Synthesis of imidazo[1,2-a]pyridines as antiviral agents

Article abstract of DOI:10.1021/jm981051y

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic

Full text of DOI:10.1021/jm981051y

5108
J . Med. Chem. 1998, 41, 5108-5112
Notes
Syn th esis of Im id a zo[1,2-a ]p yr id in es a s An tivir a l Agen ts
Alain Gueiffier,*,† Sylvie Mavel,† Mohammed Lhassani,‡ Ahmed Elhakmaoui,‡ Robert Snoeck,§ Graciela Andrei,§
Olivier Chavignon,∇ J ean-Claude Teulade,∇ Myriam Witvrouw,§ J an Balzarini,§ Erik De Clercq,§ and
J ean-Pierre Chapat‡
Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie, Universite´ de Tours, 31 Avenue Monge, 37200 Tours, France,
Laboratoire de Chimie Organique Pharmaceutique, E.A. Pharmacochimie et Biomole´cules, 15 Avenue Charles Flahault,
34060 Montpellier, France, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10,
B-3000 Leuven, Belgium, and Laboratoire de Chimie Organique Pharmaceutique, Groupe de Recherches en Pharmacochimie,
UFR de Pharmacie, 28 place H. Dunant, 63001 Clermont-Ferrand, France
Received J une 19, 1998
The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position
and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were
highly active against human cytomegalovirus with a therapeutic index superior to 150. These
compounds also showed pronounced activity against varicella-zoster virus. Their structure-
activity relationship is discussed.
Sch em e 1a
In tr od u ction
Cytomegalovirus (CMV) is a â-herpesvirus respon-
sible for severe illness in newborns1 and immunosup-
pressed patients where it can lead to severe retinitis,
pneumopathy, and encephalopathy.2 The compounds
currently used in the treatment of CMV infections are
ganciclovir (Cymevene), foscarnet (Foscavir), and cido-
fovir (Vistide), although these compounds are not free
of side effects.3 The acyclic nucleoside phosphonate
cidofovir represents a real advantage in the manage-
ment of CMV infections because it must be administered
only once a week (initially) or every 2 weeks (thereafter),
and it does not easily lead to the development of virus
drug resistance.4 In previous communications, we have
reported the synthesis of thioether derivatives in the
imidazopyridine series as potential antiviral agents.5
From these compounds, the 7- and 8-methyl-3-[(ben-
zylthio)methyl]imidazo[1,2-a]pyridines I and II (Chart
1) showed a marked activity against CMV and varicella-
a
Reagents and conditions: (i) bromoacetaldehyde, chloroacetone
or phenacyl bromide, EtOH, 4 h, reflux; (ii) HCHO, AcOH, AcONa,
4 h reflux except for 2i,j (4 h room temperature).
Ch a r t 1
Ta ble 1. Yields and Melting Points for Original Intermediates
compd yield,a
%
mp, °C
compd yield,a
%
mp, °C
1f
78
92
9
30
55
40-41
2f
2g
2h
2i
45
85
60
86
92
173-174
183-184
193-194
>260
>260
1h
2c
2d
2e
175-176
136-137
144-145
162-163
2j
a
After chromatography.
zoster virus (VZV). However, these compounds were
still relatively cytotoxic. We now report the synthesis
and the antiviral activity of novel derivatives within this
series of compounds.
Ch em istr y
The starting substituted imidazo[1,2-a]pyridines (1a -
l) were obtained according to known procedures (see
General Details in Experimental Section) or by conden-
sation of suitable 2-aminopyridine derivatives with
bromoacetaldehyde in refluxing ethanol as described by
† Universite´ de Tours.
‡ E.A. Pharmacochimie et Biomole´cules.
§ Katholieke Universiteit Leuven.
∇ UFR de Pharmacie.
