1-(4-Methane(amino)sulfonylphenyl)-3-(4-substituted-phenyl)-5-(4-trifluoromethylphenyl)-1H-2-pyrazolines/pyrazoles as potential anti-inflammatory agents

Article abstract of DOI:10.1016/j.bioorg.2015.09.002

2-Pyrazolins 14a-l and pyrazoles 15a-l were designed as celecoxib analogs for the evaluation of their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. Compounds 14i, 15a, 15d and 15f were the most COX-2 selective derivatives (S.I. = 5.93, 6.08, 5.03 and 5.27 respectively) while the pyrazoline derivatives 14g and 14i exhibited the highest AI activity (ED₅₀ = 190.5 and 160.1 μmol/kg po, respectively).

Full text of DOI:10.1016/j.bioorg.2015.09.002

Accepted Manuscript
1-(4-Methane(amino)sulfonylphenyl)-3-(4-substituted-phenyl)-5-(4-trifluoro-
methylphenyl)-1H-2-pyrazolines/ pyrazoles as potential anti-inflammatory
agents
Khaled R.A. Abdellatif, Heba A.H. Elshemy, Amany A. Azoz
PII:
S0045-2068(15)30017-1
DOI:
http://dx.doi.org/10.1016/j.bioorg.2015.09.002
YBIOO 1840
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 March 2015
23 July 2015
8 September 2015
Please cite this article as: K.R.A. Abdellatif, H.A.H. Elshemy, A.A. Azoz, 1-(4-Methane(amino)sulfonylphenyl)-3-
(4-substituted-phenyl)-5-(4-trifluoromethylphenyl)-1H-2-pyrazolines/ pyrazoles as potential anti-inflammatory
agents, Bioorganic Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bioorg.2015.09.002
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1-(4-Methane(amino)sulfonylphenyl)-3-(4-substituted-phenyl)-5-(4-
trifluoromethylphenyl)-1H-2-pyrazolines/ pyrazoles as potential anti-
inflammatory agents
Khaled R. A. Abdellatif1,*, Heba A. H. Elshemy1 Amany A. Azoz2
1Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-
Suef, Egypt, 2Pharmacology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef,
Egypt
*To whom correspondence should be addressed.
Khaled R. A. Abdellatif, Ph.D. Department of Pharmaceutical Organic Chemistry, Faculty of
Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Tel.: (002)-0100-2535444
Fax: (002)-082-2317958
E-mail address: khaled.ahmed@pharm.bsu.edu.eg
1

Abstract
2-Pyrazolins 14a-l and pyrazoles 15a-l were designed as celecoxib analogs for the evaluation of
their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity.
Compounds 14i, 15a, 15d and 15f were the most COX-2 selective derivatives (S.I = 5.93, 6.08,
5.03 and 5.27 respectively) while the pyrazoline derivatives 14g and 14i exhibited the highest AI
activity (ED50 = 190.5 and 160.1 μmol/kg po, respectively).
Keywords: Celecoxib analogs; Pyrazoline; Pyrazole; Cyclooxygenase-2; Anti-inflammatory
activity.
2

1. Introduction:
The anti-inflammatory activity of non-steroidal anti-inflammatory drugs (NSAIDs) results from
enzymatic inhibition of cyclooxygenase (COX)-mediated production of pro-inflammatory
prostaglandins (PGs) and thromboxanes (TXs) [1–3]. Cyclooxygenase enzyme exists in two distinct
isoforms, a constitutive form (COX-1) and an inducible form (COX-2); the constitutive COX-1
plays an important role in the maintenance of physiological functions such as protection of gastric
mucosa, vascular homeostasis, and platelet aggregation. While, the inducible COX-2 is over
expressed during acute and chronic inflammation [4]. Traditional NSAIDs as aspirin, ibuprofen and
indomethacin interact with both forms (COX-1 and COX-2) and therefore their long term
administration even at low prophylactic doses resulting in gastro intestinal side effects ranging from
ulcers to perforation and bleeding. For this reason, synthesis of selective COX-2 inhibitor drugs
(coxibs) takes much consideration in recent years that achieve the same anti-inflammatory activity
as traditional NSAIDs but with minimal risk of undesirable gastrointestinal side effects [5].
Celecoxib (1), rofecoxib (2), and valdecoxib (3) are the most common coxibs approved for
marketing, but adverse biochemical changes in the COX pathway are believed to be responsible for
the increased incidences of high blood pressure and myocardial infarction that caused the
withdrawal of rofecoxib and valdecoxib [6,7]. Although, celecoxib is not associated with an
increased incidence of cardiovascular events compared with placebo and with nonselective NSAIDs
and still one of the most important highly marketed COX-2 selective drugs, there are some
characteristics of celecoxib that could be improved. For example, celecoxib is not effective in all
patients and has some gastrointestinal side effects [8]. In this regard; we reported some celecoxib
derivatives (4-8) [9–14] of comparable activity with celecoxib as COX-2 selective compounds
(Figure 1).
[Please insert Figure 1 about here]
Celecoxib belongs to a tricyclic class of COX-2 inhibitors in which, two vicinal (adjacent) aryl
substituents attached to a five-membered ring acts as a scaffold. SAR studies of this class showed
that para-substituents on the adjacent aryl rings that provide optimal COX-2 selectivity, potency
and oral activity are usually a COX-2 pharmacophore on one ring (-SO2Me, -SO2NH2) and Me
substituent on the other ring [15]. Also several reports suggested that the bioisosteric substitution
of fluorine in place of hydrogen in many biologically active molecules has led to more potent
compounds without extensive stereochemical changes due to its small size. Moreover, such
substitution modulates the overall reactivity and stability of the compounds due to resistance of the
3

carbon-fluorine bond toward metabolic transformations and changes in acidity due to
electronegativity differences between the two atoms [16]. Based on these observations and in
continuation with our work related to the synthesis of safe anti-inflammatory agents, we now
describe the synthesis, in vitro evaluation as COX-1/COX-2 inhibitors, and in vivo anti-
inflammatory (AI) activity for two groups of celecoxib analogs 14a-l, 15a-l in which; i) the scaffold
consisting of two adjacent aryl rings attached to a five-membered ring with COX-2 pharmacophore
(-SO2Me in 14a-f and 15a-f, -SO2NH2 in 14g-l and 15g-l) on one aryl ring was maintained, ii) Me
group on the second aryl ring was replaced with trifluoromethyl moiety iii) trifluoromethyl moiety
at C-3 of the central five-membered ring was replaced with substituted aryl moiety since it was
reported that the substituent at C-3 of the central ring has very few steric restrictions with respect to
COX-2 binding [17]. This replacement is expected to maximize the interaction with hydrophobic
residues within COX-2 active site and enhances COX-2 selectivity, as the new compounds will be
too large to fit into the smaller COX-1 active site (Figure 2).
[Please insert Figure 2 about here]
2. Results and discussion
2.1. Chemistry:
As shown in scheme 1, two groups of celecoxib analogs 14a-l and 15a-l were synthesized using the
reaction sequence illustrated in Scheme 1. Accordingly, reaction of 4'-hydroxyactophenone (9a), 4'-
methylactophenone (9b), 4'-methoxyactophenone (9c), or 4'-ethoxyactophenone (9d) with 4-
trifluoromethylbenzaldhyde (10) in the presence of sodium hydroxide at room temperature for 2
hours provided the corresponding chalcones 11a-d. While, when the reaction for 4'-
fluoroactophenone (9e) was done for the same period (2 hours), 1,5-dicarbonyl derivative 12 was
formed via an addition reaction for further molecule of 4'-fluoroactophenone on the non separated
chalcone. So, for preparation of chalcones 11e and 11f from 4'-fluoroactophenone (9e) and 3',4'-
difluoroactophenone (9f), the reaction time was decreased to 0.5 hour only. Cyclization of the
chalcones 11a-f with (4-methane/aminosulphonylphenyl)hydrazine hydrochloride (13a-b) in
ethanol under reflux conditions gave the respective 3,5-diaryl-4,5-dihydropyrazoles (14a-l) in high
yields (75-90%). Oxidation of 4,5-dihydropyrazoles (2-pyrazolines) 14a-l using glacial acetic acid
yielded the corresponding pyrazoles 15a-l in good yields (65-90%). Also, trials for direct
conversion of the chalcones 11a-f to the respective pyrazoles 15a-l were done by performing the
reaction in acetic acid 96% and increasing reflux time till 36 h, a complete conversion had been
4

