Imidazo[1,2-b]pyridazines. XXI syntheses of some 3-acylaminomethyl-6-(chloro and iodo)-2-(substituted phenyl)-imidazo[1,2-b]pyridazines and -imidazo[1,2-a]pyridines and their interaction with central and mitochondrial benzodiazepine receptors

Article abstract of DOI:10.1071/C96130

A series of 3-acylaminomethyl-6-(chloro, iodo and methyl)-2-(phenyl, 4′-t-butylphenyl, 4′-cyclohexyl-phenyl, biphenyl-4′-yl, 4′-chlorophenyl and 4′-iodophenyl)imidazo[1,2-b]pyridazines and imidazo[1,2-a]pyridines has been prepared and examined for interac

Full text of DOI:10.1071/C96130

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 50, 1997
© CSIRO Australia 1997
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Aust. J. Chem., 1997, 50, 61–67
.
Imidazo[1,2-b]pyridazines. XXI
Syntheses of Some 3-Acylaminomethyl-6-(chloro and iodo)-
2-(substituted phenyl)-imidazo[1,2-b]pyridazines and
-imidazo[1,2-a]pyridines and Their Interaction with
Central and Mitochondrial Benzodiazepine Receptors
Gordon B. Barlin,A Les P. Davies B and Peter W. Harrison A
A
Division of Neuroscience, John Curtin School of Medical Research,
Australian National University, G.P.O. Box 334, Canberra, A.C.T. 2601.
B
Visual Sciences Group, Research School of Biological Sciences,
Australian National University, G.P.O. Box 475, Canberra, A.C.T. 2601.
A series of 3-acylaminomethyl-6-(chloro, iodo and methyl)-2-(phenyl, 40-t-butylphenyl, 40-cyclohexyl-
phenyl, biphenyl-40-yl, 40-chlorophenyl and 40-iodophenyl)imidazo[1,2-b]pyridazines and imidazo[1,2-
a]pyridines has been prepared and examined for interaction with central and mitochondrial (peripheral-
type) benzodiazepine receptors. The imidazo[1,2-b]pyridazines were generally more selective for the
mitochondrial receptors than the corresponding imidazo[1,2-a]pyridines. Of these compounds, 3-
acetamidomethyl-2-(biphenyl-40-yl)-6-chloroimidazo[1,2-b]pyridazine (9) proved to be the most selective
in studies of the displacement of [3H]diazepam from peripheral-type and central benzodiazepine receptors
(IC 2 8 nM and 0% displacement at 1000 nM, respectively).
50
Introduction
-bromoacetophenone,
one,7
cyclohexylacetophenone,2
-bromo-40-methylacetophen-
-bromo-40-t-butylacetophenone,2
-bromo-40-
In Part XX1 we reported the synthesis of some
3-acylaminomethyl-6-(chloro, uoro, methoxy, methyl-
thio, phenoxy and phenylthio)-2-(phenyl, 4-t-butyl-
phenyl, 4-cyclohexylphenyl, -naphthyl and styryl)imi-
dazo[1,2-b]pyridazines and their interaction with central
and mitochondrial (peripheral-type) benzodiazepine
receptors (BZR and PBR, respectively). Some of the
3-acylaminomethyl-6-chloroimidazo[1, 2-b]pyridazines
with relatively large substituents at the 2-position
were found to bind strongly and selectively to mito-
-bromo-40-phenylaceto-
phenone,8,9 -bromo-40-chloroacetophenone,10 and
-
bromo-40-iodoacetophenone,11 to give the 2,6-disub-
stituted imidazo[1,2-b]pyridazines (1; Y = H).
X
X
N
Y
N
N
N
N
Z
Y
Z
chondrial receptors.
We now describe an exten-
(1)
(2)
sion of this work to some new 3-acylaminomethyl-
6-(chloro and iodo)-2-(substituted phenyl)imidazo[1,2-
b]pyridazines and imidazo[1,2-a]pyridines (for compar-
ison) and we report the results of binding to both the
BZR and the PBR.
When these compounds (1; Y = H) were heated
with N -hydroxymethylacylamides, namely the N -
hydroxymethyl derivatives of formamide,12 acetamide,13
propionamide,14 butyramide,15 benzamide,13 or o-,
m- or p-chlorobenzamide,16,17 in acetic acid con-
taining a catalytic amount of sulfuric acid, they
gave the 3-acylaminomethylimidazo[1,2-b]pyridazines
(1; Y = CH2NHCOR).
The substituted imidazo[1,2-a]pyridines (2; Y = H
and CH2NHCOR) were prepared in an analogous
manner from pyridin-2-amine and 5-chloro- or 5-iodo-
pyridin-2-amine.18
Syntheses
The imidazo[1,2-b]pyridazines reported in this paper
were prepared by procedures similar to those previously
used by us for analogous compounds.1–3 The 6-chloro-4
and 6-methyl-pyridazin-3-amines,5 and 6-iodopyridazin-
3-amine (previously reported as the hydriodide6) were
condensed with the bromoacetyl compounds, namely
Part XX, Aust. J. Chem., 1996, 49, 451.
Manuscript received 24 July 1996
0004-9425/97/010061$ 05.00
10.1071/CH96130

62
G. B. Barlin, L. P. Davies and P. W. Harrison
Biological Activity
and 2-(biphenyl-40-yl) [(36) and (37)] compounds. The
6-iodo-2-(40-iodophenyl)imidazo[1,2-b]pyridazines (38)–
(40) exhibited very strong binding to the PBR: com-
The compounds reported in this paper were tested
for their ability to displace [3H]diazepam from the BZR
in rat forebrain membranes and from the PBR in rat
pounds (39) and (40) had IC values of 4 9 and 7 1
50
nM, respectively.
kidney membranes. Details of the test procedure for
19,20
Amongst the6-methylimidazo[1,2-b]pyridazines(41)–
(46), little selectivity was apparent between binding
to the BZR or the PBR.
the determination of binding to the BZR
and the
1,20,21
PBR
have been reported previously. The results of
these tests are recorded in Table 1 as IC values (nM)
50
A comparison of the 3-unsubstituted imidazo[1,2-
a]pyridines (49), (51) and (53) listed in Table 1 with the
corresponding imidazo[1,2-b]pyridazines (2), (5) and
(11) reveals that the imidazo[1,2-a]pyridines interacted
more stongly with both the BZR and the PBR. Whereas
the 3-benzamidomethyl derivatives of 2-phenyl- and
6-chloro-2-phenyl-imidazo[1,2-a]pyridine [(48) and (50)
respectively] were stronger ligands for the BZR than for
the PBR, the reverse applied to 3-benzamidomethyl-
6-chloro-2-phenylimidazo[1,2-b]pyridazine (4). Also,
3-benzamidomethyl-2-(40 -t-butylphenyl)-6-chloroimi-
dazo[1,2-a]pyridine (52) showed enhanced binding to
the PBR relative to the 2-phenyl analogue (50) but
it was signi cantly less than that shown by the
imidazo[1,2-b]pyridazine (7). The results for the 6-
chloro-2-(40-chlorophenyl)- [(53) and (54)] and 6-iodo-
2-(40-t-butylphenyl)-imidazo[1,2-a]pyridines [(55)–(57)]
did not indicate a signi cantly enhanced preference for
the PBR.
or as the percentage inhibition of binding at speci c
concentrations (in parentheses). The PBR binding data
have been measured also for some compounds for
which we have previously described the syntheses and
BZR a nities. Formula numbers are given for ease of
comparison in the text and substituents are de ned
in Table 1. GBLD numbers are also recorded (as in
earlier publications) in order to simplify comparisons
in forthcoming publications.
