140
M.S. Al-Said et al. / European Journal of Medicinal Chemistry 46 (2011) 137e141
(DMSO-d6): 12.72, 13.88, 22.80, 24.64 (3C), 25.71, 46.51 (2C), 62.22,
80.24, 115.66, 117.02, 126.89, 127.61 (2C), 129.21 (2C), 130.92 (2C),
137.70 (2C), 139.74, 144.31, 154.82, 156.01, 161.94, 163.82, 165.81. MS
m/z (%): 561 [Mþ] (0.7), 172 (100). Anal. Calcd. for C29H31N5O5S: C,
62.02; H, 5.56; N, 12.47. Found: C, 62.40; H, 5.20; N, 12.10.
4.1.8. 2-Amino-4-(4-chlorophenyl)-5-cyano-6-oxo-1-{1-[4-
(piperidine-1-sulf-onyl)phenyl]ethylideneamino}-1,6-
dihydropyridine-3-carboxylic acid ethyl ester (15)
Yield, 84%; m.p. 133e135 ꢁC; IR [(KBr, cmꢀ1): 3431, 3327 (NH2),
2980, 2939, 2852 (CH aliph.), 2214 (C^N), 1700, 1676 (2C]O), 1595
(C]N), 1396, 1166 (SO2), 715 (C-Cl). 1H NMR (DMSO-d6): 1.10 [t, 3H,
CH3 ethyl], 1.21 [s, 3H, CH3], 1.31e1.62 [m, 6H, 3CH2 cyclo], 2.94 [s, 4H,
CH2eNeCH2 cyclo], 4.21 [q, 2H, CH2 ethyl], 7.22e8.01 [m, 10H, Ar-
HþNH2]. MS m/z(%): 581[Mþ](0.6),83(100). Anal.Calcd. forC28H28Cl
N5O5S: C, 57.78; H, 4.85; N, 12.03. Found: C, 57.40; H, 4.50; N, 12.40.
4.1.4. 2-Amino-5-cyano-4-(4-hydroxyphenyl)-6-oxo-1-{1-[4-
(piperidine-1-sulf-onyl)phenyl]ethylideneamino}-1,6-
dihydropyridine-3-carboxylic acid ethyl ester (11)
Yield: 73%; m.p. 85e87 ꢁC; IR (KBr, cmꢀ1): 3460 (OH), 3288,
3255 (NH2), 3072 (CH arom.), 2983, 2939, 2854 (CH aliph.) 2218
(C^N), 1732, 1714 (2C]O), 1610 (C]N), 1396, 1168 (SO2). 1H NMR
(DMSO-d6): 1.11 [t, 3H, CH3 ethyl], 1.21 [s, 3H, CH3], 1.51e1.60 [m,
6H, 3CH2 cyclo], 2.84 [s, 4H, CH2eNeCH2 cyclo], 4.31 [q, 2H, CH2
ethyl], 6.74 [s, 2H, NH2 exchangeable with D2O], 6.91e8.04 [m, 8H,
Ar-H], 9.77 [s, 1H, OH]. 13C NMR (DMSO-d6): 13.71, 17.54, 24.02 (3C),
25.42, 46.51 (2C), 61.83, 96.90, 115.21, 115.71 (2C), 125.92, 127.62
(2C), 129.43 (2C), 130.01 (2C), 139.71, 141.74, 156.52, 157.92, 162.58,
163.00, 165.91, 166.32. MS m/z (%): 563 [Mþ], (1.4), 42 (100). Anal.
Calcd. For C28H29N5O6S: C, 59.67; H, 5.19; N, 12.43. Found: C, 59.30;
H, 5.50; N, 12.10.
4.1.9. 4,6-Diamino-2-oxo-1-[1-(1-(4-(piperidin-1-ylsulfonyl)
phenyl)ethylidene-amino]-1,2-dihydropyridine-3-carbonitrile (16),
and 4-amino-6-hydroxy-2-oxo-1-[1-(4-(piperidin-1-ylsulfonyl)
phenyl)ethylideneamino)-1,2-dihydropyridine-3-carbonitrile (17)
Equimolecular amounts of compound 3 (3.4 g, 0.01 mol) and
either malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g;
0.01 mol) in dioxane (20 mL) containing triethylamine (1 mL) was
heated under reflux for 6 h. The reaction mixture was left to cool
and evaporated under vacuum. The remaining product was tritu-
rated with ethanol and the obtained solid was recrystallized from
dioxane to give 16 and 17, respectively.