achieved for compounds 15b, 15d, 15h and 15j while mixture of 2-pyrazolines and the
corresponding pyrazoles of close polarity on TLC sheets for the other compounds were obtained.
[Please insert Scheme 1 about here]
1
All the prepared compounds have been characterized by IR, H NMR, 13C NMR, 19F NMR, mass
spectra and elemental analyses. The IR spectra of chalcone compounds 11a-f showed sharp peak at
1667-1661 cm-1 corresponding to C=O while, the IR spectra for 1,5-dicarbonyl derivative 12
displayed the carbonyl sharp peak at 1672 cm-1. The IR spectra of the 2-pyrazolines 14a-l and
pyrazoles 15a-l showed the appearance of two sharp peaks at 1327-1320 and 1169-1132 cm-1
corresponding to SO2 with disappearance of C=O peak of chalcones. The 1H NMR spectra of 11a-f
displayed two doublets, each of one proton intensity, one at δ 7.55-7.73 and the second at δ 7.81-
1
8.04 with high J value (15.6-16.8 Hz) indicating the 2 olefinic protons in E form. While, the H
NMR spectra of 1,5-dicarbonyl derivative 12 showed two characteristic signals as doublet of
doublet (dd), each of two protons intensity, one at δ 3.31, second at δ 3.48 with two different J
values (16.8, 7.2 Hz) corresponding to four protons of the two equivalent methylene, in addition to
a multiplet of one proton intensity at δ 4.06-4.13 corresponding to CH of pentane-1,5-dione. The
1H NMR spectra of dihydropyrazole compounds 14a-l showed three signals dd, each of one proton
intensity, one at δ 3.14-3.27, second at δ 3.93-4.01 and the third at δ 5.41-5.85 with three different J
values (16.8-17-6, 12.0-12.4, 4.8-5.6 Hz) corresponding to three protons of the dihydropyrazole (2-
pyrazoline) ring. Additionally, The 1H NMR spectra of pyrazole compounds 15a-l showed a singlet
of one proton intensity in the range δ 6.87-7.45 corresponrding to pyrazole H-4. The 13C NMR
spectra of 11a-f confirmed the presence of α, β-unsaturated carbonyl system of chalcones by
presence of three peaks at δ 123.00-125.21, 141.16-143.67 and 187.23-189.48 corresponding to
propenone C-2, propenone C-3 and propenone C-1 respectively. While the 13C NMR spectra of 12
confirmed the presence of pentane-1,5-dione derivative by presence of three peaks at δ 36.76, 44.34
and 196.34 corresponding to C-3, 2C (C-2, C-4) and 2C=O respectively. Also 13C NMR spectra of
14a-l confirmed the presence of the pyrazoline ring due to presence of three peaks at δ 43.18-43.64,
61.89-63.70 and 147.71-151.38 corresponding to pyrazoline C-4, C-5 and C-3 respectively. While,
these values are extremely changed in the respective pyrazoles 15a-l (106.62-108.23, 142.89-143.97
and 150.74-153.39 corresponding to pyrazole C-4, C-5 and C-3 respectively).
2.2. Pharmacological screening
2.2.1. In vitro cyclooxygenase (COX) inhibition assay
5

In vitro COX-1/COX-2 enzyme inhibition studies (Table 1) showed that these pyrazoline 14a-l and
pyrazole derivatives 15a-l are weak inhibitors of the COX-1 isozyme (IC50 = 5.6 – 24.1 μM range)
but are moderate to good inhibitors of the COX-2 isozyme (IC50 = 0.97 – 10.8 μM range). All
compounds were more selective COX-2 inhibitors (S.I = 2.23 – 6.08) than aspirin (S.I = 0.017) and
ibuprofen (S.I = 1.05) but were less COX-2 selective than celecoxib (S.I = 7.70). Compounds 14i,
15a, 15d and 15f were the most COX-2 selective derivatives with close S.I to celecoxib (S.I = 5.93,
6.08, 5.03 and 5.27 respectively).
2.2.2. In vivo anti-inflammatory activity
The AI activities exhibited by the pyrazolines 14a-l and pyrazoles 15a-l were determined using a
carrageenan-induced rat foot paw edema model (see data in Table 1). The ethoxy derivatives (14d,
14J, 15d and 15j) and pyrazoline derivatives having a sulphamoyl (SO2NH2) substituent (14g, 14i
and 14k) exhibited higher AI activities (38.8, 33.8, 33.3, 42.5, 41.3, 41.3 and 38.8 % inhibition of
inflammation, respectively) than the other compounds for the same oral dose (50 mg/kg). Another
AI evaluation for the seven aforementioned most potent AI compounds at another 2 oral doses were
done to determine ED50 (the concentration causing 50% edema inhibition). The pyrazoline
derivatives (14g and 14i) exhibited AI activity (ED50 = 190.5 and 160.1 μmol/kg po, respectively)
that was about 4-fold more potent than aspirin (ED50 = 710 μmol/kg po), 2-fold more potent than
ibuprofen (ED50 = 327 μmol/kg po), but less active than celecoxib (ED50 = 30.9 μmol/kg po). The
other five compounds (14d, 14J, 14k, 15d and 15j) exhibited an AI activity (ED50 = 239.6 – 312.0
μmol/kg po) between that observed for the reference drugs ibuprofen and celecoxib.
[Please insert Table 1 about here]
3. Conclusions:
Two groups of pyrazoline and pyrazole derivatives 14a-l and 15a-l were synthesized for evaluation
as COX-1/COX-2 isozyme inhibitors, and as AI agents. Structure-activity and biological studies
showed that i) all the compounds were more selective COX-2 inhibitors than aspirin and ibuprofen
but were of comparable COX-2 selectivity to celecoxib, ii) twenty one compounds from the twenty
four synthesized derivatives showed in vivo anti-inflammatory activity at 50 mg/kg dose and iii)
The pyrazoline derivatives (14g and 14i) exhibited AI activity about 4-fold more potent than
aspirin, 2-fold more potent than ibuprofen, but less active than celecoxib.
4. Experimental protocol
4.1. Chemistry
6

