Fluorinated derivatives of ꢀcarbolines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
201
150—160 C for 12 h. The solvent was removed in vacuo
(3 Torr). The product was extracted from the residue with CH2Cl2.
The extract was concentrated and the residue was chromatoꢀ
graphed on silica gel (60 mesh) with MeOH—CHCl3 (1 : 5) as
an eluent. Yield 0.28 g (68%), m.p. 61—63 C. Found (%):
C, 66.77; H, 5.44; N, 13.41. C23H23F3N4. Calculated (%):
C, 66.98; H, 5.62; N, 13.58. 1H NMR (CDCl3), : 2.44 (s, 3 H,
Me); 2.58 (s and t, 5 H, MeN and CH2); 2.71 (t, 2 H, CH2,
J = 7.6 Hz); 3.02 (t, 2 H, CH2ex, J = 7.6 Hz); 3.63 (s, 2 H, CH2);
Me); 2.52 (s and t, 5 H, MeN and CH2, J = 7.6 Hz); 2.75 (t, 2 H,
CH2, J = 7.6 Hz); 3.11 (t, 2 H, CH2ex, J = 7.7 Hz); 3.55
(s, 2 H, CH2); 4.26 (t, 2 H, CH2ex, J = 7.7 Hz); 6.85 (d, 1 H,
7ꢀHind, J = 8.2 Hz); 6.92 (d, 1 H, 6ꢀHind, J = 8.2 Hz); 7.09 (s, 1 H,
9ꢀHind); 7.15 (dd, 1 H, 7ꢀHim, JH,H = 9.4 Hz, JH,H = 1.6 Hz);
7.25 (d, 1 H, 8ꢀHim, J = 9.4 Hz); 7.47 (s, 1 H, 3ꢀHim); 7.69
(s, 1 H, 5ꢀHim); 10.81 (s, 1 H, NH+). 19F NMR (DMSOꢀd6),
: 16.71 (s).
2ꢀEthylꢀ8ꢀmethylꢀ5ꢀ[2ꢀ(2ꢀtrifluoromethylimidazo[1,2ꢀa]ꢀ
pyridinꢀ6ꢀyl)ethyl]ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[4,3ꢀb]indole
hydrochloride (9b) was obtained as described for comꢀ
pound 9a from indole 2b (0.125 g, 1 mmol). Yield 0.24 g (56%),
m.p. 185—187 C. Found (%): C, 62.45; H, 5.78; N, 12.33.
C24H26ClF3N4. Calculated (%): C, 62.27; H, 5.66; N, 12.10.
1H NMR (DMSOꢀd6), : 1.40 (t, 3 H, CH3CH2), J = 7.3 Hz);
2.41 (s, 3 H, Me); 3.08—3.22 (m, 4 H, CH2); 3.27 (m, 2 H,
CH2); 3.42 (m, 1 H, CH2ex); 3.76 (m, 1 H, CH2ex); 4.22 (m, 2 H,
CH2ex); 4.32 (m, 1 H, =CCH2NEt); 4.55 (m, 1 H, =CCH2NEt);
6.75 (d, 1 H, 7ꢀHind, J = 8.1 Hz); 6.90 (d, 1 H, 6ꢀHind, J = 8.2 Hz);
7.10 (br.s, 1 H, 9ꢀHind); 7.15 (dd, 1 H, 7ꢀHim, JH,H = 9.3 Hz,
JH,H = 1.6 Hz); 7.27 (d, 1 H, 8ꢀHim, J = 9.3 Hz); 7.55 (s, 1 H,
3ꢀHim); 7.72 (s, 1 H, 5ꢀHim); 10.88 (s, 1 H, NH+). 19F NMR
(DMSOꢀd6), : 14.92 (s).
4.21 (t, 2 H, CH2ex, J = 7.6 Hz); 6.88 (dd, 1 H, 7ꢀHind, JH,H
= 8.2 Hz, JH,H = 1.1 Hz); 6.98 (dd, 1 H, 7ꢀHim, JH,H
=
=
= 9.4 Hz, JH,H = 1.6 Hz); 7.01 (d, 1 H, 6ꢀHind, J = 8.2 Hz); 7.14
(br.s, 1 H, 9ꢀHind); 7.26 (d, 1 H, 8ꢀHim, J = 9.4 Hz); 7.47
(br.s, 1 H, 3ꢀHim); 7.66 (br.s, 1 H, 5ꢀHim).* 19F NMR (CDCl3),
: 14.89 (s).
