Russian Chemical Bulletin, International Edition, Vol. 62, No. 1, pp. 199—202, January, 2013 199

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0200—0202, January, 2013.

1066�5285/13/6201�199 © 2013 Springer Science+Business Media, Inc.

Modification of biologically active amides and amineswith fluorine�containing heterocycles

8.* �Carbolines modified with the2�(2�trifluoromethylimidazo[1,2�a]pyridin�6�yl)ethyl fragment

V. B. Sokolov, A. Yu. Aksinenko, V. V. Grigoriev, and S. O. Bachurin

Institute of Physiologically Active Compounds, Russian Academy of Sciences,1 Severnyi pr., 142432 Chernogolovka, Moscow Region, Russian Federation.

Fax: +7 (496) 524 9508. E�mail: alaks@ipac.ac.ru

An approach to modification of biologically active �carbolines with the 2�(2�trifluoro�methylimidazo[1,2�a]pyridin�6�yl)ethyl fragment was proposed. The modification involvesa reaction of 2�trifluoromethyl�6�vinylimidazo[1,2�a]pyridine with �carbolines. The effect ofthe compounds obtained on neuronal NMDA receptors was studied by the radioligand bindingmethod.

Key words: �carbolines, 2�trifluoromethyl�6�vinylimidazo[1,2�a]pyridine, cyclocon�densation, the Michael reaction, radioligand binding.

Development of efficient drugs for treating and espe�cially preventing neurodegenerative disorders such asAlzheimer´s and Parkinson´s diseases and amyotrophiclateral sclerosis is a challenge to modern medicinal chem�ists and pharmacologists. Many research teams concen�trate their efforts on trying to solve this problem. Specialemphasis is placed upon searching for drugs that wouldaffect both the symptoms and pathogenesis of a disease,which is very important for the design of drugs capable oftreating neurodegenerative diseases since none of the well�known drugs in use produces steady therapeutic effects,only relieving the symptoms of a disease for a while.2,3

Substituted �carbolines, e.g., the domestic medicineDimebon (1), are promising drugs for treating chronicneurodegenerative diseases, including Alzheimer´s dis�ease.4,5 For this reason, the synthesis of new 5�substituted�carbolines (also with fluorine�containing substituents6)and study of their neuroprotective activity is of cur�rent interest.

The goal of the present work was to obtain and exam�ine the physiological activity of earlier unknown 5�[2�(2�trifluoromethylimidazo[1,2�a]pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indoles 2a—c, which can beregarded as structural analogs of compound 1.

Carbolines 2a—c were obtained using the followingreaction sequence: 2�amino�5�bromopyridine (3) in boil�ing EtOH undergoes heterocyclization with 3�bromo�1,1,1�trifluoropropan�2�one (4) in the presence of an

equimolar amount of K2CO3 to give 6�bromo�2�trifluo�romethylimidazo[1,2�a]pyridine (5) in 91% yield; a reac�tion of compound 5 with tributyl(vinyl)stannane (6) inboiling toluene in the presence of catalytic amounts ofPd(Ph3P)4 affords 2�trifluoromethyl�6�vinylimidazo[1,2�a]pyridine (7) in 75% yield. According to the general meth�od developed earlier6 for alkylation of �carbolines withfluorine�containing vinylpyridines, compound 7 reactswith �carbolines 8a—c in DMSO at 150—160 C over 12h in the presence of catalytic amounts of CsF (the F– ionis a strong aprotic base7) to give compounds 2a—c. Forbiological tests, the latter were converted into the corre�sponding water�soluble hydrochlorides 9a—c (Scheme 1).

Compounds 2a—c and 9a—c are crystalline solids.Their compositions and structures were proved by ele�* For Part 7, see Ref. 1.

2: R = Me, R´ = Me (a); R = Me, R´ = Et (b); R = F, R´ = Me (c)

Sokolov et al.200 Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013

mental analysis and 1H and 19F NMR spectroscopy. The19F NMR spectra feature signals for the trifluoromethylgroup at 14—15 (2a—c) and 16—17 (9a—c).

Compounds 9a—c were tested for biological activityby a modified radioligand binding method.8,9 This meth�od allows quantitative estimation of the effect of com�pounds on neuronal receptors, specifically NMDA recep�tors, which are classified as one of three essential types ofionotropic glutamate receptors of the central nervous sys�tem in mammals that play a key role in neuroprotectionand neurotoxicity.

