Allosteric Enhancers of A1 Adenosine Agonist Binding
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1875
(s, 3H, CH3), 2.39 (s, 3H, CH3), 3.45 (s, 2H, CH2), 6.98-7.30
(m, 14H, ArH), 12.12 (br s, 1H, NH). 13C NMR (CDCl3) δ 21.2,
23.6, 48.4, 122.2, 126.6, 127.0, 128.1, 128.2, 129.2, 129.4, 129.6,
130.3, 130.5, 133.3, 133.6, 133.9, 134.8, 137.7, 149.5, 168.0,
198.1.
N-[3-Ben zoyl-4-(4-ch lor op h en yl)-5-p h en ylth iop h en -2-
yl]a ceta m id e (6m ). Yield 92%. 1H NMR (CDCl3) δ 2.33 (s,
3H, CH3), 6.77 (d, 2H, J ) 8.7 Hz, 5-C6H4Cl), 6.85 (d, 2H, J )
8.7 Hz, 5-C6H4Cl), 7.02-8.15 (m, 10H, ArH), 11.20 (br s, 1H,
NH).
N-[3-(4-Ch lor ob en zoyl-4-(4-ch lor op h en yl)-5-p h en yl-
th iop h en -2-yl]a ceta m id e (6n ). Yield 37%. Compound 6n
was deprotected directly.
N-[3-(Bip h en yl-4-ca r bon yl)-4-(4-ch lor op h en yl)-5-p h en -
ylth ioph en -2-yl]acetam ide (6o). Yield 17%. 1H NMR (CDCl3)
δ 2.35 (s, 3H, CH3), 6.79-7.78 (m, 18H, ArH), 11.28 (br s, 1H,
NH). 13C NMR (CDCl3) δ 23.7, 122.2, 126.4, 127.1, 127.3, 127.5,
127.9, 128.4, 128.7, 128.9, 129.4, 129.5, 130.7, 132.2, 132.7,
133.0, 133.8, 137.3, 140.1, 144.6, 149.3, 167.9, 194.7.
133.9, 135.9, 136.2, 137.1, 164.2, 193.7. ESMS 406 (M + H+).
Anal. (C27H19NOS) C, H, N.
(2-Am in o-5-p h en yl-4-(4-m eth ylp h en yl)th iop h en -3-yl)-
p h en ylm eth a n on e (7 g). Yield 57%. mp 161-162 °C. 1H
NMR (CDCl3) δ 2.10 (s, 3H, CH3), 5.08 (br s, 2H, NH2), 6.62-
7.27 (m, 14H, ArH). 13C NMR (CDCl3) δ 21.0, 117.9, 120.3,
126.6, 127.1, 128.2, 128.5, 128.6, 129.2, 129.8, 130.4, 132.8,
134.1, 135.9, 136.1, 140.0, 164.2, 194.0. Anal. (C24H19NOS) C,
H, N.
(2-Am in o-5-p h en yl-4-(4-m eth ylp h en yl)th iop h en -3-yl)-
(3-ch lor op h en yl)m eth a n on e (7h ). Yield 57%. mp 170-171
°C. 1H NMR (CDCl3) δ 2.13 (s, 3H, CH3), 6.18 (br s, 2H, NH2),
6.68-7.26 (m, 13H, ArH). 13C NMR (CDCl3) δ 21.0, 117.5,
120.5, 126.2, 126.6, 128.2, 128.4, 128.6, 128.7, 129.2, 129.5,
130.3, 132.7, 132.9, 133.8, 135.7, 136.2, 141.7, 165.1, 192.1.
ESMS 404 (M + H+). Anal. (C24H18ClNOS) C, H, N.
(2-Am in o-5-p h en yl-4-(4-m eth ylp h en yl)th iop h en -3-yl)-
(4-ch lor op h en yl)m eth a n on e (7i). Yield 97%. mp 170-172
°C. 1H NMR (CDCl3) δ 2.17 (s, 3H, CH3), 5.36 (br s, 2H, NH2),
6.69-7.25 (m, 13H, ArH) (s, 4H). 13C NMR (CDCl3) δ 20.9,
117.6, 120.4, 126.7, 127.2, 128.2, 128.4, 129.2, 129.7, 130.6,
132.6, 133.9, 135.7, 135.9, 136.5, 138.4, 164.9, 192.5. ESMS
404 (M + H+). Anal. (C24H18ClNOS) C, H, N.
N-[3-(Na p h t h ylen e-1-ca r b on yl)-4-(4-ch lor op h en yl)-5-
1
p h en ylth iop h en -2-yl]a ceta m id e (6p ). Yield 66%. H NMR
(CDCl3) δ 2.42 (s, 3H, CH3), 6.40-7.93 (m, 16H, ArH), 12.16
(br s, 1H, NH). 13C NMR (CDCl3) δ 23.8, 124.2, 124.5, 124.7,
125.9, 126.0, 126.2, 126.6, 126.9, 127.3, 127.9, 128.2, 128.2,
128.6, 129.3, 130.4, 131.0, 131.5, 132.8, 132.9, 133.0, 134.3,
137.6, 168.3, 196.2.
