Synthesis and quantitative structure-activity relationship study of substituted imidazophosphor ester based tetrazolo[1,5-b]pyridazines as antinociceptive/anti-inflammatory agents

Article abstract of DOI:10.3762/bjoc.9.199

A high-yielding general synthesis of imidazophosphor ester based tetrazolo[1,5-b]pyridazines is described. A conjugated reaction between 3,6-diazidopyridazine and different types of phosphonyl carbanion reagents followed by intramolecular cyclization afforded the target products, by using sodium ethanolate solution as a reaction medium. Among the products, five compounds, at a dose of 50 mg per kilogram body weight, showed a notable antinociceptive and anti-inflammatory activity without toxic side-effects.

Full text of DOI:10.3762/bjoc.9.199

Synthesis and quantitative structure–activity
relationship study of substituted imidazophosphor
ester based tetrazolo[1,5-b]pyridazines as
antinociceptive/anti-inflammatory agents
Wafaa M. Abdou*, Neven A. Ganoub and Eman Sabry
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1730–1736.
Chemical Industries Division, National Research Centre, Elbohouth
St. D-12311, Dokki, Cairo, Egypt. Fax: 202 7601877
doi:10.3762/bjoc.9.199
Received: 01 January 2013
Accepted: 07 June 2013
Published: 22 August 2013
Email:
Wafaa M. Abdou* - wabdou@link.net
* Corresponding author
Associate Editor: J. Aubé
Keywords:
© 2013 Abdou et al; licensee Beilstein-Institut.
License and terms: see end of document.
antinociceptive/anti-inflammatory agents; imidazophosphor esters;
phosphonyl carbanions; ring closure; tetrazolo[1,5-b]pyridazine
Abstract
A high-yielding general synthesis of imidazophosphor ester based tetrazolo[1,5-b]pyridazines is described. A conjugated reaction
between 3,6-diazidopyridazine and different types of phosphonyl carbanion reagents followed by intramolecular cyclization
afforded the target products, by using sodium ethanolate solution as a reaction medium. Among the products, five compounds, at a
dose of 50 mg per kilogram body weight, showed a notable antinociceptive and anti-inflammatory activity without toxic side-
effects.
Introduction
Inflammation is a characteristic feature of disease pathology cacy/safety profile of new NSAIDs, the structural–activity rela-
and progression in several neuro-degenerative disorders and tionship (SAR) has been extensively studied, taking into
physical functioning [1,2]. Recently, nonsteroidal anti-inflam- account up-to-date knowledge about the mechanism of inflam-
matory drugs (NSAIDs) are well established for the treatment mation that balanced the inhibition of COX-1, COX-2, and
of inflammatory disorders [3-5]. The anti-inflammatory effect lipoxygenase (LOX) [10-12].
of NSAIDs is mainly based on the inhibition of the cyclooxyge-
nase (COX) enzymes. Later on, it was reported that the second As a part of our continued interest in the development of con-
isoform of cyclooxygenase (COX-2) has a better effect on the venient synthetic approaches to β-enamino- and α-aminophos-
inflammation with fewer side-effects [6-9]. Despite their wide- phonates with anti-inflammatory properties [13-20], we recently
spread use, none of the presently available agents is ideal; each successfully synthesized a series of mono- and bisphosphonate-
has its own shortcomings [3]. Subsequently, to improve the effi- based tetrazolo[1,5-a]quinolines with marked anti-inflamma-
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Beilstein J. Org. Chem. 2013, 9, 1730–1736.
tory properties [21,22]. Following this, synthesis of the target droimidazo[1,2-f]tetrazolo[1,5-b]pyridazin-7-ylphosphonate (4,
compounds, substituted tetrazolo[1,5-b]pyridazinphosphor 78%) as indicated from the analytical and the spectroscopic
esters, is described herein. In this context, we applied different data.
