Thiadiazoles as Allosteric Modulators
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 669
NMR (CDCl3): δ 31.7, 121.9, 123.3, 127.8, 128.3, 130.0, 131.5,
1-E t h yl-3-(p h en yl-4-t olylim in om et h yl)t h iou r ea (6j).
Scale: 6.1 mmol. Yield: 1.70 g (94%). 1H NMR (CDCl3): δ 1.32
(t, 3H, J ) 7.3 Hz, CH3); 2.24 (s, 3H, CH3); 3.74 (m, 2H, CH2);
6.58 (d, 2H, J ) 8.0 Hz, arom); 6.94 (d, 2H, J ) 8.0 Hz, arom);
7.29 (m, 5H, arom); 7.98 (s, 1H, NH); 11.98 (broad s, 1H, NH).
13C NMR (CDCl3): δ 13.5, 20.5, 40.2, 122.0, 127.9, 128.5, 129.1,
130.1, 132.0, 132.9, 143.7, 155.3, 179.6.
1-Meth yl-3-(p h en yl-3-tolylim in om eth yl)th iou r ea (5k ).
Scale: 6.9 mmol. Yield: 1.08 g (56%). 1H NMR (CDCl3): δ 2.21
(s, 3H, CH3); 3.25 (d, 3H, J ) 4.4 Hz, NCH3); 6.43 (d, 1H, J )
8.0 Hz, arom); 6.56 (s, 1H, arom); 6.78 (d, 1H, J ) 7.3 Hz,
arom); 7.00 (dd, 1H, J ) 7.3, 8.0 Hz, arom); 7.28 (m, 5H, arom);
8.03 (s, 1H, NH); 11.83 (broad s, 1H, NH). 13C NMR (CDCl3):
δ 21.1, 31.9, 119.1, 122.9, 124.4, 128.0, 128.4, 128.6, 130.3,
132.0, 138.4, 146.4, 155.3.
1-E t h yl-3-(p h en yl-3-t olylim in om et h yl)t h iou r ea (6k ).
Scale: 7.0 mmol. Yield: 1.52 g (73%). 1H NMR (CDCl3): δ 1.32
(t, 3H, J ) 7.3 Hz, CH3); 2.21 (s, 3H, CH3); 3.75 (m, 2H, CH2);
6.44 (d, 1H, J ) 7.3 Hz, arom); 6.56 (s, 1H, arom); 6.78 (d, 1H,
J ) 7.3 Hz, arom); 7.01 (dd, 1H, J ) 7.3, 8.0 Hz, arom); 7.32
(m, 5H, arom); 7.96 (s, 1H, NH); 11.91 (broad s, 1H, NH). 13C
NMR (CDCl3): δ 13.6, 21.1, 40.3, 119.1, 122.9, 124.3, 127.9,
128.3, 128.5, 130.2, 132.0, 138.4, 146.3, 155.3, 179.7.
1-Met h yl-3-(p h en yl-4-m et h oxyp h en ylim in om et h yl)-
th iou r ea (5l). Scale: 9.2 mmol. Yield: 2.52 g (92%) of a yellow
solid. 1H NMR (CDCl3): δ 3.27 (d, 3H, J ) 4.4 Hz, NCH3);
3.72 (s, 3H, OCH3); 6.64 (m, 4H, arom); 7.27 (m, 5H, arom);
8.05 (s, 1H, NH); 11.94 (broad s, 1H, NH). 13C NMR (CDCl3):
δ 31.7, 55.0, 113.7, 123.0, 127.9, 128.4, 130.0, 131.9, 133.0,
139.4, 155.4, 155.7, 180.8.
146.3, 155.4, 180.7.
1-E t h yl-3-(p h en yl-p h en ylim in om et h yl)t h iou r ea (6a ).