An examination of the data for the imidazo[1,2-
b]pyridazines in Table 1 reveals a very low a nity
of binding to the BZR for the 6-chloro-2-(biphenyl-40-
yl)imidazo-[1,2-b]pyridazines (8)–(10) compared to their
2-phenyl analogues (2)–(4), or their 2-(40-t-butylphenyl)
analogues (5)–(7) [and the 2-(40-cyclohexyl)phenyl
analogues].1 However, compounds (9) and (10) bound
strongly to the PBR: compound (9) bound more strongly
than its 2-(40-t-butylphenyl) analogue (6), whereas com-
pound (10) bound less strongly than compound (7). Of
the compounds (1)–(10), the 2-(biphenyl-40-yl) com-
pounds (9) and (10) were the most selective for the
PBR and of these the more active was compound (9)
In summary, appropriately substituted imidazo[1,2-
b]pyridazines examined in this work were found to be
better selective ligands for the PBR (relative to the
BZR) than the corresponding imidazo[1,2-a]pyridines.
(IC 2 8 nM).
50
Compound (1), which lacked the 6-chloro substituent,
bound moderately to the BZR but not to the PBR,
and compounds (2), (5) and (8), which lacked the
3-acylaminomethyl group, did not interact signi cantly
with either the BZR or the PBR.
Experimental
All compounds were examined for the presence of impurities
by thin-layer chromatography on alumina and by 1H n.m.r.
spectroscopy. Many compounds, as indicated in the descriptions
below, were puri ed by preparative t.l.c. on aluminium oxide
60 PF254+366 (type E).
Solids for analysis were dried at 100–120 /710 mmHg for
3–24 h unless speci ed otherwise. Melting points are uncor-
rected and were taken in open Pyrex capillaries. The light
petroleum used had a b.p. of 60–80 .
The 6-chloro-2-(40-chlorophenyl) compounds (11),
(13) and (16) bound more strongly than their 6-
chloro-2-phenyl analogues (2), (3) and (4) to both
the BZR and PBR; binding was stronger to the PBR.
The selectivity of the 2-(40-chlorophenyl) compounds
(12)–(16), relative to their 2-phenyl analogues, for the
PBR was relatively modest, and decreased progressively
in compounds (12)–(15) with increasing size of the
3-acylaminomethyl group. The selectivity in the series
(11)–(19) was greatest in compounds (17) and (19).
The 6-chloro-2-(40-iodophenyl)imidazo[1,2-b]pyrid-
Analyses were performed by the Australian National Uni-
versity Analytical Services Unit.
1H n.m.r. spectra ( values) were recorded from CDCl3
solutions (unless speci ed otherwise), with tetramethylsilane
as internal standard, and at 90 MHz and 30 with a Jeol
FX90Q Fourier-transform spectrometer possessing a digital
resolution of 0 12 Hz, or at 300 MHz on a Varian VXR 300
Fourier-transform spectrometer.
Low-resolution mass spectra were recorded on an Incos data
system attached to a VG-Micromass 7070 double-focusing mass
spectrometer by using electron ionization (e.i.) at 70 eV (under
the supervision of Dr J. K. MacLeod at the Research School
of Chemistry).
azines (21)–(25) bound to the PBR with IC values
50
little di erent from those for their 2-(40-chlorophenyl)
analogues, but their higher IC values for interaction
50
with the BZR increased their selectivity for interaction
with the PBR. Of these compounds, the most selective
-Bromo-4 0-iodoacetophenone
was compound (21) with IC values for the BZR and
50
Bromine (0 64 g, 4 mmol) was added dropwise over 15 min to
a solution of 40-iodoacetophenone (1 97 g, 4 mmol) in dry ether
(20 0 ml) containing anhydrous aluminium chloride (0 02 g)
at 0 and the stirring continued for 45 min. The ether was
removed under vacuum and the residue (2 53 g) was washed
with water, then ethanol, and dried. It was recrystallized from
PBR of 235 and 1 6 nM, respectively.
Amongst the 6-iodo compounds (26)–(40) the pref-
erence is for stronger binding to the PBR. This was
enhanced in the 3-acylaminomethyl-2-(40-t-butylphenyl)
[(30) and (31)], 2-(40-cyclohexylphenyl) [(33) and (34)]

Imidazo[1,2-b]pyridazines. XXI
63
Table 1. Results for the displacement of [3H]diazepam from the BZR and the PBR by substituted imidazo[1,2-b]pyridazines and
imidazo[1,2-a]pyridines
Assays for displacements from the BZR were conducted in the presence of 100
conditions described in Barlin, G. B., Davies, L. P., and Ngu, M. M. L., Aust. J. Chem., 1988, 41, 1149. Assays for displacements
M
-aminobutyric acid under the standard assay
from the PBR were conducted in the absence of -aminobutyric acid as described in Barlin, G. B., Davies, L. P., Harrison, P.
W., Ireland, S. J., and Willis, A. C., Aust. J. Chem., 1996, 49, 451. The results are given as IC values (nM), or as percentage
50
inhibitions of control binding at 1000 nM (in parentheses)
Class
of
compound
Com-
pound
No.
GBLD
Substituents in (1) or (2)
Y
(position 3)
IC (nM) (or percentage
50
No.