4.1.1. General
Melting points were determined on a Thomas-Hoover capillary apparatus and are uncorrected.
Infrared (IR) spectra were recorded as films on NaCl plates using a Nicolet 550 Series II Magna
1
FT-IR spectrometer. H NMR and 13C NMR spectra were measured on a Bruker AM-400
spectrometer in CDCl3 with TMS as the internal standard, where J (coupling constant) values are
estimated in Hertz (Hz). Mass spectra (MS) were recorded on a Water’s Micromass ZQ 4000 mass
spectrometer using the electrospray (ES) ionization mode. Microanalyses were performed for C, H
and N by The Regional Centre for Mycology and Biotechnology, Al-Azhar University, cairo, Egypt
and were within
0.4% of theoretical values for all elements listed. Silica gel column
chromatography was performed using Merck silica gel 60 ASTM (70-230 mesh). (4-
Methanesulphonylphenyl)hydrazine hydrochloride (13a) and (4-aminosulphonyl-phenyl)hydrazine
hydrochloride (13b) were prepared according to the reported procedure [18].
4.1.2. General method for preparation of (E)-1,3-diarylprop-2-en-1-ones (11a-f). To a solution
of the appropriate substituted acetophenone (9a-f, 2.0 mmol) in ethanol (10 mL), an aqueous
sodium hydroxide solution (2 mL, 10%) was added slowly with continuous stirring. 4-
Trifluoromethyl benzaldehyde (10, 2.0 mmol, 0.35 g) was added and the resulting mixture was
stirred at 25 °C for 2 h (11a, 11b, 11c, 11d), or for 0.5 h (11e, 11f). The obtained solid was filtered,
washed with water (5 mL) and then EtOH (5 mL) followed by crystallization from absolute ethanol
to give analytically pure compounds 11a-f. Physical and spectral data are listed below.
4.1.2.1. (E)-1-(4-Hydroxyphenyl)-3-(4-trifluoromethyl-phenyl)propenone (11a): 74% yield; white
1
powder; mp 189-190 °C; IR (KBr disk) 3407 (OH), 3013 (C-H aromatic), 1662 (CO); H NMR
(DMSO-d6) δ 6.93 (d, J = 8.4 Hz, 2H, hydroxyphenyl H-3, H-5), 7.73 (d, J = 16.8 Hz, 1H,
COCH=CH), 7.76 (d, J = 8.8 Hz, 2H, trifluoromethylphenyl H-2, H-6), 8.04 (d, J = 16.8 Hz, 1H,
COCH=CH), 8.07 (d, J = 8.8 Hz, 2H, trifluoromethylphenyl H-3, H-5), 8.11 (d, J = 8.4 Hz, 2H,
hydroxyphenyl H-2, H-6), 10.52 (s, 1H, OH, D2O exchangeable); 13C NMR (DMSO-d6) δ 115.56
(hydroxyphenyl C-3, C-5), 124.50 (q, J = 270 Hz, CF3), 125.21 (propenone C-2), 126.07 (d, J = 4
Hz, trifluoromethylphenyl C-2, C-6), 129.32 (hydroxyphenyl C-1), 129.72 (d, J = 14 Hz,
trifluoromethylphenyl C-3, C-5), 130.27 (q, J = 32 Hz, trifluoromethylphenyl C-4), 131.82
(hydroxyphenyl C-2, C-6), 139.35 (trifluoromethylphenyl C-1), 141.16 (propenone C-3), 162.91
(hydroxyphenyl C-4), 187.41 (propenone C-1); MS (m/z): 292 (M+., 88.3%), 93 (100%); Anal.
Calcd for C16H11F3O2: C, 65.76; H, 3.79; Found: C, 65.71; H, 3.87.
7

4.1.2.2. (E)-1-p-Tolyl-3-(4-trifluoromethyl-phenyl)propenone (11b): 80% yield; white crystals; mp
1
134-135 °C; IR (KBr disk) 3039 (C-H aromatic), 2938 (C-H aliphatic), 1661 (CO); H NMR
(CDCl3) δ 2.46 (s, 3H, CH3), 7.34 (d, J = 8.0 Hz, 2H, tolyl H-3, H-5), 7.62 (d, J = 15.6 Hz, 1H,
COCH=CH), 7.68 (d, J = 8.4 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.75 (d, J = 8.4 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.82 (d, J = 15.6 Hz, 1H, COCH=CH), 7.97 (d, J = 8.0 Hz, 2H,
13
tolyl H-2, H-6); C NMR (CDCl3) δ 21.72 (CH3), 123.9 (q, J = 270 Hz, CF3), 124.23 (propenone
C-2), 125.88 (d, J = 4 Hz, trifluoromethylphenyl C-2, C-6), 128.48 (d, J = 4 Hz,
trifluoromethylphenyl C-3, C-5), 128.73 (tolyl C-3, C-5), 129.47 (tolyl C-2, C-6), 131.78 (q, J = 32
Hz, trifluoromethylphenyl C-4), 135.22 (tolyl C-1), 138.39 (trifluoromethylphenyl C-1), 142.30
(propenone C-3), 144.12 (tolyl C-4), 189.48 (propenone C-1); MS (m/z): 290 (M+., 77.1), 91
(100%); Anal. Calcd for C17H13F3O: C, 70.34; H, 4.51; Found: C, 70.63; H, 4.59.
4.1.2.3. (E)-1-(4-Methoxyphenyl)-3-(4-trifluoromethylphenyl)propenone (11c): 77% yield; white
crystals; mp 137-138 °C; IR (KBr disk) 3067 (C-H aromatic), 2921 (C-H aliphatic), 1667 (CO); 1H
NMR (CDCl3) δ 3.92 (s, 3H, OCH3), 7.00 (d, J = 8.8 Hz, 2H, methoxyphenyl H-3, H-5), 7.63 (d, J
= 15.6 Hz, 1H, COCH=CH), 7.68 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.75 (d, J =
8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.81 (d, J = 15.6 Hz, 1H, COCH=CH), 8.07 (d, J =
8.8 Hz, 2H, methoxyphenyl H-2, H-6); 13C NMR (CDCl3) δ 55.54 (OCH3), 114.40 (methoxyphenyl
C-3, C-5), 124.07 (propenone C-2), 125.30 (q, J = 270 Hz, CF3), 125.87 (d, J = 4 Hz,
trifluoromethylphenyl C-2, C-6), 128.43 (trifluoromethylphenyl C-3, C-5), 130.69 (methoxyphenyl
C-2, C-6), 130.94 (methoxyphenyl C-1), 131.70 (q, J = 32 Hz, (trifluoromethylphenyl C-4), 138.49
(trifluoromethylphenyl C-1), 141.90 (propenone C-3), 163.71 (methoxyphenyl C-4), 188.18
(propenone C-1); MS (m/z): 306 (M+., 97.2%), 107 (100%); Anal. Calcd for C17H13F3O2: C, 66.67;
H, 4.28; Found: C, 66.84; H, 4.42.
4.1.2.4. (E)-1-(4-Ethoxyphenyl)-3-(4-trifluoromethylphenyl)propenone (11d): 75% yield; white
crystals; mp 130-131 °C; IR (KBr disk) 3073 (C-H aromatic), 2966 (C-H aliphatic), 1667 (CO); 1H
NMR (CDCl3) δ 1.48 (t, J = 6.8 Hz, 3H, CH2CH3), 4.15 (q, J = 6.8 Hz, 2H, CH2CH3), 7.00 (d, J =
8.4 Hz, 2H, ethoxyphenyl H-3, H-5), 7.63 (d, J = 15.6 Hz, 1H, COCH=CH), 7.68 (d, J = 8.0 Hz,
2H, trifluoromethylphenyl H-2, H-6), 7.75 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5),
7.81 (d, J = 15.6 Hz, 1H, COCH=CH), 8.06 (d, J = 8.4 Hz, 2H, ethoxyphenyl H-2, H-6); 13C NMR
(CDCl3) δ 14.68 (CH2CH3), 63.85 (CH2CH3), 114.39 (ethoxyphenyl C-3, C-5), 124.09 (propenone
C-3), 125.20 (q, J = 270 Hz, CF3), 125.88 (d, J = 4 Hz, trifluoromethylphenyl C-2, C-6), 128.42
(trifluoromethylphenyl C-3, C-5),, 130.50 (ethoxyphenyl C-2, C-6), 130.94 (ethoxyphenyl C-1)
131.70 (q, J = 32 Hz, C-CF3), 138.5 (trifluoromethylphenyl C-1) (trifluoromethylphenyl C-1),
8

