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Synthesis and Molluscicidal Activity of Some 134-Triaryl-5-chloropyrazole Pyrano[23-c]pyrazole Pyrazolylphthalazine and Pyrano[23-d]thiazole Derivatives.

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Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
F. M. Abdelrazek et al.
305
Full Paper
Synthesis and Molluscicidal Activity of Some 1,3,4-Triaryl-5chloropyrazole, Pyrano[2,3-c]pyrazole, Pyrazolylphthalazine
and Pyrano[2,3-d]thiazole Derivatives
Fathy M. Abdelrazek1, Farid A. Michael1, Alaa E. Mohamed2
1
2
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Medicinal Chemical Department, National Research Center, Giza, Egypt
2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of
malononitrile 2a–d to afford the triaryl-5-chloropyrazoles 3a–d, respectively. 1a reacts with the
active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and
14a, b – depending on the substitution in the pyrazole ring. Compound 1a reacts also with the
pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a–c to
afford the pyrano[2,3-d]thiazoles 20a–c, respectively. It reacts also with the malononitrile dimer
21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively.
The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.
Keywords: Pyrazolin-3-ones / Cinnamonitriles / Triaryl-5-chloropyrazoles / Pyrano[2,3-c]pyrazoles / Pyrano[2,3-d]thiazoles /
Received: December 23, 2005; Accepted: Januar 4, 2006
DOI 10.1002/ardp.200500259
Introduction
In the last two decades, we have been involved in a program aiming at the synthesis of heterocyclic compounds
of anticipated biological activity that may find applications as biodegradable agrochemicals [1–4]. Schistosomiasis (bilharziasis) is one of the major national health problems in Egypt and great efforts are made to combat this
disease. Although praziquantel has been successfully
used as chemical therapy in Egypt, the life style and
habits among Egyptian farmers, however, which necessitate their contineous and daily contact with canal-water
during the irrigation process led to repeated infection
and there is no way to prevent this contact. Therefore,
combating the water snails Biomphalaria alexandrina and
Biomphalaria glabrata, the intermediate hosts of the infective phase of Schistosoma mansoni, through molluscicides,
becomes the first priority in such situations. Copper sulCorrespondence: Prof. Dr. Fathy Mohamed Abdelrazek, Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt.
E-mail: prof_fmrazek@yahoo.com
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
fate and niclosamide were used tentatively in Egypt
(Fayyoum Governorate) within a program developed by
Bayer AG, however it was stopped soon due to the hazardous enviromental effects. Therefore, the need to search
for synthetic or naturally occuring extracts of molluscicides is still ongoing. We have found it mandatory to participate in these efforts and directed a part of our
research towards the synthesis of heterocyclic compounds that can be used as molluscicides [5, 6]. Pyrazoles
and their fused derivatives are known to exhibit diverse
biological activities and important applications in pharmaceutical industries [1, 2, 7, 8]. In continuation of our
search for some effective synthetic molluscicides, chloropyrazole derivatives seemed promising for molluscicidal
activity evaluation. In spite of the fact that the synthesized compounds in this paper may have more hazardous
effects to the environment, however we are just making
the so called preliminary blind screening until we find
the suitable effective lead compound, then we can study
modifying its properties and expand this study to evaluation of its biodegradability/stability as well as its effect on
other water-living organisms.
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F. M. Abdelrazek et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
Scheme 1. Chemical structure of compounds 1–4.
2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a (Scheme 1) obtained from the condensation of 5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde
with malononitrile via its reaction with active methyl
and methylene reagents seemed a good precursor to fulfill our objective. Consulting the literature, we have
found a complete research paper dealing with the preparations of the desired compounds [9]. Therefore, we
started to prepare some of these compounds following
the same synthetic pathways as described by Elnagdi et
al. [9]. However, the data encountered during our preparations urged us to reinvestigate this work. The results
seemed worth publishing and are reported in the present
paper.
Results and discussion
Synthesis
2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a was claimed to react with the arylidenes 2a
and 2b (Scheme 1) in refluxing ethanol catalyzed by
piperidine to afford the fully aromatic product 3a and
the non-aromatic adduct 4 (7a and 7b, respectively, in the
original paper [9]). This result seemed non-logic, since the
authors assumed a reaction sequence involving a Michael
addition of the methyl group in 2a or 2b to the activated
double bond in 1a followed by cyclization and loss of
HCN (in case of 2-thienyl) to afford the aromatic product
3a, while the non-aromatized product 4 was their
claimed final product (in case of p-tolyl), however, they
failed to give any reasonable rationalization as to why
HCN is lost only in the first case (while the aromatization
is a driving force in both cases). Therefore, the reaction of
1a with 2a-d was reinvestigated under the same reaction
conditions as described by Elnagdi et al. [9], and found to
afford solely the fully aromatic compounds 3a-d, respectively (Scheme 1). The formation of these products is in
agreement with our previous work [10] as well as the
authors own references cited in [9].
