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D.A. Ibrahim, N.S.M. Ismail / European Journal of Medicinal Chemistry 46 (2011) 5825e5832
d6):
d
3.2e3.3 (t, 2H, CH2), 3.4e3.5 (t, 2H, CH2), 3.9 (s, 1H, OH), 5.9 (s,
7.1.6.1. 2-amino-6-(methylthio)pyridine-3,5-dicarbonitrile 6a. Yield
95%, mp 125e128 ꢀC. IR: max/cmꢁ1 3230, 3180, 2220, 2202, 1246,
1H, NH), 7.6 (s, 2H, NH2), 7.9 (s,1H, H4), 8.2 (s,1H, H7). MS (EIþ): m/z:
230. Anal. Calcd for C10H10N6O: C, 52.17; H, 4.38; N, 36.50; Found: C,
52.4; H, 4.2; N, 35.9.
1217, 1175, 1103. 1H NMR (400 MHz, DMSO-d6):
d
2.4 (s, 3H, SCH3),
7.9 (s, 2H, NH2), 8.1 (s, 1H, H4). 13C NMR (400 MHz, DMSO-d6):
d
15.1, 98.1, 107.9, 117.8, 119.2, 148.6, 166.1, 168.2. MS (EIþ): m/z: 190.
7.1.4.2. 4-amino-7-((2-hydroxyethyl)amino)-5-methylpyrido[2,3-d]
pyrimidine-6-carbonitrile 4b. Yield 70%, mp 180e183 ꢀC. IR: max/
cmꢁ1 3450, 3236, 3140, 2222, 1240, 1215, 1180, 1109. 1H NMR
Anal. Calcd for C8H6N4S: C, 50.51; H, 3.18; N, 29.45; Found: C, 50.3;
H, 3.1; N, 29.3.
(400 MHz, DMSO-d6):
3.5e3.6 (t, 2H, CH2), 4.9 (s, 1H, OH), 5.8 (s, 1H, NH), 7.5 (s, 2H, NH2),
8.1 (s,1H, H7). 13C NMR (400 MHz, DMSO-d6):
18.6, 45.5, 61.1, 86.9,
106.7, 116.7, 150.2, 151.3, 157.6, 159.4, 165.3. MS (EIþ): m/z: 244.
Anal. Calcd for C11H12N6O: C, 54.09; H, 4.95; N, 34.41; Found: C,
53.9; H, 4.5; N, 34.9.
d
2.6 (s, 3H, CH3), 3.1e3.2 (t, 2H, CH2),
7.1.6.2. 2-amino-4-methyl-6-(methylthio)pyridꢁin1e-3,5-dicarbonitrile
6b. Yield 95%, mp 125e128 ꢀC. IR: max/cm 3250, 3140, 2218,
d
2214, 1226, 1227, 1155, 1113. 1H NMR (400 MHz, DMSO-d6):
d
2.2 (s,
3H, CH3), 2.6 (s, 3H, SCH3), 7.6 (s, 2H, NH2). 13C NMR (400 MHz,
DMSO-d6): 14.1, 20.1, 86.1,102.9,114.8,118.2,150.6,161.1,170.2. MS
d
(EIþ): m/z: 204. Anal. Calcd for C9H8N4S: C, 52.92; H, 3.95; N, 27.43;
Found: C, 52.3; H, 3.7; N, 27.3.
7.1.4.3. 4-((4-amino-6-cyanopyrido[2,3-d]pyrimidin-7-yl)amino)
benzenesulfonamide 4c. Yield 61%, mp 210e213 ꢀC. IR: max/cmꢁ1
3340, 3256, 3140, 2220, 1250, 1219, 1165, 1106. 1H NMR (400 MHz,
7.1.7. 2-amino-6-((2-hydroxyethyl)amino)pyridine-3,5-dicarbonitrile
derivatives 7a,b
DMSO-d6):
NH2), 8.0 (s, 1H, H4), 8.3 (s, 1H, H7), 11.6 (s, 1H, NH). 13C NMR
(400 MHz, DMSO-d6): 106.5, 110.4, 115.3, 117.9, 135.1, 136.6, 147.1,
151.2, 153.3, 156.4, 158.6, 161.5. MS (EIþ): m/z: 341. Anal. Calcd for
C14H11N7O2S: C, 49.26; H, 3.25; N, 28.72; Found: C, 48.9; H, 3.2; N,
28.5.