141.80 (propenone C-3), 163.2 (methoxyphenyl C-4), 188.20 (propenone C-1); MS (m/z): 320
(M+., 91.8), 121 (100%); Anal. Calcd for C18H15F3O2: C, 67.50; H, 4.72; Found: C, 67.84; H, 4.92.
4.1.2.5. (E)-1-(4-Fluorophenyl)-3-(4-trifluoromethylphenyl)propenone (11e): 64% yield; white
powder; mp 99-100 °C; IR (KBr disk) 3013 (C-H aromatic), 1664 (CO); 1H NMR (CDCl3) δ 7.13-
7.23 (m, 2H, fluorophenyl H-3, H-5), 7.59 (d, J = 15.6 Hz, 1H, COCH=CH), 7.69 (d, J = 8.0 Hz,
2H, trifluoromethylphenyl H-2, H-6), 7.75 (d, J = 8.8 Hz, 2H, trifluoromethylphenyl H-3, H-5),
7.83 (d, J = 15.6 Hz, 1H, COCH=CH), 8.07-8.19 (m, 2H, fluorophenyl H-2, H-6); 13C NMR
(CDCl3) δ 115.90 (d, J = 22 Hz, fluorophenyl C-3, C-5), 123.69 (propenone C-2), 123.81 (q, J =
270 Hz, CF3), 125.93 (q, J = 4 Hz, trifluoromethylphenyl C-3, C-5), 128.54 (trifluoromethylphenyl
C-2, C-6), 131.20 (d, J = 10 Hz, fluorophenyl C-2, C-6), 131.97 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 134.12 (fluorophenyl C-1), 138.12 (trifluoromethylphenyl C-1), 142.94
(propenone C-3), 165.81 (d, J = 254 Hz, fluorophenyl C-4), 188.31 (propenone C-1); MS (m/z):
294 (M+., 83.7%), 115 (100%); Anal. Calcd for C16H10F4O: C, 65.31; H, 3.43; Found: C, 65.53; H,
3.27.
4.1.2.6. (E)-1-(3,4-Difluorophenyl)-3-(4-trifluoromethyl-phenyl)-propenone (11f): 61% yield; white
powder; mp 129-130 °C; IR (KBr disk) 3013 (C-H aromatic), 1665 (CO); 1H NMR (CDCl3) δ 7.26-
7.37 (m, 1H, difluorophenyl H-5), 7.55 (d, J = 15.6 Hz, 1H, COCH=CH), 7.69 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-2, H-6), 7.75 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.86 (d,
J = 15.6 Hz, 1H, COCH=CH), 7.86-7.93 (m, 2H, difluorophenyl H-2, H-6); 13C NMR (CDCl3) δ
117.68 (d, J = 23 Hz, difluorophenyl C-5), 117.95 (d, J = 18 Hz, difluorophenyl C-2), 123.00
(propenone C-2), 123.76 (q, J = 270 Hz, CF3), 125.44 (dd, J = 8, 3 Hz, difluorophenyl C-6), 126.00
(q, J = 4 Hz, trifluoromethylphenyl C-3, C-5), 128.63 (trifluoromethylphenyl C-2, C-6), 131.97 (q,
J = 32 Hz, trifluoromethylphenyl C-4), 134.82 (d, J = 5 Hz, difluorophenyl C-1), 137.87
(trifluoromethylphenyl C-1), 143.67 (propenone C-3), 150.61 (dd, J = 250, 13 Hz, difluorophenyl
C-3), 153.73 (dd, J = 256, 13 Hz, difluorophenyl C-4), 187.23 (propenone C-1); MS (m/z): 312
(M+., 78.2%), 153 (100%); Anal. Calcd for C16H9F5O: C, 61.55; H, 2.91; Found: C, 61.71; H, 2.87.
4.1.3. 1,5-Bis-(4-fluorophenyl)-3-(4-trifluoromethylphenyl)-pentane-1,5-dione (12). The title
compound 12 was prepared, using a similar procedure that described for the preparation of 11a-d,
in 60% yield as a white powder; mp 138-139 °C; IR (KBr disk) 3039 (C-H aromatic), 2945 (C-H
1
aliphatic), 1672 (CO); H NMR (CDCl3) δ 3.31 (dd, J = 16.8, 7.2 Hz, 2H, 2 CHH), 3.48 (dd, J =
16.8, 7.2 Hz, 2H, 2 CHH), 4.06-4.13 (m, 1H, CH), 7.08-7.12 (m, 4H, 2 fluorophenyl H-3, H-5),
7.39 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.52 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.93-7.97 (m, 4H, 2 fluorophenyl H-2, H-6); 13C NMR (CDCl3) δ
9

36.76 (C-3), 44.34 (2C, C-2, C-4), 115.82 (d, J = 21 Hz, 2 fluorophenyl C-3, C-5), 124.10 (q, J =
270 Hz, CF3), 125.65 (q, J = 4 Hz, trifluoromethylphenyl C-3, C-5), 127.91 (trifluoromethylphenyl
C-2, C-6), 129.05 (q, J = 32 Hz, trifluoromethylphenyl C-4), 131.76 (d, J = 10 Hz, 2 fluorophenyl
C-2, C-6), 133.08 (2 fluorophenyl C-1), 147.77 (trifluoromethylphenyl C-1), 165.87 (d, J = 254 Hz,
2 fluorophenyl C-4), 196.34 (2C=O); 19F NMR (CDCl3) δ -62.46, -109.39; MS (m/z): 432 (M+.,
2.1%), 123 (100%); Anal. Calcd for C24H17F5O2: C, 66.67; H, 3.96; Found: C, 66.48; H, 3.87.
4.1.4. General method for preparation of 1-(4-amino(methane)sulfonylphenyl)-3-substituted-
phenyl-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-pyrazoles (14a-l). A mixture of the
appropriate chalcone (11a-f, 2.0 mmol) and the respective phenylhydrazine hydrochloride (13a or
13b, 2.0 mmol) was heated under reflux in methanol (15 mL) for 24 h. After cooling, the formed
solid was filtered off, dried and crystallized from methanol to give the respective dihydropyrazoles
14a-l. Physical and spectral data are listed below.
4.1.4.1.
1-(4-Methanesulfonylphenyl)-3-(4-hydroxyphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-di-
hydro-1H-pyrazole (14a): 75% yield; white powder; mp 295-296 °C; IR (KBr disk) 3407 (OH),
1
3056 (C-H aromatic), 2932 (C-H aliphatic), 1321, 1138 (SO2); H NMR (DMSO-d6) δ 3.07 (s, 3H,
SO2CH3), 3.20 (dd, J = 17.6, 4.8 Hz, 1H, pyrazole H-4), 3.97 (dd, J = 17.6, 12.0 Hz, 1H, pyrazole
H'-4), 5.74 (dd, J = 12.0, 4.8 Hz, 1H, pyrazole H-5), 6.85 (d, J = 8.0 Hz, 2H, hydroxyphenyl H-3,
H-5), 7.08 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6)), 7.48 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.65 (d, J = 8.4 Hz, 2H, hydroxyphenyl H-2, H-6), 7.66 (d, J =
8.0 Hz, 2H, methanesulphonylphenyl H-2, H-6), 7.74 (d, J = 8.0 Hz, 2H, methanesulphonylphenyl
H-3, H-5), 9.96 (s, 1H, OH, D2O exchangeable); 13C NMR (DMSO-d6) δ 43.52 (pyrazole C-4),
44.63 (SO2CH3),
61.89 (pyrazole C-5), 112.25 (hydrxyphenyl C-3, C-5), 116.06
(methanesulphonylphenyl C-2, C-6), 122.82 (hydroxyphenyl C-1), 124.57 (q, J = 270 Hz, CF3),
126.61 (d, J = 4 Hz, trifluoromethylphenyl C-3, C-5), 127.12 (methanesulphonylphenyl C-3, C-5),
128.57 (trifluoromethylphenyl C-2, C-6) , 128.75 (q, J = 32 Hz, trifluoromethylphenyl C-4), 129.16
(methanesulphonylphenyl C-4), 129.19 (hydroxyphenyl C-2, C-6), 146.73 (trifluoromethylphenyl
C-1), 147.50 (methanesulphonylphenyl C-1), 151.38 (pyrazole C-3), 159.55 (hydroxyphenyl C-4);
19F NMR (DMSO-d6) δ -61.00; MS (m/z): 460 (M+., 66.8%), 64 (100%); Anal. Calcd for
C23H19F3N2O3S: C, 59.99; H, 4.16; N, 6.08; Found: C, 59.71; H, 4.07; N, 6.18.
4.1.4.2.
1-(4-Methanesulfonylphenyl)-3-(p-tolyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-
pyrazole (14b): 87% yield; white crystals; mp 252-253 °C; IR (KBr disk) 3056 (C-H aromatic),
1
2932 (C-H aliphatic), 1325, 1132 (SO2); H NMR (DMSO-d6) δ 2.31 (s, 3H, CH3), 2.93 (s, 3H,
SO2CH3), 3.14 (dd, J = 16.8, 5.6 Hz, 1H, pyrazole H-4), 3.93 (dd, J = 16.8, 12.0 Hz, 1H, pyrazole
10