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Structures 3a–d were assigned to these reaction products on the basis of their elemental analyses as well as
spectral data (see Experimental). The IR spectra of these
compounds show generally two conjugated cyanoabsorption bands at tmax = 2185 and 2215 cm–1 beside the
amino-group absorption. The 1H-NMR spectrum of 3b
(which was claimed to be 4; 7b in the original paper [9])
revealed signals at d = 2.35 (s, 3H, CH3), 6.5 (s, 2H, exch.,
NH2), and 7.15-7.6 (m, 15 H) ppm assignable to the
methyl, amino, and aromatic protons, respectively (the
same 1H-NMR data were given in reference [9] for 7b). If
the structure would have been 4 (7b as claimed by
Elnagdi et al. [9]), two doublets would have appeared at
d l3–4 ppm, due to an aliphatic H and at d l5–6 ppm,
due to the olefinic H [11], which we could not find in our
spectra and no mentioning of these signals in the original paper [9]. So the spectral data given in the original
paper for the claimed structure 4 are completely applicable to structure 3b and the other mass spectral data
given in support of structure 4 (7b) seem to be imaginary
and even wrong. The 13C-NMR data of 3b (see Experimental) did not reveal any sp3 carbon signals which would
have appeared at d l10–20 and 30–40 ppm if the structure was 4 (7b) [11].
Furthermore, the reaction of 1a with 2,5-disubstituted
2,4-dihydropyrazol-3-one derivatives 5a and 5b (8b, c in
the original paper) was also claimed [9] to afford the arylidene exchange products 6a, b (Scheme 2), (13a, b in the
original paper). In a previous work from the same group,
Elnagdi et. al. claimed that compound 5a reacts with benzylidenemalononitrile 1b (Scheme 1) to afford the pyranopyrazole 7 [12] (Scheme 2).
This contradiction urged us to reinvestigate the reaction of 5a, b with 1a under the same reaction conditions
described by Elnagdi et al. [9]. In our hands, we could isolate two products from each reaction of 5a and 5b with
1a for which structures 8, 9 and 10, 11 were assigned
respectively on the basis of their elemental analyses and
spectral data (See Experimental). The data given in reference [9] for structures 6a, b (13a, b in the original paper)
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Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
Biologically active Chloropyrazole Derivatives
307
Scheme 2. Synthetic route of title compounds 8–11 and 14a, b.
seem to be fabricated, since a structure like 6 should have
revealed the olefinic proton as a singlet at d l6–7 ppm
[11] which is not mentioned. The resulting compounds 8,
9 and 10, 11 are in agreement with the reported literature [13, 14]. The product of the reaction of benzylidenemalononitrile 1b (11 in the original paper) with 5methyl-2,4-dihydropyrazol-3-one 12a (Scheme 2) (number
8a in the original paper; wrongly named) described for
contrast is wrong.
The IR spectra of these two products in each case did
not show any carbonyl absorption bands and the claimed
absorption at t = 1720 cm–1 for 6b (13b) [9] is out of imagination, since it is valid for an ester carbonyl not a pyrazolone carbonyl. The 1H-NMR data given for the claimed 6b
(13b in the original paper) mentioned (m, 21H, aromatic
protons; as if the olefinic H is enclosed) but one can not
decide that the multiplet is 21 protons while there are no
reference signals to calibrate against.
It is worth to mention that refluxing the pyrazolones
5a, b with 5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde in ethanol catalyzed by piperidine (aiming to obtain
the arylidenes 6a, b for comparison), afforded solely the
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
pyrano bis-pyrazol derivatives 8, 10; presumably, via the
intermediacy of 6a, b which undergo a further addition
of 5a, b followed by elimination of water.
However, we could obtain the claimed arylidene derivatives 6a, b by fusing the respective pyrazolones 5a, b
with 5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde
(1:1) in presence of piperidine at 2508C. The obtained products are completely different from those claimed by
Elnagdi et al. [9] (see Experimental).
Refluxing 5a, b with 1a in presence of sodium ethoxide
lead only to the pyrano[2,3-c]pyrazole derivatives 9, 11.
