Synthesis, characterization, and antidiabetic activity of 6-methoxyimidazo[1,2-b]pyridazine derivatives

Article abstract of DOI:10.1002/jccs.201800332

The present article describes the synthesis, characterization, and antidiabetic activity of 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a-l. The synthetic sequence for the preparation of these derivatives involves the following prominent reactions: (a) Step 1: involves the high-pressure amination reaction; (b) Step 2: involves the Zinc oxide nanoparticle-catalyzed cyclization reaction; (c) Step 3: involves the methoxylation; (d) Step 4: involves the bromination reaction; (e) Step 5: involves the Suzuki coupling reaction; (f) Step 6: involves the reduction of the –NO₂ group; (g) Step 7: involves Boc protection of the 1^o amino group (h) Step 8: involves diazotization of the amine group and finally the last of the synthesis (i) Step 9: involves the saponification of the ethyl ester group. Furthermore, the structures of the newly synthesized 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a–l were determined using ¹H NMR, ¹³C NMR, and Mass and IR spectroscopic analyses. These derivatives were evaluated for their antidiabetic property and the results revealed that most of the compounds exhibited significant potency. It is worth mentioning that compounds 7b (69.87%), 7f (69.0%), 7h (68.79%), and 7l (68.61%) with substitution R = para-NH₂, para-COOH, meta-NH₂, and meta-COOH, respectively, showed significant (good) hypoglycemic activity when compared to the standard drug insulin (50 mg/kg b.w) in reducing the blood glucose level.

Full text of DOI:10.1002/jccs.201800332

Received: 29 August 2018
Revised: 22 January 2019
Accepted: 25 January 2019
DOI: 10.1002/jccs.201800332
A R T I C L E
Synthesis, characterization, and antidiabetic activity of
-methoxyimidazo[1,2-b]pyridazine derivatives
6
1,2
3
3
Tata Veereswara Rao Kota | Himabindu Gandham | Paul Douglas Sanasi
1
Department of Chemistry, BVC Engineering
The present article describes the synthesis, characterization, and antidiabetic activ-
ity of 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a-l. The synthetic sequence
for the preparation of these derivatives involves the following prominent reactions:
College, Odalarevu, Allavaram Mandal, Andhra
Pradesh, India
2
Department of Chemistry, Jawaharlal Nehru
Technological University, Kakinada, Andhra
Pradesh, India
(a) Step 1: involves the high-pressure amination reaction; (b) Step 2: involves the
Zinc oxide nanoparticle-catalyzed cyclization reaction; (c) Step 3: involves the
methoxylation; (d) Step 4: involves the bromination reaction; (e) Step 5: involves
3
Department of Engineering Chemistry, AU
College of Engineering (A), Andhra University,
Visakhapatnam, Andhra Pradesh, India
the Suzuki coupling reaction; (f) Step 6: involves the reduction of the –NO group;
2
o
Correspondence
(g) Step 7: involves Boc protection of the 1 amino group (h) Step 8: involves diaz-
Paul Douglas Sanasi, Department of Engineering
Chemistry, AU College of Engineering (A),
Andhra University, Visakhapatnam 530003, India.
Email: pauldouglas12@gmail.com
otization of the amine group and finally the last of the synthesis (i) Step 9: involves
the saponification of the ethyl ester group. Furthermore, the structures of the newly
synthesized 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a–l were determined
1
13
using H NMR, C NMR, and Mass and IR spectroscopic analyses. These deriva-
tives were evaluated for their antidiabetic property and the results revealed that
most of the compounds exhibited significant potency. It is worth mentioning that
compounds 7b (69.87%), 7f (69.0%), 7h (68.79%), and 7l (68.61%) with substitu-
tion R = para-NH , para-COOH, meta-NH , and meta-COOH, respectively,
2
2
showed significant (good) hypoglycemic activity when compared to the standard
drug insulin (50 mg/kg b.w) in reducing the blood glucose level.
KEYWORDS
6-methoxyimidazo[1,2-b]pyridazine, antidiabetic, Suzuki reaction, zinc oxide
nanoparticles
[
5]
1
| INTRODUCTION
activities viz., anticancer
immunodeficiency virus.
and activity against human
[
6]
The chemistry of pyridazines and their fused heterocyclic
derivatives has attracted significant attention due to their
synthetic and operative biological importance. Numerous
derivatives of pyridazine including 1,2,4-triazole, imidazole,
isoxazole, and triazine rings have been revealed to show
potential for an extensive range of applications in biological
Several imidazo[1,2-b]pyridazines have demonstrated
biological activity including inhibition of the central nervous
system, antipyretic and hypothermal activities, anticonvul-
sant activity, analgesic, and antispasmotic activities. In addi-
tion to the above activities, imidazo[1,2-b]pyridazine has
been shown to exhibit the following biological activities
[1,2]
[5]
[7]
[8]
and therapeutic areas.
Some of the examples of imidazole
such as antitumor, antileukemic, antiviral, and inhibi-
[
9]
[10]
[11]
[12]
and pyridazine rings that are fused together to form unique
tion of protein kinase, mTOR,
and Syk.
IKKβ,
VEGFR2,
[
3]
[13]
heterocyclic ring systems are imidazo[1,2-b]pyridazine
and imidazo[4,5-d] pyridazine.
[4]
The combination of two moieties upsurges the biological
activity of both and thus it was worth synthesizing some
new heterocyclic derivatives having two moieties in the
Presently, imidazopyridazines are importantly consid-
ered by researchers because of their varied biological
©
2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–8.
http://www.jccs.wiley-vch.de
1

2
KOTA ET AL.
same molecules. Therefore encouraged at the importance of
these heterocyclic nuclei, it is of interest to synthesize new
imidazo[1,2-b]pyridazine derivatives. The present article
describes the synthesis, characterization, and antidiabetic
activity of 6-methoxyimidazo[1,2-b]pyridazine derivatives.