10.1021/jm981051y CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5109
Ta ble 2. 1H NMR Spectral Data for New Intermediate Derivatives
compd
H-2
H-3
H-5
H-6
H-7
H-8
others
1f
1h
2c
2d
2e
2f
2g
2h
2i
7.62
7.56*
7.06
7.12
7.19
7.23
7.32
7.47
7.55
7.69*
8.17
7.07
7.56*
6.98
2.63 (Me)
2.66 (Me)
8.04
7.34
7.02
2.26 (Me); 4.84 (CH2); 5.88 (OH)
2.25 (Me); 2.88 (Me); 4.84 (CH2); 4.87 (OH)
2.49 (Me); 2.90 (Me); 4.89 (CH + OH)
2.50 (Me); 3.40 (OH); 4.85 (CH2)
2.32 (Me); 4.87 (CH2)
3.09 (Me); 4.94 (CH2)
2.46 (Me); 5.14 (CH2); 7.40 (3H); 7.78 (2H)
2.66 (Me); 5.06 (CH2); 7.40 (3H); 7.72 (2H)
6.31
6.44
6.88
7.04
7.29
8.25
8.05
7.62
6.75
6.78
8.20
8.14
7.45
2j
7.05
Ta ble 3. Structures and Physical Properties of Synthesized Thioethers
compd R1
R2
7-Me
R3
yield,a
%
mp, °C
compd
R1
R2
R3
yield,a
%
mp, °C
oil
3
4
H
H
H
H
H
H
H
H
H
H
cyclohexyl
90
90
91
90
87
97
83
81
50
95
111-112
83-84
87-88
96-97
70-71
112-113
oil
oil
oil
94-95
13
14
15
16
17
18
19
20
21
H
5,7-(Me)2
5,8-(Me)2
8-Me-6-Br
6-Me-8-Br
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
70
98
93
92
90
62
55
54
76
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
CH2CH2C6H5
cyclopentyl
CH2CF3
CH2-2ClC6H4
CH2-4ClC6H4
CH2CH2CH3
CH(CH3)2
H
H
H
H
66-67
5
6
96-97
97-98
7
8
9
5-Me-6,8-(Br)2 CH2C6H5
136-137
111-113
74-76
C6H5 7-Me
C6H5 8-Me
CH3
CH3
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
10
11
12
7-Me
H
107-109
82-83
6-CF3-8-Cl CH2C6H5
6-Me CH2C6H5
a
After chromatography.
Ta ble 4. 1H NMR Spectral Data for Thioethers
compd
H-2
H-5
H-6
H-7
H-8
others
3
4
5
6
7
7.32
7.42
7.31
7.35
7.39
7.29
7.36
7.40
7.56
7.44
7.26
7.32
7.40
7.44
7.35
7.95
7.97
7.92
7.84
7.80
7.82
7.98
8.03
8.30
7.75
6.56
6.66
6.54
6.59
6.52
6.56
6.63
6.67
7.27
7.38
7.25
7.25
7.28
7.29
7.32
7.35
1.10-1.76 (11H); 2.30 (Me); 3.93 (CH2)
2.39 (Me); 2.71 (4H); 7.06-7.28 (5Harom
)
1.33-1.80 (8Hcyclopentyl); 2.27 (Me); 2.66-2.80 (CH); 3.90 (CH2)
2.27(Me); 2.69 (CH2); 4.00 (CH2)
2.27 (Me); 3.58 (CH2); 3.86 (CH2); 7.10 (3Harom); 7.26 (1Harom)
2.31 (Me); 3.38 (CH2); 3.78 (CH2); 7.09 (H-2′,6′); 7.12 (H-3′,5′)
0.85 (CH3); 1.47 (CH2); 2.25 (CH2); 2.34 (Me); 3.92 (CH2)
1.17 (2CH3); 2.38 (Me); 2.62 (CH); 4.01 (CH2)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
7.39
7.05
3.52 (CH2); 3.89 (CH2); 7.21 (5Harom
)
7.53
7.17
2.34 (Me); 3.58 (CH2); 3.88 (CH2); 7.31 (5Harom
2.27 (Me); 2.78 (Me); 3.59 (CH2);3.98 (CH2); 7.26 (5Harom
2.58 (Me); 2.81 (Me); 3.65 (CH2); 4.04 (CH2)
2.56 (Me); 3.53 (CH2); 3.81 (CH2); 7.26 (5Harom
2.26 (Me); 3.52 (CH2); 3.82 (CH2); 7.27 (5Harom
2.88 (Me); 3.57 (CH2); 3.92 (CH2); 7.21 (5Harom
2.33 (Me); 3.60 (CH2); 4.00 (CH2); 7.14-7.45 (8Harom); 7.77 (2Harom
2.67 (Me); 3.66 (CH2); 4.11 (CH2); 7.19-7.77 (10Harom
2.25 (Me); 2.34 (Me); 3.54 (CH2); 3.87 (CH2); 7.26 (5Harom
)
6.30
6.38
)
6.84
7.06
7.06
7.48
7.98
7.67
)
)
)
7.63
7.77
7.73
7.88
6.53
6.73
6.55
6.74
7.37
)
7.01
7.14
)
7.23
7.50
)
2.32 (Me); 3.58 (CH2); 3.93 (CH2); 7.27 (5Harom
)
Roe.6 Direct hydroxymethylation was carried out ac-
cording to the procedure of Teulade7 modified as follows.