Sodium ethoxide catalyst apparently enhances the enolization of 5b and the hydroxyl group adds to the neighboring cyano group in the in situ formed acyclic intermediate.
5-Methyl-2,4-dihydropyrazol-3-one 12a (number 8a in
the original paper; wrongly named) reacts with 1a (2 in
the original paper [9]) to afford the 1:1 adduct pyrano[2,3c]pyrazole derivative 14a (Scheme 2), presumably via the
intermediate 13, (this perhaps is what happened to
Elnagdi et al., who assigned structure 9 in their paper;
wrongly drawn and the analyses are calculated on the
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F. M. Abdelrazek et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
Scheme 3. Synthetic route of title compounds 16–22.
wrong structure and the found values are fabricated to
fit with the calculated). 5-Phenyl-2,4-dihydropyrazol-3one 12b reacts also with 1a to afford 14b. The presence of
the proton on the nitrogen adjacent to the carbonyl
group apparently enhanced the enolization in the pyrazole ring irrespective of the catalyst used. This conclusion
is in complete agreement with our previously reported
mechanism [14].
Compound 1a reacts with ethyl 5-cyano-4-methyl-6oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylate 15 (14
in [9]) under the same reaction conditions described in
[9], we could obtain a dark yellow substance with a m.p.
1638C. Analytical and spectral data approved the phthalazine structure 16 (18 in the original paper [9]) (see Scheme
3).
The reaction of 1a with 2-substituted 2-thiazolin-4-ones
17a–c (19a–c in the original paper) was claimed to afford
the thiazolo[3,2-a]pyridine derivatives 18a–c (21a–c) [9].
In our hands, this reaction afforded three compounds
with nearly the same melting points as given in [9],
respectively. However the spectral data in our hands and
those cited in reference [9] suggest the pyrano[2,3-d]thiazole derivatives 20a–c (Scheme 3), which were denied in
reference [9] (No. 22). The 1H-NMR data obtained for the
three compounds did not show any signals at d l1.0 ppm
which was assigned by the authors to the thiazole CH2
(which is wrong even if it was present). Furthermore, all
the spectra revealed a singlet (2H) at d l3.6 ppm (not
mentioned in the original paper [9]), which is mostly
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attributed to the –CH2X side chain rather than the thizole ring CH2 which is expected to appear rather downfield (l3.8 ppm) [11]. Also the singlet at d l4.7 ppm for
the three compounds is mostly attributed to the 4Hpyran rather than to a 4H-pyridine as assigned by the
authors [9], since a 4H-pyridine would have appeared at a
higher field (l4.3 ppm) [11]. The 13C-NMR spectrum of
20a (see Experimental) afforded a conclusive evidence of
this structure since it revealed the methylene group (t) at
d 19.85 ppm which is mostly assigned to a side chain
rather than the thiazole ring CH2 which would have
appeared at a value downfield 30 ppm, and also revealed
a doublet at 13 ppm which is assigned to the pyran 4-H
rather than a pyridine 4-H that should have appeared a
little more upfield [11]. Thus, structures 20a–c were
assigned to these reaction products and are assumed to
be formed via a Michael addition of the thiazole ring
active methylene in 17a-c to the activated double bond in
1a, to give the acyclic intermediates 19, which in turn
underwent cyclization through addition of the hydroxy
group of the enol tautomer to one of the adjacent cyano
groups to afford the final products 20.
The reaction of 1a with malononitrile dimer 21a and
with ethyl cyanoacetate dimer 21b (24a, b in the original
paper [9]) was also reinvestigated. In our hands, the dihydropyridine derivatives 22a and 22b were obtained,
respectively. The same structures were assigned in reference [9] (27a, b, respectively), but the authors have drawn
it as a tautomeric pair, however all our data and those
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Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
Biologically active Chloropyrazole Derivatives
cited by the authors themselves strongly suggest structures 22a, b (Scheme 3). The structures of the products of
the reaction of 21a, b (24a, b) with benzylidenemalononitrile 1b (11 in [9]) seem to be of no meaning in this
respect, since both groups of researchers denoted by the
authors (references 25, 26 for one group and ref. 27 for
another [9]) are one and the same group and all coauthored by M. H. Elnagdi; the main author of reference [9]
and show the contradiction of their interpretation.
