918
A. Gaspar et al. / European Journal of Medicinal Chemistry 54 (2012) 914e918
[23] M.F.M. Borges, A.M.N. Gaspar, J.M.P.J. Garrido, N.J.S.P. Milhazes, M.C.C.
Batoreu, WO2008104925A1 and PT103665.
[24] M.F.M. Borges, A.M.N. Gaspar, J.M.P.J. Garrido, N.J.S.P. Milhazes, E. Uriarte, M.
Yáñez, F. Orallo, PT104487, 2009.
[25] A. Gaspar, F. Teixeira, E. Uriarte, N. Milhazes, A. Melo, M.N. Cordeiro, F. Ortuso,
S. Alcaro, F. Borges, Towards the discovery of a novel class of monoamine
oxidase inhibitors: structure-property-activity and docking studies on chro-
mone amides, ChemMedChem 6 (2011) 628e632.
[26] The 2-carboxychromone (1) or 3-carboxychromone (7) (2.63 mmol; 0.50 g) was
dissolved in DMF (6 mL) and DIPEA (0.37 mL). The solution was cooled at 0 ꢁC (ice
water bath)and a solution ofBOP(2.63mmol; 1.16 g)inCH2Cl2 (6mL)wasadded.
The mixture is stirred at the mentioned temperature during 30 min. After then
the corresponding amine was added (phenylamine, 4-hydroxyphenylamine, 3-
hydroxy-4-methoxyphenylamine or 3,4-dimethoxyphenylamine). The temper-
ature was gradually increased to room temperature being the reaction kept, with
stirring, for 4 h. The crude material was then purified by flash chromatography,
using the most suitable elution system for each compound (normally acetyl
acetate or acetyl acetate/dichloromethane 5:5). The appropriate fractions were
combined and the solvent evaporated under reduced pressure. Then, if found
necessary, mixed solvent recrystallization was used to purify the product. N-(4-
Hydroxyphenyl)-4-oxo-4H-1-benzopyran-2-carboxamide (3): Yield: 51%; MP:
d, J ¼ 7.3 H(5)), 7.73e7.68 (1H, m, H(7)), 9.87/9.83 (1H, s, OH), 8.71/8.76 (1H, s,
H(2)), 11.85/13.53 (1H, s, NH)., MS/EI m/z (%): 282 (19), 281 (Mþꢂ, 100), 207 (29),
121 (15), 58 (21). N-(3-Hydroxy-4-methoxyphenyl)-4-oxo-4H-1-benzopyran-3-
carboxamide (10): Yield: 45%; MP: 255e257 ꢁC; 1H NMR:
d
¼ 3.81 (3H, s, OCH3),
7.08e6.99 (3H, m, H(20), H (50) H(60)), 7.38e7.32 (2H, m, H(6), H(8)), 7.99 (1H, d,
J ¼ 7.7 H(5)), 7.73e7.68 (1H, m, H(7)), 8.72/8.68 (1H, s, H(2)), 9.55 (1H, s, OH),
11.78/13.42 (1H, s, NH)., MS/EI m/z (%.): 312 (19), 311 (Mþꢂ, 100), 296 (31), 207
(15), 176 (15), 121 (38). N-(3,4-Dimethoxyphenyl)-4-oxo-4H-1-benzopyran-3-
carboxamide (11): Yield: 50%; MP: 248e254 ꢁC; 1H NMR:
d
¼
3.77 (3H, s, 30-
OCH3), 3.85 (3H, s, 40-OCH3), 7.01 (1H, d, J ¼ 8,6 H(50), H(60)), 7.14 (1H, dd, J ¼ 8.6;
1.6 H(50)), 7.37e7.30 (3H, m, H(6), H(8), H(20)), 7.73e7.68 (1H, m, H(7)), 7.96 (1H,
d, J ¼ 7.7H(5)), 8.86/8.83 (1H, s, H(2)), 11.82/13.58 (1H, s, NH)., MS/EI m/z (%): 326
(21), 325 (Mþꢂ, 100), 311 (10), 310 (63), 207 (60), 173 (62), 121 (17), 93 (20), 79
(15), 77 (15).
[27] A. Gaspar, T. Silva, M. Yáñez, D. Vina, F. Orallo, F. Ortuso, E. Uriarte, S. Alcaro,
F. Borges, Chromone, a privileged scaffold for the development of monoamine
oxidase inhibitors, J. Med. Chem. 54 (2011) 5165e5173.
