2-Aminothiophenes as modulators of NMDARs Russ. Chem. Bull., Int. Ed., Vol. 68, No. 8, August, 2019
Table 2. 1H NMR spectra of compounds 4—6, 8a—c, 9a—c, and 10a—c in CDCl3
1631
Compound
1H NMR, (J/Hz)
4
1.67—1.94 (m, 4 H, CH2); 2.58—2.89 (m, 4 H, CH2); 3.91 (s, 3 H, CH3O); 4.27 (s, 2 H, CH2Cl);
12.15 (s, 1 H, NH)
1.07 (d, 3 H, CH3CH, JH,H = 6.5); 1.27—1.50 (m, 1 H, CH3CH); 1.78—2.00 (m, 2 H, CH2); 2.16—2.36 (m, 1 H,
CH2); 2.54—2.90 (m, 2 H, CH2); 2.86—3.03 (m, 1 H, CH2); 3.90 (s, 3 H, CH3O); 4.26 (s, 2 H, CH2Cl);
2.09 (s, 1 H, NH)
10.93 (s, 9 H, CH3CH, JH,H = 6.5); 1.14—1.56 (m, 2 H, CH3CH + CH2); 1.92—2.08 (m, 1 H, CH2); 2.29—2.78
(m, 3 H, CH2); 2.93—3.11 (m, 1 H, CH2); 3.88 (s, 3 H, CH3O); 4.25 (s, 2 H, CH2Cl); 12.09 (s, 1 H, NH)
1.60—1.96 (m, 4 H, CH2); 2.52—2.82 (m, 4 H, CH2); 3.01 (s, 3 H, CH3O); 5.17 (s, 2 H, CH2N);
7.22—7.65 (m, 6 H, CArH); 8.20 (d, 2 H, CArH, JH,H = 7.6); 10.70 (s, 1 H, NH)
1.62—1.92 (m, 4 H, CH2); 2.52—2.82 (m, 4 H, CH2); 3.37 (s, 3 H, CH3O); 5.12 (s, 2 H, CH2N); 7.33 (d, 2 H,
CArH, JH,H = 8.8); 7.49 (dd, 2 H, CArH, JH,H = 8.8, 1.8); 8.07 (d, 2 H, CArH, JH,H = 1.8); 11.08 (s, 1 H, NH)
1.64—1.91 (m, 4 H, CH2); 2.56—2.75 (m, 4 H, CH2); 3.38 (s, 3 H, CH3O); 5.10 (s, 2 H, CH2N); 7.29 (d, 2 H,
CArH, JH,H = 8.7); 7.62 (dd, 2 H, CArH, JH,H = 8.7, 1.9); 8.22 (d, 2 H, CArH, JH,H = 1.9); 11.09 (s, 1 H, NH)
1.06 (d, 3 H, CH3CH, JH,H = 6.3); 1.22—1.46 (m, 1 H, CH3CH); 1.72—1.99 (m, 2 H, CH2);
2.15—2.37 (m, 1 H, CH2); 2.43—2.95 (m, 3 H, CH2); 3.01 (s, 3 H, CH3O); 5.16 (s, 2 H, CH2N);
7.26—7.64 (m, 6 H, CArH); 8.19 (d, 2 H, CArH, JH,H = 7.6); 10.69 (s, 1 H, NH)
5
6
8a
8b
8c
9a
9b
9c
1.06 (d, 3 H, CH3CH, JH,H = 6.5); 1.21—1.46 (m, 1 H, CH3CH); 1.73—1.99 (m, 2 H, CH2); 2.15—2.36 (m,
1 H, CH2); 2.43—2.94 (m, 3 H, CH2); 3.37 (s, 3 H, CH3O); 5.11 (s, 2 H, CH2N); 7.33 (d, 2 H, CArH,
JH,H = 8.8); 7.49 (dd, 2 H, CArH, JH,H = 8.8, 2.0); 8.07 (d, 2 H, CArH, JH,H = 2.0); 11.07 (s, 1 H, NH)
1.07 (d, 3 H, CH3CH, JH,H = 6.5); 1.22—1.46 (m, 1 H, CH3CH); 1.72—1.98 (m, 2 H, CH2);
2.14—2.36 (m, 1 H, CH2); 2.44—2.94 (m, 3 H, CH2); 3.38 (s, 3 H, CH3O); 5.11 (s, 2 H, CH2N);
7.29 (d, 2 H, CArH, JH,H = 8.7); 7.63 (dd, 2 H, CArH, JH,H = 8.7, 1.9); 8.23 (d, 2 H, CArH, JH,H = 1.9);
11.08 (s, 1 H, NH)
10a
10b
0.90 (s, 9 H, CH3CH, JH,H = 6.5); 1.09—1.54 (m, 2 H, CH3CH + CH2); 1.82—2.08 (m, 1 H, CH2);
2.21—2.52 (m, 2 H, CH2); 2.57—3.01 (m, 2 H, CH2); 3.10 (s, 3 H, CH3O); 5.17 (s, 2 H, CH2N);
7.17—7.63 (m, 6 H, CArH); 8.13 (d, 2 H, CArH, JH,H = 7.6); 10.74 (s, 1 H, NH)
0.90 (s, 9 H, CH3CH, JH,H = 6.5); 1.06—1.52 (m, 2 H, CH3CH + CH2); 1.85—2.06 (m, 1 H, CH2);
2.22—2.54 (m, 2 H, CH2); 2.56—2.75 (m, 1 H, CH2); 2.78—3.01 (m, 1 H, CH2); 3.33 (s, 3 H, CH3O);