Molluscicidal activity
The toxicity of compounds 3a–d, 8, 9, 10, 11, 14a, b, 16,
20a–c, and 22a, b to Biomphalaria alexandrina snails was
evaluated as shown in Table 1. The half lethal dose (LC50)
and the sublethal dose (LC90) in ppm [nM] for each compound was determined and is shown in Table 2. An
insight inspection of the results listed in Table 2 shows
that all compounds have generally moderate to low
effect on the snails, and they all showed nearly no effect
below 5 ppm. The most effective of them are 9, 14a, and
22a (LC50 and LC90 = 6 and 8; 8 and 10, and 7 and 10 ppm,
respectively). The pyranopyrazole derivative 9 is superior
to 11 apparantly due to the presence of methyl substituent in the pyrazole ring, and for the same reason, compound 14a is more active than 14b. Compound 3a shows
lower activity despite having a methyl substituent in the
phenyl group. It seems that the presence of methyl substituent in the pyrazole ring activates the biological activity
more than in a phenyl substituent. The thiophene carrying compound show low activity in the present case as
observed previously [5] and likewise the thiazole fused
derivatives 20a–c. The moderate activity of the dihydro-
309
Table 2. Molluscicidal activity of compounds 3a–d, 8, 9, 10, 11,
14a, b, 16, 20a–c, and 22a, b expressed as LC50 and LC90 in
ppm [nM].
Compound
LC50
LC90
3a
3b
3c
3d
8
9
10
11
14a
14b
16
20a
20b
20c
22a
22b
13 [27.20]
13 [26.75]
12 [23.70]
11 [23.31]
11 [18.49]
6 [11.88]
13 [18.08]
13 [22.93]
8 [18.65]
14 [28.51]
9 [15.33]
13 [27.61]
15 [28.96]
14 [28.63]
7 [15.12]
9 [16.16]
>15 [>31.38]
>15 [>30.86]
14 [27.65 ]
>15 [>31.78]
>15 [25.21]
8 [15.84]
>>15 [>>20.86]
>>15 [>>26.46]
10 [23.32]
>>15 [>>30.55]
13 [22.15]
>>15 [>>31.85]
>>15 [>>28.96]
>>15 [>>30.67]
10 [21.60]
15 [26.93]
pyridine 22a is apparently attributed to the toxic effect of
four cyano groups. A comparison of the molluscicidal
activity of our compounds with an international standard: 2,5-dichloro-4-nitrosalicylanilide which is reported
to posses LC100 = 1 ppm [15, 16] showed that our compounds are far inferior as molluscicidal agents. Compound 9 seems promising after some modifications
which will be considered in a future study.
F. M. Abdelrazek thanks the Alexander von Humboldt-Foundation (Germany) for granting a fellowship and Prof Dr. P. Metz,
Institut fr Organische Chemie, TU-Dresden; for kind hospitality.
Table 1. The mean number of snails killed €1 after an exposure
time of 24 h at concentration in ppm.
Compound
No.
4
3a
3b
3c
3d
8
9
10
11
14a
14b
16
20a
20b
20c
22a
22b
0
0
0
0
0
1
0
0
0
0
1
0
0
0
2
2
i
5
7
9
11
13
15 ppm
Experimental
Chemistry
0
0
0
0
1
4
1
1
2
2
2
0
0
1
3
3
0
0
1
2
1
7
1
2
4
2
4
1
1
1
5
3
3
2
2
4
2
10
2
4
7
3
5
2
2
2
8
5
4
3
4
5
5
10
4
4
10
4
7
3
2
2
10
7
5
5
7
6
7
10
5
5
10
4
9
5
4
4
10
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
7
6
10
6
7
10
6
6
10
6
10
5
5
6
10
9
General
Melting points were determined on an electrothermal (9100)
apparatus (Kleinfeld, Gehrden, Germany) and are uncorrected.
The IR spectra were recorded as KBr pellets on a Perkin Elmer
1430 spectrophotometer (Perkin Elmer, Norwalk, CT, USA). The
1
H-NMR and 13C-NMR spectra were taken on a Varian Gemini 300
MHz spectrometer (Varian Inc., Palo Alto, CA USA)in deuterated
DMSO using TMS as internal standard and chemical shifts are
expressed in d (ppm) values. Assignments were made by correlation of the off-resonance decoupled 13C-NMR spectra and determination of the 1H chemical shifts. Mass spectra were taken on a
Shimadzu GCMS-GB 1000 PX (70 eV; Shimadzu, Tokyo, Japan).
Elemental analyses were carried out by the Microanalytical Center at Cairo University. Satisfactory elemental analysis results
(€0.4%) have been obtained for all compounds. Molluscicidal
activity tests were conducted in the Medicinal Chemical Departwww.archpharm.com
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F. M. Abdelrazek et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
ment, Laboratory of Parasitology, National Research Center of
Egypt.