To the best of our knowledge, so far, the synthesis and anti-
diabetic properties of these derivatives have not been
reported in the literature.
room temperature for 4.5 hr gave the corresponding amine
compounds 7b and 7h. Bocylation of 7b and 7h in the pres-
ence of Boc anhydride, aq.10% acetic acid in 1,4-dioxane at
room temperature for 12 hr gave the corresponding bocy-
lated compounds 7c and 7i. Diazotization of amine com-
pounds 7b and 7h in the presence of para-toluenesulfonic
acid, sodium nitrite, and potassium bromide in acetonitrile at
ꢀ
2
0 C, 4 hr produced the respective bromide compounds 7d
and 7j. Hydrolysis of 7e and 7k in the presence of lithium
hydroxide monohydrate in the mixture of THF:MeOH:water
at room temperature for 16 hr resulted in the corresponding
carboxylic acids 7f and 7l.
2
| RESULTS AND DISCUSSION
The synthesis of 6-methoxyimidazo[1,2-b]pyridazine deriva-
The structural characterization of all the synthesized
tives 7a–l is presented in Scheme 1. Amination of
6
-methoxyimidazo[1,2-b]pyridazine derivatives 7a–l and
1
3
,6-dichloropyridazine 1 in the presence of aq.ammonia in a
their associated intermediates was carried out using
NMR, C NMR, IR, and Mass spectroscopy techniques. As
a representative example, the structural elucidation of
H
ꢀ
13
pressure bomb vessel at 125 C for 24 hr produced 6-Chloro-
[14]
pyridazin-3-ylamine 2. ZnO NP-catalyzed
cyclization of
amine 2 in the presence of 40% aq. chloroacetaldehyde in n-
butanol at 100 C for 3 hr produced 6-chloro-imidazo[1,2-b]
pyridazine 3. Methoxylation of chloro compound 3 in the
presence of sodium methoxide in 2-methyl-tetrahydrofuran
4-(6-methoxy-imidazo[1,2-b]pyridazin-3-yl)-benzoic
acid
ꢀ
1
ethyl ester 7e is described here. H NMR interpretation: The
proton signals resonating at 8.30 ppm as singlets with one
proton integration are assigned to the imidazole ring, while
the proton signals resonating at 8.14 and 7.03 ppm as dou-
blets (J = 9.7 Hz) with one proton integration are assigned
to the pyridazine ring. The proton signals resonating at 8.39
and 8.09 ppm as doublets (J = 8.6 Hz) with two proton inte-
gration correspond to a new para-substituted ethyl benzoate
(aromatic) ring. The ethyl group protons flanked to the aro-
matic ring resonated at 4.34 ppm (quartet, 2H) and
1.34 ppm (triplet, 3H), respectively, and the characteristic
methoxy group protons resonated at 4.05 ppm as singlets.
(
[
[
2-Me THF) at reflux for 2 hr produced 6-methoxy-imidazo
1,2-b]pyridazine 4. Bromination of 6-methoxy-imidazo
1,2-b]pyridazine 4 in the presence of 1,3-dibromo-
5,5-dimethylhydantoin in dichloromethane at room tempera-
ture for 2 hr produced 3-Bromo-6-methoxy-imidazo[1,2-b]
pyridazine 5. The Suzuki reaction of bromide 5 with aryl
boronic acid 6a–6d in the presence of Pd(PPh ) , K CO in
3
4
2
3
2
-Me-THF, and water at reflux for 10 hr resulted in the cor-
responding heteroaryl-aryl-coupled products 7a, 7e, 7g, and
k, respectively. Reduction of nitro compounds 7a and 7g in
the presence of stannous chloride, conc. HCl in ethanol at
+
7
Mass interpretation: m/z, 298.1 with [M + H] corre-
sponds to the molecular weight of the desired compound 7e.
N
N N
N N
N
a
b
c
Cl
Cl
Cl
NH2
N
N
Step 2 Cl
Step 3
O
N
Step 1
N
1
2
3
4
Step 6 f 7a. R = 4-NO2
B(OH)2
7
b. R = 4-NH2
g
N
R
N
Step 7
h
d
e
7c. R = 4-NHBoc
Step 8
7
d. R = 4-Br
Step 4
N
Step 5
N
O
N
O
N
7e. R = 4-CO Et
Step 9 i
f
2
Br
6
6
6
6
a. R = 4-NO2
b. R = 4-CO Et
c. R = 3-NO2
d. R = 3-CO Et
7f. R = 4-CO H
2
5
7g. R = 3-NO2
7h. R = 3-NH2
7i. R = 3-NHBoc
2
R
g
h
2
7
7
7
j. R = 3-Br
k. R = 3-CO Et
l. R = 3-CO H
i
2
2
ꢀ
SCHEME 1 Synthesis of 6-methoxyimidazo[1,2-b]pyridazine derivatives 7a–l. Reaction conditions: (a) Aq. Ammonia, pressure bomb vessel, 125 C, 24 hr;
ꢀ
(
b) 40% aq. Chloroacetaldehyde, ZnO NP's, n-butanol, 100 C, 3 hr; (c) sodium methoxide, 2-me THF, reflux, 2 hr; (d) 1,3-Dibromo-5,5-dimethylhydantoin,
3 4
dichloromethane, room temperature, 2 hr; (e) arylboronic acid 6a–6d, potassium carbonate, Pd(PPh ) , 2-me-THF, water, reflux, 10 hr; (f) stannous chloride
dehydrate, conc. HCl, ethanol, room temperature, 4.5 hr; (g) Boc anhydride, aq. 10% acetic acid, 1,4-dioxane, room temperature, 12 hr; (h) para-
ꢀ
toluenesulfonic acid, sodium nitrite, potassium bromide, acetonitrile, 20 C, 4 hr; and (i) Lithium hydroxide monohydrate, THF: MeOH: Water, room
temperature, 16 hr

KOTA ET AL.