X
(position 6)
Z
(position 2)
displacementA)
BZR
PBR
Imidazo[1,2-b]pyridazine (1)
(1)
331
H
CH2NHCOPh
Ph
214B
>1000
(2)
(3)
(4)
325
318
302
Cl
Cl
Cl
H
Ph
Ph
Ph
>3000C
474C
(0%)D
177D
114D
CH2NHCOMe
CH2NHCOPh
140C
(5)
(6)
699
934
700
677
471
470
Cl
Cl
Cl
Cl
Cl
Cl
H
C6H4But-p
C6H4But-p
C6H4But-p
C6H4C6H5-p
C6H4C6H5-p
C6H4C6H5-p
(12%)B
(39%)D
(8%)B
(5%)
(0%)
(0 6%)
(4%)D
10D
CH2NHCOMe
CH2NHCOPh
H
CH2NHCOMe
CH2NHCOPh
(7)
6 2D
(19%)
2 8
(8)E
(9)
(10)E
13 3
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
584
945
943
938
940
812
932
930
931
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
C6H4Cl-p
(46%)C
(71%)
92
40
11
26
488
67
401
(14%)
CH2NHCOH
CH2NHCOMe
CH2NHCOEt
CH2NHCOPr
59
4
5
6
8
13
20
10
CH2NHCOPh
CH2NHCOC6H4Cl-o
CH2NHCOC6H4Cl-m
CH2NHCOC6H4Cl-p
(20)
(21)
(22)
(23)
(24)
(25)
946
951
947
948
949
950
Cl
Cl
Cl
Cl
Cl
Cl
H
C6H4I-p
C6H4I-p
C6H4I-p
C6H4I-p
C6H4I-p
C6H4I-p
(41%)
235
3362
(54%)
1 6
15
4 1
15
CH2NHCOMe
CH2NHCOPh
CH2NHCOC6H4Cl-o
CH2NHCOC6H4Cl-m
CH2NHCOC6H4Cl-p
329, (80%)
233, (85%)
370, (85%)
3 0
(26)
(27)
(28)
960
979
959
I
I
I
H
Ph
Ph
Ph
(18%)
(43%)
229, (76%)
(26%)
(90%)
(90%)
CH2NHCOMe
CH2NHCOPh
(29)
(30)
(31)
953
955
952
I
I
I
H
C6H4But-p
C6H4But-p
C6H4But-p
(2%)
(8%)
(9%)
(8%)
11
4 2
CH2NHCOMe
CH2NHCOPh
(32)
(33)
(34)
980
957
956
I
I
I
H
C6H4C6H11-p
C6H4C6H11-p
C6H4C6H11-p
(0%)
(2%)
(5%)
(0%)
88
67
CH2NHCOMe
CH2NHCOPh
(35)
(36)
(37)
981
958
954
I
I
I
H
C6H4C6H5-p
C6H4C6H5-p
C6H4C6H5-p
(0%)
(7%)
(0%)
(8%)
173
37
CH2NHCOMe
CH2NHCOPh
(38)
(39)
(40)
988
987
982
I
I
I
H
C6H4I-p
C6H4I-p
C6H4I-p
(0%)
(30%)
(61%)
(47%)
4 9, (93%)
7 1, (97%)
CH2NHCOMe
CH2NHCOPh
(41)
(42)
(43)
692
998
996
Me
Me
Me
H
Ph
Ph
Ph
(24%)
(62%)
(85%)
(0%)
(51%)
(59%)
CH2NHCOMe
CH2NHCOPh
(44)
(45)
(46)
999
1009
1001
Me
Me
Me
H
C6H4Me-p
C6H4Me-p
C6H4Me-p
(57%)
(81%)
25, (95%)
(2%)
(84%)
(89%)
CH2NHCOMe
CH2NHCOPh
Imidazo[1,2-a]pyridine (2)
(47)F
(48)
1007
1002
H
H
H
Ph
Ph
(6%)
(88%)
(17%)
(20%)
CH2NHCOPh
(49)
(50)
839
830
Cl
Cl
H
Ph
Ph
(26%)G
47G
(64%)
(65%)
CH2NHCOPh

64
G. B. Barlin, L. P. Davies and P. W. Harrison
Table 1 (Continued)
Class
of
compound
Com-
pound
No.
GBLD
Substituents in (1) or (2)
Y
(position 3)
IC (nM) (or percentage
50
No.
X
(position 6)
Z
(position 2)
displacementA)
BZR
PBR
Imidazo[1,2-a]pyridine (2)
(continued)
(51)
(52)
873
877
Cl
Cl
H
C6H4But-p
C6H4But-p
(47%)H
(7%)H
134D
487D
CH2NHCOPh
(53)I
(54)
1003
1000
Cl
Cl
H
C6H4Cl-p
C6H4Cl-p
(42%)
17, (96%)
(84%)
(86%)
CH2NHCOPh
(55)
(56)
(57)
1004
1005
1006
I
I
I
H
C6H4But-p
C6H4But-p
C6H4But-p
(11%)
(19%)
(13%)
(62%)
(71%)
(62%)
CH2NHCOMe
CH2NHCOPh
Diazepam
4 3
73
A
B
C
D
E
F
G
At 1000 nM.
Ref. 2.
Ref. 17.
Ref. 1.
Syntheses reported in ref. 9.
H
Ref. 23.
Barlin, G. B.,
Davies, L. P., and Harrison, P. W., Aust. J. Chem., 1995, 48, 1031.
and 3% respectively.
The values given in ref. 1 for GBLD 873 and 877 are 43
I
Ref. 24.
light petroleum and gave the title compound (1 20 g, 46%),
m.p. 111–113 (lit.11 113 5 ) (Found, for a sample dried at 50
and 1 mmHg for 6 h: C, 29 8; H, 1 6. Calc. for C8H6BrIO:
C, 29 6; H, 1 9%). 1H n.m.r.: 4 39, s, CH2; 7 68, d, J 8 5
Hz, H 30,50 (or 20,60); 7 88, d, J 8 5 Hz, H 20,60 (or 30,50).
(or 20,60); 7 61, d, J 9 5 Hz, H 8; 7 87, d, J 8 5 Hz, H 20,60
(or 30,50); 8 20, s, H 3.
2-(Biphenyl-4 0-yl)-6-iodoimidazo[1,2-b]pyridazine
(35)
(70%), m.p. 252–253 (from toluene) (Found: C, 54 2; H, 2 8.
C
18H10IN3 requires C, 54 4; H, 3 0%). 1H n.m.r.:
7 31,
d, J 9 5 Hz, H 7; 7 38–7 74, complex, H 8,30,50 (or 20,60) and
Ph; 8 02, d, J 8 5 Hz, H 20,60 (or 30,50); 8 28, s, H 3. Mass
spectrum: m/z 397 (M, 100%), 368 (14), 313 (9), 270 (15).
6-Iodopyridazin-3-amine
6-Chloropyridazin-3-amine4 (1 04 g, 8 mmol) and 50% hydri-
odic acid (8 0 ml) were heated with stirring in an oil bath
at 110 for 14 h and then cooled. The precipitate (1 80 g)
was ltered o and washed with ethyl acetate. This solid was
suspended in 1 N sodium hydroxide (30 ml) and the mixture
stirred for 10 min. The pale yellow 6-iodopyridazin-3-amine
(1 18 g, 67%) was ltered o and dried. It had m.p. 161–161 5
(Found: C, 21 8; H, 1 5; N, 19 1. C4H4IN3 requires C, 21 7;
6-Iodo-2-(4 0-iodophenyl)imidazo[1,2-b]pyridazine
(38)
(60%), m.p. 266–267 (from toluene) (Found: C, 32 4; H,
1 3; N, 9 2. C12H7I2N3 requires C, 32 2; H, 1 6; N, 9 4%).
1H n.m.r.: 7 31, d, J 9 5 Hz, H 7; 7 63, d, J 9 5 Hz, H 8;
7 67, d, J 8 5 Hz, H 30,50 (or 20,60); 7 81, d, J 8 5 Hz, H 20,60
(or 30,50); 8 22, s, H 3.
6-Methyl-2-phenylimidazo[1,2-b]pyridazine (41) (78%), m.p.
162–163 (from ethanol) (lit.22 157–158 ) (Found: C, 74 2;
H, 5 7; N, 20 1. Calc. for C13H11N3: C, 74 6; H, 5 3; N,
H, 1 8; N, 19 0%). 1H n.m.r. (CD3SOCD3):
4 64, br s,
NH2; 6 75, d, J 9 5 Hz, H 5; 7 70, d, J 9 5 Hz, H 4.