4-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-2,5diphenyl-2,4-dihydropyrazole-3-one 6b
Preparation of triaryl-5-chloropyrazoles 3a-d
Brown crystalline solid (yield 3.85 g, 77%), m.p. 268–2698C
(EtOH/DMF). (C31H21ClN4O). tmax = 1674 (C=O) cm–1. dH = 6.85 (s,
1H), 7.0–7.68 (m, 20H, arom. H).
General procedure
To a solution of 1a (10 mmol) in absolute ethanol (50 mL) was
added each of 2a, 2b, 2c, or 2d (10 mmol) followed by 5 drops of
piperidine. The reaction mixture was refluxed for 4 h, then evaporated in vacuo to one third of its original volume. The contents
of the flask was then poured on ice-cold water and acidified by
HCl. The solid products thus formed were collected by filteration
and recrystallized from ethanol/DMF to afford:
2-Amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-6thien-2-yl-isophthalonitrile 3a
Brown crystals (yield 4.1 g, 87%); m.p.167–1688C (EtOH/DMF) (lit.
1658C [9]). (C27H16ClN5S). tmax = 3645–3350 (NH2), 2205 & 2192 (2
CN). dH = 3.8–4.0 (brs, 2H, NH2), 7.05–7.75 (m, 14H, arom. H).
3-Amino-5-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-49methylbiphenyl-2,4-dicarbonitrile 3b
Orange crystals (yield 4.3 g, 88%); m.p. 235-2368C (EtOH/DMF)
(lit. 2388C [9]). (formula) C30H20ClN5. tmax = 3460–3355 (NH2), 2206
& 2190 (2 CN). dH = 2.35 (s, 3H, CH3), 6.45 (brs, 2H, NH2), 7.15–7.80
(m, 15H, arom. H). dC: 21(t), 97.5(s), 98.9(s), 115.9(s), 116.1(s),
117.4(d), 118.7(d), 125.2(s)(pyrazole C-5), 126.3(d), 127.1(s)(pyrazole C-4), 127.4(d), 127.6(d), 128.4(d), 129.2(d), 129.4(d) 129.6(d),
133.7(s), 136.4(s), 136.7(s), 139.6(s), 145.6(s), 145.8(s), 155.6(s),
156.1(s) (pyrazole C-3).
3-Amino-49-chloro-5-(5-chloro-1,3-diphenyl-1H-pyrazol-4yl)-biphenyl-2,4-dicarbonitrile 3c
Greenish-yellow solid (yield 4.6 g, 92%); m.p. 211–2138C (EtOH/
DMF). (C29H17Cl2N5). tmax = 3610–3348 (NH2), 2210 & 2202 (2 CN).
dH = 4.75–5.0 (brs, 2H, NH2), 7.3–7.85 (m, 15H, arom. H).
3-Amino-5-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)biphenyl-2,4-dicarbonitrile 3d
Dark yellow Crystals (yield 4.2 g, 89%); m.p. 216–2178C (EtOH/
DMF). (C29H18ClN5). tmax = 3480–3365 (NH2), 2206 & 2195 (2 CN).
dH = 6.35 (brs, 2H, NH2), 7.18–7.75 (m, 16H, arom. H).
Preparation of the arylidene derivatives 6a, b
The respective pyrazolone 5a or 5b (10 mmol) was mixed with 5chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde (10 mmol) and
few drops of piperidine were added. The reaction mixture was
heated on a metal bath at 250–2708C for 1 h. After cooling to
room temperature, the solid mass was treated with ethanol, filtered, and recrystallized from the proper solvent:
4-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-5methyl-2-phenyl-2,4-dihydropyrazole-3-one 6a
Pale yellow crystalline solid (yield 3.3 g, 75%), m.p. 246–2488C
(EtOH/DMF). (C26H19ClN4O). tmax = 1666 (C=O) cm–1. dH = 1.2 (s,
3H), 6.45 (s, 1H), 7.0-7.65 (m, 15H, arom. H).
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Reaction of 1a with the pyrazolone derivatives 5a, b
To a solution of 1a (10 mmol) in 50 mL of absolute ethanol was
added (10 mmol) of the appropriate pyrazolone derivative 5a or
5b followed by 0.5 mL of piperidine and the reaction mixture
was refluxed. After 20 min a yellowish-white insoluble product
was observed in each case which was filtered off, dried, and
recrystallized from the proper solvent and found to be 8 and 10,
respectively. The reflux of the filtrate was continued up to 2.5 h.