H'-4), 5.48 (dd, J = 12.0, 5.6 Hz, 1H, pyrazole H-5), 7.02 (d, J = 7.6 Hz, 2H,
methanesulphonylphenyl H-2, H-6), 7.16 (d, J = 7.2 Hz, 2H, tolyl H-3, H-5), 7.37 (d, J = 7.6 Hz,
2H, trifluoromethylphenyl H-2, H-6), 7.54-7.67 (m, 6H, tolyl H-2, H-6, trifluoromethylphenyl H-3,
13
H-5, methanesulphonylphenyl H-3, H-5); C NMR (DMSO-d6) δ 21.47 (CH3), 43.37 (pyrazole C-
4), 44.60 (SO2CH3), 62.05 (pyrazole C-5), 112.51 (methanesulphonylphenyl C-2, C-6), 124.45 (q,
J = 270 Hz, CF3), 126.65 (d, J =4 Hz, trifluoromethylphenyl C-3, C-5), 126.76
(methanesulphonylphenyl C-3, C-5), 127.15 (trifluoromethylphenyl C-2, C-6), 129.12 (tolyl C-1),
129.17 (tolyl C-2, C-6), 129.65 (q, J = 32 Hz, trifluoromethylphenyl C-4), 129.81 (tolyl C-3, C-5),
133.19 (methanesulphonylphenyl C-4), 139.94 (tolyl C-4), , 146.62 (trifluoromethylphenyl C-1),
147.37 (methanesulphonylphenyl C-1), 151.20 (pyrazole C-3); 19F NMR (DMSO-d6) δ -61.47; MS
(m/z): 458 (M+., 100%); Anal. Calcd for C24H21F3N2O2S: C, 62.87; H, 4.62; N, 6.11; Found: C,
62.90; H, 4.85; N, 5.93.
4.1.4.3.
1-(4-Methanesulfonylphenyl)-3-(4-methoxyphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-
dihydro-1H-pyrazole (14c): 81% yield; off-white powder; mp 262-263 °C; IR (KBr disk) 3057 (C-
H aromatic), 2926 (C-H aliphatic), 1324, 1132 (SO2); 1H NMR (DMSO-d6) δ 3.08 (s, 3H,
SO2CH3), 3.23 (dd, J = 17.6, 4.8 Hz, 1H, pyrazole H-4), 3.81 (s, 3H, OCH3), 4.00 (dd, J = 17.6,
12.0 Hz, 1H, pyrazole H'-4), 5.77 (dd, J = 12.0, 4.8 Hz, 1H, pyrazole H-5), 7.02 (d, J = 8.4 Hz, 2H,
methoxyphenyl H-3, H-5), 7.09 (d, J = 8.4 Hz, 2H, methoxyphenyl H-2, H-6), 7.49 (d, J = 8.0 Hz,
2H, trifluoromethylphenyl H-2, H-6), 7.66 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5),
7.74-7.76 (m, 4H, methanesulphonylphenyl H-2, H-3, H-5, H-6); 13C NMR (DMSO-d6) δ 43.47
(pyrazole C-4), 44.61 (SO2CH3), 55.80 (OCH3), 62.00 (pyrazole C-5), 112.35 (methoxyphenyl C-3,
C-5), 114.69 (methanesulphonylphenyl C-2, C-6), 124.39 (methoxyphenyl C-1), 125.80 (q, J = 270
Hz, CF3), 125.93 (trifluoromethylphenyl C-3, C-5), 126.66 (trifluoromethylphenyl C-2, C-6),
127.14 (methanesulphonylphenyl C-3, C-5), 128.70 (q, J = 32 Hz, trifluoromethylphenyl C-4),
128.87 (methanesulphonylphenyl C-4), 129.17 trifluoromethylphenyl C-1), 129.37 (methoxyphenyl
C-2, C-6), 146.69 (trifluoromethylphenyl C-1), 147.43 (methanesulphonylphenyl C-1), 151.09
(pyrazole C-3), 160.69 (methoxyphenyl C-4); 19F NMR (DMSO-d6) δ -60.74; MS (m/z): 474 (M+.,
93.1), 107 (100%); Anal. Calcd for C24H21F3N2O3S: C, 60.75; H, 4.46; N, 5.90; Found: C, 60.86; H,
4.72; N, 5.83.
4.1.4.4. 3-(4-Ethoxyphenyl)-1-(4-methanesulfonylphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazole (14d): 83% yield; off-white crystals; mp 220-221 °C; IR (KBr disk) 3053 (C-H
1
aromatic), 2926 (C-H aliphatic), 1326, 1134 (SO2); H NMR (CDCl3) δ 1.45 (t, J = 6.8 Hz, 3H,
CH2CH3), 3.01 (s, 3H, SO2CH3), 3.18 (dd, J = 17.2, 5.6 Hz, 1H, pyrazole H-4), 3.93 (dd, J = 17.2,
11

12.0 Hz, 1H, pyrazole H'-4), 4.09 (q, J = 6.8 Hz, 2H, CH2CH3), 5.41 (dd, J = 12.0, 5.6 Hz, 1H,
pyrazole H-5), 6.94 (d, J = 8.4 Hz, 2H, ethoxyphenyl H-3, H-5), 7.06 (d, J = 8.4 Hz, 2H,
ethoxyphenyl H-2, H-6), 7.40 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.62 (d, J = 8.0
Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.68 (d, J = 7.2 Hz, 2H, methanesulphonylphenyl H-2, H-
6), 7.70 (d, J = 7.2 Hz, 2H, methanesulphonylphenyl H-3, H-5); 13C NMR (CDCl3) δ 14.75
(CH2CH3), 43.64 (pyrazole C-4), 44.95 (SO2CH3), 62.8 (CH2CH3), 63.70 (pyrazole C-5), 112.41
(ethoxyphenyl C-3, C-5), 114.70 (methanesulphonylphenyl C-2, C-6) , 123.90 (q, J = 270 Hz, CF3),
123.95
(trifluoromethylphenyl
C-3,
C-5),
126.49
(ethoxyphenyl
C-1),
126.52
(methanesulphonylphenyl C-3, C-5), 127.80 (trifluoromethylphenyl C-2, C-6) , 128.88
(methanesulphonylphenyl C-4), 128.99 (ethoxyphenyl C-2, C-6), 130.32 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 145.22 trifluoromethylphenyl C-1), 147.70 (methanesulphonylphenyl
C-1), 149.83 (pyrazole C-3), 160.39 (ethoxyphenyl C-4); 19F NMR (CDCl3) δ -62.15; MS (m/z):
488 (M+., 85.2%), 121 (100%); Anal. Calcd for C25H23F3N2O3S: C, 61.47; H, 4.75; N, 5.73; Found:
C, 61.71; H, 4.87; N, 5.83.
4.1.4.5. 3-(4-Fluorophenyl)-1-(4-Methanesulfonylphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazole (14e): 85% yield; off-white crystals; mp 214-215 °C; IR (KBr disk) 3056 (C-H
aromatic), 2932 (C-H aliphatic), 1325, 1137 (SO2); 1H NMR (CDCl3) δ 3.01 (s, 3H, SO2CH3),
3.19 (dd, J = 17.2, 5.6 Hz, 1H, pyrazole H-4), 3.96 (dd, J = 17.2, 12.4 Hz, 1H, pyrazole H'-4), 5.46
(dd, J = 12.4, 5.6 Hz, 1H, pyrazole H-5), 7.09 (d, J = 8.8 Hz, 2H, methanesulphonylphenyl H-2, H-
6), 7.14 (d, J = 8.4 Hz, 2H, fluorophenyl H-2, H-6), 7.41 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl
H-2, H-6), 7.64 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.71-7.77 (m, 4H,
fluorophenyl H-3, H-5, methanesulphonylphenyl H-3, H-5); 13C NMR (CDCl3) δ 43.56 (pyrazole
C-4), 44.93 (SO2CH3), 63.00 (pyrazole C-5), 112.63 (methanesulphonylphenyl C-2, C-6), 114.70
(d, J = 22 Hz, fluorophenyl C-3, C-5), 123.82 (q, J = 270 Hz, CF3), 126.08 (trifluoromethylphenyl
C-3, C-5), 126.54 (trifluoromethylphenyl C-2, C-6), 127.81 (fluorophenyl, C-1), 128.12
(fluorophenyl C-2, C-6)
,
129.04 (methanesulphonylphenyl C-3, C-5), 129.48
(methanesulphonylphenyl C-4), 130.40 (q, J = 32 Hz, trifluoromethylphenyl C-4), 144.91
trifluoromethylphenyl C-1), 147.51 (methanesulphonylphenyl C-1), 148.81 (pyrazole C-3), 163.63
(d, J = 249 Hz, fluorophenyl C-4); 19F NMR (DMSO-d6) δ -60.84, -110.11; MS (m/z): 462 (M+.,
92.7%), 64 (100%); Anal. Calcd for C23H18F4N2O2S: C, 59.74; H, 3.92; N, 6.06; Found: C, 59.71;
H, 3.87; N, 6.23.
4.1.4.6. 3-(3,4-Difluoroluorophenyl)-1-(4-methanesulfonylphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-
dihydro-1H-pyrazole (14f): 82% yield; off-white powder; mp 207-208 °C; IR (KBr disk) 3046 (C-
12

