Journal of Medicinal Chemistry
ARTICLE
3-[4-(Biphenyl-4-ylamino)-phenyl]-3-imidazol-1-yl-2,2-dimethyl-propionic
Acid Methyl Ester (17). Prepared by the reaction of 7 with CDI and
imidazole. After 2 h reflux, the resulting precipitate was filtered and the
precipitate was washed with H2O (10 mL) and hot CH3CN (10 mL) to
give the product as a white solid in 59% yield without further purifica-
tion. Mp 200ꢀ202 °C; TLC (EtOAc, Rf = 0.43). 1H NMR (CDCl3): δ
1.32 (s, 6H, H-4, H-5), 3.71 (s, 3H, H-1), 5.51 (s, 1H, H-6), 5.92 (s, 1H,
NH), 7.07 (m, 4H, Ar), 7.14 (m, 4H, Ar), 7.32 (m, 1H, H-1000), 7.45 (m,
2H, Ar), 7.53 (d, J = 8.0 Hz, 2H, H-300, H-500), 7.61 (d, J = 7.9 Hz, 2H,
H-800, H-1200), 7.68 (s, 1H, H-1000). 13C NMR (CDCl3): δ 23.00 (CH3,
C-4), 23.39 (CH3, C-5), 47.68 (C, C-3), 52.40 (CH3, C-1), 67.50 (CH,
C-6), 116.82 (CH, C-30, C-50), 118.73 (CH, C-200, C-600, C-2000), 126.59
(CH, C-800, C-1200, C-3000), 126.77 (CH, C-1000), 128.04 (CH, C-300,
C-500), 128.46 (C, C-400), 128.77 (CH, C-900, C-1100), 129.05 (CH,
C-1000), 129.64 (CH, C-20, C-60), 134.61 (C, C-10), 140.69 (C, C-700),
141.57 (C, C-40), 143.30 (C, C-100), 176.25 (C, C-2). Anal. C, H, N.
3-Imidazol-1-yl-2,2-dimethyl-3-[4-(naphthalen-1-ylamino)-phenyl]-pro-
pionic Acid Methyl Ester (18). Prepared by the reaction of 8 with CDI and
imidazole. Column chromatography (CH2Cl2 - MeOH 100:0 v/v
increasing to 97:3 v/v) gave this product in 52% yield as a pale yellow
oil. TLC (97:3 CH2Cl2/MeOH, Rf = 0.61). 1H NMR (CDCl3): δ 1.32
(s, 6H, H-4, H-5), 3.65 (s, 3H, H-1), 5.51 (s, 1H, H-6), 6.11 (s, 1H,
H-NH), 6.89 (d, J = 8.0 Hz, 2H, H-30, H-50), 7.03 (s, 1H, H-3000), 7.09 (s,
1H, H-2000), 7.14 (d, J = 8.1 Hz, 2H, H-20, H-60), 7.41 (m, 2H, H-200,
H-300), 7.48 (m, 2H, H-400, H-700), 7.61 (m, 2H, H-800, H-1000), 7.88
(d, J = 8.0 Hz, 1H, H-600), 8.12 (d, J = 8.2 Hz, 1H, H-900). 13C NMR
(CDCl3): δ 22.92 (CH3, C-4), 23.42 (CH3, C-5), 47.72 (C, C-3), 52.37
(CH3, C-1), 67.57 (CH, C-6), 116.13 (CH, C-200), 117.56 (CH, C-30,
C-50), 121.97 (CH, C-400), 123.96 (CH, C-900), 125.89 (CH, C-2000),
125.94 (CH, C-800), 126.23 (CH, C-700), 127.59 (CH, C-3000), 128.33
(CH, C-300, C-600), 128.56 (C, C-1000), 128.95 (C, C-10), 129.90
(CH, C-20, C-600, C-1000), 134.74 (C, C-500), 137.85 (C, C-40), 145.34
(C, C-100), 176.28 (C, C-2). Anal. C, H, N.
C-400), 126.23 (CH, C-500, C-700), 127.37 (CH, C-900), 127.96 (C, C-800),
128.00 (CH, C-3000), 128.10 (C, C-10), 128.82 (CH, C-1000), 129.79
(CH, C-20, C-60), 134.29 (C, C-300), 140.68 (C, C-40), 142.99 (C, C-100),
175.31 (C, C-2). Anal. C, H, N.
3-Imidazol-1-yl-3-[4-(6-methoxy-naphthalen-2-ylamino)-phenyl]-
2,2-dimethyl-propionic Acid Methyl Ester (21). Prepared by the reac-
tion of 11 with CDI and imidazole. After 2 h reflux, the resulting
precipitate was filtered and washed with H2O (10 mL) and hot CH3CN
(10 mL) to give the product as a white solid in 68% yield without further
purification. Mp 220ꢀ222 °C; TLC (97:3 CH2Cl2/MeOH, Rf = 0.64).