Most of the solvent was evaporated and the reaction mixture
was cooled and acidified with ice-cold acetic acid. The colored
solid product so obtained was filtered off, dried, and recrystallized from the appropriate solvent to be compound 9 and 11,
respectively. The overall yield of the reaction was l84%, with
the ratio of l1:1 in each reaction.
Alternative route for the preparation of 8 and 10
To a solution of 5a or 5b (10 mmol) in 30 mL of absolute ethanol
was added an equimolar amount (2.83 g, 10 mmol) of 5-chloro1,3-diphenyl-1H-pyrazole-4-carbaldehyde followed by 5 drops of
piperidine. The reaction mixture was refluxed for 20 minutes by
which time a precipitate appears. The reflux was stopped, the
flask was left to cool, and the precipitate was filtered off and
washed thoroughly with cold ethanol to afford analytically pure
8 and 10 in 83% yield.
Alternative route for preparation of compounds 9 and 11
To a solution of 1a (10 mmol) in 30 mL of absolute ethanol was
added an equimolar amount of 5a or 5b (10 mmol), and the mixture was heated gently until complete dissolution was reached,
then sodium ethoxide (0.23 g, 10 mmol of sodium metal in
20 mL of absolute ethanol) was added and the reaction mixture
was heated under reflux for 1 h. The reaction mixture was then
cooled in an ice bath and acidified with ice-cold hydrochloric
acid. The solid product so obtained was filtered off, dried, and
recrystallized from the appropriate solvent to give 9 and 11 with
86% yield.
4-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-yl)-3,5-dimethyl1,7-diphenyl-4,7-dihydro-1H-pyrano[2,3-c;6,5c9]dipyrazole 8
White powder (yield 2.5 g, 42%); m.p. 256–2578C (EtOH/DMF).
(C36H27ClN6O). dH = 1.8 (s, 6H, 2CH3), 5.31 (s,1H, pyran 4-H), 7.157.65 (m, 20H, arom.).
6-Amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-3methyl-1-phenyl-1,4-dihydropyrano [2,3-c]pyrazole-5carbonitrile 9
Pale yellow crystals (yield 2 g, 41%); m.p. 203–2048C (EtOH/
dioxan). (C29H21ClN6O). tmax = 3455-3330 (NH2), 2212 (CN) cm–1. dH
= 1.9 (s, 3H, CH3), 4.76 (s,1H, pyran H), 5.4 (brs, 2H, NH2), 7.18–
7.76 (m, 15H, arom.). MS: m/e = 504, 506.
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Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
4-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-yl)-1,3,5,7tetraphenyl-4,7-dihydro-1H-pyrano[2,3-c; 6,5c9]dipyrazole 10
White powder (yield 3.1 g, 43%); m.p. 256–2578C (EtOH/DMF).
(C46H31ClN6O). tmax = no characteristic bands. dH = 5.32 (s, 1H,
pyran H), 7.2–7.7 (m, 30H, arom.).
6-Amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-1,3diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
11
Light orange crystals (yield 2.38 g, 42%); m.p. 192–1938C (EtOH/
dioxan). (C34H23ClN6O). tmax = 3450–3320 (NH2), 2210 (CN). dH =
4.75 (s, 1H, pyran H), 5.4 (brs, 2H, NH2), 7.15–7.62 (m, 20H,
arom.). MS: m/e = 566, 568.
Biologically active Chloropyrazole Derivatives
311
5-Amino-7-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-2cyanomethyl-7H-pyrano[2,3-d]thiazole-6-carbonitrile 20a
Yellow powder (yield 3.4 g, 72%). m.p. 182–1838C (EtOH);
(C24H15ClN6OS). tmax = 3360–3312 (NH2) and 2195 & 2205 (CN); dH
= 3.6 (s, 2H, CH2) 4.7 (s, 1H, pyran 4-H), 6.90 (s, 2H, NH2, exch.),
7.25-7.62 (m, 10H, arom.). dC = 13(d), 19.85(t), 58.9(s), 114.5(s),
115(s), 117(s), 118.5(d), 125.4(s), 126.1(d), 127.1(d), 128.3(d),
129(d), 129.2(d), 130.6(s), 136.3(s), 140(s), 143.2(s), 154(s), 158.1(s),
174.6(s). MS: m/e = 470 (M–1), 472 (M+1).