20 1%). 1H n.m.r.:
2 55, s, CH3; 6 87, d, J 9 5 Hz, H 7;
6-Chloro-2-(4 0-iodophenyl)imidazo[1,2-b]pyridazine (20) and
Related Compounds
7 81, d, J 9 5 Hz, H 8; 7 30–7 55 and 7 86–8 02, complex,
Ph; 8 16, s, H 3.
6-Methyl-2-(4 0-methylphenyl)imidazo[1,2-b]pyridazine (44)
(54%), m.p. 165 5–166 5 (from ethanol) (Found: C, 74 9; H,
5 8; N, 18 7. C14H13N3 requires C, 75 3; H, 5 9; N, 18 8%).
1H n.m.r.: 2 39, s, 40-Me; 2 56, s, 6-Me; 6 89, d, J 9 5 Hz,
H 7; 7 25, d, J 8 5 Hz, H 20,60 (or 30,50); 7 82, d, J 9 5 Hz,
H 8; 7 85, d, J 8 5 Hz, H 30,50 or (20,60); 8 13, s, H 3.
A mixture of 6-chloropyridazin-3-amine4 (0 19 g, 1 5 mmol)
and -bromo-40-iodoacetophenone11 (0 49 g, 1 5 mmol) in
ethanol (15 ml) was re uxed for 3 h. Sodium hydrogen car-
bonate (0 12 g, 1 5 mmol) was then added and the re uxing
continued for 3 h. After being cooled, the precipitate (0 14 g,
77%) was collected and recrystallized from ethanol to give the
title compound (20) (0 28 g), m.p. 228–229 (Found: C, 40 9;
3-Acetamidomethyl-2-(biphenyl-4 0-yl)-6-chloroimidazo-
[1,2-b]pyridazine (9)
H, 1 6; N, 11 8.
C
12H7ClIN3 requires C, 40 5; H, 2 0; N,
7 06, d, J 9 5 Hz, H 7; 7 67, d, 7 80,
11 8%). 1H n.m.r.:
2-(Biphenyl-40-yl)-6-chloroimidazo[1,2-b]pyridazine9 (4 0 g,
13 mmol) was added to a mixture of N -hydroxymethylaceta-
mide13 (2 3 g, 26 mmol) in acetic acid (100 ml) containing
concentrated sulfuric acid (0 20 ml) and the mixture was
re uxed with stirring in an oil bath at 120 for 14 h. The acetic
acid was then evaporated under reduced pressure, the residue
diluted with water, aqueous 25% ammonium hydroxide added
to pH 10, and the mixture was extracted with chloroform.
The solvent was evaporated and the product was recrystallized
from toluene to give the title compound (9) (1 317 g, 27%),
m.p. 276–278 (Found: C, 66 8; H, 4 4; N, 14 7. C21H17ClN4O
d, J 8 Hz, H 20,30,50,60; 7 89, d, J 9 5 Hz, H 8; 8 19, s, H 3.
Mass spectrum: m/z 357 (45%), 355 (M, 100), 228 (21), 193
(40), 107 (48).
In a similar manner from the compounds mentioned above (or
from the compounds under Syntheses) the following compounds
were prepared.
6-Iodo-2-phenylimidazo[1,2-b]pyridazine (26) (53%), m.p.
194–196 (from ethanol) (Found: C, 45 2; H, 2 4; N, 13 0.
C
12H8IN3 requires C, 44 9; H, 2 5; N, 13 1%). 1H n.m.r.:
7 31, d, J 9 5 Hz, H 7; 7 38–7 48 and 7 90–8 02, complex,
Ph; 7 65, d, J 9 5 Hz, H 8; 8 24, s, H 3.
requires C, 66 9; H, 4 5; N, 14 9%). 1H n.m.r.:
2 08, s,
2-(4 0-t-Butylphenyl)-6-iodoimidazo[1,2-b]pyridazine
(29)
(49%), m.p. 174–175 (from ethanol) (Found: C, 51 1; H, 4 2;
Me; 5 10, d, J 5 5 Hz, CH2; 6 38, br s, NH; 7 15, d, J 9 5
Hz, H 7; 7 36–7 79, complex, and 8 10, d, J 8 Hz, C6H4Ph;
7 98, d, J 9 5 Hz, H 8.
N, 11 0.
C16H16IN3 requires C, 50 9; H, 4 3; N, 11 1%).
1H n.m.r.: 1 36, s, CMe3; 7 28, d, J 9 5 Hz, H 7; 7 49, d,
J 8 Hz, H 30,50 (or 20,60); 7 63, d, J 9 5 Hz, H 8; 7 89, d, J 8
Hz, H 20,60 (or 30,50); 8 22, s, H 3.
6-Chloro-2-(4 0-chlorophenyl)-3-formamidomethylimidazo-
[1,2-b]pyridazine (12)
2-(4 0 -Cyclohexylphenyl) -6 -iodoimidazo[1 , 2 -b]pyridazine
(32) (48%), m.p. 244–246 (from ethanol) (Found: C, 54 1; H,
4 5; N, 10 4. C18H18IN3 requires C, 53 6; H, 4 5; N, 10 4%).
1H n.m.r.: 7 28, d, J 9 5 Hz, H 7; 7 28, d, J 8 5 Hz, H 30,50
A
mixture of 6-chloro-2-(4 0-chlorophenyl)imidazo[1,2-b]-
pyridazine17 (0 2 g, 0 76 mmol), N -hydroxymethylformamide12
(0 2 g, 2 7 mmol), acetic acid (4 ml) and concentrated sulfuric

Imidazo[1,2-b]pyridazines. XXI
65
acid (0 05 ml) was heated with stirring under re ux in an
oil bath at 120 for 14 h. The acetic acid was evaporated
under vacuum, the residue diluted with water, adjusted to pH
10, and extracted with chloroform. The extract was washed
with water, dried (Na2SO4) and the solvent evaporated. The
product was subjected to t.l.c. (alumina; chloroform) and
recrystallized from toluene to give the title compound (12)
(0 054 g, 22%), m.p. 237–239 (Found: C, 52 5; H, 2 9; N,
stallization from toluene] (Found: C, 56 0; H, 2 9; N, 12 9.
C20H13Cl3N4O requires C, 55 6; H, 3 0; N, 13 0%). 1H n.m.r.:
5 21, d, J 5 5 Hz, CH2; 7 13, d, J 9 5 Hz, H 7; 7 30–8 08,
complex, H 8,30,40,50,60,200,300,500,600. Mass spectrum: m/z 432,
430 (M, 8%), 293 (75), 291 (100), 139 (45).
6-Chloro-3-(3 0-chlorobenzamidomethyl)-2-(4 00-chlorophen-
yl)imidazo[1,2-b]pyridazine (18) (35%), m.p. 234–235 [after
t.l.c. (alumina; chloroform/light petroleum, 3 : 1) and recrys-
tallization from toluene] (Found: C, 55 7; H, 3 0; N, 12 8.
17 1.
C14H10Cl2N4O requires C, 52 4; H, 3 1; N, 17 4%).