2ꢀEthylꢀ8ꢀmethylꢀ5ꢀ[2ꢀ(2ꢀtrifluoromethylimidazo[1,2ꢀa]ꢀ
pyridinꢀ6ꢀyl)ethyl]ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[4,3ꢀb]indole
(2b) was obtained as described for compound 2a from ꢀcarboꢀ
line 8b (0.214 g, 1 mmol) and 2ꢀtrifluoromethylꢀ6ꢀvinylimidꢀ
azo[1,2ꢀa]pyridine (7) (0.21 g, 1 mmol). Yield 0.24 g (56%), m.p.
56—58 C. Found (%): C, 67.75; H, 5.72; N, 13.35. C24H25F3N4.
Calculated (%): C, 67.59; H, 5.91; N, 13.14. 1H NMR (CDCl3),
: 1.18 (t, 3 H, CH3CH2, J = 7.2 Hz); 2.42 (s, 3 H, Me);
2.46—2.56 (m, 2 H, CH2); 2.63 (q, 3 H, MeCH2, J = 7.2 Hz);
2.65—2.75 (m, 2 H, CH2); 2.98 (t, 2 H, CH2ex, J = 6.6 Hz); 3.68
(s, 2 H, CH2); 4.21 (t, 2 H, CH2ex, J = 7.5 Hz); 6.85 (dd, 1 H,
2ꢀFluoroꢀ8ꢀmethylꢀ5ꢀ[2ꢀ(2ꢀtrifluoromethylimidazo[1,2ꢀa]ꢀ
pyridinꢀ6ꢀyl)ethyl]ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[4,3ꢀb]indole
hydrochloride (9c) was obtained as described for comꢀ
pound 9a from indole 2c (0.12 g, 0.3 mmol). Yield 0.24 g (58%),
m.p. 183—195 C. Found (%): C, 58.11; H, 4.46; N, 12.14.
C22H21ClF4N4. Calculated (%): C, 58.35; H, 4.67; N, 12.37.
7ꢀHind, JH,H = 8.2 Hz, JH,H =1.0 Hz); 6.96 (dd, 1 H, 7ꢀHim
,
JH,H = 9.3 Hz, JH,H =1.6 Hz); 7.04 (d, 1 H, 6ꢀHind, JH,H = 8.2 Hz);
7.21 (br.s, 1 H, 9ꢀHind); 7.39 (br.s, 1 H, 3ꢀHim); 7.56 (d, 1 H,
8ꢀHim, J = 9.3 Hz); 7.61 (br.s, 1 H, 5ꢀHim). 19F NMR (CDCl3),
: 14.92 (s).
1H NMR (DMSOꢀd6), : 2.51 (s and t, 5 H, Me and CH2,
ex
J = 7.4 Hz); 2.68 (t, 2 H, CH2, J = 7.4 Hz); 3.11 (t, 2 H, CH2
,
8ꢀFluoroꢀ2ꢀmethylꢀ5ꢀ[2ꢀ(2ꢀtrifluoromethylimidazo[1,2ꢀa]ꢀ
pyridinꢀ6ꢀyl)ethyl]ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[4,3ꢀb]indole
(2c) was obtained as described for compound 2a from ꢀcarboꢀ
line 8c (0.205 g, 1 mmol) and 2ꢀtrifluoromethylꢀ6ꢀvinylimidꢀ
azo[1,2ꢀa]pyridine (7) (0.21 g, 1 mmol). Yield 0.24 g (58%),
m.p. 71—73 C. Found (%): C, 63.65; H, 5.06; N, 13.24.
C22H20F4N4. Calculated (%): C, 63.46; H, 4.84; N, 13.45.