A mixture of the imidazopyridine 1 with formaldehyde
and sodium acetate in acetic acid media was heated at
100 °C for 4 h to give the suitable alcohol 2 in moderate
to good yield. In the case of 2-phenyl compounds, the
reaction occurred smoothly at room temperature and led
to the hydroxymethyl derivative in 86-92% yield
(Scheme 1, Tables 1 and 2).
Sch em e 2a
a
Reagents and conditions: R3SH, AcOH, 100 °C, 2 h.
Biologica l Assa ys
Preparation of thioethers 3-21 was achieved by
reaction of substituted (imidazo[1,2-a]pyridin-3-yl)-
methanol derivatives with thiol in acetic acid media at
100 °C for 2 h according to the procedure of Del Corona8
(Scheme 2). The structure, yields, and physical proper-
ties of these compounds are reported in Tables 3-5.
Antiviral activity was determined against a broad
range of RNA and DNA viruses Table 6). The following
structure-activity relationship (SAR) emerged:
1. In flu en ce of th e n a tu r e of th e th ioeth er sid e
ch a in : This chain must contain a cyclic ring. Indeed,
aliphatic compounds led to a dramatic decrease of the

5110 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Ta ble 5. 13C NMR Spectral Data of Thioethers
Notes
compd C-2
C-3
C-5
C-6
C-7
C-8
C-8a
others
3
4
132.3 118.7 123.2 114.4 134.7 116.0 146.4 21.0 (Me); 23.2 (CH2); 25.5 (CH2); 25.6 (2CH2); 32.8 (2CH2); 42.5 (CH)
132.8 118.0 123.2 114.5 134.9 116.1 146.1 21.1 (Me); 24.9 (CH2); 32.1 (CH2); 35.7 (CH2); 126.2 (C-4′);
128.3 (4CHarom); 139.9 (C-1′)
5
6
7
131.9 118.4 122.9 114.1 134.3 115.6 146.1 20.7 (Me); 24.3 (CH2); 24.7 (CH2); 32.8 (2CH2); 42.5 (CH)
134.1 116.0 123.0 115.0 135.5 116.3 147.1 21.3 (Me); 25.7 (CH2); 32.1 (CH2, J ) 32.8 Hz); 125.9 (CF3, J ) 277.3 Hz)
132.6 117.6 122.8 114.1 135.5 115.6 146.2 20.7 (Me); 24.4 (CH2); 32.5 (CH2); 126.5 (C-5′); 128.0 (C-3′); 129.3 (C-4′);
130.0 (C-6′); 134.6 (C-1′); 135.0 (C-2′)
8
132.6 117.2 122.6 114.1 132.1 115.6 146.1 20.6 (Me); 23.7 (CH2); 33.8 (CH2); 127.9 (C-2′,6′); 129.5 (C-3′,5′);
134.5 (C-1′); 135.5 (C-4′)
9
10
11
132.8 118.4 123.3 114.6 135.0 116.2 146.7 13.3 (CH3); 21.2 (Me); 22.3 (CH2); 24.8 (CH2); 33 (CH2)
132.3 118.7 123.4 114.7 135.0 116.2 146.7 21.7 (Me); 22.8 (2CH3); 24.0 (CH); 34.2 (CH2)
135.3 124.6 122.2 116.4 119.1 122.6 143.3 23.8 (CH2); 35.5 (CH2); 127.3 (C-4′); 128.5 (C-3′,5′); 128.7 (C-2′,6′);
136.9 (C-1′); 123.0 (CF3, J ) 271.7 Hz)
12
13
14
15
16
17
18