types of phosphonyl carbanion reagents to 3,6-diazidopyri-
dazine (1) as an adopted substrate. The anti-inflammatory and In the 1H NMR spectrum (CDCl3) of 4 (δP = 28.4 ppm) there is
the antinociceptive properties of the prepared compounds were a doublet peak (2JP–H = 22.3 Hz) at δ 5.36 ppm corresponding
screened and the structure–activity relationships were studied. to H(4) of the imidazole ring while its C(4)–P appeared at δC =
The anti-inflammatory properties of many tetrazole [21-23] and 59.4 (d, 1JP–C = 148.6 Hz). A plausible mechanism for the for-
pyridazine derivatives have also led to their clinical application mation of tetrazolopyridazinophosphonate 4 is presented in
as NSAIDs (e.g. Bucolome) [24]. Several phosphonate deriva- Scheme 1. Upon heating, the equilibrium between the azido-1a
tives also exhibit marked potency as inhibitors of COX-1 and and its isomeric tetrazolo-1b form [1a
1b] lies exclu-
COX-2 and are therefore believed to be useful as anti-inflam- sively at the tetrazole isomer 1b [29]. Compound 1b is then
matory drugs [25,26]. Thus, we considered that it is of interest intercepted by the nucleophilic attack of the phosphonyl
to gather these three motifs in one molecule.
carbanion 2a or 2b on the azido-function in 1b yielding the
phosphonate intermediate 3 along with the evolution of a
nitrogen molecule. Subsequent intramolecular ring closure, the
Results and Discussion
It has been reported that 3,6-diazidopyridazine presents azido fused imidazolo-phosphonate 4 would be obtained under elimi-
(1a)
tetrazolo tautomerism (1b) whereby it is mainly in nation of an appropriate alcohol moiety.
the tetrazole form 1b [27-29]. Accordingly, and as indicated
from the spectral data of our products, we considered that the In the same fashion, the substrate 1b reacted with the phos-
substrate 3,6-diazidopyridazine (1a) is exclusively, throughout phonyl carbanion, diethyl cyanomethylphosphonate 5, in
our investigation, reacted in the tetrazolo-form 1b [28,29] ethanolate solution to yield diethyl 8-aminoimidazo[1,2-f]tetra-
(Scheme 1). The required [3,6-diazidopyridazine (1a)
zolo[1,5-b]pyridazin-7-ylphosphonate (7) in 74% yield. The IR
6-azidotetrazolo[1,5-b]pyridazine (1b)] was prepared by spectrum of the phosphonate 7 (δP = 27.8 ppm) showed the
treating the readily available 3,6-dichloropyridazine with NH2, P=O, and P–O–C motifs at ν 3377–3330, 1226, and 1123
sodium azide [30]. The reactions studied and the products cm−1, respectively. Its 1H NMR (CDCl3) spectrum showed the
obtained are depicted in Schemes 1–7 (see below). Reaction of NH2-protons at δ 6.44 (HA, br) and 8.88 ppm (HB, br), which
1b with 1.3 equivalents of methyl diethyl phosphonoacetate are attributed to the P=O bonding with one proton of the amino-
(2a) or the ethyl analogue 2b in sodium ethanolate solution group. Furthermore, the 13C NMR spectrum of 7 revealed,
resulted in the same product assigned as diethyl 8-oxo-7,8-dihy- among others, three doublets at: δ 153.6 [d, 3JP–C = 11.4 Hz,
C(2)], 141.2 (d, 1JP–C = 188.4 Hz, C(4)–P), and at δ 126.4 (d,
2JP–C = 14.6 Hz, C(5)–NH2) ppm. As displayed in Scheme 2,
the formation of the fused imidazophosphonate 7 was formed
via the initial condensation intermediate 6. Further alkaline
hydrolysis of the cyano group and the intramolecular cycliza-
tion led to the product 7 (Scheme 2).
Scheme 2: Synthesis of substituted diethyl aminophosphonate 7.
Scheme 1: Synthesis of substituted diethyl oxophosphonate 4.
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Beilstein J. Org. Chem. 2013, 9, 1730–1736.