3
IR interpretation: The stretching frequencies in the region
while the compounds 7c (67.08%), 7e (66.34%), 7i
(65.15%), and 7k (64.54%) with substitution R = para-
NHBoc, para-CO Et, meta-NHBoc, and meta-CO Et
2 2
showed moderate hypoglycemic activity. The remaining
compounds in the series viz., compounds 7a (58.55%), 7d
−
1
2,981, 1,726, 1,454, 1,260, and 1,099 cm correspond to –
C–H, –C=O, –C=C, –C–N, and C–O groups, respectively.
The above analytical interpretation thus confirms the struc-
1
3
tures of the compound 7e. C NMR interpretation: The
spectra revealed that the compound contains 16 carbon
atoms. A peak at 56.06 is assigned to “methoxy” carbon and
the carbon signal at 168.32 is the characteristic carbonyl sig-
nal (carboxylic group).The peaks at 165.66, 121.92, and
(54.91%), 7g (51.21%), and 7j (53.23%) with substitution
R = para-nitro, para-Bromo, meta-Nitro para-bromo, meta-
nitro, and meta-bromo displayed weak hypoglycemic activ-
ity. Furthermore, it is observed that para substituted “R”
group in the main scaffold exhibited more potency compared
to the meta substituted ‘R’ group especially the following
123.84 are assigned to the pyridazine ring, while the peaks
in the region 139.06, 132.34, and 117.48 are assigned to the
imidazole ring. The carbon signals in the region
groups such as para-NH and para-COOH.
2
Further exploration of the above-established results
toward the synthesis, toxicity studies, and mode of action of
hypoglycemic activity may lead to the development of an
efficient drug candidate for diabetes mellitus.
125.78–130.42 and 143.12 are assigned to the benzene ring.
Similarly, the structure of the remaining compounds in the
series was characterized as described above.
2
.1 | Antidiabetic activity
The results of the antidiabetic activity of the synthesized
-methoxyimidazo[1,2-b]pyridazine derivatives 7a–l are tab-
3
| EXPERIMENTAL
6
ulated in Table 1. Insulin was used as a standard drug for the
purpose of the study and showed 70.28% blood glucose-
lowering activity at the dose of 50 mg/kg.p.o. All these
derivatives exhibited significant hypoglycemic properties,
but with a certain degree of variation, and showed a signifi-
cant reduction in blood glucose as compared to control dia-
betic rats at 50 mg/kg body weight for 3rd and 7th days.
From Table 1, it is observed that compounds 7b
3.1 | Materials and methods
All the chemicals were commercially procured from Alfa
Aesar. Melting points were determined in open glass capil-
laries on a Stuart SMP30 apparatus and are uncorrected. IR
spectra were recorded as KBr pellets on a Shimadzu FTIR
1
13
8
400S spectrophotometer. H NMR (400 MHz) and
NMR (100 MHz) spectra were recorded on a Bruker DPX
00 spectrophotometer using tetramethylsilane (TMS) as
internal standard, CDCl and DMSO-d as solvents and the
C
4
(69.87%), 7f (69.0%), 7h (68.79%), and 7l (68.61%) with
3
6
substitution R = para-NH , para-COOH, meta-NH , and
signals are reported as s (singlet), d (doublet), dd (doublet of
doublet), t (triplet), q (quartet), m (multiplet), and coupling
constants in Hz. HRMS spectra were recorded on a XevoQ-
Tof mass spectrometer. Elemental analysis was performed
2
2
meta-COOH, respectively, showed significant (good) hypo-
glycemic activity when compared to the standard drug insu-
lin (50 mg/kg b.w) in reducing the blood glucose level,
TABLE 1 Results of hypoglycemic effects of hydrazone derivatives 7a–l
a
Blood glucose level (mg/dL)
Treatment (mg/kg b.Wp.o)
Control (0.5% CMC)
Insulin
Day 0
Day 3
Day 7
Hyperglycemic activity (%)
342.0 ± 1.44
350.00 ± 2.26
358.33 ± 3.84
355.20 ± 3.16
346.44 ± 1.86
351.88 ± 3.22
341.46 ± 4.40
359.46 ± 2.85
339.54 ± 2.22
356.64 ± 3.36
337.38 ± 1.54
353.72 ± 4.22
339.78 ± 3.85
348.88 ± 2.58
368.4 ± 2.84**
146.30 ± 2.74**
272.65 ± 4.68**
277.44 ± 5.18**
245.22 ± 3.16**
288.20 ± 4.40**
251.28 ± 4.46**
281.84 ± 2.88**
294.46 ± 2.92
276.00 ± 4.32**
234.42 ± 2.46**
291.84 ± 1.65
240.66 ± 2.13**
294.32 ± 5.28**
387.2 ± 3.18**
104.10 ± 1.56**
148.50 ± 4.25**
107.00 ± 4.36**
115.50 ± 5.65**
158.64 ± 1.92**
114.92 ± 2.82**
111.40 ± 3.74**
165.64 ± 5.01
111.30 ± 2.88**
117.55 ± 3.60**
165.40 ± 3.68
120.48 ± 1.96**
108.50 ± 3.82**
70.28
58.55
69.87
67.08
54.91
66.34
69.00
51.21
68.79
65.15
53.23
64.54
68.61
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
g
h
i
j
k
l
a
Values are represented as mean ± SEM. Data were analyzed using analysis of variance and group means were compared with the Tukey–Kramer Post ANOVA test.