1H n.m.r.: 5 03, d, J 5 5 Hz, CH2; 7 12, d, J 9 5 Hz, H 7;
7 47, d, 7 94, d, J 8 5 Hz, H 20,30,50,60; 7 82, d, J 9 5 Hz,
H 8; 8 26, br s, CHO.
C
20H13Cl3N4O requires C, 55 6; H, 3 0; N, 13 0%). 1H n.m.r.:
5 19, d, J 5 5 Hz, CH2N; 7 14, d, J 9 5 Hz, H 7; 7 27–8 04,
complex, H 8,20,40,50,60,200,300,500,600. Mass spectrum: m/z 432,
430 (M, 10%), 293 (75), 291 (100), 255 (15), 139 (42).
6-Chloro-3-(4 0-chlorobenzamidomethyl)-2-(4 00-chlorophen-
yl)imidazo[1,2-b]pyridazine (19) (35%), m.p. 236–237 [after
t.l.c. (alumina; chloroform/light petroleum, 3 : 1) and recrys-
tallization from toluene] (Found: C, 55 9; H, 2 9; N, 12 7.
3-Benzamidomethyl-6-chloro-2-(4 0-iodophenyl)imidazo-
[1,2-b]pyridazine (22) and Related Compounds
A mixture of 6-chloro-(40-iodophenyl)imidazo[1,2-b]pyrid-
azine (0 18 g, 0 5 mmol), N -hydroxymethylbenzamide13
(0 076 g, 0 5 mmol), glacial acetic acid (5 ml) and concentrated
sulfuric acid (0 09 ml) was heated with stirring under re ux in
an oil bath at 120 for 14 h. The acetic acid was evaporated
under vacuum, the residue diluted with water, adjusted to
pH 10, and extracted with chloroform. The product obtained
was subjected to t.l.c. (alumina; chloroform/light petroleum,
2 : 1) and recrystallized from toluene to give the title compound
(22) (0 08 g, 33%), m.p. 267–268 (Found: C, 49 4; H, 2 7.
C
20H13Cl3N4O requires C, 55 6; H, 3 0; N, 13 0%). 1H n.m.r.:
5 18, d, J 5 5 Hz, CH2N; 7 13, d, J 9 5 Hz, H 7; 7 35–8 05,
complex, H 8,20,30,50,60,200,300,500,600. Mass spectrum: m/z 432,
430 (M, 8%), 293 (72), 291 (100), 255 (13), 139 (45).
3-Acetamidomethyl-6-chloro-2-(4 0-iodophenyl)imidazo[1,2-
b]pyridazine (21) (33%), m.p. 300–301 [after t.l.c. (alumina;
chloroform/light petroleum, 2 : 1) and recrystallization from
toluene] (Found: C, 42 7; H, 2 6. C15H12ClIN4O requires C,
42 2; H, 2 8%). 1H n.m.r.: 2 07, s, CH3; 5 02, d, J 5 5 Hz,
CH2; 6 35, br s, NH; 7 16, d, J 9 5 Hz, H 7; 7 81, d, 7 88, d,
J 8 Hz, H 20,30,50,60; 7 96, d, J 9 5 Hz, H 8. Mass spectrum:
m/z 428 (9%), 426 (M, 25), 383 (100), 349 (20), 256 (21).
6-Chloro-3-(2 0-chlorobenzamidomethyl)-2-(400-iodophenyl)-
imidazo[1,2-b]pyridazine (23) (4%), as cream crystals, m.p. 218–
220 [after t.l.c. (alumina; chloroform/light petroleum, 3 : 1)
and recrystallization from toluene] (Found: C, 46 1; H, 2 8;
N, 10 5. C20H13Cl2IN4O requires C, 45 9; H, 2 5; N, 10 7%).
1H n.m.r.: 5 21, d, J 5 5 Hz, CH2; 7 13, d, J 9 5 Hz, H 7;
7 30–7 42, 7 66–7 74 and 7 76–7 89, complex, H 30,40,50,60
and ArH; 7 92, d, J 9 5 Hz, H 8. Mass spectrum: m/z 524,
522 (M, 1 5, 3%), 347 (100), 278 (45), 187 (67), 172 (40), 128
(55).
C
20H14ClIN4O requires C, 49 1; H, 2 9%). 1H n.m.r.: 5 22,
d, J 5 5 Hz, CH2; 7 15, d, J 9 5 Hz, H 7; 7 40–7 55 and
7 80–7 90, complex, Ph and H 20,30,50,60; 7 95, d, J 9 5 Hz,
H 8. Mass spectrum: m/z 490, 488 (M, 3, 11%), 385 (37), 383
(100), 105 (50), 91 (40), 77 (45).
In a similar manner the following compounds were prepared.
3-Acetamidomethyl-6-chloro-2-(4 0 -chlorophenyl)imidazo-
[1,2-b]pyridazine (13) (62%), m.p. 258–261 [after t.l.c. (alu-
mina; chloroform) and recrystallization from ethanol] (Found:
C, 53 6; H, 3 6; N, 16 5.
C15H12Cl2N4O requires C, 53 7;
H, 3 6; N, 16 7%). 1H n.m.r.: 2 02, s, CH3; 4 98, d, J 5 5
Hz, CH2; 6 37, br s, NH; 7 11, d, J 9 5 Hz, H 7; 7 46, d,
7 96, d, J 8 5 Hz, H 20,30,50,60; 7 83, d, J 9 5 Hz, H 8.
6-Chloro-2-(4 0 -chlorophenyl)-3-propionamidomethylimid-
azo[1,2-b]pyridazine (14) (77%), m.p. 227 5–229 [after t.l.c.
(alumina; chloroform/light petroleum, 2 : 3 then 1 : 1) and
recrystallization from ethanol] (Found: C, 54 7; H, 4 3; N,
6-Chloro-3-(3 0-chlorobenzamidomethyl)-2-(4 00-iodophenyl)-
imidazo[1,2-b]pyridazine (24)(27%), asyellowcrystals, m.p. 222–
224 [after t.l.c. (alumina; chloroform/light petroleum, 2 : 1)
and recrystallization from toluene] (Found: C, 46 5; H, 2 1;
N, 10 4. C20H13Cl2IN4O requires C, 45 9; H, 2 5; N, 10 7%).
1H n.m.r.: 5 19, d, J 5 5 Hz, CH2; 7 15, d, J 9 5 Hz, H 7;
7 30–7 68, complex, H 20,40,50,60; 7 78, d, J 8 Hz, 7 85, d, J
8 Hz, H 200,300,500,600; 7 93, d, J 9 5 Hz, H 8. Mass spectrum:
m/z 524, 522 (M, 31, 50%), 383 (100), 149 (60), 57 (30).
6-Chloro-3-(4 0-chlorobenzamidomethyl)-2-(4 00-iodophenyl)-
imidazo[1,2-b]pyridazine (25) (58%), as a white solid, m.p. 260–
261 [after t.l.c. (alumina; chloroform/light petroleum, 2 : 1)
and recrystallization from toluene] (Found: C, 45 7; H, 2 7;
N, 10 5. C20H13Cl2IN4O requires C, 45 9; H, 2 5; N, 10 7%).
15 8.