The results obtained in in vitro binding of indoles 9a—cto a modulatory segment of NMDA receptors (2,3) ina concentration range from 10–9 to 10–4 mol L–1 revealedan increased affinity of carboline 9a for the ifenprodil�binding segment located on the NR2B subunit of theNMDA receptor compared to that of Dimebon 1.

To sum up, using our unique approach to modificationof �carbolines at the indole N atom with fluorinated fusedheterocycles, we obtained earlier unknown 5�[2�(2�tri�fluoromethylimidazo[1,2�a]pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indoles and their hydrochlor�ides. Since radioligand binding revealed their high biolog�ical activity, we find it promising to synthesize new poten�tial neuroprotectors belonging to this class of compoundsand test them for physiological activity.

Experimental

1H and 19F NMR spectra were recorded on a Bruker DPX200 spectrometer (200.13 and 188.29 MHz, respectively) withSiMe4 as an internal standard and CF3COOH as an external

standard. Melting points were determined in glass capillaries.The starting �carbolines 8a—c were prepared according toa known procedure.10 2�Amino�5�bromopyridine (3), 3�bromo�1,1,1�trifluoropropan�2�one (4), and tributyl(vinyl)stannane (6)(Aldrich) were used as purchased.

6�Bromo�2�trifluoromethylimidazo[1,2�a]pyridine (5). Potas�sium carbonate (1.4 g, 10 mmol) was added to a stirred solutionof 2�amino�5�bromopyridine (3) (1.73 g, 10 mmol) and 3�bro�mo�1,1,1�trifluoropropan�2�one (4) (1.91 g, 10 mmol) in EtOH(20 mL). The reaction mixture was refluxed for 2 h, filtered, andconcentrated. The residue was recrystallized from 50% EtOH.Yield 2.4 g (91%), m.p. 148—150 C. Found (%): C, 36.44; H,1.31; N, 10.36. C8H4BrF3N2. Calculated (%): C, 36.26; H, 1.52;N, 10.57. 1H NMR (DMSO�d6), : 7.41 (dd, 1 H, C(7)H,J1 = 9.3 Hz, J2 = 1.7 Hz); 7.62 (d, 1 H, C(8)H, J = 9.3 Hz); 7.91(s, 1 H, C(3)H); 8.36 (dd, 1 H, C(5)H, J = 1.7 Hz, J = 0.6 Hz).19F NMR (DMSO�d6), : 14.48 (s).

2�Trifluoromethyl�6�vinylimidazo[1,2�a]pyridine (7). Tetra�kis(triphenylphosphine)palladium (0.2 g) was added to a solu�tion of 6�bromo�2�trifluoromethylimidazo[1,2�a]pyridine (5)(2.65 g, 10 mmol) and tributyl(vinyl)stannane (6) (3.17 g,10 mmol) in toluene (20 mL). The reaction mixture was refluxedfor 4 h, filtered, and concentrated. The residue was recrystal�lized from hexane. Yield 1.6 g (75%), m.p. 79—81 C. Found (%):C, 56.42; H, 3.54; N, 13.39. C10H7F3N2. Calculated (%):C, 56.61; H, 3.33; N, 13.20. 1H NMR (CDCl3), : 5.41 (d, 1 H,CH2=, J = 13.5 Hz); 5.79 (d, 1 H, CH2=, J = 17.3 Hz); 6.65(dd, 1 H, CH=, J = 17.3 Hz, J = 13.5 Hz); 7.50 (dd, 1 H, C(7)H,J1 = 9.5 Hz, J2 = 1.6 Hz); 7.63 (d, 1 H, C(8)H, J = 9.5 Hz); 7.85(s, 1 H, C(3)H); 8.05 (br.s, 1 H, C(5)H). 19F NMR (CDCl3),: 14.87 (s).

2,8�Dimethyl�5�[2�(2�trifluoromethylimidazo[1,2�a]pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indole (2a).A mixture of �carboline 8a (0.2 g, 1 mmol), 2�trifluoromethyl�6�vinylimidazo[1,2�a]pyridine (7) (0.21 g, 1 mmol), CsF (0.1 g),and hydroquinone (0.02 g) in DMSO (1.5 mL) was stirred at

Scheme 1

8, 9: R = Me, R´ = Me (a); R = Me, R´ = Et (b); R = F, R´ = Me (c)

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 chromato�graphed on silica gel (60 mesh) with MeOH—CHCl3 (1 : 5) asan 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, CH2

ex, J = 7.6 Hz); 3.63 (s, 2 H, CH2);4.21 (t, 2 H, CH2

ex, J = 7.6 Hz); 6.88 (dd, 1 H, 7�Hind, JH,H == 8.2 Hz, JH,H = 1.1 Hz); 6.98 (dd, 1 H, 7�Him, JH,H == 9.4 Hz, JH,H = 1.6 Hz); 7.01 (d, 1 H, 6�Hind, J = 8.2 Hz); 7.14(br.s, 1 H, 9�Hind); 7.26 (d, 1 H, 8�Him, J = 9.4 Hz); 7.47(br.s, 1 H, 3�Him); 7.66 (br.s, 1 H, 5�Him).* 19F NMR (CDCl3),: 14.89 (s).

