C4-H), 7.25 (s, 1H, H-2), 7.45 (t, 1H, H-6), 7.63 (d, 1H, H-8), 7.78 (t, 1H, H-7), 8.12 (d, 1H, H-5), 8.25 (s, 1H, N3H), 9.32 (s, 1H, N1H); Ms: m/z (%), 255 (100), 239 (8), 153 (18), 146 (26), 121 (31), 105 (35). Analysis: for C16H14N2O4 (298.29), calcd: C, 64.42; H, 4.73; N, 9.39%. Found: C, 64.56; H, 4.42; N, 9.61%.

5-Acetyl-4-(2-hydroxy-3-methoxy-5-phenylazo-phenyl)-6-methyl-3,4-dihydro-1H-pyrimidin-2-one (27)

Yield 74%, m.p. 228–230°C, IR (KBr, cm−1): 3383 (OH), 3255 (NH), 3112 (NH), 1707 (CO), 1663 (CO). 1H-NMR (d6-DMSO, δ, ppm); MS, m/z (%): 379 (M+_1, 7), 350 (52), 335 (21), 322 (27), 258 (39), 244 (9), 153 (17), 93 (100), 124 (43). Analysis: for C20H20N4O4 (380.40), calcd: C, 63.15; H, 5.30; N, 14.73%. Found: C, 63.40; H, 5.31; N, 14.55%.

5-Acetyl-4-(2-hydroxy-5-phenylazo-phenyl)-6-methyl-3,4-dihydro-1H-pyrimidin-2-one (28)

Yield 78%, m.p. 202–205°C, IR (KBr, cm−1): 3400 (OH), 3235 (NH), 3150 (NH), 1681 (CO), 1621 (CO); 1H-NMR (d6-DMSO, δ, ppm): 2.11 (s, 3H, CH3), 2.33 (s, 3H, COCH3), 5.63 (s, 1H, C4-H), 7.00 (d, 1H, Ar-H), 7.04 (s, 1H, N3H, D2O exchangeable), 7.53 (t, 3H, Ar-Hs), 7.62 (s, 1H, Ar-H), 7.72 (d, 1H, Ar-H), 7.82 (d, 2H, Ar-Hs), 9.27 (s, 1H, N1H, D2O exchangeable), 10.59 (s, 1H, OH, D2O exchangeable); MS m/z (%): 350 (M+, 13), 307 (10), 198 (23), 153 (16), 93 (100). Analysis: for C19H18N4O3 (350.37), calcd: C, 65.13; H, 5.18; N, 15.99%. Found: C, 65.33; H, 5.28; N, 16.25%.

5-Acetyl-4-[2-hydroxy-5-(2-nitro-phenylazo)-phenyl]-6-methyl-3,4-dihydro-1H-pyrimidin-2-one (29)

Yield 70%, m.p. 213–216°C, IR (KBr, cm−1): 3364 (OH), 3281 (NH), 3230 (NH), 1697 (CO), 1650 (CO); MS m/z (%): 396 (M++1, 10), 350 (12), 337 (17), 257 (30), 243 (13), 337 (17), 257 (30), 243 (13), 226 (15), 153 (20%), 93 (100). Analysis: for C19H17N5O5 (395.37), calcd: C: 57.72; H, 4.33; N, 17.71%. Found: C, 57.58; H, 4.41; N, 17.63%.



Chemistry

The aldehydes 3-(substituted-phenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 3–5 23 4-oxo-4H-chromene-3-carbaldehyde (6) 24 and substituted phenylazo-benzaldehyde 7–9 25 reacted with ethyl acetaoaetate and urea in ethanol in the presence of acetic acid to yield DHPs 1015.

Compound 8 reacted similarly but underwent intramolecular condensation and aromatization to yield 2,4-dimethyl-5-oxo-9-phenylazo-5H-chromeno [3,4–c]pyridine-1-carboxylic acid ethyl ester (15). Similar behavior has been reported previously 26.