1H NMR (DMSO-d6): δ 1.22 (s, 6H, H-4, H-5), 3.57 (s, 3H, H-1), 3.89
(s, 3H, OCH3), 5.60 (s, 1H, H-6), 6.85 (s, 1H, Ar), 7.18 (m, 3H, Ar),
7.20 (s, 1H, H-3000), 7.24 (d, J = 7.8 Hz, 1H, Ar), 7.29 (d, J = 7.7 Hz, 2H,
H-20, H-60), 7.41 (s, 1H, H-2000), 7.45 (s, 1H, H-1000), 7.61 (d, J = 8.2 Hz,
1H, H-400), 7.69 (d, J = 8.3 Hz, 1H, H-900), 7.82 (s, 1H, H-200), 8.33 (s,
1H, NH). 13C NMR (DMSO-d6): δ 22.69 (CH3, C-4), 22.91 (CH3,
C-5), 47.35 (C, C-3), 51.91 (CH3, C-1), 55.06 (CH3, OCH3), 66.75
(CH, C-6), 106.08 (CH, C-700), 111.59 (CH, C-200), 112.59 (CH,
C-2000), 115.37 (CH, C-30, C-50, C-1000), 118.60 (CH, C-400), 119.73
(CH, C-3000), 120.94 (CH, C-500), 127.25 (CH, C-1000), 127.67 (C,
C-800), 127.86 (CH, C-900), 128.08 (CH, C-20, C-60), 129.45 (C, C-10),
129.78 (C, C-300), 138.53 (C, C-40), 143.65 (C, C-100), 155.54 (C,
C-600), 175.32 (C, C-2). Anal. C, H, N.
3-[4-(Benzooxazol-2-ylamino)-phenyl]-3-imidazol-1-yl-2,2-dimethylpro-
pionic Acid Methyl Ester (23). Prepared by the reaction of 13 with CDI
and imidazole. Column chromatography (EtOAc) gave this product in
47% yield as a white solid. Mp 158ꢀ160 °C; TLC (EtOAc, Rf = 0.28). 1H
NMR (DMSO-d6): δ 1.21 (s, 6H, H-4, H-5), 3.57 (s, 3H, H-1), 5.62 (s,
1H, H-6), 6.91 (s, 1H, H-3000), 7.14 (t, J = 7.7 Hz, 1H, H-400), 7.23 (t, J =
7.6 Hz, 1H, H-500), 7.48 (m, 5H, H-30, H-50, H-300, H-600, H-2000), 7.75 (d,
J = 8.1 Hz, 2H, H-20, H-60), 7.84 (s, 1H, H-1000), 10.71 (s, 1H, NH). 13C
NMR (DMSO-d6): δ 22.78 (CH3, C-4, C-5), 47.30 (C, C-3), 51.97
(CH3, C-1), 66.62 (CH, C-6), 108.99 (CH, C-600), 116.64 (CH, C-2000),
117.20 (CH, C-30, C-50, ꢀ300), 121.77 (CH, C-3000), 124.03 (CH, C-400,
C-500), 128.15 (CH, C-1000), 129.55 (CH, C-20, C-60), 130.34
(C, C-10), 138.47 (C, C-200), 142.26 (C, C-40), 146.97 (Cþ, C-700),
157.79 (C, C-100), 175.20 (C, C-2). EI-HRMS (M þ H) found
391.1761, calculated for C22H22N4O3 391.1765.
3-[4-(Benzothiazol-2-ylamino)-phenyl]-3-imidazol-1-yl-2,2-dimethyl-
propionic Acid Methyl Ester (24). Prepared by the reaction of 14 with CDI
and imidazole. Column chromatography (CH2Cl2/MeOH 100:0 increas-
ing to 95:5 v/v) gave this product in 44% yield as a yellow oil. TLC
(CH2Cl2/MeOH 95:5, Rf = 0.46). 1H NMR (DMSO-d6): δ 1.22 (s, 6H,
H-4, H-5), 3.61 (s, 3H, H-1), 5.62 (s, 1H, H-6), 6.85 (s, 1H, H-3000), 7.09
(m, 3H, H-400, H-600, H-2000), 7.34 (t, J = 7.6 Hz, 1H, H-500), 7.46 (d, J = 8.2
Hz, 2H, H-30, H-50), 7.61 (d, J = 7.9 Hz, 1H, H-300), 7.78 (d, J = 8.1 Hz, 1H,
H-20), 7.81 (d, J = 7.9 Hz, 1H, H-60), 7.85 (s, 1H, H-1000), 10.59 (s, 1H,
NH). 13C NMR (DMSO-d6): δ 22.91 (CH3, C-4), 23.53 (CH3, C-5),
47.56 (C, C-3), 52.50 (CH3, C-1), 67.63 (CH, C-6), 118.49 (CH, C-30,
C-50), 119.76 (CH, C-300), 120.73 (CH, C-600, C-2000), 122.66 (CH, C-400),
126.08 (CH, C-500, C-3000), 128.66 (CH, C-1000), 129.35 (CH, C-20, C-60),
130.25 (C, C-700), 130.58 (C, C-10), 140.54 (C, C-40), 151.71 (C, C-200),
162.54 (C, C-100), 176.15 (C, C-2). EI-HRMS (M þ H)þ found 407.1535,
calculated for C22H22N4O2S 407.1536.