19
20
21
133.2 121.6 121.7 118.2 127.0* 117.01 45.3 18.2 (Me); 23.9 (CH2); 35.2 (CH2); 127.2 (C-4′)*; 128.4 (C-3′,5′);
128.9 (C-2′,6′); 137.5 (C-1′)
135.7 120.3 134.8* 114.3 135.6 116.3 148.6 19.8 (Me); 20.8 (Me), 27.0 (CH2); 35.1 (CH2); 127.0 (C-4′); 128.5 (C-3′,5′);
128.9 (C-2′,6′); 137.5 (C-1′)
134.4 124.7 133.8 113.0 123.2 121.0 148.1 16.6 (Me); 19.4 (Me); 26.6 (CH2); 34.8 (CH2); 126.7 (C-4′); 128.1 (C-3′,5′);
128.6 (C-2′,6′); 137.2 (C-1′)
133.1 119.5 121.9 106.8 126.2 128.5 145.0 16.6 (Me); 23.8 (CH2); 35.2 (CH2); 127.0 (C-4′); 128.4 (C-3′,5′);
128.7 (C-2′,6′); 137.1 (C-1′)
133.2 120.1 121.7 120.9 129.2 110.7 142.6 17.8 (Me); 23.7 (CH2); 35.0 (CH2); 126.7 (C-4′); 128.1 (C-3′,5′);
128.5 (C-2′,6′); 137.0 (C-1′)
136.3 124.2 134.3 108.2 130.3 109.3 144.1 18.5 (Me); 27.1 (CH2); 35.0 (CH2); 126.9 (C-4′); 128.2 (C-3′,5′);
128.4 (C-2′,6′); 136.7 (C-1′)
143.6 114.1* 122.8 114.3* 135.2 115.4* 145.2 21.0 (Me); 24.5 (CH2); 36.0 (CH2); 126.7 (C-4′); 127.3 (C-4′′); 128.0 (2CH);
128.1 (2CH); 128.3 (2CH); 128.5 (2CH); 134.0 (C-1′′); 137.6 (C-1′)
143.6 115.1 121.5 111.7 123.0 127.0 145.1 16.8 (Me); 24.6 (CH2); 36.0 (CH2); 126.7 (C-4′); 127.3 (C-4′′); 128.1 (2CH);
128.3 (4CH); 128.5 (2CH); 134.1 (C-1′′); 137.6 (C-1′)
141.4 113.8 123.1 114.1 134.9 115.1 145.2 13.3 (Me); 21.2 (Me); 24.0 (CH2); 35.5 (CH2); 127.0 (C-4′); 128.5 (C-3′,5′);
128.7 (C-2′,6′); 137.6 (C-1′)
141.6 114.5 123.7 111.4 123.7 116.4 144.5 13.2 (Me); 23.8 (CH2); 35.5 (CH2); 126.9 (C-4′); 128.3 (C-3′,5′);
128.4 (C-2′,6′); 137.4 (C-1′)
Ta ble 6. Anti-CMV and Anti-VZV Activities and Cytotoxic Properties of Test Compounds in Human Embryonic Lung (HEL) Cells
50% virus-inhibitory concentration (µg/mL)a
CMV
VZV
50% cytotoxic
concentration
(µg/mL)b
AD-169
strain
Davis
strain
OKA
YS
07/1
YS/R
selectivity
indexc
compd
strain TK+
strain TK+
strain TK-
strain TK-
I
3.5
0.2
3
0.33
5
3.5
0.2
3.4
0.35
6.3
42
0.7
1.6
14
>5
0.5
>2
0.12
1.1
>50
>20
>2
3.5
0.13
0.5
d
15
0.9
3.8
0.2
18
17
0.3
8.3
d
0.4
>5
10
>1
5.7
0.66
13
>50
>5
>5
29
9.8
1.2
>2
0.86
4
>20
>50
2
45
8
>50
>50
12
>50
18
19
>50
40
23
3
>50
>50
>50
>50
13
13
40
II
3
4
5
6
7
8
9
11
12
14
15
16
17
18
19
20
21
>17
>151
2.4
>1.2
36
0.5
0.95
>5
>20
>50
>5
>5
>50
8.8
6.4
>2
7
>50
>50
>20
>2
>5
0.23
d
40
>50
>50
>5
>5
41
>5
2.58
>2
1.4
9
>50
>50
>2
14.1
0.5
d
0.5
1.2
12
1.8
2
16
>50
>4.2
>5
0.3
1.2
0.12
1.1
>50
>20
1.2
3.4
0.12
0.5
d
6.6
<8