C16H14Cl2N4O requires C, 55 0; H, 4 0; N, 16 0%).
1H n.m.r.: 1 23, t, J 7 Hz, CH3; 2 25, q, J 7 Hz, CH3CH2;
4 99, d, J 5 5 Hz, CH2N; 6 39, br s, NH; 7 12, d, J 9 5 Hz,
H 7; 7 45, d, 7 96, d, J 8 5 Hz, H 20,30,50,60; 7 91, d, J 9 5
Hz, H 8.
3-Butyramidomethyl-6-chloro-2-(4 0 -chlorophenyl)imidazo-
[1,2-b]pyridazine (15) (43%), m.p. 194–195 [after t.l.c. (alu-
mina; chloroform/light petroleum, 1 : 1) and recrystallization
from ethanol] (Found: C, 55 8; H, 4 4; N, 15 4. C17H16Cl2N4O
requires C, 56 2; H, 4 4; N, 15 4%). 1H n.m.r.:
0 93, t,
1H n.m.r.:
5 19, d, J 5 5 Hz, CH2; 7 14, d, J 9 5 Hz,
H 7; 7 43, d, 7 75, d, J 8 Hz, H 20,30,50,60; 7 85, d, J 8 Hz,
H 200,300,500,600; 7 92, d, J 9 5 Hz, H 8. Mass spectrum: m/z
524, 522 (M, 7, 13%), 385 (46), 383 (100), 139 (42).
J 7 Hz, CH3; 1 67, q, J 7 Hz, CH3CH2; 2 16, dt, J 7 Hz,
CH3CH2CH2; 5 99, d, J 5 5 Hz, CH2N; 6 33, br s, NH; 7 09,
d, J 9 5 Hz, H 7; 7 45, d, 7 95, d, J 8 5 Hz, H 20,30,50,60;
8 90, d, J 9 5 Hz, H 8.
3-Acetamidomethyl-6-iodo-2-phenylimidazo[1,2-b]pyridazine
(27) (15%), m.p. 251–252 (from toluene) (Found: C, 45 9;
3-Benzamidomethyl-6-chloro-2-(4 0 -chlorophenyl)imidazo-
[1,2-b]pyridazine (16) (29%), m.p. 237–238 [after t.l.c. (alu-
mina; chloroform/light petroleum, 3 : 1) and recrystallization
from toluene] (Found: C, 60 6; H, 3 5; N, 14 1. C20H14Cl2N4O
H, 3 2; N, 13 7.
C
15H13IN4O requires C, 45 9; H, 3 3;
2 03, s, Me; 5 03, d, J 5 5 Hz,
N, 14 3%). 1H n.m.r.:
CH2; 6 24, br s, NH; 7 36, d, J 9 5 Hz, H 7; 7 43–7 60
and 7 91–8 02, complex, Ph; 7 66, d, J 9 5 Hz, H 8. Mass
spectrum: m/z 392 (M, 26%), 349 (100), 301 (4), 223 (49).
3-Benzamidomethyl-6-iodo-2-phenylimidazo[1,2-b]pyridazine
(28) (43%), m.p. 223–224 (from toluene) (Found: C, 52 8;
requires C, 60 5; H, 3 6; N, 14 1%). 1H n.m.r.:
5 20,
d, J 5 5 Hz, CH2; 7 11, d, J 9 5 Hz, H 7; 7 40–7 52 and
7 72–8 06, complex, H 8,20,30,50,60 and Ph. Mass spectrum:
m/z 400, 398, 396 (M, 2, 6, 8%), 295 (17), 293 (70), 291 (100),
105 (38).
6-Chloro-3-(2 0-chlorobenzamidomethyl)-2-(4 00-chlorophen-
yl)imidazo[1,2-b]pyridazine (17) (68%), m.p. 239–240 [after
t.l.c. (alumina; chloroform/light petroleum, 3 : 1) and recry-
H, 3 2; N, 12 0.
C20H15IN4O requires C, 52 9; H, 3 3; N,
12 3%). 1H n.m.r.: 5 24, d, J 5 5 Hz, CH2; 7 19, br s, NH;
7 34, d, J 9 5 Hz, H 7; 7 40–7 51 and 7 74–8 05, complex,
2
Ph; 7 63, d, J 9 5 Hz, H 8.

66
G. B. Barlin, L. P. Davies and P. W. Harrison
3-Acetamidomethyl-2-(4 0-t-butylphenyl)-6-iodoimidazo[1,2-
b]pyridazine (30) (22%), m.p. 223–224 (from toluene) (Found:
toluene] (Found: C, 69 5; H, 6 0; N, 19 1. C17H18N4O
requires C, 69 4; H, 6 2; N, 19 0%). 1H n.m.r.:
2 05, s,
C, 50 9; H, 4 7; N, 12 5. C19H21IN4O requires C, 50 9; H,
CH3CO; 2 42, s, 40-CH3; 2 60, s, 6-CH3; 5 00, d, J 5 5 Hz,
CH2; 6 58, br s, NH; 6 92, d, J 9 5 Hz, H 7; 7 27, d, J 8 Hz,
7 79, d, J 9 Hz, H 8,20,30,50,60.
4 7; N, 12 5%). 1H n.m.r.:
1 36, s, CMe3; 2 02, s, Me;
5 02, d, J 5 5 Hz, CH2; 6 33, br s, NH; 7 32, d, J 9 5 Hz,
H 7; 7 51, d, J 9 Hz, H 30,50 (or 20,60); 7 62, d, J 9 5 Hz, H 8;
7 89, d, J 9 Hz, H 20,60 (or 30,50).
3-Benzamidomethyl-6-methyl-2-(4 0 -methylphenyl)imidazo-
[1,2-b]pyridazine (46) (70%), m.p. 203–204 [after t.l.c. (alu-
mina; chloroform) and recrystallization from cyclohexane or
3-Benzamidomethyl-2-(4 0-t-butylphenyl)-6-iodoimidazo[1,2-
b]pyridazine (31) (54%), m.p. 216–218 (from toluene) (Found:
C, 56 8; H, 4 2; N, 10 9. C24H23IN4O requires C, 56 5; H,
toluene] (Found: C, 74 0; H, 5 6; N, 15 4.
C
22H20N4O
2 42, s,
requires C, 74 1; H, 5 7; N, 15 7%). 1H n.m.r.:
4 5; N, 11 0%). 1H n.m.r.:
1 35, s, CMe3; 5 25, d, J 5 5
40-Me; 2 65, s, 6-Me; 5 26, d, J 5 5 Hz, CH2; 6 99, d, J 9 5
Hz, H 7; 7 12, br s, NH; 7 31–7 50 and 7 77–7 92, complex,
H 8,20,30,50,60 and Ph.
Hz, CH2; 7 31, d, J 9 5 Hz, H 7; 7 35–7 83, complex, Ph;
7 52, d, J 9 Hz, H 30,50 (or 20,60); 7 72, d, J 9 5 Hz, H 8;
7 93, d, J 9 Hz, H 20,60 (or 30,50).