Rep r esen ta tive P r oced u r e for Dep r otection . Method
A. The acetamide (0.63 mmol) was dissolved in warm EtOH
(2 mL) and stirred with 2 M NaOH (2 mL) for 5 h at 50 °C.
The initial red color faded, and a precipitate formed and was
collected by filtration. Additional product was obtained by
EtOAc extraction.
Method B. The trifluoroacetamide (0.54 mmol) was stirred
with aqueous K2CO3 in ethanol at room-temperature overnight
and then warmed to 50 °C for 2 h to complete the reaction.
(2-Am in o-4,5-d ip h e n ylt h iop h e n -3-yl)p h e n ylm e t h a -
n on e (7a ). Yield 46%. mp 155 °C. 1H NMR (CDCl3) δ 5.17 (br
s, 2H, NH2), 6.86-7.34 (m, 15H, ArH). 13C NMR (DMSO) δ
115.7, 118.7, 126.4, 126.6, 127.1, 127.5, 128.1, 128.4, 128.7,
129.9, 130.3, 133.5, 135.6, 135.9, 140.2, 165.1, 192.0. ESMS
356 (M + H+). Anal. (C23H17NOS) C, H, N.
(2-Am in o-4,5-d ip h en ylth iop h en -3-yl)(3-ch lor op h en yl)-
m eth a n on e (7b). Yield 54%. mp 143-144 °C. 1H NMR
(CDCl3) δ 6.57 (br s, 2H, NH2), 6.88-7.26 (m, 14H, ArH). 13C
NMR (CDCl3) δ 117.1, 120.8, 126.2, 126.6, 126.8, 127.7, 128.1,
128.6, 128.7, 129.2, 129.8, 130.4, 132.9, 133.6, 135.6, 137.7,
141.6, 165.5, 191.9. ESMS 390 (M + H+). Anal. (C23H16ClNOS)
C, H, N.
(2-Am in o-4,5-d ip h en ylth iop h en -3-yl)(4-ch lor op h en yl)-
m eth a n on e (7c). Yield 58%. mp 151-152 °C. 1H NMR
(CDCl3) δ 5.53 (br s, 2H, NH2), 6.82-7.26 (m, 14H, ArH). 13C
NMR (CDCl3) δ 117.4, 120.9, 126.5, 126.8, 127.3, 127.7, 128.2,
129.2, 129.5, 129.8, 130.7, 133.7, 135.7, 136.0, 138.4, 164.8,
192.4. Anal. (C23H16ClNOS) C, H, N.
(2-Am in o-5-p h en yl-4-(4-m eth ylp h en yl)th iop h en -3-yl)-
(4-p h en ylp h en yl)m eth a n on e (7j). Yield 59%. mp 188-189
1
°C. H NMR (DMSO) δ 1.93 (s, 3H, CH3), 6.63-7.24 (m, 18H,
ArH), 8.09 (br s, 2H, NH2). 13C NMR (DMSO) δ 20.6, 115.9,
118.3, 125.4, 126.5, 126.7, 127.7, 128.1, 128.3, 128.6, 128.7,
128.9, 130.3, 133.0, 134.1, 135.4, 135.6, 139.0, 139.7, 141.4,
165.3, 191.7. ESMS 446 (M + H+). Anal. (C30H23NOS) C, H,
N.
(2-Am in o-5-p h en yl-4-(4-m eth ylp h en yl)th iop h en -3-yl)-
n a p h th a len -1-ylm eth a n on e (7k ). Yield 34%. mp 225-226
1
°C. H NMR (CDCl3) δ 1.92 (s, 3H, CH3), 6.19-7.86 (m, 16H,
ArH). 13C NMR (CDCl3) δ 20.7, 118.8, 120.0, 124.2, 125.4,
125.5, 125.7, 126.1, 126.4, 127.1, 127.6, 128.0, 128.5, 128.8,
129.5, 130.1, 132.2, 132.9, 133.8, 135.3, 136.3, 138.8, 165.5,
194.4. ESMS 420 (M + H+). Anal. (C28H21NOS) C, H, N.
(2-Am in o-5-p h en yl-4-(4-m eth ylp h en yl)th iop h en -3-yl)-
2-p h en yleth a n on e (7l). Yield 77%. mp 147-149 °C. 1H NMR
(CDCl3) δ 2.37 (s, 3H, CH3), 3.31 (s, 2H, CH2), 6.19 (br s, 2H,
NH2), 6.96-7.27 (m, 14H, ArH). 13C NMR (CDCl3) δ 21.0, 46.6,
116.3, 118.7, 126.2, 126.7, 128.1, 128.5, 128.6, 129.4, 129.7,
130.4, 134.0, 134.6, 135.2, 136.3, 137.2, 165.4, 193.8. ESMS
384 (M + H+). Anal. (C25H21NOS) C, H, N.