d
4.9 (s, 2H, NH2), 7.2e7.5 (m, 4H, AreH), 7.9 (s, 2H,
Was prepared from 6a,b with the same manner as compound 4.
d
7.1.7.1. 2-amino-6-((2-hydroxyethyl)amino)pyridine-3,5-
dicarbonitrile 7a. Yield 55%, mp 145e148 ꢀC. IR: max/cmꢁ1 3450,
3350, 3210, 3150, 2219, 2215, 1236, 1227, 1165, 1113. 1H NMR
(400 MHz, DMSO-d6):
3.6 (s, 1H, OH), 7.5 (s, 2H, NH2), 8.0 (s, 1H, H4), 11.6 (s, 1H, NH). 13
NMR (400 MHz, DMSO-d6): 40.5, 60.6, 100.1, 115.9, 148.6, 162.1,
d 3.1e3.2 (t, 2H, CH2), 3.3e3.4 (t, 2H, CH2),
C
7.1.4.4. 4-((4-amino-6-cyano-5-methylpyrido[2,3-d]pyrimidin-7-yl)
amino)benzenesulfonamide 4d. Yield 63%, mp 220e223 ꢀC. IR: max/
cmꢁ1 3420, 3280, 3190, 2222, 1260, 1229, 1155, 1105. 1H NMR
d
165.2. MS (EIþ): m/z: 203. Anal. Calcd for C9H9N5O: C, 53.20; H,
4.46; N, 34.47; Found: C, 53.3; H, 4.2; N, 34.3.
(400 MHz, DMSO-d6): d 2.2 (s, 3H, CH3), 4.5 (s, 2H, NH2), 7.1e7.4 (m,
4H, AreH), 7.7 (s, 2H, NH2), 7.9 (s, 1H, H4), 8.1 (s, 1H, H7), 12.1 (s, 1H,
NH). MS (EIþ): m/z: 355. Anal. Calcd for C15H13N7O2S: C, 50.70; H,
3.69; N, 27.59; Found: C, 50.9; H, 3.4; N, 27.5.
7.1.7.2. 2-amino-6-((2-hydroxyethyl)amino)-4-methylpyridiꢁn1e-3,5-
dicarbonitrile 7b. Yield 62%, mp 151e153 ꢀC. IR: max/cm 3430,
3310, 3190, 3110, 2220, 2216, 1256, 1217, 1175, 1106. 1H NMR
(400 MHz, DMSO-d6):
3.5e3.6 (t, 2H, CH2), 3.7 (s, 1H, OH), 7.9 (s, 2H, NH2), 12.2 (s, 1H, NH).
13C NMR (400 MHz, DMSO-d6):
19.1, 43.5, 63.6, 80.1, 114.9, 155.6,
d 2.1 (s, 3H, CH3), 3.3e3.4 (t, 2H, CH2),
7.1.5. 1,7-diaminothieno[30,40:4,5]pyrido[2,3-d]pyrimidin-6-yl)
amino derivatives 5a,b
d
A
mixture of 4-amino-5-methylpyrido[2,3-d]pyrimidine-6-
167.1, 170.2. MS (EIþ): m/z: 217. Anal. Calcd for C10H11N5O: C, 55.29;
carbonitrile derivatives 4b,d (0.01 mol) and sulfur (0.35 g,
0.01 mol) in 20 mL DMF in the presence of morpholine (3e4 drops)
as catalyst was heated under reflux for 3 h. The reaction mixture
was cooled to room temperature and diluted with cold water. The
separated solid was filtered, washed with cold ethanol and dried.
The crude product was recrystallized from DMF-ethanol to give
pure 5.
H, 5.10; N, 32.24; Found: C, 55.3; H, 5.2; N, 32.3.
7.1.8. 4-amino-7-((2-hydroxyethyl)amino)-2-mercaptopyrido[2,3-
d]pyrimidine-6-carbonitrile derivatives 8a,b
A mixture of Compound 7a,b (30 mmol) and thiourea (90 mmol,
7 g) was heated at 180 ꢀC for 30 min until the clear solution became
mushy. Heating was then continued at 200 ꢀC for an additional
10 min. The cooled melt was dissolved in hot dilute sodium
hydroxide. The hot solution was treated with charcoal and filtered
and the boiling filtrate was carefully acidified with glacial acetic
acid. The product was filtered from hot solution to yield light tan
material.