3-Acetamidomethyl-2-(4 0-cyclohexylphenyl)-6-iodoimidazo-
[1,2-b]pyridazine (33) (32%), m.p. 235–236 (from toluene)
(Found: C, 52 9; H, 4 8; N, 11 5. C21H23IN4O requires C,
3-Benzamidomethyl-2-phenylimidazo[1,2-a]pyridine (48)
A mixture of 2-phenylimidazo[1,2-a]pyridine23 (0 2 g,
1
mmol), N -hydroxymethylbenzamide13 (0 233 g, 1 5 mmol),
acetic acid (5 ml) and concentrated sulfuric acid (0 05 ml) was
heated under re ux with stirring in an oil bath at 116 for
14 h. The acetic acid was evaporated, the residue diluted
with water, adjusted with ammonium hydroxide to pH 10, and
the mixture extracted with chloroform. The product obtained
was subjected to t.l.c. (alumina; chloroform) and recrystal-
lized from toluene to give the title compound (0 180 g, 53%),
m.p. 199–200 (Found: C, 77 1; H, 5 4; N, 12 9. C21H17N3O
requires C, 77 0; H, 5 2; N, 12 8%). 1H n.m.r.: 4 94, d, J
5 5 Hz, CH2; 6 65, t, J 6 5 Hz, 7 05, t, J 6 5 Hz, 7 18–7 49,
7 77, t, J 6 5 Hz, 7 84, d, J 7 Hz, 8 08, d, J 7 Hz, H 5,6,7,8
and 2 Ph.
53 2; H, 4 9; N, 11 8%). 1H n.m.r.:
1 25–1 90, complex,
cyclohexyl; 2 02, s, Me; 5 02, d, J 5 5 Hz, CH2; 6 29, br s,
NH; 7 34, d, J 9 5 Hz, H 7; 7 34, d, J 8 5 Hz, H 30,50 (or
20,60); 7 63, d, J 9 5 Hz, H 8; 7 87, d, J 8 5 Hz, H 20,60 (or
30,50).
3-Benzamidomethyl-2-(4 0-cyclohexylphenyl)-6-iodoimidazo-
[1,2-b]pyridazine (34) (52%), m.p. 239–241 (from toluene)
(Found: C, 58 2; H, 4 6; N, 10 3. C26H25IN4O requires C,
58 2; H, 4 7; N, 10 4%). 1H n.m.r.:
1 25–1 90, complex,
cyclohexyl; 5 23, d, J 5 5 Hz, CH2; 7 30, d, J 9 5 Hz, H 7;
7 27–7 50 and 7 74–7 80, complex, H 30,50 (or 20,60) and Ph;
7 60, d, J 9 5 Hz, H 8; 7 88, d, J 8 5 Hz, H 20,60 (or 30,50).
3-Acetamidomethyl-2-(biphenyl-4 0 -yl)-6-iodoimidazo[1,2-
b]pyridazine (36) (21%), m.p. 247–248 (from toluene) (Found:
C, 54 9; H, 3 6; N, 11 6. C21H17IN4O.0 15C7H8 requires C,
54 9; H, 3 8; N, 11 6%). 1H n.m.r.: 2 05, s, Me; 5 07, d, J
5 5 Hz, CH2; 7 26–8 13, complex, H 7,8,20,30,50,60 and ArH.
3-Benzamidomethyl-2-(biphenyl-4 0 -yl)-6-iodoimidazo[1,2-
b]pyridazine (37) (19%), m.p. 223–225 (from toluene) (Found:
3-Benzamidomethyl-6-chloro-2-(4 0-chlorophenyl)imidazo-
[1,2-a]pyridine (54)
Amixtureof6-chloro-2-(40-chlorophenyl)imidazo[1,2-a]pyrid-
ine24 [1H n.m.r.: 7 17, dd, J7,8 9 5 Hz, J5,7 2 Hz, H 7; 7 42,
d, J 8 Hz, H 20,60 (or 30,50); 7 59, d, J 9 5 Hz, H 8; 7 83, s,
H 3; 7 87, d, J 8 Hz, H 30,50 (or 20,60); 8 18, br s, H 5] (0 20 g,
0 87 mmol), N -hydroxymethylbenzamide (0 198 g, 1 3 mmol),
acetic acid (5 ml) and concentrated sulfuric acid (0 05 ml) was
heated under re ux with stirring in an oil bath at 116 for 4 h.
The acetic acid was evaporated, the residue diluted with water,
adjusted with ammonium hydroxide to pH 10, and extracted
with chloroform. The product was recrystallized from toluene
and the crystalline solid (0 240 g, 69%) after t.l.c. (alumina;
chloroform) and recrystallization from toluene gave the title
compound (54), m.p. 260–261 (Found: C, 64 0; H, 4 1; N,
C, 59 0; H, 3 3.
C26H19IN4O requires C, 58 9; H, 3 6%).
1H n.m.r.: 5 28, d, J 5 5 Hz, CH2; 7 35, d, J 9 5 Hz, H 7;
7 38–7 88, complex, H 30,50 (or 20,60) and 2 Ph; 7 65, d, J
9 5 Hz, H 8; 8 09, d, J 8 Hz, H 20,60 (or 30,50).
3-Acetamidomethyl-6-iodo-2-(4 0 -iodophenyl)imidazo[1,2-
b]pyridazine (39) (19%), m.p. 242–243 (from toluene) (Found:
C, 34 3; H, 2 0. C15H12I2N4O requires C, 34 8; H, 2 3%).
Mass spectrum: m/z 518 (M, 43%), 475 (100), 447 (9), 394
(4), 368 (12), 349 (45).
3-Benzamidomethyl-6-iodo-2-(4 0 -iodophenyl)imidazo[1,2-
b]pyridazine (40) (9%), m.p. 237–238 (from toluene) (Found:
C, 41 7; H, 2 4. C20H14I2N4O requires C, 41 4; H, 2 4%).
1H n.m.r.: 5 21, d, J 5 5 Hz, CH2; 7 38, d, J 9 5 Hz, H 7;
7 30–7 52 and 7 74–7 85, complex, H 20,30,50,60 and Ph; 7 67,
d, J 9 5 Hz, H 8. Mass spectrum: m/z 580 (M, 18%), 475
(100), 349 (12), 105 (60).
10 4.
C21H15Cl2N3O requires C, 63 6; H, 3 8; N, 10 6%).
1H n.m.r.: 5 12, d, J 5 5 Hz, CH2; 6 61, br s, NH; 7 23, d,
J 9 Hz, H 7; 7 42–7 57, complex, 7 86, d, J 8 Hz, H 20,30,50,60
and Ph; 7 66, d, J 9 Hz, H 8; 8 41, br s, H 5.
2-(4 0-t-Butylphenyl)-6-iodoimidazo[1,2-a]pyridine (55)
A mixture of 5-iodopyridin-2-amine18 (1 0 g, 4 5 mmol),
-
3-Acetamidomethyl-6-methyl-2-phenylimidazo[1,2-b]pyrid-
azine (42) (29%), m.p. 240–242 [after t.l.c. (alumina; chlo-
roform) and recrystallization from toluene] (Found: C, 68 5;
bromo-40-t-butylacetophenone2 (1 15 g, 4 5 mmol) in ethanol
(25 ml) was re uxed with stirring in an oil bath at 105 for
4 h. Sodium hydrogen carbonate (0 38 g, 4 5 mmol) was then
added and the re uxing continued for 12 h. The solvent was
removed under reduced pressure, the residue diluted with water
and the product (1 93 g) extracted into chloroform. It was
recrystallized from cyclohexane with charcoal ltration to give
the title compound (55) (0 783 g, 46%), m.p. 110–112 (Found,
for a sample dried at 80 and 710 mmHg for 4 h: C, 54 2; H,
4 5; N, 7 2. C17H17IN2 requires C, 54 3; H, 4 6; N, 7 4%).