The values were considered when p < 0.01. **p < 0.001; Tabulated data are expressed as mean ± SEM; (n = 6).

4
KOTA ET AL.
on a perkin CHNS elemental analyzer. Silica gel 60F24 of
Merck precoated plates was employed for their thin layer
chromatography (TLC) analysis to check the purity of the
compounds, the spot being located under UV light and
iodine vapors.
(–C–H str), 1,460 (–C=N str), 1,410 (–C=C– str), and 1,105
−
1 1
(–C–N str) cm ; H NMR (400 MHz,CDCl ) δ 7.79 (d,
3
J = 9.5, 1H), 7.74 (s, 1H), 7.6 (s, 1H), 6.68 (d, J = 9.6 Hz,
13
1H), and 4.0 (s, 3H); C NMR (100 MHz, CDCl ): δ
3
1.65.7, 135.1, 127.8, 125.5, 119.3, 115.4, and 55.9; ESI MS:
+
m/z, 150.1 [M + H] ; Elemental analysis, C H N O, calcd.
7
7 3
3
.1.1 | 6-Chloro-pyridazin-3-ylamine (2)
(found) %: C 56.37 (56.28), H 4.73 (4.69), and N
A mixture of 3,6-dichloropyridazine 1 (5 g, 33.56 mmol)
28.17 (28.15).
and aq. ammonia (125 mL) was taken in a steel pressure
bomb vessel and heated at 125 C for 24 hr. The reaction
ꢀ
3.1.4 | 3-Bromo-6-methoxy-imidazo[1,2-b]pyridazine (5)
mixture was cooled to room temperature for 24 hr and the
precipitated solid was filtered and washed with water fol-
To a solution of compound 4 (5 g, 33.52 mmol) in dichloro-
methane (100 mL), 1,3-Dibromo-5,5-dimethylhydantoin
(5.36 g, 18.77 mmol) was added. The reaction mixture was
stirred at room temperature for 2 hr. After completion of the
reaction (checked by TLC), it was diluted with water
lowed by pet-ether and dried to obtain compound 2. Brown
ꢀ
solid; Yield: 3.0 g, 70%; M.p.: 226–228 C; IR (KBr): υ
max
3
1
,473 (–N–H str), 3,136 (–C–H str), 1,634 (–C=N str),
,551 (–C=C– str), 1,051 –C–N str), and 753 (C–Cl) cm ;
−
1
(
50 mL) and stirred for 15 min. The organic layer was sepa-
rated and washed with water followed by brine solution, and
dried over Na SO , filtered, and evaporated under reduced
1
H NMR (400 MHz, DMSO-d ): δ 7.37(d, J = 9.5 Hz, 1H),
6
1
3
6.85(d, J = 9.5 Hz, 1H), and 6.62 (brs, 2H); C NMR
2
4
pressure to obtain compound 5. Pale yellow solid; Yield:
(
1
100 MHz, DMSO-d ): δ 121.32, 130.51, 145.02, and
60.63; ESI MS: m/z, 130 [M + H] ; Elemental analysis
6
ꢀ
+
4
.4 g, 58%; M.p.: 201–202 C; IR (KBr): υ
3,007 (–C–H
max
str), 1,460 (–C=N str), 1,410 (–C=C– str), 1,105 (–C–N str),
C H ClN calcd. (found) %: C 37.09 (36.99), H 3.11 (3.10),
4
4
3
−
1
1
and 811 (C–Br str) cm ; H NMR (400 MHz,CDCl ) δ
and N 32.44 (32.40).
3
7
.79 (d, J = 9.7 Hz, 1H), 7.6 (s, 1H), 6.75 (d, J = 9.7 Hz,
6-Chloro-imidazo[1,2-b]pyridazine (3)[14]
13
3
.1.2
|
1H), and 4.1 (s, 3H); C NMR (100 MHz, CDCl
): δ
3
1
67.22, 138.14, 138.04, 130.01, 126.23, 120.06, and 56.13;
To a suspension of compound 2 (2.5 g, 19.38 mmol), 40%
aq. chloroacetaldehyde (4.54 g, 58.14 mmol) in n-butanol
+
ESIMS: m/z, 230 [M + 2] ; Elemental analysis,
C H BrN O, calcd. (found) %: C 36.87 (36.81), H 2.65
(2.63), and N 18.43 (18.40).
[14]
(
30 mL), ZnO nanoparticles
(15 mol%) were added and
7
6
3
ꢀ
heated to 100 C for 3 hr. The reaction mixture was filtered
while hot and the catalyst was recovered back. The filtrate
was cooled to 0 C and the precipitated solid was collected
ꢀ
3.2 | General experimental procedure for the
preparation of compounds 7a, 7e, 7g, and 7k (Suzuki
reaction)
by filtration and washed with n-Hexane to obtain compound
ꢀ
3
. Light Brown solid; Yield: 2.6 g, 93%; M.p.: 120–122 C;
IR (KBr): υmax 3,081 (–C–H str), 1,607 (–C=N str), 1,513
To a stirred solution of 5 (1 g, 4.38 mmol) and aryl boronic
acids 6a–6d (4.38 mmol) in 2-methyl tetrahydrofuran
−
1 1
(
–C=C– str), 1,123 (–C–N str), and 791 (C–Cl) cm ; H
NMR (400 MHz,DMSO-d ) δ: 8.5 (brs, 1H), 8.32 (brs, 1H),
6
(
2-Me-THF) (25 mL) and H O (10 mL), K CO (0.72 g,
2 2 3
1
3
7
.95 (brs, 1H), and 7.54 (brs, 1H); C NMR (100 MHz,
5
.25 mmol) was added. The reaction mixture was degassed
DMSO-d ): δ 153.69, 139.67, 130.64, 128.56, 126.64, and
6
and then under the flow of nitrogen, Pd (PPh ) (0.1 g,
3
4
+
1
15.68; ESI MS: m/z, 154.1 [M + H] ; Elemental analysis,
0
.088 mmol) was added and heated to reflux for 10 hr. After
C H ClN , calcd. (found) %: C 46.93 (46.90), H 2.63 (2.59),
6
4
3
the completion of the reaction, checked by TLC, the reaction
mixture was cooled to room temperature and diluted with
water (20 mL). The organic layer was washed with water,
followed by brine solution, dried over Na SO , filtered, and
and N 27.36 (27.31); Note: the ZnO NP catalyst was recov-
ered from the reaction by centrifugation. After washing with
ꢀ
EtOAc and drying at 300 C, the recovered ZnO NP was
2
4
reused three consecutive times.