[28] Biological assay procedures. (i) A1 receptor assay: a radioligand binding assay
was performed in membranes from CHO transfected cells with human A1AR,
using [3H]DPCPX as specific radioligand for this type of receptors; (ii) A2B
receptor assay: a radioligand binding assay was performed in membranes
from HEK 293 transfected cells with human A2B receptor, using [3H]DPCPX as
a specific radioligand for this type of receptors; (iii) A2A receptor assay:
a radioligand binding assay was performed in membranes from HeLa trans-
fected cells with human A2A receptor, using [3H]ZM241385 as a specific
radioligand for this type of receptors; (iv) A3 receptor assay: a radioligand
binding assay was performed in membranes from HeLa transfected cells with
human A3 receptor, using [3H]NECA as a specific radioligand for this type of
receptors. For details see V. Yaziji, D. Rodríguez, H. Gutiérrez-de-Terán,
A. Coelho, O. Caamaño, X. García-Mera, J. Brea, M.I. Loza, M.I. Cadavid,
E. Sotelo, Pyrimidine derivatives as potent and selective A3 adenosine receptor
antagonists, J. Med. Chem. 54 (2011) 457e471.
277e281 ꢁC; 1H NMR:
d
¼ 6.80 (2H, d, J ¼ 8.9 H(30), H(50)), 6.95 (1H, s, H(3)), 7.57
(1H, ddd, J ¼ 7.9; 7.0; 1.1 H(6)), 7.58 (2H, d, J ¼ 8.8 H(20), H(60)), 7.84 (1H, d, J ¼ 8,0
H(8)), 7.94 (1H, ddd, J ¼ 8.5; 7.0; 1.6 H(7)), 8.09 (1H, dd, J ¼ 7.9; 1.4 H(5)), 10.60
(1H, s, NH). MS/EI m/z (%): 282(18), 281 (Mþꢂ, 100), 280 (23), 146 (51), 108 (25),
105 (17), 89 (22). N-(3-Hydroxy-4-methoxyphenyl)-4-oxo-4H-1-benzopyran-2-
carboxamide (4): Yield: 57%; MP: 266e267 ꢁC; 1H NMR:
d
¼ 3.78 (3H, s, OCH3),
6.95 (1H, s, H(3)), 6.96 (1H, d, J ¼ 8.8 H(50)), 7.18 (1H, dd, J ¼ 8.8; 2.5 H(60)), 7.36
(1H, d, J ¼ 2.5 H(20)), 7.57 (1H, ddd, J ¼ 8.0; 6.8; 1.2 H(6)), 7.85 (1H, d, J ¼ 7,5 H(8)),
7.94 (1H, ddd, J ¼ 8.5; 7.0; 1.6 H(7)), 8.09 (1H, dd, J ¼ 7.9; 1.6 H(5)), 9.23 (1H, s, 30-
OH),10.55 (1H,s, NH). MS/EIm/z(%):312(18),311(Mþꢂ, 100),310(54), 268(36),
207 (26), 145 (15), 89 (31). N-(3,4-Dimethoxyphenyl)-4-oxo-4H-1-benzopyran-
2-carboxamide (5): Yield: 45%; MP: 196e198 ꢁC; 1H NMR:
d
¼ 3.77, 3.79 (6H, 2s,
2ꢃ OCH3), 6.97 (1H, s, H (3)), 7.01 (1H, d, J ¼ 8.7 H(50)), 7.40 (1H, dd, J ¼ 8.7; 2.4
H(60)), 7.48 (1H, d, J ¼ 2.4 H(20)), 7.58 (1H, ddd, J ¼ 8.0; 6.8; 1.2 H(6)), 7.86 (1H, d,
J ¼ 7.7 H(8)), 7.95 (1H, ddd, J ¼ 8.5; 7.0; 1.6 H(7)), 8.10 (1H, dd, J ¼ 8.0; 1.5 H(5)),
10.66 (1H, s, NH). MS/EI m/z (%): 326 (20), 325 (Mþꢂ, 100), 310 (21), 308 (15),
173(24), 145 (22), 89 (37). N-(4-Hydroxyphenyl)-4-oxo-4H-1-benzopyran-3-
[30] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and
computational approaches to estimate solubility and permeability in drug
discovery and development settings, Adv. Drug Deliv. Rev. 23 (1997) 3e25.
[31] P. Ertl, B. Rohde, P. Selzer, Fast calculation of molecular polar surface area as
a sum of fragment-based contributions and its application to the prediction of
drug transport properties, J. Med. Chem. 43 (2000) 3714e3717.
carboxamide (9): Yield: 55%; MP: 290e293 ꢁC; 1H NMR:
d
¼
6.96 (2H, m, H
(30),H(50)), 7.38e7.32(2H,m, H(6),H(8)), 7.50(2H,d, J¼ 8.6H(20),H(60)), 7.98(1H,