H aromatic), 2922 (C-H aliphatic), 1322, 1133 (SO2); 1H NMR (DMSO-d6) δ 3.09 (s, 3H,
SO2CH3), 3.27 (dd, J = 17.2, 5.6 Hz, 1H, pyrazole H-4), 4.01 (dd, J = 17.2, 12.4 Hz, 1H, pyrazole
H'-4), 5.85 (dd, J = 12.4, 5.6 Hz, 1H, pyrazole H-5), 7.16 (d, J = 8.8 Hz, 2H,
methanesulphonylphenyl H-2, H-6), 7.50 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.55-
7.57 (m, 1H, difluorophenyl H-5), 7.64-7.66 (m, 1H, difluorophenyl H-2), 7.69 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.75 (d, J = 8.8 Hz, 2H, methanesulphonylphenyl H-3, H-5),7.84-
13
7.89 (m, 1H, difluorophenyl H-6); C NMR (DMSO-d6) δ 43.18 (pyrazole C-4), 44.54 (SO2CH3),
62.51 (pyrazole C-5), 112.82 (methanesulphonylphenyl C-2, C-6), 115.63 (d, J = 19 Hz,
difluorophenyl C-5), 118.49 (d, J = 17 Hz, difluorophenyl C-2), 123.94 (dd, J = 8, 3 Hz,
difluorophenyl C-6), 124.55 (q, J = 270 Hz, CF3), 126.67 (trifluoromethylphenyl C-3, C-5), 127.16
(trifluoromethylphenyl C-2, C-6), 127.70 (difluorophenyl, C-1), 128.85 (q, J = 32 Hz,
trifluoromethylphenyl
C-4),
129.15
C-4),
(methanesulphonylphenyl
C-3,
C-5),
C-1),
130.25
147.16
(methanesulphonylphenyl
146.34 trifluoromethylphenyl
(methanesulphonylphenyl C-1), 149.34 (pyrazole C-3), 150.04 (dd, J = 244, 13 Hz, difluorophenyl
C-3), 150.64 (dd, J = 244, 13 Hz, difluorophenyl C-4); 19F NMR (DMSO-d6) δ -60.52, -136.37, -
138.01; MS (m/z): 480 (M+., 100%); Anal. Calcd for C23H17F5N2O2S: C, 57.50; H, 3.57; N, 5.83;
Found: C, 57.71; H, 3.87; N, 5.89.
4.1.4.7. 1-(4-Aminosulfonylphenyl)-3-(4-hydroxyphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazole (14g): 76% yield; pale yellow powder; mp 197-198 °C; IR (KBr disk) 3427- 3374
1
(OH, NH2), 3050 (C-H aromatic), 2932 (C-H aliphatic), 1325, 1137 (SO2); H NMR (DMSO-d6) δ
3.18 (dd, J = 17.6, 4.8 Hz, 1H, pyrazole H-4), 3.95 (dd, J = 17.6, 12.0 Hz, 1H, pyrazole H'-4), 5.72
(dd, J = 12.0, 4.8 Hz, 1H, pyrazole H-5), 6.83 (d, J = 8.0 Hz, 2H, hydroxyphenyl H-3, H-5), 7.02-
7.04 (m, 4H, trifluoromethylphenyl H-2, H-6, NH2 (D2O exchangeable)), 7.47 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.58 (d, J = 8.4 Hz, 2H, hydroxyphenyl H-2, H-6), 7.64 (d, J =
8.0 Hz, 2H, aminosulphonylphenyl H-2, H-6), 7.73 (d, J = 8.0 Hz, 2H, aminosulphonylphenyl H-3,
13
H-5), 9.92 (s, 1H, OH, D2O exchangeable) ; C NMR (DMSO-d6) δ 43.39 (pyrazole C-4), 61.94
(pyrazole C-5), 112.08 (hydrxyphenyl C-3, C-5), 116.02 (aminosulphonylphenyl C-2, C-6), 123.00
(hydroxyphenyl C-1), 124.59 (q, J = 270 Hz, CF3), 126.54 (d, J = 4 Hz, trifluoromethylphenyl C-3,
C-5), 127.18 (aminosulphonylphenyl C-3, C-5), 127.72 (trifluoromethylphenyl C-2, C-6) , 128.41
(hydroxyphenyl C-2, C-6), 128.75 (q, J = 32 Hz, trifluoromethylphenyl C-4), 133.15
(aminosulphonylphenyl C-4), 146.34 (trifluoromethylphenyl C-1), 146.88 (aminosulphonylphenyl
C-1), 150.54 (pyrazole C-3), 159.35 (hydroxyphenyl C-4); 19F NMR (DMSO-d6) δ -60.71; MS
13