1H n.m.r.: 1 39, s, CMe3; 7 34–7 39, 7 46–7 52, 7 88–7 92,
complex, H 7,8,20,30,50,60; 7 81, s, H 3; 8 41, m, H 5.
H, 5 6; N, 19 9.
C
16H16N4O requires C, 68 6; H, 5 8; N,
2 04, s, MeCO; 2 62, s, 6-Me; 5 03,
20 0%). 1H n.m.r.:
d, J 5 5 Hz, CH2; 6 42, br, NH; 6 96, d, J 9 5 Hz, H 7;
7 38–7 52, complex, and 7 92–7 96, complex, Ph; 7 84, d, J
9 5 Hz, H 8.
3-Benzamidomethyl-6-methyl-2-phenylimidazo[1,2-b]pyrid-
azine (43) (65%), m.p. 219–220 [after t.l.c. (alumina; chlo-
roform) and recrystallization from toluene] (Found: C, 73 7;
H, 5 3; N, 16 1.
C
21H18N4O requires C, 73 7; H, 5 3; N,
2 66, s, Me; 5 27, d, J 5 5 Hz, CH2;
16 4%). 1H n.m.r.:
7 00, d, J 9 5 Hz, H 7; 7 19, br s, NH; 7 41–7 56, 7 77–7 81
and 7 99–8 04, complex, 2 Ph; 7 89, d, J 9 5 Hz, H 8.
3-Acetamidomethyl-6-methyl-2-(4 0 -methylphenyl)imidazo-
[1,2-b]pyridazine (45) (5%), m.p. 249–251 [after t.l.c. (alu-
mina; chloroform, developed twice) and recrystallization from
3-Acetamidomethyl-2-(4 0-t-butylphenyl)-6-iodoimidazo-
[1,2-a]pyridine (56)
A
mixture of the imidazo[1,2-a]pyridine (55) (0 2 g,
0 5 mmol), N -hydroxymethylacetamide (0 122 g, 1 4 mmol),

Imidazo[1,2-b]pyridazines. XXI
67
acetic acid (4 ml) and concentrated sulfuric acid (0 05 ml) was
heated with stirring under re ux in an oil bath at 120 for
14 h. The acetic acid was evaporated under reduced pressure,
the residue diluted with water, ammonium hydroxide added
to pH 10–11, and the mixture extracted with chloroform.
The glassy product (0 267 g) obtained from the extract was
subjected to t.l.c. (alumina; chloroform/light petroleum, 1 : 1,
developed twice), and the solid (0 126 g) from the band at low
RF was recrystallized from toluene to give the title compound
(56) (0 038 g, 16%), m.p. 253–255 (Found: C, 53 7; H, 4 7;
References
1
Barlin, G. B., Davies, L. P., Harrison, P. W., Ireland, S.
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Barlin, G. B., Davies, L. P., Glenn, B., Harrison, P. W.,
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2
3
4
5
N, 9 1.
C20H22IN3O requires C, 53 7; H, 5 0; N, 9 4%).
1H n.m.r.: 1 33, s, CMe3; 2 02, s, CH3; 4 71, d, J 5 5 Hz,
CH2; 7 09, t, NH; 7 17–7 41, complex, H 7,8,20,30,50,60; 8 36,
s, H 5.
6
7
3-Benzamidomethyl-2-(4 0-t-butylphenyl)-6-iodoimidazo[1,2-a]-
pyridine (57)
8
Drake, N. L., and Bronitsky, J. J., J. Am. Chem. Soc.,
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Barlin, G. B., Davies, L. P., Ireland, S. J., and Zhang, J.,
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This compound was prepared in a similar manner from 2-(4 0-
t-butylphenyl)-6-iodoimidazo[1,2-a]pyridine (0 2 g, 0 5 mmol)
and N -hydroxymethylbenzamide (0 12 g, 0 79 mmol). The
product was extracted into chloroform and the glass-like mate-
rial (0 309 g) was recrystallized from toluene to give a white
solid (0 214 g, 79%). Part of this material was subjected to
t.l.c. (alumina; chloroform, developed twice), and the major
product was recrystallized from cyclohexane to give the title
compound (57), m.p. 230 (with prior softening) (Found: C,
59 2; H, 4 5; N, 8 1. C25H24IN3O requires C, 58 9; H, 4 7;
N, 8 2%). 1H n.m.r.: 1 36, s, CMe3; 5 07, d, J 5 5 Hz,
CH2; 6 96, br s, NH; 7 29–7 90; complex, H 6,7,20,30,50,60 and
Ph; 8 52, s, H 5. Mass spectrum: m/z 509 (M, 100%), 389
(82), 105 (78).
9
10
Lutz, R. E., Allison, R. K., Ashburn, G., Bailey, P. S.,
Clark, M. T., Codington, J. F., Deinet, A. J., Freek, J. A.,
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11
12
13
14
15
Biological Testing: BZR and PBR Binding Assays
Evaluation of the compounds for their ability to displace
[3H]diazepam bound to rat brain membrane (BZR) preparations
in the presence of 100
M
-aminobutyric acid19,20 and to
displace [3H]diazepam bound to rat kidney membrane (PBR)
preparations in the absence of -aminobutyric acid1 was carried
out as described previously.1,20,21
16
17
18
19
20
21
22
23
Schonenberger, H., Bindl, L., and Adam, A., Arch. Pharm.
(Weinheim, Ger.), 1973, 306, 64.
Barlin, G. B., Davies, L. P., Ireland, S. J., Ngu, M. M. L.,
and Zhang, J., Aust. J. Chem., 1992, 45, 731.
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Skerritt, J. H., Chen Chow, S., Johnston, G. A. R., and
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Kaye, I. A., Parris, C. L., and Burlant, W. J., J. Am.
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Am. Chem. Soc., 1954, 76, 1845.
Percentage inhibitions of control binding at 1000 nM were
measured rstly, and in appropriate cases IC values (nM)
50
were determined. In the latter, tests were conducted over a
range of four concentrations which were selected to span the
estimated IC value and, within each determination, assays
50
were performed in triplicate or quadruplicate. In all experiments
the correlation coe cients of the lines of best t to log–logit
curves were greater than 0 95.
The results are listed in Table 1 as IC values (nM), or in
50
parentheses as percentage displacement at 1000 nM.
Acknowledgments
We thank Dr D. J. Brown for helpful discussion,
and the Australian National University for the award
of a scholarship to P.W.H.
24
Buu-hoi, Ng. Ph., Xuong, Ng. D., and Suu, V. T., J. Chem.
Soc., 1958, 2815.