1H NMR (CDCl3), : 2.53 (s and t, 5 H, Me and CH2); 2.71
(t, 2 H, CH2, J = 7.4 Hz); 3.02 (t, 2 H, CH2ex, J = 7.5 Hz); 3.63
(s, 2 H, CH2); 4.21 (t, 2 H, CH2ex, J = 7.5 Hz); 6.85 (ddd, 1 H,
7ꢀHind, JH,H = JH,F = 9.4 Hz, JH,H = 2.6 Hz); 6.99 (dd, 1 H,
J = 7.6 Hz); 3.61 (s, 2 H, CH2); 4.29 (t, 2 H, CH2ex, J = 7.6 Hz);
6.80 (br.dd, 1 H, 7ꢀHind, JH,H = 8.2 Hz, JH,F = 9.4 Hz); 7.03
(br.d, 1 H, 9ꢀHind, JH,F = 4.9 Hz); 7.10 (d, 1 H, 6ꢀHind
,
JH,H = 8.2 Hz, JH,F = 4.9 Hz); 7.18 (dd, 1 H, 7ꢀHim, J1 = 9.4 Hz,
J2 = 1.6 Hz); 7.28 (d, 1 H, 8ꢀHim, J = 9.4 Hz); 7.51 (s, 1 H,
3ꢀHim); 7.72 (br.s, 1 H, 5ꢀHim); 10.93 (s, 1 H, HCl). 19F NMR
(DMSOꢀd6), : –47.55 (td, 1 F, JF,H = 9.2 Hz, JF,H = 4.9 Hz);
16.95 (s).
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 11ꢀ03ꢀ00480ꢀa,
11ꢀ03ꢀ00496ꢀa, 11ꢀ03ꢀ12076ꢀofiꢀmꢀ2011, and 12ꢀ03ꢀ
00828ꢀa).
9ꢀHind, JH,F = 9.4 Hz, JH,H = 2.6 Hz); 7.09 (d, 1 H, 6ꢀHind, JH,H
=
= 9.4 Hz, JH,F = 4.3 Hz); 7.14 (dd, 1 H, 7ꢀHim, J1 = 9.4 Hz,
J2 = 1.6 Hz); 7.26 (d, 1 H, 8ꢀHim, J = 9.4 Hz); 7.47 (s, 1 H,
3ꢀHim); 7.66 (br.s, 1 H, 5ꢀHim). 19F NMR (CDCl3), : –47.13
(td, 1 F, JF,H = 9.4 Hz, JF,H = 4.3 Hz); 14.95 (s).
References
2,8ꢀDimethylꢀ5ꢀ[2ꢀ(2ꢀtrifluoromethylimidazo[1,2ꢀa]pyridinꢀ
6ꢀyl)ethyl]ꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrido[4,3ꢀb]indole hydroꢀ
chloride (9a). Concentrated HCl (0.1 mL) was added to a susꢀ
pension of indole 2a (0.12 g, 0.3 mmol) in water (5 mL). The
resulting mixture was heated to complete homogenization and
concentrated in vacuo. The residue was recrystallized from 50%
EtOH. Yield 0.12 g (89%), m.p. 178—179 C. Found (%):
C, 61.35; H, 5.18; N, 12.31. C23H24ClF3N4. Calculated (%):
C, 61.54; H, 5.39; N, 12.48. 1H NMR (DMSOꢀd6), : 2.42 (s, 3 H,
1. V. B. Sokolov, A. Yu. Aksinenko, Russ. Chem. Bull. (Int. Ed.),
2012, 61, 11 [Izv. Akad. Nauk, Ser. Khim., 2012, 2108].
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ka preparatov dlya lecheniya i preduprezhdeniya neiroꢀ
degenerativnykh zabolevanii na primere bolezni Al´tsgeimera
[Medicinal Chemistry Aimed at Targeted Searching for
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tive Diseases with Alzheimer´s Disease as an Example], in
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* Hereafter, Hind and Him denote the protons of the tetrahydroꢀ
1Hꢀpyrido[4,3ꢀb]indole and imidazo[1,2ꢀa]pyridine moieties,
respectively, in compounds 2a—c and 9a—c; CH2ex denotes the
protons of the ethylene linker.
3. V. V. Grigoriev, A. N. Proshin, A. S. Kinzirskii, S. O.
Bachurin, Usp. Khim., 2009, 78, 524 [Russ. Chem. Rev.
(Engl. Transl.), 2009, 78].