5.08 (s, 2 H, CH2N); 7.29 (d, 2 H, CArH, JH,H = 8.7); 7.45 (dd, 2 H, CArH, JH,H = 8.7, 1.9);
8.04 (d, 2 H, CArH, JH,H = 1.9); 11.02 (s, 1 H, NH)
0.90 (s, 9 H, CH3CH, JH,H = 6.5); 1.08—1.50 (m, 2 H, CH3CH + CH2); 1.84—2.06 (m, 1 H, CH2);
2.21—2.53 (m, 2 H, CH2); 2.55—2.74 (m, 1 H, CH2); 2.77—3.00 (m, 1 H, CH2); 3.33 (s, 3 H, CH3O);
5.06 (s, 2 H, CH2N); 7.24 (d, 2 H, CArH, JH,H = 8.8); 7.57 (dd, 2 H, CArH, JH,H = 8.8, 2.0);
8.17 (d, 2 H, CArH, JH,H = 2.0); 11.00 (s, 1 H, NH)
10c
easily alkylate carbazoles 7а—с at the nitrogen atom to
form the target compounds 8—10 (Scheme 1). To complete
the reaction, the mixture was stirred for 3 h at 20 С. After
work-up with water and extraction with chloroform, ami-
nothiophenes 8—10 were isolated and purified by column
chromatography. The composition and structure of com-
pounds 8a—c, 9a—c, and 10a—c, which are crystalline
solids obtained in 86—93% yield, were confirmed by el-
emental analysis and NMR spectroscopy (Tables 1 and
2). Chloroacetylamidothiophenes 4,12,13 5, and 6 were
obtained in 58—86% yield by the reaction of 2-amino-
thiophenes 11—13 with chloroacetyl chloride in the pres-
ence of Et3N in solution in DMF with subsequent work-
up with water, extraction with dichloromethane, and
crystallization.
system of mammals playing a key role in the mechanisms
of neuroprotection and neurotoxicity.
Table 3 presents the results on the effect of compounds
8a—c, 9a—c, and 10a—c on the binding of labeled
MK-801 and ifenprodil to NMDA receptor binding
sites in the in vitro experiments at a concentration of
10–4 mol L–1. The results show that almost all of the test
compounds increase the binding of labeled ligands to both
the MK-801 binding site and the ifenprodil binding site,
i.e., act as positive allosteric modulators of NMDA recep-
tors, which recently are considered as potential therapeu-
tic agents for the treatment of neuropsychiatric dis-
eases.16,17 The introduction of the carbazolylacetyl frag-
ment into the aminothiophene molecules significantly
increases the binding to the sites as compared to the pre-
viously described aminothiophenes containing five-mem-
bered trifluoromethyl-containing heterocycles at the ni-
trogen atom.6 Compounds with the But-substituent in the
cyclohexyl ring and dibromocarbazole derivatives showed
the highest binding.
The biological activity of compounds 8a—c, 9a—c, and
10a—c was studied by radioligand binding,14,15 which allows
one to quantify the effect of compounds on neuronal, in
particular, NMDA receptors — one of the three main types
of ionotropic glutamate receptors of the central nervous