evaporated under reduced pressure to obtain the crude com-
pounds 7a, 7e, 7g, and 7k. The crude products were purified
using column chromatography (silica gel, 100–200 mesh,
eluted with 35% isopropylacetate-n-Hexane) to afford the
respective purified compounds 7a, 7e, 7g, and 7k.
3
.1.3 | 6-Methoxy-imidazo[1,2-b]pyridazine (4)
To a solution of compound 3 (5 g, 32.55 mmol) in
-MeTHF (30 mL), sodium methoxide (3.5 g, 65.1 mmol)
2
was added and heated to reflux for 2 hr. The reaction mix-
ture was cooled to rt and poured into ice cold water
3.2.1
| 6-methoxy-3-(4-nitrophenyl)imidazo[1,2-b]
(
200 mL), further extracted with 2-Me-THF (4 × 25 mL),
and the combined organics were washed with water
2 × 50 mL), brine (3 × 20 mL), dried over Na SO , con-
pyridazine 7a
ꢀ
Yellow solid; M.p.: 125–126 C; Yield: (1 g, 72%); IR (KBr):
υmax 3,064 (–C–H str), 1,595 (–C=N str), 1,526 (C–NO str)
(
2
4
2
centrated to obtain compound 4. Pale yellow solid;
Yield:3.4 g, 75%; M.p.: 129–130 C; IR (KBr): υ
1,450 (–C=C– str), 1,142 (–C–N str), and 1,016 (C–O–C)
ꢀ
−1
1
3,007
cm ; H NMR (400 MHz, DMSO–d ) δ 8.58 (d,
max
6

KOTA ET AL.
5
J = 8.4 Hz 2H), 8.48 (s, 1H), 8.32 (d, J = 9.5 Hz, 1H), 8.20
3.3 | Experimental procedure for the preparation of
compounds 7b and 7h: (reduction of NO to NH
(
d, J = 8.6 Hz, 2H), 7.15 (d, J = 9.7 Hz, 1H), and 3.99 (s,
2
)
2
13
3
1
1
H); C NMR (100 MHz, CDCl ): δ 166.46, 148.33,
3
To a stirred solution of ethanol (20 mL) containing com-
pound 7a (1 g, 3.7 mmol), stannous chloride dihydrate
40.11, 135.62, 128.32, 125.18, 122.82, 119.05, 115.92, and
+
11.26; ESI MS: m/z, 271.3 [M + H] ; Elemental analysis,
(SnCl .2H O, 2.7 g, 11.84 mmol) and concentrated HCl
2 2
C H N O , calcd. (found) %: C 57.78 (57.73), H 3.73
1
3 10 4 3
(0.5 mL) were added. The reaction mixture was stirred at
(3.69), and N 20.73 (20.65).
room temperature for 4.5 hr. After completion of the reac-
tion, (checked by TLC), the reaction mixture was diluted
with isopropyl acetate (150 mL) and water (150 mL). The
pH of the reaction contents was adjusted to 12–13 with 20%
aq sodium hydroxide solution (30 mL). The inorganic pre-
cipitate was filtered through the celite bed and the organic
layer was washed with water (3 × 25 mL), brine solution
(2 × 25 mL), and dried over anhydrous sodium sulfate and
evaporated to afford compound 7b, and was utilized in the
next step without any further purification. Yellow viscous
liquid; Yield: 0.72 g, 82%; Similarly, compound 7h was pre-
pared from the corresponding 3-nitro compound 7g as per
the above procedure.
3
.2.2
| 4-(6-Methoxy-imidazo[1,2-b]pyridazin-3-yl)-benzoic
acid ethyl ester (7e)
ꢀ
Yellow solid; M.p.: 88–89 C; Yield: (1 g, 67%); IR (KBr):
υmax 2,981 (–C–H str), 1,726 (–C=O str), 1,454 (–C=C–
−
1 1
str), 1,099 (–C–N str), and 1,260 (C–O) cm ; H NMR
400 MHz, DMSO-d ) δ 8.39 (d, J = 8.6 Hz 2H), 8.30 (s,
(
6
1
7
3
H), 8.14 (d, J = 9.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 2H),
.03 (d, J = 9.7 Hz, 1H), 4.34 (q, J = 7.22 Hz, 2H), 4.05 (s,
1
3
H), and 1.34 (t, J = 7.22 Hz, 3H); C NMR (100 MHz,
CDCl ): δ 168.32, 165.66, 143.12, 139.06, 132.34, 130.42,
3
1
1
28.22, 125.78, 123.84, 121.92, 117.48, 69.33, 56.06, and
5.26; ESI MS: m/z, 298.1 [M + H] ; Elemental analysis:
+
4-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)benzenamine
(7b): The crude compound was utilized as such in the
next step.
C H N O , calcd. (found) %: C 64.64 (64.61), H 5.09
1
6 15 3 3
(5.04), and N 14.13 (14.08).