Ethyl-[5-amino-7-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)6-cyano-7H-pyrano[2,3-d]thiazol-2-yl]acetate 20b
Yellow powder (yield 3.6 g, 70%). m.p. 146–1488C (EtOH);
(C26H20ClN5O3S). tmax = 3417–3330 (NH2), 2193 & 2207 (CN) and
1710 (ester CO); dH = 1.3 (t, 3H, CH3), 3.48 (s,2H, CH2), 4.05 (q, 2H,
CH2), 4.71 (s, 1H, pyran 4-H), 6.95 (s, 2H, NH2, exch.), 7.28-7.65 (m,
10H, arom.). MS: m/e = 517 (M–1), 519 (M+1).
Reaction of 1a with 12a, b; 15; 17a–c; 21a, b
General procedure
To a solution of 1a (10 mmol) in ethanol (20 mL) was added each
of the pyrazole-3-ones 12a, b, the pyridazine derivative 15, 2-substituted 2-thiazoline-4-ones 17a–c, malononitrile dimer 21a or
ethylcyanoacetate dimmer 21b (10 mmol) followed by 5 drops of
piperidine and the reaction mixture was heated under reflux for
1–3 h (TLC control). The reaction mixture was allowed to cool to
room temperature, then poured onto ice-cold water and neutralized with HCl. The solid products so obtained were filtered off,
dried, and recrystallized from the appropriate solvent to give
14a,b; 16; 20a–c and 22a,b, respectively:
6-Amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-3methyl-1,4-dihydropyrano[2,3-c]pyra-zole-5-carbonitrile
14a
Yellow powder (yield 3.25 g, 76%). m.p. 245–2468C (EtOH/DMF),
(lit. claimed 1738C [9]); (C23H17ClN6O). tmax = 3410, 3315, 3170
(NH2 and NH) and 2197 (CN); dH = 1.95 (s, 3H, CH3), 4.65 (s, 1H,
pyran 4-H), 6.8 (s, 2H, NH2, exch.), 7.20–7.50 (m, 10H, arom.) and
12.1 (s, 1H, NH).
6-Amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-3phenyl-1,4-dihydropyrano[2,3-c]pyra-zole-5-carbonitrile
14b
Pale yellow powder (yield 2.3 g, 75%). m.p. 265–2678C (EtOH/
DMF); (C28H19ClN6O). tmax = 3417, 3312, 3170 (NH2 and NH) and
2195 (CN); dH = 4.85 (s, 1H, pyran 4-H), 6.90 (s, 2H, NH2, exch.),
7.25-7.62 (m, 15H, arom.) and 12.4 (s, 1H, NH). MS: m/e = 490 (M–
1), 492 (M+1).
Ethyl-5-amino-7-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)6-cyano-4-oxo-3-phenyl-3,4-dihydro-phthalazine-1carboxylate 16
Dark yellow powder (yield 4.5 g, l76%). m.p. 162–1638C (EtOH);
(C33H23ClN6O3). tmax = 3450–3320 (NH2), 2207 (CN) and 1715 (ester
CO), 1680 (ring CO); dH = 1.25 (t, 3H, CH3), 4.25 (q, 2H, CH2), 7.4–
7.7 (m, 18H, arom. and NH2). MS: m/e = 586 (M–1), 588 (M+1).
i
2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2-[5-Amino-7-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-6cyano-7H-pyrano[2,3-d]thiazol-2-yl]-acetamide 20c
Dark yellow powder (yield 3.6 g, l75%). m.p. 277–2798C (EtOH/
DMF); (C24H17ClN6O2S). tmax = 3415–3260 (NH2), 2198 (CN), 1678
(amide CO); dH = 3.4 (s, 2H, CH2), 4.7 (s, 1H, pyran 4-H), 6.90 (s, 2H,
NH2 exch.), 7.20–7.65 (m, 12H, arom. and NH2). MS: m/e = 488 (M–
1), 490 (M+1).
2-Amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)-6dicyanomethyl-1,4-dihydropyridine-3,5-dicarbonitrile 22a
Yellow crystalline solid (yield 3.6 g, 78%). m.p. 210–2118C (EtOH/
dioxan); (C25H15ClN8). tmax = 3435–3255 (NH2 and NH), 2198,
2200, 2210 (CN groups); dH = 4.20 (s, 1H, CH), 4.35 (s, 1H, pyridine
4-H), 6.80 (s, 2H, NH2, exch.), 7.20–7.64 (m, 10H, arom.), 10.60 (s,
1H, NH).