Scale: 9.2 mmol. Yield: 2.30 g (88%) of a pale yellow solid. 1H
NMR (CDCl3): δ 1.33 (t, 3H, J ) 7.3 Hz, CH3); 3.76 (m, 2H,
CH2); 6.68 (d, 2H, J ) 8.8 Hz, arom); 6.97 (m, 1H, arom); 7.24
(m, 7H, arom); 8.00 (s, 1H, NH); 11.90 (broad s, 1H, NH). 13C
NMR (CDCl3): δ 13.6, 40.3, 122.2, 123.5, 127.9, 128.5, 130.3,
131.9, 146.4, 155.5, 189.7.
1-[(4-Ch lor op h en yl)-(4-ch lor op h en ylim in o)m eth yl]-3-
m eth ylth iou r ea (5b). Scale: 6.6 mmol. Yield: 1.65 g (73%)
of a pale yellow solid. 1H NMR (CDCl3): δ 3.25 (d, 3H, J ) 4.4
Hz, NCH3); 6.59 (d, 2H, J ) 8.8 Hz, arom); 7.14 (m, 4H, arom);
7.30 (d, 2H, J ) 8.8 Hz, arom); 8.07 (s, 1H, NH); 11.60 (broad
s, 1H, NH). 13C NMR (CDCl3): δ 32.0, 123.5, 128.8, 129.1,
129.4, 129.8, 136.7, 144.9, 154.9, 180.8.
1-[(4-Ch lor op h en yl)-(4-ch lor op h en ylim in o)m eth yl]-3-
eth ylth iou r ea (6b). Scale: 6.9 mmol. Yield: 1.35 g (57%) of
a yellow solid. 1H NMR (CDCl3): δ 1.32 (t, 3H, J ) 7.3 Hz,
CH3); 3.75 (m, 2H, CH2); 6.59 (d, 2H, J ) 8.8 Hz, arom); 7.14
(m, 3H, arom); 7.28 (m, 3H, arom); 7.95 (s, 1H, NH); 11.60
(broad s, 1H, NH). 13C NMR (CDCl3): δ 13.6, 40.4, 123.5, 128.9,
129.1, 129.4, 136.7, 144.8, 154.9, 179.5.
1-Meth yl-3-(4-tolyl-4-tolylim in om eth yl)th iou r ea (5e).
Scale: 13.1 mmol. Yield: 2.20 g (57%) of a yellow solid. 1H
NMR (CDCl3): δ 2.24 (s, 3H, CH3); 2.31 (s, 3H, CH3); 3.24 (d,
3H, J ) 4.7 Hz, NCH3); 6.57 (d, 2H, J ) 8.0 Hz, arom); 6.95
(d, 2H, J ) 8.0 Hz, arom); 7.05 (m, 4H, arom); 8.00 (s, 1H,
NH); 11.93 (broad s, 1H, NH). 13C NMR (CDCl3): δ 20.5, 21.1,
31.7, 121.8, 127.8, 129.0, 132.7, 140.3, 143.8, 155.3, 180.9.
1-E t h yl-3-(4-t olyl-4-t olylim in om et h yl)t h iou r ea (6e).
Scale: 13.0 mmol. Yield: 2.44 g (60%) of a brown solid. 1H
NMR (CDCl3): δ 1.31 (t, 3H, J ) 7.3 Hz, CH3); 2.24 (s, 3H,
CH3); 2.31 (s, 3H, CH3); 3.74 (m, 2H, CH2); 6.57 (d, 2H, J )
8.0 Hz, arom); 6.95 (d, 2H, J ) 8.0 Hz, arom); 7.09 (m, 4H,
arom); 7.94 (s, 1H, NH); 12.00 (broad s, 1H, NH). 13C NMR
(CDCl3): δ 13.5, 20.5, 21.1, 40.2, 121.9, 127.8, 129.1, 132.8,
140.4, 143.8, 155.3, 179.7.