Conversely, similar treatment of 1b with diethyl (methylthio-
alkyl)phosphonates 8a and 8b under the same reaction condi-
tions yielded the fused diazaphospholo-substituted compounds
10a and 10b in 72 and 74% yield, respectively. The 31P NMR
spectrum (CDCl3) of the diazaphospholes 10a and10b showed a
sharp singlet around 14.5 ppm, which is within the range
expected for the assigned structure [31].
A mechanism for the formation of the heterophosphole struc-
ture 10 can be rationalized as in Scheme 3 through the conden-
sation of 1b with 8a or 8b to elaborate the intermediates 9a or
9b accompanied by the elimination of a N2 molecule. Further
intramolecular cyclization of 9 afforded the diazaphospholes
10a and 10b, respectively, through the loss of an ethanol mole-
cule [31] (Scheme 3).
Scheme 4: Synthesis of fused imidazophosphono-substituted com-
pound 13.
accordance with the assigned structure (see Supporting Infor-
mation File 1). The formation of 15 can be rationalized as
occurring in Scheme 5 through the addition of 14 to the azido
group with concomitant evolution of a molecule of N2
(Scheme 5). Bisphosphonates belong to an important class of
BP-drugs used for the treatment of bone diseases such as osteo-
porosis, hypocalcemia, inflammation and rheumatoid arthritis
[32,33].
Scheme 3: Synthesis of fused diazaphospholo-substituted com-
pounds 10a, 10b.
Scheme 5: Synthesis of β-enaminobisphosphonate 15.
Next, the fused imidazophosphono-substituted compound 13
(68% yield) was obtained from the reaction of 1b with diethyl
(2-amino-2-thioxoethyl)phosphonate (11) in ethanolate solu- Finally, we studied the behavior of the azidotetrazole 1b toward
tion. Obviously, 13 resulted in the same manner from the inter- the unsaturated HE reactant, diethyl vinylphosphonate (16), and
mediate 12 initially formed, as outlined in Scheme 4.
diethyl 2-methylallylphosphonate (18) in EtONa solution to
give the fused imidazophosphono-substituted compounds 17
Further, the azidotetrazole 1b was allowed to react with the (76%) and 19 (74%). Obviously, according to Scheme 6, the
Horner–Emmons (HE) reactant, tetraethyl methylenebis(phos- coupling cyclization reaction of 1b with 16 and auto-oxidation
phonate) (14) under the same reaction conditions to give the resulted in formation of the final product 17 in one step. This
respective β-enaminobisphosphonate 15 (≈73% yield). The behavior is familiar in similar reactions. On the other hand, we
gem-diphosphonate structure 15 was delineated from IR, NMR presume that the allyl reagent 18, which could be present in the
and MS spectra. The IR absorptions for 15 showed the 2 P=O isomeric forms 18a
18b (Scheme 7), had been conju-
stretching frequencies as two bands at 1262 (P=O, free) and gated in 18b form with 1b to give the phosphonate 19.
1226 (P=O, bonded) cm−1, which could be explained by a
preferred conformation of intramolecular hydrogen bonding In summary, it has been found that the substrate 3,6-diazidopy-
between the NH proton and one of the P=O moieties. The ridazine reacts with nucleophilic phosphorus reagents, HE reac-
31P NMR spectrum (CDCl3) of 15 showed the presence of two tants, mainly in the tetrazole-form leading to the formation of
separate doublets with equal 2JP–P coupling constants 28.4 Hz tetrazolopyridazino-imidazophosphor esters or β-enaminophos-
at δ 25.6 and 24.8 ppm. The 1H and 13C NMR data were also in phor esters.
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Beilstein J. Org. Chem. 2013, 9, 1730–1736.
Biological assays
Based on previous reports [24-26] that recognized the pyri-
dazine nucleus is being suitable for anti-inflammatory and
antinociceptive agents, and by the fact that ring-fused hetero-
cycles containing more than one nitrogen atom (e.g., tetrazole
nuclei [21-23]) are key structures in a large variety of biochem-
ical processes, bioscreening of the synthesized substituted tetra-
zolo[1,5-b]pyridazine-phosphor derivatives was carried out.