7.1.5.1. 2-((1,7-diaminothieno[30,40:4,5]pyrido[2,3-d]pyrimidin-6-yl)
amino)ethanol 5a. Yield 80%, mp 210e213 ꢀC. IR: max/cmꢁ1 3350,
3236, 3140, 2218, 1240, 1215, 1180, 1109. 1H NMR (400 MHz, DMSO-
d6):
1H, CH), 7.1 (s, 2H, NH2), 7.6 (s, 1H, NH2), 8.3 (s, 1H, H7), 11.2 (s, 1H,
NH). 13C NMR (400 MHz, DMSO-d6):
44.5, 60.8, 86.9, 109.7, 121.7,
d 3.2e3.3 (t, 2H, CH2), 3.4e3.5 (t, 2H, CH2), 3.7 (s,1H, OH), 6.6 (s,
d
7.1.8.1. 4-amino-7-((2-hydroxyethyl)amino)-2-mercaptopyrido[2,3-
d]pyrimidine-6-carbonitrile 8a. Yield 75%, mp 245e248 ꢀC. IR: max/
cmꢁ1 3450, 3320, 3220, 3120, 2229, 1256, 1237, 1175, 1105. 1H NMR
129.2, 140.3, 150.6, 155.9, 158.4, 160.3. MS (EIþ): m/z: 276. Anal.
Calcd for C11H12N6OS: C, 47.81; H, 4.38; N, 30.41; Found: C, 47.9; H,
4.5; N, 30.3.
(400 MHz, DMSO-d6):
3.5 (s, 1H, OH), 7.8 (s, 2H, NH2), 8.1 (s, 1H, H4), 11.3 (s, 1H, NH), 11.9
(s, 1H, SH). 13C NMR (400 MHz, DMSO-d6):
44.5, 63.6, 102.1, 111.9,
d 3.0e3.1 (t, 2H, CH2), 3.3e3.4 (t, 2H, CH2),
7.1.5.2. 4-((1,7-diaminothieno[30,40:4,5]pyrido[2,3-d]pyrimidin-6-yl)
amino)benzenesulfonamide 5b. Yield 84%, mp 230e233 ꢀC. IR: max/
cmꢁ1 3250, 3236, 3140, 2220, 1250, 1220, 1140, 1104. 1H NMR
d
118.6, 140.6, 155.4, 160.1, 163.2, 175.4. MS (EIþ): m/z: 262. Anal.
Calcd for C10H10N6OS: C, 45.79; H, 3.84; N, 32.04; Found: C, 45.3; H,
3.5; N, 32.3.
(400 MHz, DMSO-d6):
d 5.3 (s, 2H, NH2), 6.5 (s, 1H, CH), 6.9 (s, 2H,
NH2), 7.1e7.3 (m, 4H, AreH), 7.8 (s, 1H, NH2), 8.3 (s, 1H, H7), 12.2 (s,
1H, NH). MS (EIþ): m/z: 387. Anal. Calcd for C15H13N7O2S2: C, 46.50;
H, 3.38; N, 25.31; Found: C, 46.9; H, 3.5; N, 25.3.
7.1.8.2. 4-amino-7-((2-hydroxyethyl)amino)-2-mercapto-5-
methylpyrido[2,3-d]pyrimidine-6-carbonitrile 8b. Yield 72%, mp
265e268 ꢀC. IR: max/cmꢁ1 3410, 3300, 3240, 3160, 2220, 1236,
7.1.6. 2-amino-6-(methylthio)pyridine-3,5-dicarbonitrile derivatives
6a,b
1227, 1155, 1115. 1H NMR (400 MHz, DMSO-d6):
d 2.1 (s, 3H, CH3),
3.1e3.2 (t, 2H, CH2), 3.3e3.4 (t, 2H, CH2), 3.6 (s, 1H, OH), 7.7 (s, 2H,
NH2), 11.6 (s, 1H, NH), 12.2 (s, 1H, SH). MS (EIþ): m/z: 276. Anal.
Was prepared from 1a,b with the same manner as compound 3.