3
-(6-Methoxy-imidazo[1,2-b]pyridazin-3-yl)phenylamine
3
.2.3
|
6-methoxy-3-(3-nitrophenyl)imidazo[1,2-b]
(7h): Light brown syrupy liquid; Yield: Quantitative yield;
IR (KBr): υmax 3,484 (–N–H str), 2,980 (–C–H str), 1,605 (–
C=N str), 1,468 (–C=C– str), 1,213 (–C–O str), and 1,060
pyridazine 7g
ꢀ
Light brown solid; M.p.:134–135 C; Yield: 663 mg, 56%;
IR (KBr): υmax 3,064 (–C–H str), 1,595 (–C=N str), 1,526
−
1
1
(C–N str) cm ; HNMR (400 MHz, DMSO-d
exchangeable) δ 8.27 (s, 1H), 8.23 (d, J = 9.6 Hz, 1H), 7.92
brs, 1H), 7.78 (brs, 1H), 7.48 (m, 1H), 7.20–7.10 (m, 2H),
, D O
6
2
(C–NO str) 1,450 (–C=C– str), 1,142 (–C–N str), and 1,016
2
−1 1
(
(C–O–C) cm ; H NMR (400 MHz, CDCl ) δ 8.55 (s, 1H),
3
13
and 4.07 (s, 3H); C NMR (100 MHz, DMSO-d ): δ
8
.22 (s, 1H), 8.10 (d, J = 9.5 Hz, 1H), 7.92 (d, J = 7.4 Hz,
6
1
1
65.74, 148.76, 135.16, 133.92, 130.13, 125.53, 122.02,
1
H), 7.76 (t, J = 8 Hz, 1H), 7.50 (d, J = 1.56 Hz, 1H), 6.90
1
3
20.02, 119.33, 117.52, 116.31, 114.28, and 55.92; ESI MS:
(d, J = 9.5 Hz, 1H), and 4.08 (s, 3H); C NMR (100 MHz,
+
m/z, 241 [M + H] ; Elemental analysis: C H N O, calcd.
CDCl ): δ 165.72, 148.93, 135.12, 134.06, 133.66, 130.26,
1
ESI MS:m/z, 271.1 [M + H] ; Elemental analysis:
13 12
4
3
(found) %: C 64.99 (64.93), H 5.03 (4.99), and N
25.52, 122.13, 121.15, 120.06, 119.34, 122.08, and 55.92;
+
23.32 (23.28).
C H N O , calcd. (found) %: C 57.78 (57.71), H 3.73
1
3 10 4 3
(3.66), and N 20.73 (20.70).
3.4 | Experimental procedure for the preparation of
compounds 7c and 7i: (Boc protection of NH to NHBoc)
2
3
.2.4
| Ethyl3-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)
To a solution of compound 7h (0.5 g, 2.08 mmol) in 10%
benzoate 7k
aqAcOH (20 mL), a solution of Boc-anhydride (Boc O)
2
ꢀ
Light brown solid; M.p.: 92–94 C; Yield: 663 mg, 56%; IR
(0.48 g, 2.18 mmol) in 1,4-dioxane (20 mL) was added. The
(KBr): υmax 2,972 (–C–H str), 1,719 (–C=O str), 1,437
reaction mixture was stirred at room temperature for 12 hr.
After the completion of the reaction (checked by TLC),
water (30 mL) was added and the mixture was extracted
with cyclopentyl methyl ether (2 × 25 mL). The aqueous
phase was basified to pH 14 using 1N NaOH and extracted
with cyclopentyl methyl ether (2 × 25 mL). The combined
organic layer was washed with water (2 × 20 mL), dried
over Na SO , filtered, and concentrated under reduced pres-
−
1 1
(
–C=N str), 1,240 (–C–O str), and 1,119 (C–N) cm ; H
NMR (400 MHz, CDCl ) δ 8.50 (s, 1H), 8.30 (s, 1H), 8.26
3
(d, J = 7.8 Hz, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.70 (t,
J = 8.0 Hz, 1H),7.55 (d, J = 2.2 Hz, 1H), 6.88 (d,
J = 9.7 Hz, 1H), 3.99 (s, 3H); 4.30 (q, J = 7.20 Hz, 2H),
and 1.30 (t, J = 7.22 Hz, 3H); C NMR (100 MHz,
1
3
CDCl ): δ 166.04, 165.74, 135.12, 133.06, 131.84, 130.76,
3
2
4
1
6
30.31, 129.95, 129.23, 125.52, 122.04, 120.08, 119.35,
0.92, 55.96, and 14.14; ESI MS: m/z, 298.3 [M + H] ; Ele-
sure to obtain compound 7i. Pale yellow syrupy liquid;
Yield: 600 mg, 85%; Similarly, compound 7c was prepared
from the corresponding amino compound 7b as per the
above procedure.
+
mental analysis: C H N O , calcd. (found) %: C 64.64
16 15 3 3
(64.60), H 5.09 (5.04), and N 14.13 (14.10).

6
KOTA ET AL.