2�Ethyl�8�methyl�5�[2�(2�trifluoromethylimidazo[1,2�a]�pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indole(2b) was obtained as described for compound 2a from �carbo�line 8b (0.214 g, 1 mmol) and 2�trifluoromethyl�6�vinylimid�azo[1,2�a]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, CH2

ex, J = 6.6 Hz); 3.68(s, 2 H, CH2); 4.21 (t, 2 H, CH2

ex, J = 7.5 Hz); 6.85 (dd, 1 H,7�Hind, JH,H = 8.2 Hz, JH,H =1.0 Hz); 6.96 (dd, 1 H, 7�Him,JH,H = 9.3 Hz, JH,H =1.6 Hz); 7.04 (d, 1 H, 6�Hind, JH,H = 8.2 Hz);7.21 (br.s, 1 H, 9�Hind); 7.39 (br.s, 1 H, 3�Him); 7.56 (d, 1 H,8�Him, J = 9.3 Hz); 7.61 (br.s, 1 H, 5�Him). 19F NMR (CDCl3),: 14.92 (s).

8�Fluoro�2�methyl�5�[2�(2�trifluoromethylimidazo[1,2�a]�pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indole(2c) was obtained as described for compound 2a from �carbo�line 8c (0.205 g, 1 mmol) and 2�trifluoromethyl�6�vinylimid�azo[1,2�a]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, CH2

ex, J = 7.5 Hz); 3.63(s, 2 H, CH2); 4.21 (t, 2 H, CH2

ex, J = 7.5 Hz); 6.85 (ddd, 1 H,7�Hind, JH,H = JH,F = 9.4 Hz, JH,H = 2.6 Hz); 6.99 (dd, 1 H,9�Hind, JH,F = 9.4 Hz, JH,H = 2.6 Hz); 7.09 (d, 1 H, 6�Hind, JH,H == 9.4 Hz, JH,F = 4.3 Hz); 7.14 (dd, 1 H, 7�Him, J1 = 9.4 Hz,J2 = 1.6 Hz); 7.26 (d, 1 H, 8�Him, J = 9.4 Hz); 7.47 (s, 1 H,3�Him); 7.66 (br.s, 1 H, 5�Him). 19F NMR (CDCl3), : –47.13(td, 1 F, JF,H = 9.4 Hz, JF,H = 4.3 Hz); 14.95 (s).

2,8�Dimethyl�5�[2�(2�trifluoromethylimidazo[1,2�a]pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indole hydro�chloride (9a). Concentrated HCl (0.1 mL) was added to a sus�pension of indole 2a (0.12 g, 0.3 mmol) in water (5 mL). Theresulting mixture was heated to complete homogenization andconcentrated 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 (DMSO�d6), : 2.42 (s, 3 H,

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, CH2

ex, J = 7.7 Hz); 3.55(s, 2 H, CH2); 4.26 (t, 2 H, CH2

ex, J = 7.7 Hz); 6.85 (d, 1 H,7�Hind, J = 8.2 Hz); 6.92 (d, 1 H, 6�Hind, J = 8.2 Hz); 7.09 (s, 1 H,9�Hind); 7.15 (dd, 1 H, 7�Him, JH,H = 9.4 Hz, JH,H = 1.6 Hz);7.25 (d, 1 H, 8�Him, J = 9.4 Hz); 7.47 (s, 1 H, 3�Him); 7.69(s, 1 H, 5�Him); 10.81 (s, 1 H, NH+). 19F NMR (DMSO�d6),: 16.71 (s).