1-[(4-Ch lor op h e n ylim in o)p h e n ylm e t h yl]-3-m e t h yl-
th iou r ea (5g). Scale 6.1 mmol. Yield: 1.23 g (68%) of a white
solid. 1H NMR (CDCl3): δ 3.26 (d, 3H, J ) 4.4 Hz, NCH3);
6.62 (d, 2H, J ) 8.8 Hz, arom); 7.10 (d, 2H, J ) 8.8 Hz, arom);
7.31 (m, 5H, arom); 8.06 (s, 1H, NH); 11.67 (broad s, 1H, NH).
13C NMR (CDCl3): δ 32.0, 123.6, 128.0, 128.7, 130.0, 131.6,
145.5, 156.0, 181.0.
1-Eth yl-3-(p h en yl-4-m eth oxyp h en ylim in om eth yl)th io-
u r ea (6l). Scale: 4.68 mmol. Yield: 1.32 g (90%) of a yellow
1
solid. H NMR (CDCl3): δ 1.33 (t, 3H, J ) 7.3 Hz, CH3); 3.72
(s, 3H, OCH3); 3.78 (m, 2H, CH2); 6.67 (m, 4H, arom); 7.32 (m,
5H, arom); 7.94 (s, 1H, NH); 11.99 (broad s, 1H, NH). 13C NMR
(CDCl3): δ 13.6, 40.2, 55.1, 113.8, 123.2, 127.9, 128.6, 130.1,
132.1, 139.4, 155.3, 155.9, 179.7.
1-[(4-Ch lor op h e n yl)p h e n ylim in om e t h yl]-3-m e t h yl-
th iou r ea (5m ). Scale: 6.4 mmol. Yield: 1.60 g (88%). 1H NMR
(CDCl3): δ 3.24 (d, 3H, J ) 5.1 Hz, NCH3); 6.67 (d, 2H, J )
7.3 Hz, arom); 6.99 (dd, 1H, J ) J ) 7.3 Hz, arom); 7.20 (m,
6H, arom); 8.08 (s, 1H, NH); 11.75 (broad s, 1H, NH). 13C NMR
(CDCl3): δ 31.9, 122.1, 123.7, 128.7, 128.8, 129.5, 130.0, 131.0,
136.4, 146.2, 154.5, 180.9.
Gen er a l P r oced u r e for th e P r ep a r a tion of [1,2,4]-
Th ia d ia zoles.12b The thiourea was dissolved in a minimal
amount of CH2Cl2 (usually 2-4 mL/mmol) and then diluted
with double the volume of ethyl acetate. At room temperature,
a 0.5 M solution of bromine in ethyl acetate (2 equiv) was
added dropwise. The thiadiazole hydrobromide precipitated.
The mixture was left to stand at 5 °C overnight. Filtering,
washing (2×) of the residue with pentane/ethyl acetate (3:1),
and drying in vacuo afforded the almost pure [1,2,4]thiadia-
zole. The products can be recrystallized from methanol.
2,3-Diph en yl-5-N-m eth ylim in o-2H-[1,2,4]th iadiazole Hy-
d r obr om id e (7a ). Scale: 16.3 mmol. Yield: 4.50 g (79%),
product was recrystallized from methanol giving a white
solid: mp 248-250 °C. 1H NMR (MeOD-d3): δ 3.37 (s, 3H,
NCH3); 7.49 (m, 10H, arom). 13C NMR (DMSO-d6): δ 31.5,
126.6, 127.6, 128.6, 130.1, 130.6, 132.4, 134.5, 164.6, 175.6.
Anal. (C15H13N3S‚HBr) C, H, N.
1-[(4-Ch lor op h en ylim in o)p h en ylm et h yl]-3-et h ylt h io-
u r ea (6g). Scale: 6.0 mmol. Yield: 1.75 g (92%) of a white
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solid. H NMR (CDCl3): δ 1.33 (t, 3H, J ) 7.3 Hz, CH3); 3.76
(m, 2H, CH2); 6.60 (d, 2H, J ) 8.8 Hz, arom); 7.10 (d, 2H, J )
8.0 Hz, arom); 7.31 (m, 5H, arom); 7.99 (s, 1H, NH); 11.72
(broad s, 1H, NH). 13C NMR (CDCl3): δ 13.6, 40.4, 123.6, 127.9,
128.8, 130.6, 131.7, 145.1, 156.0, 179.7.