3
.4.1
|
[4-(6-Methoxy-imidazo[1,2-b]pyridazin-3-yl)-phenyl]
(400 MHz, DMSO-d ) δ 8.52 (d, J = 8.2 Hz 2H), 8.42 (s,
6
carbamic acid tert-butyl ester (7c)
1
H), 8.28 (d, J = 9.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 2H),
ꢀ
13
Compound 7c: Off-white solid; M.p.: 78–79 C; Yield:1 g,
7.10 (d, J = 9.7 Hz, 1H), and 3.98 (s, 3H); C NMR
6
1
1
7%; IR (KBr): υmax 3,310 (–N–H str), 2,932 (–C–H str),
(100 MHz, DMSO-d ): δ 165.76, 135.14, 132.26 (2C),
6
,648 (–C=O str), 1,502 (–C=N str), 1,427 (–C=C– str),
132.10, 129.72 (2C), 125.54, 123.18, 122.06, 120.08,
−
1
1
+
,152 (–C–N str), and 1,247 (C–O str) cm ; H NMR
119.33, and 55.92; ESI MS: m/z,305.1 [M + H] ; Elemental
(
400 MHz, CDCl ) δ 8.02 (d, J = 6.8 Hz, 2H), 7.89–7.80
analysis: C H BrN O, calcd. (found) %: C 51.34 (51.30),
3
13 10
3
(
6
m, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 9.7 Hz, 1H),
.59 (br s, 1H), 4.05 (s, 3H), and 1.75 (s, 9H); C NMR
H 3.31 (3.29), and N 13.82 (13.77).
1
3
3
.5.2
| 3-(3-bromophenyl)-6-methoxyimidazo[1,2-b]
(100 MHz, CDCl ): δ 166.48, 154.02, 138.22, 135.66,
3
pyridazine (7j)
1
5
30.34, 126.20, 123.32, 121.88, 117.78, 115.66, 80.05,
+
ꢀ
6.02, and 26.82; ESI MS: m/z, 341 [M + H] .Elemental
White solid;M.p.: 141–142 C; Yield: 1 g, 85%; IR (KBr):
υmax 2,992 (–C–H str), 1,450 (–C=N str), 1,412 (–C=C–
analysis: C H N O , calcd. (found) %: C 63.52 (63.50), H
5
18 20 4 3
−
11
.92 (5.86), and N 16.46 (16.42).
str), 1,104(–C–N str), and 810 (C–Br str) cm ; H NMR
400 MHz, CDCl ) δ 8.46 (s, 1H), 7.92 (s, 1H,), 7.85 (d,
(
3
3
.4.2
|
[3-(6-Methoxy-imidazo[1,2-b]pyridazin-3-yl)-phenyl]
J = 9.5 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.38 (t,
J = 8.0 Hz, 1H), 7.20 (d, J = 1.56 Hz, 1H), 6.74 (d,
J = 9.5 Hz, 1H), 4.10 (s, 3H), and 1.53 (s, 9H); C NMR
carbamic acid tert-butyl ester (7i)
1
3
Compound 7i: Pale yellow syrupy liquid; Yield: 600 mg,
8
1
1
5%; IR (KBr): υmax 3,313 (–N–H str), 2,934 (–C–H str),
(100 MHz, CDCl ): δ 165.73, 135.36, 135.18, 133.13,
3
,685 (–C=O str), 1,543 (–C=N str), 1,482 (–C=C– str),
131.56, 131.74, 126.52, 125.55, 123.64, 122.10, 120.08,
−
1
1
+
,174 (C–O str), and 1,107 (–C–N str) cm ; H NMR
119.38, and 55.94; ESI MS: m/z, 341.0[M + H] ; Elemental
(
400 MHz, CDCl , D O exchange) δ 8.46 (s, 1H), 7.92 (s,
analysis: C H BrN O, calcd. (found) %: C 51.34 (51.30),
3
2
13 10
3
1H), 7.85(d, J = 9.5 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.38
H 3.31 (3.29), and N 13.84 (13.81).
(
t, J = 8.0 Hz, 1H), 7.20 (d, J = 1.56 Hz, 1H), 6.74 (d,
1
3
J = 9.5 Hz, 1H), 4.10 (s, 3H), and 1.53 (s, 9H); C NMR
100 MHz, CDCl ): δ 165.72, 153.95, 136.42, 135.16,
3
.6 | Experimental procedure for the preparation of 7f
(
3
and 7l: (hydrolysis of ethyl ester)
1
1
33.32, 129.58, 125.53, 123.14, 122.08, 121.62, 119.50,
To a solution of compound 7e (1 g, 3.39 mmol) in a mixture
of THF (30 mL), MeOH (6 mL), and H O (6 mL), LiOH.
2
H O (0.42 g, 10.17 mmol) was added at room temperature
2
19.32, 79.51, 55.93, and 28.5 (3C); ESI MS: m/z, 341.0
+
[M + H] . Elemental analysis: C H N O , calcd. (found)
1
8 20 4 3
%
: C 63.52 (63.47), H 5.92 (5.88), and N 16.46 (16.41).
and stirred for 16 hr. The reaction mixture was concentrated
in vacuo and the residue was dissolved in water (30 mL),
washed with EtOAc (30 mL), the aqueous layer was acidi-
fied (pH 2) with 6N HCl, and the precipitated solid was col-
lected by filtration, washed with water, and dried to
obtain 7f.
3
.5 | Experimental procedure for the preparation of
compounds 7d and 7j: (diazotization reaction)
To a solution of compound 7b (1 g, 4.16 mmol) in acetoni-
trile
1
salt (7b) was cooled to 10–15 C and to this was added, grad-
ually, a solution of sodium nitrite (0.57 g, 8.26 mmol) and
potassium bromide (1.24 g, 10.42 mmol) in water (5 mL).
The reaction mixture was stirred for 15 min then allowed to
(15 mL),
para-toulenesulfonic
acid
(2.15 g,
2.48 mmol) was added. The resulting suspension of amine
ꢀ
3.6.1
|
4-(6-Methoxy-imidazo[1,2-b]pyridazin-3-yl)-benzoic
acid (7f)
ꢀ
Pale brown solid; M.p.:150–152 C; Yield: 0.80 g, 88%; IR
(KBr): υmax 3,437 (–O–H str), 2,970 (–C–H str), 1,697 (–
C=O str), 1,550 (–C=N str), 1,431 (–C=C– str), 1,213 (C–
ꢀ
come to 20 C and stirred for 4 hr. To the reaction mixture
−
1
1
was then added water (30 mL), 1M aqueous sodium bicar-
bonate solution (adjusted to pH = 9–10), and sodium thio-
sulfate(2M, 12 mL). The precipitated was filtered, washed
with pet-ether, and dried to obtain compound 7d. Pale yel-
low solid; Yield: 0.73 g, 58%; similarly, compound 7j was
prepared from the corresponding amino compound 7h as per
the above procedure.