4.1.5. 2-Amino-5-cyano-4-(4-methoxyphenyl)-6-oxo-1-{1-[4-
(piperidine-1-sulf-onyl)phenyl]ethylideneamino}-1,6-
dihydropyridine-3-carboxylic acid ethyl ester (12)
16: Yield, 81%; m.p. 295e297 ꢁC; IR (KBr, cmꢀ1): 3412, 3334,
3248, 3178 (2NH2), 2918, 2860 (CH aliph.), 2214 (C^N), 1653 (C]
O), 1579 (C]N), 1380, 1170 (SO2). 1H NMR (DMSO-d6): 1.21 [s, 3H,
CH3], 1.31e1.52 [m, 6H, 3CH2 cyclo], 2.91 [s, 4H, CH2eNeCH2 cyclo],
4.10 [s, 3H, CH þ NH2], 7.01e8.02 [m, 6H, Ar-H þ NH2]. 13C NMR
(DMSO-d6): 14.22, 24.64, 25.82 (2C), 46.51 (2C), 70.90, 81.31, 116.30,
127.01 (2C), 127.42 (2C), 137.81, 141.22, 143.11, 161.50, 186.81, 197.33.
MS m/z (%): 414 [Mþ] (5.5), 47(100). Anal. Calcd. for C19H22N6O3S: C,
55.06; H, 5.35; N, 20.28. Found: C, 55.40; H, 5.00; N, 20.50.
17: Yield, 73%; m.p. 220e222 ꢁC; IR (KBr, cmꢀ1): 3412 (OH),
3367, 3190 (NH2), 3074 (CH arom.), 2943, 2843 (CH aliph.), 2264
(C^N), 1685 (C]O), 1360, 1168 (SO2). 1H NMR (DMSO-d6): 1.21 [s,
3H, CH3], 1.30e1.54 [m, 6H, 3CH2 cyclo], 2.80 [s, 4H, CH2eNeCH2
cyclo], 4.21 [s, 2H, NH2 exchangeable with D2O], 4.40 [s, 1H, CH],
7.71,8.02 [2d, 4H, Ar-H, AB system, J ¼ 7.1 Hz], 11.21 [s, 1H, OH]. 13C
NMR (DMSO-d6): 14.20, 24.62, 24.91 (2C), 46.51 (2C), 66.33, 84.64,
116.01, 127.12 (2C), 127.42 (2C), 141.86, 147.42, 151.31, 159.62, 166.01,
174.62. MS m/z (%): 415 [Mþ] (2.1), 78 (100). Anal. Calcd. for
C19H21N5O4S: C, 54.93; H, 5.09; N,16.86. Found: C, 54.60; H, 4.70; N,
16.50.
Yield, 89%; m.p. 153e155 ꢁC; IR (KBr, cmꢀ1): 3414, 3387 (NH2),
2939, 2852 (CH aliph.), 2216 (C^N), 1707, 1662 (2C]O), 1608 (C]
N),1340,1166 (SO2). 1H NMR (DMSO-d6): 1.21 [t, 3H, CH3 ethyl],1.30
[s, 3H, CH3], 1.51e1.72 [m, 6H, 3CH2 cyclo], 2.94 [s, 4H, CH2eNeCH2
cyclo], 3.83 [s, 3H, OCH3], 4.21 [q, 2H, CH2 ethyl], 6.60 [s, 2H, NH2
exchangeable with D2O], 7.02e8.01 [m, 8H, Ar-H]. MS m/z (%): 577
[Mþ] (1.2), 84 (100). Anal. Calcd. for C29H31N5O6S: C, 60.30; H, 5.41;
N, 12.12. Found: C, 60.00; H, 5.10; N, 12.50.
4.1.6. 2-Amino-5-cyano-4-(4-hydroxy-3-methoxyphenyl)-6-oxo-1-
{1-[4-(piperidine-1-sulfonyl)phenyl]ethylideneamino}-1,6-
dihydropyridine-3-carboxylic acid ethyl ester (13)
Yield, 67% m.p. 132e134 ꢁC; IR (KBr, cmꢀ1): 3275 (OH), 3199,
3113 (NH2), 2980, 2923, 2843 (CH aliph.), 2227 (C^N), 1718, 1689
(2C]O), 1577 (C]N), 1398, 1192 (SO2). 1H NMR (DMSO-d6): 1.31 [t,
3H, CH3 ethyl], 1.40 [s, 3H, CH3], 1.51e1.72 [m, 6H, 3CH2 cyclo], 2.84
[s, 4H, CH2eNeCH2 cyclo], 3.82 [s, 3H, OCH3], 4.21 [q, 2H, CH2
ethyl], 6.82 [s, 2H, NH2 exchangeable with D2O], 7.51e8.10 [m, 7H,
Ar-H], 11.22 [s, 1H, OH]. 13C NMR (DMSO-d6): 13.81, 14.18, 24.40,
24.92 (2C), 46.53 (2C), 55.51, 61.82, 96.61, 113.94, 115.03, 115.81,
116.61, 122.02; 126.87, 127.21 (2C), 128.90 (2C), 135.73, 141.71,
147.81, 153.02, 154.81, 159.62, 162.61, 164.22, 166.02. MS m/z (%):
593 [Mþ] (3.2), 84 (100). Anal. Calcd. for C29H31N5O7S: C, 58.67; H,
5.26; N, 11.80. Found: C, 58.30; H, 5.50; N, 12.10.