0.74
>2
5.5
77
2.5
>417
>45
d
d
11
>15
275
>200
d
31
>50
>20
>2
10.5
0.37
d
10
0.28
d
>40
>20
>50
33
>100
>100
>50
ganciclovir
acyclovir
brivudin
0.82
0.0009
0.95
0.002
>25
>50
d
d
d
a
b
Compound concentration required to inhibit virus-induced cytopathogenicity by 50%. Compound concentration required to inhibit
cell proliferation by 50%. c Ratio of 50% cytotoxic concentration to 50% virus-inhibitory concentration [the latter based on the 50% inhibitory
d
concentration for CMV (AD-169 strain)]. Not determined.
anti-CMV and anti-VZV activity, while cycloalkyl groups
gave antiviral activity in the range of that of I. From a
comparison of I with 4, it appears that the replacement
of the benzyl by a phenylethyl group improves anti-CMV
activity by 11-fold and anti-VZV activity by 15-75-fold.
Finally, introduction of a chlorine atom ortho or para
on the phenyl ring enhanced both antiviral activity and
cytotoxicity.
2. In flu en ce of th e n a tu r e a n d th e p osition of
th e su bstitu en t on th e p yr id in ic m oiety: The
importance of a methyl group on the pyridinic moiety
was confirmed. The dimethyl derivatives were less

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5111
material in TLC. After cooling (if necessary), the reaction
media were diluted in water and made basic with sodium
carbonate. After evaporation to dryness, the residue was
chromatographed on neutral alumina eluted with dichlo-
romethane-methanol (95/5 v/v).
Gen er a l P r oced u r e for Acyclon u cleosid e An a logu es:
A solution of alcohol (2 mmol) with the suitable thiol (1.8
mmol) in acetic acid (2 mL) was heated at 80 °C for 2 h. After
cooling, the solution was made basic with sodium carbonate
and extracted with dichloromethane. The organic layers were
dried over calcium chloride and evaporated to dryness, and
the residue was chromatographed on neutral alumina eluted
with dichloromethane.
potent. A bromine in the 8 position decreased the anti-
CMV activity, while a bromine in the 6 position en-
hanced it. In both cases, a decrease in anti-VZV activity
was observed. Both substitutions were accompanied by
a marked decrease in cytotoxicity.
3. In flu en ce of th e su bstitu en t in th e 2 p osition :
This substitution had no marked effect. A 2-methyl
group seemed compatible with antiviral activity only
when the pyridinic moiety remained unsubstituted.