(m/z): 461 (M+., 88.3%), 93 (100%); Anal. Calcd for C22H18F3N3O3S: C, 57.26; H, 3.93; N, 9.11;
Found: C, 57.51; H, 3.87; N, 9.01.
4.1.4.8.
1-(4-Aminosulfonylphenyl)-3-(p-tolyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-
pyrazole (14h): 90% yield; white crystals; mp 228-229 °C; IR (KBr disk) 3428 (NH2), 3067 (C-H
aromatic), 2933 (C-H aliphatic), 1327, 1134 (SO2);1H NMR (CDCl3) δ 2.42 (s, 3H, CH3), 3.20 (dd,
J = 16.8, 4.8 Hz, 1H, pyrazole H-4), 3.95 (dd, J = 16.8, 12.0 Hz, 1H, pyrazole H'-4), 4.62 (s, 2H,
NH2, D2O exchangeable), 5.44 (dd, J = 12.0, 4.8 Hz, 1H, pyrazole H-5), 7.06 (d, J = 8.8 Hz, 2H,
aminosulphonylphenyl H-2, H-6), 7.24 (d, J = 7.6 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.41
(d, J = 7.6 Hz, 2H, tolyl H-3, H-5), 7.63 (d, J = 7.6 Hz, 2H, tolyl H-2, H-6), 7.65 (d, J = 7.6 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.73 (d, J = 8.8 Hz, 2H, aminosulphonylphenyl H-3, H-5); 13C
NMR (DMSO-d6) δ 21.46 (CH3), 43.23 (pyrazole C-4), 62.11 (pyrazole C-5), 112.34
(aminosulphonylphenyl C-2, C-6), 124.69 (q, J = 270 Hz, CF3), 126.55 (trifluoromethylphenyl C-3,
C-5), 126.62 (aminosulphonylphenyl C-3, C-5), 127.18 (trifluoromethylphenyl C-2, C-6), 127.73
(tolyl C-2, C-6), 128.65 (q, J = 32 Hz, trifluoromethylphenyl C-4), 129.28 (tolyl C-1), 129.78 (tolyl
C-3, C-5), 133.60 (aminosulphonylphenyl C-4), 139.68 (tolyl C-4), , 146.17 (trifluoromethylphenyl
C-1), 146.74 (aminosulphonylphenyl C-1), 150.32 (pyrazole C-3); 19F NMR (DMSO-d6) δ -60.73;
MS (m/z): 459 (M+., 73.5%), 64 (100%); Anal. Calcd for C23H20F3N3O2S: C, 60.12; H, 4.39; N,
9.14; C, 60.31; H, 4.67; N, 9.11.
4.1.4.9. 1-(4-Aminosulfonylphenyl)-3-(4-methoxyphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazole (14i): 87% yield; off-white powder; mp 246-247 °C; IR (KBr disk) 3422 (NH2), 3057
(C-H aromatic), 2922 (C-H aliphatic), 1323, 1134 (SO2);1H NMR (DMSO-d6) δ 3.22 (dd, J = 17.6,
4.8 Hz, 1H, pyrazole H-4), 3.80 (s, 3H, OCH3), 3.98 (dd, J = 17.6, 12.0 Hz, 1H, pyrazole H'-4),
5.74 (dd, J = 12.0, 4.8 Hz, 1H, pyrazole H-5), 7.02 (d, J = 8.4 Hz, 2H, methoxyphenyl H-3, H-5),
7.05-7.07 (m, 4H, trifluoromethylphenyl H-2, H-6, NH2 (D2O exchangeable)), 7.48 (d, J = 8.0 Hz,
2H, trifluoromethylphenyl H-3, H-5), 7.61 (d, J = 8.4 Hz, 2H, methoxyphenyl H-2, H-6), 7.73-7.75
(m, 4H, aminosulphonylphenyl H-2, H-3, H-5, H-6); 13C NMR (DMSO-d6) δ 43.35 (pyrazole C-4),
55.76 (OCH3), 62.09 (pyrazole C-5), 112.21 (methoxyphenyl C-3, C-5), 114.66
(aminosulphonylphenyl C-2, C-6), 124.58 (methoxyphenyl C-1), 124.59 (q, J = 270 Hz, CF3),
126.53 (d, J = 3 Hz, trifluoromethylphenyl C-3, C-5), 127.18 (aminosulphonylphenyl C-3, C-5),
127.73 (trifluoromethylphenyl C-2, C-6) , 128.17 (methoxyphenyl C-2, C-6), 128.64 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 133.38 (aminosulphonylphenyl C-4), 146.29 (trifluoromethylphenyl C-
1), 146.81 (aminosulphonylphenyl C-1), 150.21 (pyrazole C-3), 160.82 (methoxyphenyl C-4); 19F
14

NMR (DMSO-d6) δ -60.74; MS (m/z): 475 (M+., 55.0%), 64 (100%); Anal. Calcd for
C23H20F3N3O3S: C, 58.10; H, 4.24; N, 8.84; Found: C, 57.81; H, 4.37; N, 8.89.
4.1.4.10. 1-(4-Aminosulfonylphenyl)-3-(4-ethoxyphenyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazole (14j): 89% yield; white crystals; mp 22-223 °C; IR (KBr disk) 3427 (NH2), 3066 (C-H
aromatic), 2926 (C-H aliphatic), 1325, 1132 (SO2);1H NMR (DMSO-d6) δ 1.45 (t, J = 6.8 Hz, 3H,
CH2CH3), 3.18 (dd, J = 17.6, 4.8 Hz, 1H, pyrazole H-4), 3.96 (dd, J = 17.6, 12.0 Hz, 1H, pyrazole
H'-4), 4.07 (q, J = 6.8 Hz, 2H, CH2CH3), 5.74 (dd, J = 12.0, 4.8 Hz, 1H, pyrazole H-5), 6.99 (d, J =
8.4 Hz, 2H, ethoxyphenyl H-3, H-5), 7.05 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.47
(d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.60 (d, J = 8.4 Hz, 2H, ethoxyphenyl H-2, H-
6), 7.71-7.74 (m, 4H, aminosulphonylphenyl H-2, H-3, H-5, H-6); 13C NMR (DMSO-d6) δ 15.01
(CH2CH3), 43.33 (pyrazole C-4), 62.07 (CH2CH3), 63.70 (pyrazole C-5), 112.19 (ethoxyphenyl C-
3, C-5), 115.06 (aminosulphonylphenyl C-2, C-6), 124.42 (trifluoromethylphenyl C-3, C-5),
124.58 (q, J = 270 Hz, CF3), 127.18 (ethoxyphenyl C-1), 127.73 (aminosulphonylphenyl C-3, C-5),
128.48 (trifluoromethylphenyl C-2, C-6) , 128.64 (ethoxyphenyl C-2, C-6), 128.95 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 133.34 (aminosulphonylphenyl C-4), 146.29 (trifluoromethylphenyl C-
1), 146.81 (aminosulphonylphenyl C-1), 150.22 (pyrazole C-3), 160.10 (ethoxyphenyl C-4); 19F
NMR (DMSO-d6) δ -60.74; MS (m/z): 489 (M+., 100%); Anal. Calcd for C24H22F3N3O3S: C, 58.89;
H, 4.53; N, 8.58; Found: C, 58.81; H, 4.87; N, 8.80.
4.1.4.11. 1-(4-Aminosulfonylphenyl)-3-(4-fluorophenyl)-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazole (14k): 78% yield; off-white crystals; mp 209-210 °C; IR (KBr disk) 3430 (NH2), 3062
(C-H aromatic), 2932 (C-H aliphatic), 1327, 1137 (SO2); 1H NMR (DMSO-d6) δ 3.26 (dd, J = 17.6,
4.8 Hz, 1H, pyrazole H-4), 4.01 (dd, J = 17.6, 12.0 Hz, 1H, pyrazole H'-4), 5.80 (dd, J = 12.0, 4.8
Hz, 1H, pyrazole H-5), 7.08 (d, J = 8.4 Hz, 2H, aminosulphonylphenyl H-2, H-6), 7.28-7.32 (m,
2H, fluorophenyl H-3, H-5), 7.48 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.51 (s, 2H,
NH2, D2O exchangeable), 7.61 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.74 (d, J =
8.4 Hz, 2H, aminosulphonylphenyl H-3, H-5), 7.83-7.86 (m, 2H, fluorophenyl H-2, H-6); 13C NMR
(DMSO-d6)
δ
13C NMR
δ
43.22 (pyrazole C-4), 62.33 (pyrazole C-5), 112.44
(aminosulphonylphenyl C-2, C-6), 116.23 (d, J = 21 Hz, fluorophenyl C-3, C-5) , 124.58 (q, J =
270 Hz, CF3), 126.58 (d, J = 3 Hz, trifluoromethylphenyl C-3, C-5), 127.21 (trifluoromethylphenyl
C-2, C-6), 127.73 (aminosulphonylphenyl C-3, C-5), 128.62 (q, J = 32 Hz, trifluoromethylphenyl
C-4), 128.70 (fluorophenyl, C-1), 128.87 (d, J = 8 Hz, fluorophenyl C-2, C-6) , 133.81
(aminosulphonylphenyl C-4), 146.10 trifluoromethylphenyl C-1), 146.63 (aminosulphonylphenyl
C-1), 149.42 (pyrazole C-3), 163.21 (d, J = 246 Hz, fluorophenyl C-4); 19F NMR (DMSO-d6) δ -
15