3-[4-(2-Ethoxy-naphthalen-1-ylamino)-phenyl]-3-imidazol-1-yl-2,2-di-
methyl-propionic Acid Methyl Ester (19). Prepared by the reaction of 9
with CDI and imidazole. Purified by column chromatography
(CH2Cl2ꢀMeOH 100:0 v/v increasing to 97:3 v/v) and obtained as a
1
brown oil in 38% yield (97:3 CH2Cl2/MeOH, Rf = 0.64). H NMR
(CDCl3): δ 1.21 (s, 3H, H-4), 1.25 (s, 3H, H-5), 1.36 (t, J = 7.6 Hz, 3H,
H-2000), 3.66 (s, 3H, H-1), 4.16 (q, J = 7.5 Hz, 2H, H-1000), 5.51 (s, 1H,
H-6), 5.96 (s, 1H, NH), 6.62 (d, J = 7.8 Hz, 2H, H-30, H-50), 7.03 (d, J =
8.0 Hz, 2H, H-20, H-60), 7.08 (d, J = 2.2 Hz, 1H, Ar), 7.32ꢀ7.38 (m, 4H,
Ar), 7.72 (d, J = 8.2 Hz, 1H, Ar), 7.81ꢀ7.86 (m, 3H, H-600, H-900, H-1000).
13C NMR (CDCl3): 15.10 (CH3, OEt), 22.59 (CH3, C-4), 23.81 (CH3,
C-5), 47.67 (C, C-3), 52.42 (CH, C-1), 65.13 (CH2 OEt), 68.29 (CH,
C-6), 114.90 (CH, C-30, C-50), 115.09 (CH, C-300), 123.44 (CH, C-900,
C-2000), 123.90 (CH, C-400), 124.03 (C, C-100, C-1000), 125.76 (CH,
C-700, C-3000), 126.27 (CH, C-800), 126.36 (CH, C-600), 129.31 (CH,
C-20, C-60, C-1000), 129.42 (C, C-500), 130.68 (C, C-10), 147.47 (C, C-40),
150.24 (C, C-200), 176.17 (C, C-2). EI-HRMS (M þ H)þ found
444.2280, calculated for C27H30N3O3 444.2282.
3-Imidazol-1-yl-2-methyl-3-[4-(naphthalen-2-ylamino)-phenyl]-propionic
Acid Methyl Ester (20). Prepared by the reaction of 10 with CDI and
imidazole. Column chromatography (CH2Cl2 - MeOH 100:0 v/v
increasing to 97:3 v/v) gave this product in 54% yield as a light brown
Methyl anti-3-(1H-1-Imidazolyl)-3-[4-(phenylamino)phenyl]-2-methyl-
propanoate (30). Prepared by the reaction of 26 with CDI and
imidazole. Purified by column chromatography (CH2Cl2ꢀMeOH
100:0 v/v increasing to 97:3 v/v) and obtained in 65% yield as a brown
solid. Mp 218ꢀ222 °C; TLC (9:1 CH2Cl2/MeOH, Rf = 0.4). 1H NMR
(CDCl3): δ 1.11 (d, 3H, J = 6.9 Hz, CH-CH3), 3.33ꢀ3.39 (m, 1H, CH-
CH3), 3.52 (s, 3H, OCH3), 5.18 (d, 1H, J = 11.3 Hz, CH-imidazole),
7.79 (s, 1H, NH), 6.87ꢀ6.95 (m, 1H, H-400), 6.97ꢀ7.01 (m, 4H, H-30,
H-50, H-200, H-600), 7.04ꢀ7.07 (m, 2H, H-20, H-60), 7.20ꢀ7.24 (m, 2H,
H-300, H-500), 7.20ꢀ7.24 (m, 2H, H-2000, H-3000), 7.57 (s, 1H, H-1000). 13C
1
solid. Mp 190ꢀ192 °C; TLC (97:3 CH2Cl2/MeOH, Rf = 0.61). H
NMR (DMSO-d6): δ 1.21 (s, 6H, H-4, H-5), 3.55 (s, 3H, H-1), 5.58 (s,
1H, H-6), 6.91 (s, 1H, H-200), 7.17 (d, J = 8.0 Hz, 2H, H-30, H-50), 7.28
(m, 2H, H-600, H-1000), 7.38 (m, 3H, H-20, H-60, H-500), 7.44 (s, 1H,
H-3000), 7.50 (s, 1H, H-2000), 7.71 (d, J = 8.2 Hz, 1H, H-400), 7.77 (m, 2H,
H-700, H-900), 7.83 (s, 1H, H-1000), 8.51 (s, 1H, NH). 13C NMR (DMSO-
d6): δ 22.70 (CH3, C-4), 22.90 (CH3, C-5), 47.34 (C, C-3), 51.92 (CH3,
C-1), 66.73 (CH, C-6), 109.84 (CH, C-200), 112.84 (CH, C-1000),
116.20 (CH, C-30, C-50), 120.10 (CH, C-600. C-2000), 122.98 (CH,
2787
dx.doi.org/10.1021/jm101583w |J. Med. Chem. 2011, 54, 2778–2791