Thus, keeping the tetrazolopyridazine core structure intact, we
studied the effect of different phosphorus-containing moieties
on their antinociceptive and anti-inflammatory effects. Sub-
strate 1 was also tested to reflect the effect of its transforma-
tions to our products.
Scheme 6: Synthesis of fused imidazophosphono-substituted com-
pounds 17 and 19.
Antinociceptive evaluation para-Benzo-
quinone (p-BQ)-induced writhing test
The evaluation of antinociceptive activity of the synthesized
compounds was assessed in vivo in mice by using the p-benzo-
quinone-induced writhing test [26]. Ibuprofen was used as a
positive control in our experiments; the antinociceptive capacity
was expressed as the percentage change compared to writhing
controls. The results shown in Table 1 indicated that β-enam-
Scheme 7: Isomeric forms of diethyl 2-methylallylphosphonate (18).
Table 1: Antinociceptive/anti-inflammatory effects of the tested compounds on the p-BQ-induced abdominal constriction test and carrageenan (CG)-
induced hind paw edema model in mice.a
tested
compound
no. of writhings ± SEM
(antinociceptive effect, %b)
Swelling in thickness (× 10−2 mm) ± SEM
(inhibition of edema, %)c
anti-inflammatory activity
after 360 min, %
90 min
180 min
270 min
360 min
control
28.6 ± 2.4
41.4 ± 3.3
55.2 ± 2.7
74.8 ± 3.6
78.2 ± 4.1
—
4d
6.8 ± 2.2
(76.2)*
30.2 ± 3.8
(27.1)*
28.9 ± 4.6
(47.6)**
37.4 ± 5.7
(50.0)**
31.3 ± 5.6
(60)***
(96.8)**
7d
5.4 ± 4.3
(81.1)**
31.8 ± 5.3
(23.2)*
25.1 ± 5.6
(54.5)*
33.8 ± 3.4
(54.8)***
27.4 ± 6.4
(65.0)*
104.8
103.7
102
10ad
5.8 ± 2.9
(79.7)***
30.6 ± 6.3
(26.1)**
26.3 ± 5.6
(52.4)**
34.6 ± 3.6
(53.7)***
27.9 ± 4.3
(64.3)***
10bd
6.3 ± 2.9
(77.9)*
30.8 ± 3.8
(25.6)*
27.1 ± 4.7
(50.9)*
35.6 ± 6.0
(52.4)***
28.8 ± 4.8
(63.2)***
13d
4.4 ± 2.2
(84.6)*
30.7 ± 3.3
(25.8)**
23.4 ± 5.6
(57.6)**
33.2 ± 3.6
(55.6)***
25.8 ± 4.3
(67.0)***
108
15d
3.9 ± 2.1
(86.4)**
28.9 ± 5.2
(30.2)***
21.6 ± 7.4
(60.9)***
28.2 ± 5.0
(62.3)***
22.8 ± 6.7
(70.8)***
114
17d
7.6 ± 1.7
(73.4)***
30.4 ± 7.2
(26.5)***
29.3 ± 4.1
(46.9)**
39.1 ± 4.2
(47.7)***
30.7 ± 4.5
(60.7)***
97.9
95.5
32.6
19d
7.2 ± 2.1
(74.8)***
29.7 ± 4.6
(28.0)*
28.7 ± 5.6
(48.0)**
38.5 ± 5.2
(48.6)***
31.9 ± 3.8
(59.2)***
1
24.6 ± 2.3
(14.0)**
36.8 ± 6.9
(11.1)**
44.6 ± 5.4
(19.2)**
56.8 ± 5.5
(24.0)**
62.4 ± 3.8
(20.2)***
ibuprofen
indomethacin
8.7 ± 3.1
(69.6)***
34.6 ± 4.6
(16.4)**
32.4 ± 4.4
(41.3)*
31.4 ± 1.6
(58.02)***
29.8 ± 3.4
(62.0)***
100
aData obtained from animal experiments are expressed as means ± SEM (dose = 50 mg per kilogram body weight, administered subcutaneously to
mice (n = 6–8). bp-BQ-induced writhing; cCG-induced paw edema tests, respectively. dStatistical significance was evaluated from the control by one-
way ANOVA post hoc Dunnett’s test (*p < 0.05, **p < 0.01, ***p < 0.001).