Also, compound 9 yielded a mixture of products that were hardly separable; perhaps, decomposition occurred because of the long reaction time.

Moreover, aldehydes 3–9 reacted with urea and ethyl acetoacetate in the presence of p-toluene sulfonic acid to yield dihydropyrimidinones 16–22.



Furthermore, reaction of the aldehydes 3–9 with urea and acetyl acetone in alcohol as a solvent in the presence of either acetic acid or p-toluene sulfonic acid yielded the corresponding dihydropyrimidinones 23–29.

Antihypertensive activity

Ten of the newly synthesized substituted DHPs 10–14 and tetrahydropyrimidines 16–20 were screened for their hypotensive activity using normotensive cat models 27.


  Materials and methods Top


Male cats of local strains weighing from 2.5 to 4.0 kg were housed (one per cage) in the animal facility (Faculty of Medicine, El-Azhar University) for 7 days before the experiment. Animals were always kept at 22±2 h and a 12 h light/12 h dark cycle. Stressful conditions or manipulation were avoided. Cats were divided into groups; each group included four cats and one group was used as a control. All cats were anesthetized with phenobarbital sodium (35 mg/kg, intraperitoneally) and their blood pressures (BP) were recorded from the carotid artery. BP of each cat was measured before and 30 min after the intravenous injection of the tested compounds. The tested compounds were dissolved in DMSO and administered at different doses (0.6, 1.2, 2.4 mg/kg) in 0.5 ml volume in the same way as the reference drug nifedipine. The same volume of DMSO was administered to animals in the control group. The reduction of BP between two measurements was recorded as mmHg. These results were expressed as mean±SEM; analysis variance (two-way) was used for statistical analysis. LD50 was preformed according to the procedure described in the study conducted by Kerber 28.




  Results and discussion Top


The hypotensive effect of the tested DHP derivatives 1014 and DHPMs 1620 is shown in [Table 1] in comparison with nifedipine as a reference drug. In the DHP series, the test compounds showed significant hypotensive activity at all dose levels (0.6, 1.2, and 2.4 mg/kg). The 4-(1,3-diphenyl-1H-pyrazolyl) derivative 10 was the most active at all dose levels. Also, it had more or less similar potency as nifidipine (refrerence standerd) at doses of 1.2 and 2.4 mg/kg. The other tested DHPs 11 and 12 bearing 3-aryl-1-phenyl-1H-pyrazolyl as well as the chromonyl derivative 13 and 4-hydroxy-3-methoxy-5-(phenylazo)-phenyl substituent at the 4-position 14 showed weak activities compared with the reference drug. For tetrahydropyrimidine series 1620, the evaluated data showed that the 4-chromonyl derivative 19 had significant hypertensive activity (61.00±1.10), which was higher than the 4-pyrazolyl analogous 16–18 at a dose of 0.6 mg/kg. A nonsignificant change was observed in the presence of 4-[4-hydroxy-3-methoxy-5-(phenylazo)-phenyl] derivative 20 when administered at the same dose level. The hypotensive values of this series were negligible compared with those of nifedipine at doses of 0.6, 1.2, and 2.4 mg/kg.
Table 1 Effect of tested compounds (10–14 and 16–20) on the mean blood pressure of anesthetized normotensive cats compared with the reference drug nifedipine

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Moreover, [Table 2] shows that LD50 of the most active compound 10 was equal to 298 mg/kg body weight.
Table 2 LD50 in male mice after an intraperitoneal administration of compound 10

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Conclusively, the 4-aryl-DHP derivatives 10–14 showed higher hypotensive activity than the tetrahydropyrimidines 16–20 carrying the same aryl substituents at the same position. The most active compound was 4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 10 at dose levels of 0.6, 1.2, and 2.4 mg/kg. It showed more or less similar hypotensive activity as the reference drug nifedipine at doses of 1.2 and 2.4 mg/kg.