While several compounds (i.e., 4, 15, and 21) proved
quite promising as anti-CMV and anti-VZV agents, none
showed appreciable activity against human immuno-
deficiency virus (HIV-1 and HIV-2) in cell culture (data
not shown). Also, compounds 3, 4, 11, 12, 15, 18, 20,
and 21 were evaluated for their activity against herpes
simplex virus type 1 (HSV-1) (strain KOS), HSV-2
(strain G), vaccinia virus, and vesicular stomatitis virus
(VSV) in human embryonic skin muscle (E6SM) cells;
VSV, Coxsackie virus B4, and respiratory syncytial
virus (RSV) in HeLa cells; and parainfluenza-3 virus,
reovirus-1, Sindbis virus, Coxsackie virus B4, and Punta
Toro virus in Vero cells. None of the compounds showed
activity against these viruses at subtoxic concentrations.
Biologica l Assa ys. All antiviral assays were performed
as described before.16-18
Ack n ow led gm en t. We thank Ann Absillis, Anita
Camps, Frieda De Meyer, Katrin Saelen, and Anita Van
Lierde for excellent technical assistance. These inves-
tigations were supported by the Biomedical Research
Programme of the European Commission and grants
from the Fonds voor Wetenschappelijk Onderzoek (FWO)
- Vlaanderen and the Geconcerteerde Onderzoeksacties
(GOA) - Vlaamse Gemeenschap.
Refer en ces
Con clu sion s
(1) Fowler, K. B.; Stagno, S.; Pass, R. F.; Britt, W. J .; Boll, T. J .;
Alford, C. A. The outcome of congenital cytomegalovirus infection
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326 (10), 663-667.
Chemical modifications of the imidazo[1,2-a]pyridines
enabled us to improve the therapeutic index of this new
class of antiviral agents. From the reported series,
compounds 4, 15, and 21 emerged as the most potent
and selective inhibitors of CMV and VZV. Further
studies are in progress to understand the mechanism
and target of interaction of these compounds.
(2) Tyms, A. S.; Taylor, D. L.; Parkin, J . M. Cytomegalovirus and
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idines. Nucleosides Nucleotides 1995, 14 (3-5), 551-554. (c)
Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei,
G.; Chavignon, O.; Teulade, J . C.; Kerbal, A.; Essassi, E. M.;
Debouzy, J . C.; Blache, Y.; Balzarini, J .; De Clercq, E.; Chapat,
J . P. Synthesis of acyclo-C-nucleosides in the imidazo[1,2-a]-
pyridine and pyrimidine series as antiviral agents. J . Med.
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Exp er im en ta l Section
Gen er a l Deta ils. Melting points were determined on a
Totolli capillary apparatus and are uncorrected. Elemental
analyses were performed by Microanalytical Center, ENSCM,
Montpellier. NMR spectra were recorded on a Bru¨ker AC 100
or AM 400 WB spectrometer. Substituted 2-aminopyridines
were purchased from Aldrich except for 5-bromo-3-methyl-2-
aminopyridine,9 5-methyl-3-bromo-2-aminopyridine,10 and
6-methyl-3,5-dibromo-2-aminopyridine.11 Previously reported
imidazo[1,2-a]pyridines synthesized by the described procedure
were 7-methylimidazo[1,2-a]pyridine (1a ),12 8-chloro-6-(triflu-
oromethyl)imidazo[1,2-a]pyridine (1b),5c 6-methylimidazo[1,2-
a]pyridine (1c),12 5,7-dimethylimidazo[1,2-a]pyridine (1d ),13
5,8-dimethylimidazo[1,2-a]pyridine (1e),6 8-bromo-6-methyl-
imidazo[1,2-a]pyridine (1g),10 7-methyl-2-phenylimidazo[1,2-
a]pyridine (1i),14 8-methyl-2-phenylimidazo[1,2-a]pyridine (1j),14
2-methylimidazo[1,2-a]pyridine (1k ),13 2,7-dimethylimidazo-
[1,2-a]pyridine (1l),15 (7-methylimidazo[1,2-a]pyridin-3-yl)-
methanol (2a ),5a and (8-chloro-6-(trifluoromethyl)imidazo[1,2-
a]pyridin-3-yl)methanol (2b).5c
(6) Roe, A. M. The thermal condensation of imidazole with carbonyl
compounds. J . Chem. Soc. 1963, 2195-2200.