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Beilstein J. Org. Chem. 2013, 9, 1730–1736.
inobisphosphonate 15 is the most potent antinociceptive struc- 108%) in inflammation inhibition after 360 min comparing to A
ture (86.4%), which was followed by α-aminophosphonates 13 without toxic effects. Percentage inhibition of granuloma for the
(84%) and 7 (81%). Indeed, while the azido substrate 1 showed tested compounds at a dose of 50 mg per kilogram body weight
only a weak antinociceptive effect (14%), the eight phosphor at successive intervals is displayed in Figure 1.
compounds demonstrated higher capacity than the reference
ibuprofen drug (69.9%) at the same dose of 50 mg per kilo- According to the results of the biological assay in Table 1, we
gram body weight.
could deduce the structure–activity relationship (SAR) as
follows: (1) among the tested compounds, β-enaminobisphos-
phonate 15 has the most antinociceptive/anti-inflammatory
activity, even higher than the references ibuprofen and
Anti-inflammatory screening
Carrageenan-induced hind paw edema test
Anti-inflammation properties of the new tetrazolo[1,5-b]pyri- indomethacin; (2) there is a parallel correlation between the
dazines-bearing mono- (4, 7, 10a, 10b, 13, 17, 19) and diphos- anti-inflammatory activities and the antinociceptive activity
phonate nuclei (15) were evaluated in an animal model, by the results (Table 1); (3) the amino group substituent has a positive
carrageenan–induced paw edema (CPE) method. Following the effect (see 7 and 13); (4) like indomethacin, the tested phospho-
standard procedures [34,35], these compounds were adminis- nates showed gradual increase in the second phase (after 270
tered subcutaneously by using 50 mg per kilogram body weight, min).
and the anti-inflammatory effect was measured at successive
time intervals (90, 180, 270, and 360 min, after carrageenan LD50 of the most promising products
injection). The results are profiled in Table 1 and are compared In an acute-toxicity experiment, the most promising anti-inflam-
to the substrate 1 and to indomethacin (A). β-Enaminobisphos- matory compounds 15, 7, and 13 were tested using the LD50
phonate 15 showed the most potent inflammatory properties standard method in mice at doses of 500, 750 and 1000 mg per
(e.g., 114% after 360 min) relative to indomethacin. Neverthe- kilogram body weight, which is 10–20 times the used anti-
less, other compounds displayed good to excellent effects (95 to inflammatory effective dose (50 mg per kilogram body weight).
Figure 1: Percentage inhibition of granuloma for the tested compounds at a dose of 50 mg per kilogram body weight after the given time intervals.
Error bar: 5%.
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Beilstein J. Org. Chem. 2013, 9, 1730–1736.
7. Vane, J. R.; Bakhle, Y. S.; Botting, R. M.
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In summary, we have offered a practical and efficient proce-
dure for the synthesis of imidazophosphor esters based tetra-
zolo[1,5-b]pyridazine in high yields by application of different
types of Horner–Emmons (HE) reagents on 3,6-diazidopyri-
dazine. Among the products, the β-enaminobisphosphonate
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See Supporting Information File 1 for full experimental data
13.Abdou, W. M.; Barghash, R. F.; Bekheit, M. S. Arch. Pharm. 2012, 345,
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The experimental section, the general procedures, the
experimental data, the results of the analyses, and the
bioassay procedures are included in Supporting Information
File 1.
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19.Abdou, W. M.; Shaddy, A. A.; Sediek, A. A. J. Chem. Res. 2009, 8–13.
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