2�Ethyl�8�methyl�5�[2�(2�trifluoromethylimidazo[1,2�a]�pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indolehydrochloride (9b) was obtained as described for com�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 (DMSO�d6), : 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, CH2

ex); 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, 7�Hind, J = 8.1 Hz); 6.90 (d, 1 H, 6�Hind, J = 8.2 Hz);7.10 (br.s, 1 H, 9�Hind); 7.15 (dd, 1 H, 7�Him, JH,H = 9.3 Hz,JH,H = 1.6 Hz); 7.27 (d, 1 H, 8�Him, J = 9.3 Hz); 7.55 (s, 1 H,3�Him); 7.72 (s, 1 H, 5�Him); 10.88 (s, 1 H, NH+). 19F NMR(DMSO�d6), : 14.92 (s).

2�Fluoro�8�methyl�5�[2�(2�trifluoromethylimidazo[1,2�a]�pyridin�6�yl)ethyl]�2,3,4,5�tetrahydro�1H�pyrido[4,3�b]indolehydrochloride (9c) was obtained as described for com�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, 12.37.1H NMR (DMSO�d6), : 2.51 (s and t, 5 H, Me and CH2,J = 7.4 Hz); 2.68 (t, 2 H, CH2, J = 7.4 Hz); 3.11 (t, 2 H, CH2

ex,J = 7.6 Hz); 3.61 (s, 2 H, CH2); 4.29 (t, 2 H, CH2

ex, J = 7.6 Hz);6.80 (br.dd, 1 H, 7�Hind, JH,H = 8.2 Hz, JH,F = 9.4 Hz); 7.03(br.d, 1 H, 9�Hind, JH,F = 4.9 Hz); 7.10 (d, 1 H, 6�Hind,JH,H = 8.2 Hz, JH,F = 4.9 Hz); 7.18 (dd, 1 H, 7�Him, J1 = 9.4 Hz,J2 = 1.6 Hz); 7.28 (d, 1 H, 8�Him, J = 9.4 Hz); 7.51 (s, 1 H,3�Him); 7.72 (br.s, 1 H, 5�Him); 10.93 (s, 1 H, HCl). 19F NMR(DMSO�d6), : –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 RussianFoundation for Basic Research (Project Nos 11�03�00480�a,11�03�00496�a, 11�03�12076�ofi�m�2011, and 12�03�00828�a).

References

1. V. B. Sokolov, A. Yu. Aksinenko, Russ. Chem. Bull. (Int. Ed.),2012, 61, 11 [Izv. Akad. Nauk, Ser. Khim., 2012, 2108].

2. S. O. Bachurin, Meditsinskaya khimiya napravlennogo pois�ka preparatov dlya lecheniya i preduprezhdeniya neiro�degenerativnykh zabolevanii na primere bolezni Al´tsgeimera[Medicinal Chemistry Aimed at Targeted Searching forDrugs Capable of Treating and Preventing Neurodegenera�tive Diseases with Alzheimer´s Disease as an Example], inNeirodegenerativnye bolezni i starenie [Neurodegenerative Dis�eases and Aging], Moscow, 2001, 399 (in Russian).

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].

* Hereafter, Hind and Him denote the protons of the tetrahydro�1H�pyrido[4,3�b]indole and imidazo[1,2�a]pyridine moieties,respectively, in compounds 2a—c and 9a—c; CH2

ex denotes theprotons of the ethylene linker.

Sokolov et al.202 Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013

4. R. S. Doody, S. I. Gavrilova, M. Sano, R. G. Thomas, P. S.Aisen, S. O. Bachurin, L. Seely, D. Hung, Lancet, 2008,372, 207.

5. S. O. Bachurin, A. A. Ustyugov, O. Peters, T. A. Shelkovni�kova, V. L. Bukhman, N. N. Ninkina, Dokl. Akad. Nauk,2009, 428, 262 [Dokl. Chem. (Engl. Transl.), 2009].

6. S. Sablin, S. Bachurin, B. Beznosko, V. Sokolov, A. Aksinen�ko, US Pat. 7935823 B2, 2009.

7. G. G. Yakobson, V. V. Bardin, Ftorid�ion v organicheskoikhimii [The Fluoride Ion in Organic Chemistry], Nauka, Novo�sibirsk, 1986, 315 pp. (in Russian).

Received May 28, 2012;in revised form November 15, 2012

8. C. Dana, J. Benavides, H. Schoemaker, B. Scatton, Neuro�sci. Lett., 1991, 125, 45.

9. G. Nowak, R. Trullas, R. T. Layer, P. Skolnick, I. A. Paul,J. Pharmacol. Exp. Ther., 1993, 265, 1380.

10. N. K. Kochetkov, N. F. Kucherova, I. G. Zhukova,Zh. Obshch. Khim., 1961, 31, 924 [J. Gen. Chem. (Engl. Transl.),1961, 31].