  Conclusion Top


The synthesis of substituted DHPs 1015 and pyrimidinones 1629 was achieved. The comparison of the tested compounds 1014 and 1620 for their hypotensive activity using the nonselective cat models led to the conclusion that the 4-aryl-DHP derivatives 1014 showed higher hypotensive activity than the pyrimidinones derivatives carrying the same aryl substituent at the same position. The most active compound was 4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 10 at dose levels of 0.6, 1.2, and 2.4 mg/kg. It showed more or less similar hypotensive activity as the reference drug nifedipine at doses of 1.2 and 2.4 mg/kg. Its LD50 is 298 mg/kg body weight, which would present a fruitful matrix for the development of a potent antihypertensive agent.[28]

 
  References Top

1.Biginelli P. The first synthesis of dihydropyrimidinone by refluxing a mixture of an aldehyde, a β-ketoester, and urea under strongly acidic condition. Gazz Chim Ital. 1893;23:360–413  Back to cited text no. 1
    
2.Kappe CO. 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron. 1993;49:6937–6963  Back to cited text no. 2
    
3.Folkers K, Harwood HJ, Johnson TB. Researches on pyrimidines. cxxx. synthesis of 2-keto-1,2,3,4-tetrahydropyrimidines. J Am Chem Soc. 1932;54:3751–3758  Back to cited text no. 3
    
4.Folkers K, Johnson TB. Researches on pyrimidines. cxxxvi. The mechanism of formation of tetrahydropyrimidines by the Biginelli reaction. J Am Chem Soc. 1933;55:3784–3791  Back to cited text no. 4
    
5.Dandia A, Saha M, Taneja H. Synthesis of fluorinated ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-one/thione-5-carboxylates under microwave irradiation. J Fluorine Chem. 1998;90:17–21  Back to cited text no. 5
    
6.Lu J, Bai Y, Wang Z, Yang B, Ma H. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using lanthanum chloride as a catalyst. Tetrahedron Lett. 2000;41:9075–9078  Back to cited text no. 6
    
7.Ananda Kumar K, Kasthuraiah M, Suresh Reddy C, Devendranath Reddy C. Mn(OAc)3·2H2O-mediated three-component, one-pot, condensation reaction: an efficient synthesis of 4-aryl-substituted 3,4-dihydropyrimidin-2-ones. Tetrahedron Lett. 2001;42:7873–7875  Back to cited text no. 7
    
8.Hantzsch A. Hantzsch dihydropyridine synthesis. Just Leib Ann Chem. 1882;215:1–82  Back to cited text no. 8
    
9.Hilgeroth A, Billich A, Lilie H. Synthesis and biological evaluation of first N-alkyl syn dimeric 4-aryl-1,4-dihydropyridines as competitive HIV-1 protease inhibitors. Eur J Med Chem. 2001;36:367–374  Back to cited text no. 9
    
10.Heys L, Moore CG, Murphy PJ. The guanidine metabolites of Ptilocaulis spiculifer and related compounds; isolation and synthesis. Chem Soc Rev. 2000;29:57–67  Back to cited text no. 10
    
11.Yoshida J, Ishibashi T, Nishio M. Antitumor effects of amlodipine, a Ca2+ channel blocker, on human epidermoid carcinoma A431 cells in vitro and in vivo. Eur J Pharmacol. 2004;492(2–3):103–112  Back to cited text no. 11
    
12.Haggarty SJ, Mayer TU, Miyamoto DT, Fathi R, King RW, Mitchison TJ, Schreiber SL. Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis. Chem Biol. 2000;7:275–286  Back to cited text no. 12
    
13.Fisher-Maliszewska L, Wieczorek J, Mordarski M. Biological activity of 1,4-dihydropyridine derivatives. Arch Immunol Ther Exp. 1985;33:345–352  Back to cited text no. 13
    
14.George S, Parameswaran MK, Chakraborty AR, Ravi TK. Synthesis and evaluation of the biological activities of some 3-{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3, 4-oxadiazol-2-yl]-imino}-1,3-dihydro-2H-indol-2-one derivatives. Acta Pharm. 2008;58:119–129  Back to cited text no. 14
    