Ethyl-6-amino-4-(5-chloro-1,3-diphenyl-1H-pyrazol-4-yl)5-cyano-2-(cyanoethoxycarbonylmethyl)-1,4dihydropyridine-3-carboxylate 22b
Yellow crystalline solid (yield 4.2 g, 75%), m.p. 259–2618C (EtOH/
dioxan); (C29H25ClN6O4). tmax = 3452–3252 (NH2 and NH), 2220,
2198 (2 CN), 1712 and 1718 (2 ester C=O); dH = 1.2 (t, 3H, CH3),
1.25 (t, 3H, CH3), 3.95 (s, 1H, CH), 4.2-4.3 (m, 4H, 2CH2), 4.38 (s, 1H,
pyridine 4-H), 6.80 (s, 2H, NH2, exch.), 7.15–7.60 (m, 10H, arom.),
10.68 (s, 1H, NH).
Biology
Molluscicidal activity tests
The molluscicidal activity tests were carried out by determination of the half lethal dose LC50 and the sublethal dose LC90 of
each compound under investigation. Biomphalaria alexandrina
snails were our test snails and were collected from the field
(water canals), maintained under laboratory conditions for a
period of 15 days before use, and were fed daily with lettuce
leaves. The snails were then examined to ensure that they were
free from parasitic infection. A series of concentrations (seven)
ranging from 4 ppm to 15 ppm of each compound under investigation was prepared. The required weight of the compound
under investigation was mixed thoroughly with a few drops of
Tween 20 and 2 mL of DMSO to render the compounds complewww.archpharm.com
312
F. M. Abdelrazek et al.
tely soluble followed by addition of the appropriate volume of
non-treated raw water (taken direcly from the River Nile or its
anabranches/canals) to get a homogeneous suspension with the
requisite concentration. It was placed in glass jar vessels
(15625620 cm) fitted with air bubblers. Ten snails having the
same size and diameter (ca. 5 mm) were used in each experiment
and maintained in the test solution under laboratory conditions
at ambient temperature for 24 h. Each experiment was repeated
three times and the mean number of killed snails was taken for
each concentration as shown in Table 1. A control group was
taken by placing 10 snails in water containing few drops of
Tween 20 and 2 mL of DMSO. These bioassays are in accordance
with the WHO guidelines slightly modified by using two mixed
solvents to dissolve the compounds [17].
References
[1] F. M. Abdelrazek, A. W. Erian, K. M. H. Hilmy, Synthesis
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[2] F. M. Abdelrazek, J. Prakt. Chem. 1989, 331, 475 – 478.
[3] F. M. Abdelrazek, Synthetic Communications 2005, 35,
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[4] N. H. Metwally, F. M. Abdelrazek, Synthetic Communications 2005, 35, 2481 – 87.
[5] F. M. Abdelrazek, P. Metz, E. K. Farrag, Arch. Pharm.
Pharm. Med. Chem. 2004, 337, 482 – 485.
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2006, 339, 305 – 312
[6] F. M. Abdelrazek, A. E. M. Fathy, Arch. Pharm. Chem. Life
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[7] The Merck Index, Ed. M. Windholz, Merck Co., Rahway,
New Jersey, 9th Ed., 1979.
[8] G. Koyama, H. Umezawa, J. Antibiot. 1965, 18A, 175 – 177.
Chem. Abstr. 1965, 63, 15158d.
[9] I. S. Abdel Hafiz, M. E. Eldin Rashad, M. A. Eldin Mahfouz,
M. H. Elnagdi, J. Chem. Res. 1998 (S), 690 – 691; (M) 2946 –
2957.
[10] F. M. Abdelrazek, A. M. Salah, Bull. Chem. Soc. Jpn. 1993,
66, 1722 – 1726.
[11] M. Hesse, H. Meier, B. Zeeh, Spektroskopische Methoden in
der Organischen Chemie, 4th Edition, Georg Thieme Verlag,
Stuttgart. New York 1991, 110 – 117 and 179 – 181.
[12] S. Abdou, S. M. Fahmy, K. U. Sadek, M. H. Elnagdi, Heterocycles 1981, 16, 2177 – 2180.
[13] Yu. A. Sharamin, V. K. Promonenkov, J. Org. Chem. (USSR)
1982, 18, 544 – 548.
[14] H. M. F. Madkour, M. R. Mahmoud, H. M. Nassar, H. M.
Habashy, Molecules 2000, 5, 746 – 755.
[15] R. Gonnert, Bull. Wld. Hlth Org. 1961, 25, 483 – 487.
[16] R. Gonnert, R. Strufe, Ciba Found. Symp. Bilharziasis 1962,
326 – 338; Chem. Abstr. 1963, 59, 5714f.
[17] K. Memoranda, Bull. Wld. Hlth. Org. 1965, 33, 567 – 581.
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