O), and 1,117 (–C–N str) cm ; H NMR (400 MHz,
DMSO-d ) δ 8.42 (brs, 1H), 8.33 (d, J = 8.0 Hz, 2H), 8.23
(brs, 1H), 8.09 (d, J = 8 Hz, 2H), 7.20 (brs, 1H), and 4.05
6
13
(s, 3H); C NMR (100 MHz, DMSO-d ): δ 169.40, 165.76,
6
138.34, 135.16, 130.83 (2C), 130.33, 127.48 (2C), 125.54,
122.06, 120.0, 119.36, and 55.92; ESI MS: m/z, 270.0
+
[M + H] ; Elemental analysis: C H N O , calcd. (found)
1
4 11 3 3
%
: C 62.45 (62.40), H 4.12 (4.09), and N 15.61 (15.56).
3
.5.1
| 3-(4-bromophenyl)-6-methoxyimidazo[1,2-b]
pyridazine (7d)
3.6.2
acid 7l
|
3-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)benzoic
ꢀ
White solid; M.p.: 133–134 C; Yield: (1 g, 82%); IR (KBr):
υmax 2,988 (–C–H str), 1,454 (–C=N str), 1,408 (–C=C–
str), 1,110(–C–N str), and 806 (C–Br str) cm ; H NMR
ꢀ
White solid; M.p.: 138–139 C; Yield: 720 mg, 80%; IR
(KBr): υmax 3,428 (–O–H str), 2,966 (–C–H str), 1,692
−1 1

KOTA ET AL.
7
(
(
–C=O str), 1,544 (–C=N str), 1,434 (–C=C– str), 1,201
(68.61%) with substitution R = para-NH , para-COOH,
meta-NH , and meta-COOH, respectively, showed signifi-
2
2
−1 1
C–O), and 1,117 (–C–N str) cm ; H NMR (CDCl , D O
3
2
exchangeable) δ 8.52 (s, 1H), 8.38 (s, 1H), 8.20 (d,
J = 9.5 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.44 (t,
J = 8 Hz, 1H), 7.35 (d, J = 1.56 Hz, 1H), 6.86 (d,
cant (good) hypoglycemic activity when compared to the
standard drug insulin (50 mg/kg b.w) in reducing the blood
glucose level, while the compounds 7c (67.08%), 7e
(66.34%), 7i (65.15%), and 7k (64.54%) with substitution
1
3
J = 9.5 Hz, 1H), and 3.99 (s, 3H); C NMR (100 MHz,
R = para-NHBoc, para-CO Et, meta-NHBoc, and meta-
CDCl ): δ 169.46, 165.77, 135.18, 132.76, 133.08, 130.82,
2
3
CO Et showed moderate hypoglycemic activity. The
remaining compounds in the series viz., compounds 7a
1
30.74, 130.34, 129.28, 125.56, 122.06, 120.11, and 55.92;
2
+
ESI MS: m/z, 270.1 [M + H] ; Elemental analysis:
C H N O , calcd. (found) %: C 62.45 (62.41), H, 4.12
(58.55%), 7d (54.91%), 7g (51.21%), and 7j (53.23%) with
1
4 11 3 3
substitution R = para-Nitro, para-Bromo, meta-Nitro, and
meta-Bromo displayed weak hypoglycemic activity.
(
4.10), and N 15.61 (15.59).
[15–18]
3
.6.3 | Experimental procedure for antidiabetic studies
(
a) Acute toxicity: These studies were carried out as per the
ACKNOWLEDGMENTS
standard experimental procedures. The LD50 cut-off value of
the test compounds was fixed as 50 mg/kg, as screening
dose for evaluation of antidiabetic activity. All the animal
experiments were conducted by the approval of Institutional
Animal Ethics Committee, Anurag Group of Institutions
The authors thank the Advanced Analytical Laboratories,
Andhra University and IICT, Hyderabad for spectral chrac-
terization of samples and Anurag Group of Institutions (for-
merly Lalitha College of Pharmacy), Hyderabad, India for
antidiabetic activity studies.
(formerly Lalitha college of Pharmacy), Hyderabad, India.
During the study period, guidelines of Committee for the
Purpose of Control and Supervision of Experiments on Ani-
mals (CPCSEA), Institutional Animals Ethics Committee
ORCID
Paul Douglas Sanasi https://orcid.org/0000-0002-5839-
(IAEC) were followed for the maintenance of animals.
0
959
(b) Alloxan induction of experimental diabetes: Overnight-
fasted swiss albino mice are injected with alloxan
50 mg/kg) in saline buffer intraperitoneally and hyperglyce-
mia was confirmed in animals after 72 hr. Blood glucose
levels were determined and mice having blood glucose levels
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In summary, the present article describes the synthesis and
characterization of certain 6-methoxyimidazo[1,2-b]pyrida-
zine derivatives 7a–l. The structure of these derivatives was
confirmed using H NMR, C NMR, Mass, and IR spectro-
scopic analyses. These derivatives were further evaluated for
their antidiabetic properties and the results revealed that
most of the compounds exhibited significant potency. Com-
pounds 7b (69.87%), 7f (69.0%), 7h (68.79%), and 7l
[
[
[
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13
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8
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of the article.