15.Takahara A, Fujita S-I, Moki K, Ono Y, Koganei H, Iwayama S, Yamamoto H. Neuronal Ca 2+ channel blocking action of an antihypertensive drug, cilnidipine, in IMR-32 human neuroblastoma cells. Hypertension Res. 2003;26:743–747  Back to cited text no. 15
    
16.Takahara A, Konda T, Enomoto A, Kondo N. Neuroprotective effects of a dual L/N-type Ca2+ channel blocker cilnidipine in the rat focal brain ischemia model. Biol Pharm Bull. 2004;27:1388–1391  Back to cited text no. 16
    
17.Yamamoto T, Niwa S, Ohno S, Onishi T, Matsueda H, Koganei H, et al. Structure-activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels. Bioorg Med Chem Lett. 2006;16:798–802  Back to cited text no. 17
    
18.Sadanandam YS, Shety MM, Diwan PV. Synthesis and biological evaluation of new 3,4-dihydro-6-methyl-5-N-methyl-carbamoyl-4-(substituted phenyl)-2(1H)pyrimidinones and pyrimidinethiones. Eur J Med Chem. 1992;27:87–92  Back to cited text no. 18
    
19.Kappe CO. Biologically active dihydropyrimidones of the Biginelli-type-A literature survey. Eur J Med Chem. 2000;35:1043–1052  Back to cited text no. 19
    
20.Yadav JS, Subba Reddy BV, Reddy PT. Unprecedented synthesis of hantzsch 1,4-dihydropyridines under biginelli reaction conditions. Synthetic Commun. 2001;31:425–430  Back to cited text no. 20
    
21.Atwal KS, Swanson BN, Unger SE, Floyd DM, Moreland S, Hedberg A, O’Reilly BC. Dihydropyrimidine calcium channel blockers. 3,3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J Med Chem. 1991;34:806–811  Back to cited text no. 21
    
22.Rovnyak GC, Atwal KS, Hedberg A, David Kimball S, Moreland S, Gougoutas JZ, et al. Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. J Med Chem. 1992;35:3254–3263  Back to cited text no. 22
    
23.Arbačiauskiene E, Martynaitis V, Krikštolaityte S, Holzer W, Šačkus A. Synthesis of 3-substituted 1-phenyl-1H-pyrazole-4-carbaldehydes and the corresponding ethanones by Pd-catalysed cross-coupling reactions. Arkivoc. 2011;11:1–21  Back to cited text no. 23
    
24.El-Sayed Ali T, Abdel-Aghfaar Abdel-Aziz S, Metwali El-Shaaer H, Ismail Hanafy F, Zaky El-Fauomy A. Synthesis of some new 4-oxo-4H-chromene derivatives bearing nitrogen heterocyclic systems as antifungal agents. Turk J Chem. 2008;32:365–374  Back to cited text no. 24
    
25.Alok K, Pareek PE, Seth JosephDS. A convenient route for the synthesis and characterization of novel substituted azo-coumarins and schiff’s bases. Oriental J Chem. 2009;25:1149–1152  Back to cited text no. 25
    
26.Dehghanpour S, Heravi MM, Derikvand F. N,Nº-ethylene-bis(benzoylacetoniminato) copper (II), Cu(C 22H22N2O2), a new reagent for aromatization of Hantzsch 1,4-dihydropyridines. Molecules. 2007;12:433–438  Back to cited text no. 26
    
27.McLeod LJ Pharmacological experiments on intact preparations. 1970 London Churchill livingstone:49  Back to cited text no. 27
    
28.Kerber GDr Leopold T. Pharmacological approaches for the discovery of drugs and poisons and their mode of action analysis. Pharmakologische methoden zur auffinding von Arzneimittel und Gifte und Analyse ihner Wirkungweise. 1941 Wissenschaftliche Verlag GmbH  Back to cited text no. 28
    



 
 
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