(7) Teulade, J . C.; Bonnet, P. A.; Rieu, J . N.; Viols, H.; Chapat, J .
P.; Grassy, G.; Carpy, A. C-3-hydroxylation of some imidazo-
[1,2-a]azines. J . Chem. Res. (M) 1986, 1842-1874.
(8) Del Corona, L.; Pellegatta, C.; Signorelli, G.; Buron, V.; Massa-
roli, G.; Turba, C.; Farni, D.; Pagella, P. G. Imidazo[1,2-a]-
pyridine ad azione antiulcera. Farmaco, Ed. Sci. 1981, 36 (12),
994-1003.
(9) Van der Does, H.; Hertog, H. J . Bromination of methylpyridines
in fuming sulfuric acid. Recl. Trav. Chim. Pays-Bas 1965, 84,
951-964.
(10) Yamanaka, M.; Miyake, K.; Suda, S.; Ohhara, H.; Ogawa, T.
Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of
new imidazo[1,2-a]pyridinyl-2-(1H)-pyridinone derivatives. Chem.
Pharm. Bull. 1991, 39 (6), 1556-1567.
(11) Lindstroem, S.; Ahmad, T.; Grivas, S. Synthesis of the mutagenic
2-amino-1,6-dimethylimidazo[4,5-b]pyridine (1,6-DMIP) and five
of its isomers. Heterocycles 1994, 38 (3), 529-540.
Ch em istr y. Gen er a l P r oced u r e for Cycliza tion :
A
solution of 2-aminopyridine derivative (0.1 mol) and R-halo-
genocarbonyl compound (0.12 mol) was refluxed in ethanol
(250 mL) for 4 h. After cooling, the solution was concentrated
in vacuo and the residue diluted in water. The solution was
made basic with sodium carbonate and extracted with dichlo-
romethane. The dried organic layers were evaporated to
dryness and the residue chromatographed on neural alumina
eluted with dichloromethane.
(12) Paudler, W. W.; Blewitt, H. L. Ten π-electron nitrogen hetero-
cyclic compounds. V. The site of protonation and N-methylation
of imidazo[1,2-a]pyridine and the planarity of the ring system.
J . Org. Chem. 1966, 31, 1295-1298.
(13) Paudler, W. W.; Blewitt, H. L. Ten π-electron nitrogen hetero-
cyclic compounds. II. Bromination of imidazo[1,2-a]pyridine. J .
Org. Chem. 1965, 30, 4081-4084.
Gen er a l P r oced u r e for Hyd r oxym eth yla tion : To a
solution of the heterocycle (3.45 mmol) in acetic acid (0.74 mL)
were added sodium acetate (1.06 g, 13 mmol) and then a 37%
formaldehyde solution in water (1.8 mL, 22 mmol), and the
mixture was stirred at room temperature for 1i,j and heated
at 100 °C for the others until disappearance of starting

5112 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Notes
(14) Matu, F.; Marongui, E. Synthesis of methylphenylimidazo[1,2-
a]pyridine isomers of pharmaceutical interest Ann. Chim. (Rome)
1964, 54 (5), 496-509.
(17) Balzarini, J .; Naesens, L.; Slachmuylders, J .; Niphuis, H.;
Rosenberg, I.; Holy, A.; Schellekens, H.; De Clercq, E. 9-(2-
Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits
retrovirus replication in vitro and simian immunodeficiency
virus infection in rhesus monkeys. AIDS 1991, 5, 21-28.
(18) De Clercq, E.; Holy´, A.; Rosenberg, I.; Sakuma, T.; Balzarini,
J .; Maugdal, P. C. A novel selective broad-spectrum anti-DNA
virus agent. Nature 1986, 323, 464-467.
(15) Buu-Ho¨ı, N. P.; Petit, L.; Xuong, N. D. Some new pyrimidazoles,
2-substituted 6-aza and 8-aza pyrimidazoles. C. R. Acad. Sci.
1959, 248, 1832-1834.
(16) De Clercq, E.; Descamps, J .; Verhelst, G.; Walker, R. T.; J ones,
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