4.1.10. 3,5-Diamino-4-cyano-N`-(1-(4-(piperidin-1-ylsulfonyl)
phenyl)ethylidene] thiophene-2-carbohydrazide (18) and ethyl-2,4-
diamino-5-[2-(1-(4-piperidin-1-ylsulfonyl)phenyl)ethylidene)
hydrazinecarbonyl]thiophene-3-carboxylate (19)
To a solution of compound 3 (3.4 g, 0.01 mol) in absolute ethanol
(30 mL) containing triethylamine (1 mL) either malononitrile
(0.66 g, 0.01 mol), or ethyl cyanoacetate (1.13 g, 0.01 mol) together
with elemental sulfur (0.32 g, 0.01 mol) were added. The reaction
mixture was heated under reflux for 1h. then poured onto ice/water
and the solid obtained was recrystallized from dioxane to give 18
and 19, respectively.
4.1.7. 2-Amino-5-cyano-4-(4-dimethylaminophenyl)-6-oxo-1-{1-
[4-(piperidine-1-sulfonyl)phenyl]ethylideneamino}-1,6-
dihydropyridine-3-carboxylic acid ethyl ester (14)
Yield, 76%; m.p. 205e207 ꢁC; IR (KBr, cmꢀ1): 3197, 3111 (NH2),
2922, 2841 (CH aliph.), 2209 (C^N), 1707, 1689 (2C]O), 1610 (C]
N),1350,1166 (SO2). 1H NMR (DMSO-d6): 1.32 [t, 3H, CH3 ethyl], 1.41
[s, 3H, CH3], 1.51e1.62 [m, 6H, 3CH2 cyclo], 2.82 [s, 4H, CH2eNeCH2
cyclo], 3.31 [s, 6H, N(CH3)2], 4.20 [q, 2H, CH2 ethyl], 6.82 [s, 2H, NH2
exchangeable with D2O], 7.21e8.20 [m, 8H, Ar-H]. 13C NMR (DMSO-
d6): 13.81, 14.22, 24.21, 24.80 (2C), 39.88 (2C), 46.51 (2C), 61.41,
92.02, 111.61 (2C), 115.90, 117.41, 118.22, 126.90 (2C), 127.11 (2C),
127.32 (2C), 135.94, 141.71, 147.41, 151.22, 154.04, 159.61, 163.42,
166.01. MS m/z (%): 590 [Mþ] (0.6), 83(100). Anal. Calcd. for
C30H34N6O5S: C, 61.00; H, 5.80; N, 14.23. Found: C, 61.30; H, 5.75; N,
14.13.
18: Yield, 88%; m.p. >300 ꢁC; IR (KBr, cmꢀ1): 3446, 3385, 3346
(NH, NH2), 2939, 2852 (CH aliph.), 2204 (C^N), 1680 (C]O), 1610
(C]N), 1370, 1165 (SO2). 1H NMR (DMSO-d6): 1.10 [s, 3H, CH3],
1.31e1.52 [m, 6H, 3CH2 cyclo], 3.02 [s, 4H, CH2eNeCH2 cyclo], 6.41
[s, 2H, NH2 exchangeable with D2O], 7.01e8.02 [m, 6H, Ar-H þ NH2],
8.30 [s, 1H, NH]. MS m/z (%): 446 [Mþ] (1.9), 84 (100). Anal. Calcd.
for C19H22N6O3S2: C, 51.10; H, 4.97; N, 18.82. Found: C, 51.40; H,
4.60; N, 18.50.
19: Yield, 69% m.p. 230e232 ꢁC; IR (KBr, cmꢀ1): 3412, 3348, 3192
(NH, NH2), 3095 (CH arom.), 2943, 2852 (CH aliph), 1700, 1647
(2C]O), 1616 (C]N), 1382, 1166 (SO2). 1H NMR (DMSO-d6): 1.03 [t,