[2-Am in o-4-(4-ch lor op h en yl)-5-p h en ylt h iop h en -3-yl]-
p h en ylm eth a n on e (7m ). Yield 72%. mp 207-208 °C. 1H
NMR (CDCl3) δ 5.68 (br s, 2H, NH2), 6.74-7.31 (m, 14H, ArH).
13C NMR (DMSO) δ 115.4, 119.1, 126.8, 127.2, 127.5, 128.1,
128.5, 128.7, 128.8, 129.8, 132.1, 133.6, 134.2, 134.9, 140.3,
165.5, 191.8. ESMS 390 (M + H+). Anal. (C23H16ClNOS) C, H,
N.
[2-Am in o-4-(4-ch lor op h en yl-5-p h en ylth iop h en -3-yl](4-
ch lor op h en yl)m eth a n on e (7n ). Yield 57%. mp 211-215 °C.
1H NMR (CDCl3) δ 7.14-7.32 (m, 13H, ArH). 13C NMR (CDCl3)
δ 118.0, 121.0, 126.9, 127.5, 127.9, 128.8, 128.9, 129.3, 129.8,
131.7, 131.9, 133.4, 133.7, 134.4, 136.2, 164.0, 195.9. ESMS
424 (M + H+). Anal. (C23H15Cl2NOS) C, H, N.
(2-Am in o-4-(4-ch lor op h en yl-5-p h en ylth iop h en -3-yl)(4-
p h en ylp h en yl)m eth a n on e (7o). Yield 88%. mp 205-207 °C.
1H NMR (CDCl3) δ 6.72 (br s, 2H, NH2), 6.77-7.46 (m, 18H,
ArH). 13C NMR (CDCl3) δ 117.5, 121.2, 126.2, 127.0, 127.3,
127.6, 127.7, 128.3, 128.6, 128.9, 129.4, 132.0, 132.4, 133.5,
134.5, 134.6, 138.7, 140.6, 143.4, 164.7, 193.2. ESMS 466 (M
+ H+). Anal. (C29H20ClNOS) C, H, N.
[2-Am in o-4-(4-ch lor op h en yl)-5-p h en ylt h iop h en -3-yl)-
(n a p h th a len -1-yl)m eth a n on e (7p ). Yield 47%. mp 175 °C.
1H NMR (CDCl3) δ 5.28 (br s, 2H, NH2), 6.33-7.81 (m, 16H,
ArH). 13C NMR (DMSO) δ 116.7, 119.2, 124.5, 125.1, 125.4,
125.8, 126.2, 126.3, 126.8, 127.9, 128.4, 128.6, 129.5, 130.7,
131.1, 132.5, 133.5, 134.1, 134.4, 139.2, 143.1, 166.8, 192.2.
Anal. (C27H18ClNOS) C, H, N.
(2-Am in o-4,5-diph en ylth ioph en -3-yl)biph en yl-4-ylm eth -
1
a n on e (7d ). Yield 56%. mp 188-189 °C. H NMR (CDCl3) δ
5.71 (br s, 2H, NH2), 6.86-7.42 (m, 19H, ArH). 13C NMR
(CDCl3) δ 117.9, 125.9, 126.3, 126.7, 127.0, 127.1, 127.6, 128.1,
128.5, 128.7, 129.0, 129.3, 130.8, 133.9, 135.9, 138.8, 140.6,
140.8, 142.7, 164.2, 195.0. ESMS 432 (M + H+). Anal. (C29H21
NOS) C, H, N.
-
(2-Am in o-4,5-d ip h en ylth iop h en -3-yl)n a p h th a len -1-yl-
m eth a n on e (7e). Yield 30% (over two steps). mp 221-222
°C. 1H NMR (CDCl3) δ 6.44-7.46 (m, 17H, ArH). 13C NMR
(CDCl3) δ 118.6, 120.5, 124.1, 125.4, 125.5, 125.9, 126.0, 126.2,
126.6, 127.8, 128.0, 128.7, 128.9, 129.2, 129.7, 130.2, 133.0,
133.7, 135.4, 136.2, 138.6, 165.7, 194.3. ESMS 406 (M + H+).
Anal. (C27H19NOS) C, H, N.
(2-Am in o-4,5-d ip h en ylth iop h en -3-yl)n a p h th a len -2-yl-
m eth a n on e (7f). Yield 30%. mp 212-214 °C. 1H NMR (CDCl3)
δ 6.09 (br s, 2H, NH2), 6.51-7.65 (m, 17H, ArH). 13C NMR
(CDCl3) δ 118.2, 120.9, 124.8, 125.7, 126.0, 126.7, 127.0, 127.1,
127.3, 127.4, 128.1, 128.7, 129.2, 129.9, 130.3, 131.5, 133.8,
Rep r esen ta tive P r oced u r e for th e Gew a ld Syn th esis
of th e Su bstitu ted 2-Am in o-5-br om o-4-p h en ylth iop h en es