1-[(3-Ch lor op h e n ylim in o)p h e n ylm e t h yl]-3-m e t h yl-
th iou r ea (5h ). Scale: 4.2 mmol. Yield: 1.25 g (97%). 1H NMR
(CDCl3): δ 3.26 (d, 3H, J ) 4.4 Hz, NCH3); 6.50 (d, 1H, J )
7.3 Hz, arom); 6.76 (s, 1H, arom); 7.00 (m, 2H, arom); 7.29 (m,
5H, arom); 8.08 (s, 1H, NH); 11.63 (broad s, 1H, NH). 13C NMR
(CDCl3): δ 31.9, 120.4, 122.4, 123.5, 127.8, 128.6, 129.5, 130.5,
131.3, 134.0, 147.8, 156.0, 180.8.
1-[(3,4-Dich lor op h en ylim in o)p h en ylm et h yl]-3-et h yl-
th iou r ea (6i). Scale: 5.3 mmol. Yield: 0.80 g (45%) of a yellow
2,3-Dip h en yl-5-N-eth ylim in o-2H-[1,2,4]th ia d ia zole Hy-
d r obr om id e (8a ). Scale: 8.1 mmol. Yield: 2.41 g (82%),
product was recrystallized from methanol giving a white
1
solid. H NMR (CDCl3): δ 1.33 (t, 3H, J ) 7.3 Hz, CH3); 3.77
(m, 2H, CH2); 6.46 (d, 1H, J ) 8.8 Hz, arom); 6.86 (s, 1H, arom);
7.30 (m, 6H, arom); 8.03 (s, 1H, NH); 11.56 (broad s, 1H, NH).
13C NMR (CDCl3): δ 13.5, 40.3, 113.0, 121.7, 124.1, 126.9,
127.8, 128.8, 130.0, 131.1, 132.1, 146.1, 156.5, 179.4.
1
solid: mp 240-242 °C. H NMR (MeOD-d3): δ 1.40 (t, 3H, J
) 7.3 Hz, CH3); 3.85 (q, 2H, J ) 7.3 Hz, NCH2); 7.48 (m, 10H,
arom). 13C NMR (DMSO-d6): δ 14.1, 40.0, 126.7, 127.7, 128.7,
130.3, 130.7, 132.6, 134.6, 164.9, 175.0. Anal. (C16H15N3S‚
0.8HBr‚1.3H2O) C, H, N.
1-Meth yl-3-(p h en yl-4-tolylim in om eth yl)th iou r ea (5j).
Scale: 6.1 mmol. Yield: 1.72 g (99%). 1H NMR (CDCl3): δ 2.23
(s, 3H, CH3); 3.26 (d, 3H, J ) 5.1 Hz, NCH3); 6.57 (d, 2H, J )
8.0 Hz, arom); 6.94 (d, 2H, J ) 8.0 Hz, arom); 7.29 (m, 5H,
arom); 8.03 (s, 1H, NH); 11.91 (broad s, 1H, NH). 13C NMR
(CDCl3): δ 20.6, 31.9, 122.0, 127.9, 128.6, 129.2, 130.2, 132.0,
133.0, 143.8, 155.3, 181.0.
2,3-Bis(4-ch lor op h en yl)-5-N-m eth ylim in o-2H-[1,2,4]th i-
a d ia zole Hyd r obr om id e (7b). Scale: 4.85 mmol. Yield: 1.76
g (89%), product was recrystallized from methanol giving a
1
yellow solid: mp 238-239 °C. H NMR (MeOD-d3): δ 3.37 (s,
3H, NCH3); 7.53 (m, 8H, arom). 13C NMR (DMSO-d6): δ 31.6,