60.20, -110.06; MS (m/z): 463 (M+., 67.8%), 115 (100%); Anal. Calcd for C22H17F4N3O2S: C,
57.02; H, 3.70; N, 9.07; Found: C, 57.11; H, 3.87; N, 9.20.
4.1.4.12.
1-(4-Aminosulfonylphenyl)-3-(3,4-difluorophenyl)-5-(4-trifluoromethyl-phenyl)-4,5-
dihydro-1H-pyrazole (14l): 82% yield; pale yellow powder; mp 235-236 °C; IR (KBr disk) 3432
(NH2), 3067 (C-H aromatic), 2930 (C-H aliphatic), 1327, 1135 (SO2); 1H NMR (CDCl3) δ 3.17
(dd, J = 17.2, 5.6 Hz, 1H, pyrazole H-4), 3.95 (dd, J = 17.2, 12.4 Hz, 1H, pyrazole H'-4), 5.49 (dd, J
= 12.4, 5.6 Hz, 1H, pyrazole H-5), 7.09 (d, J = 9.2 Hz, 2H, aminosulphonylphenyl H-2, H-6), 7.19-
7.26 (m, 1H, difluorophenyl H-5), 7.40 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.35-
7.47 (m, 1H, difluorophenyl H-2), 7.65 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.65-
7.68 (m, 1H, difluorophenyl H-6), 7.73 (d, J = 9.2 Hz, 2H, aminosulphonylphenyl H-3, H-5); 13C
NMR (CDCl3) δ 43.35 (pyrazole C-4), 63.25 (pyrazole C-5), 112.81 (aminosulphonylphenyl C-2,
C-6), 115.03 (d, J = 19 Hz, difluorophenyl C-5), 117.71 (d, J = 18 Hz, difluorophenyl C-2), 122.52
(dd, J = 7, 4 Hz, difluorophenyl C-6), 123.78 (q, J = 270 Hz, CF3), 126.04 (trifluoromethylphenyl
C-3, C-5), 126.58 (trifluoromethylphenyl C-2, C-6), 128.74 (difluorophenyl, C-1), 129.04
(aminosulphonylphenyl C-3, C-5), 130.05 (aminosulphonylphenyl C-4), 130.64 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 144.67 trifluoromethylphenyl C-1), 147.32 (aminosulphonylphenyl C-
1), 147.71 (pyrazole C-3), 150.51 (dd, J = 247, 13 Hz, difluorophenyl C-3), 151.16 (dd, J = 247, 13
Hz, difluorophenyl C-4); 19F NMR (DMSO-d6) δ -61.10, -136.37, -138.80; MS (m/z): 481 (M+.,
100%); Anal. Calcd for C22H16F5N3O2S: C, 54.89; H, 3.35; N, 8.73; Found: C, 54.82; H, 3.49; N,
9.07.
4.1.5. General method for preparation of 1-(4-amino(methane)sulfonylphenyl)-3-substituted-
phenyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazoles (15a-l). Method 1: a solution of the
appropriate dihydrropyrazole (14a-l, 2.0 mmol) in glacial acetic acid (10 mL) was heated under
reflux for 24 h. After cooling, the reaction mixture was poured onto ice-water (20 mL) and the
formed solid was filtered off, dried and crystallized from ethanol to yield the respective pyrazoles
15a–l.
Method 2 (for 15b, 15d, 15h and 15j): To a solution of the appropriate chalcone (11b or 11d, 2.0
mmol) in acetic acid 96% (10 mL), the respective phenylhydrazine hydrochloride (13a or 13b, 2.0
mmol) was added. The reaction mixture was heated under reflux for 36 h. After cooling, the
reaction mixture was poured onto ice-water (20 mL); the formed solid was filtered, dried and
crystallized from aqueous ethanol to yield the corresponding pyrazoles 15b, 15d, 15h and 15j.
Physical and spectral data for 15a–l are listed below.
16

4.1.5.1.
1-(4-Methanesulfonylphenyl)-3-(4-hydroxyphenyl)-5-(4-trifluoromethylphenyl)-1H-
pyrazole (15a): 69% yield; yellow powder; mp 187-188 °C; IR (KBr disk) 3407 (OH), 3073 (C-H
1
aromatic), 2926 (C-H aliphatic), 1321, 1147 (SO2); H NMR (DMSO-d6) δ 3.28 (s, 3H, SO2CH3),
6.87 (d, J = 8.8 Hz, 2H, hydroxyphenyl H-3, H-5), 7.23 (s,1H, pyrazole H-4), 7.57 (d, J = 8.8 Hz,
2H, trifluoromethylphenyl H-2, H-6), 7.59 (d, J = 8.8 Hz, 2H, trifluoromethylphenyl H-3, H-5),
7.77 (d, J = 8.8 Hz, 2H, hydrxyphenyl H-2, H-6), 7.82 (d, J = 8.4 Hz, 2H, methanesulphonylphenyl
H-2, H-6), 7.99 (d, J = 8.4 Hz, 2H, methanesulphonylphenyl H-3, H-5), 9.71 (s, 1H, OH, D2O
exchangeable); 13C NMR (DMSO-d6) δ 43.87 (SO2CH3), 107.53 (pyrazole C-4) , 115.81
(hydroxyphenyl C-3, C-5), 123.40 (hydroxyphenyl C-1), 124.48 (q, J = 270 Hz, CF3), 125.61
(methanesulphonylphenyl C-2, C-6), 126.24 (d, J = 4 Hz, trifluoromethylphenyl C-3, C-5), 127.48
(trifluoromethylphenyl C-2, C-6), 128.74 (methanesulphonylphenyl C-3, C-5), 129.34 (q, J = 32
Hz,
trifluoromethylphenyl
C-4),
C-4),
129.81
139.66
(hydroxyphenyl
C-2,
C-6),
C-1),
134.22
143.23
(methanesulphonylphenyl
,
(trifluoromethylphenyl
(methanesulphonylphenyl C-1), 143.65 (pyrazole C-5),
152.92 (pyrazole C-3), 158.38
(hydroxyphenyl C-4); 19F NMR (DMSO-d6) δ -61.00; MS (m/z): 458 (M+., 67.2%), 93 (100%);
Anal. Calcd for C23H17F3N2O3S: C, 60.26; H, 3.74; N, 6.11; Found: C, 60.41; H, 3.87; N, 6.08.
4.1.5.2. 1-(4-Methanesulfonylphenyl)-3-(p-tolyl)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15b):
79% yield; off-white crystals; mp 218-219 °C; IR (KBr disk) 3069 (C-H aromatic), 2924 (C-H
1
aliphatic), 1320, 1152 (SO2); H NMR (CDCl3) δ 2.42 (s, 3H, CH3), 3.05 (s, 3H, SO2CH3), 6.90
(s,1H, pyrazole H-4),7.29 (d, J = 8.0 Hz, 2H, tolyl H-3, H-5), 7.43 (d, J = 7.6 Hz, 2H,
trifluoromethylphenyl H-2, H-6), 7.57 (d, J = 8.4 Hz, 2H, methanesulphonylphenyl H-2, H-6), 7.66
(d, J = 8.0 Hz, 2H, tolyl H-2, H-6), 7.82 (d, J = 7.6 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.95
(d, J = 8.4 Hz, 2H, methanesulphonylphenyl H-3, H-5); 13C NMR (CDCl3) δ 21.38 (CH3), 44.50
(SO2CH3), 107.39 (pyrazole C-4) , 123.79 (q, J = 270 Hz, CF3), 125.16 (methanesulphonylphenyl
C-2, C-6), 125.91 (methanesulphonylphenyl C-3, C-5), 125.98 (trifluoromethylphenyl C-3, C-5),
128.56 (trifluoromethylphenyl C-2, C-6), 129.05 (tolyl C-2, C-6), 129.47 (tolyl C-1), 129.56 (tolyl
C-3, C-5), 130.85 (q, J = 32 Hz, trifluoromethylphenyl C-4), 133.59 (methanesulphonylphenyl C-
4), 138.70 (tolyl C-4), , 138.85 trifluoromethylphenyl C-1), 143.13 (methanesulphonylphenyl C-1),
143.91 (pyrazole C-5), 153.39 (pyrazole C-3); 19F NMR (DMSO-d6) δ -60.89; MS (m/z): 456 (M+.,
100%); Anal. Calcd for C24H19F3N2O2S: C, 63.15; H, 4.20; N, 6.14; Found: C, 63.36; H, 4.37; N,
6.10.
4.1.5.3.
1-(4-Methanesulfonylphenyl)-3-(4-methoxy)-5-(4-trifluoromethylphenyl)-1H-pyrazole
(15c): 90% yield; yellow powder; mp 192-193 °C; IR (KBr disk) 3066 (C-H aromatic), 2927 (C-H
17

aliphatic), 1322, 1150 (SO2); 1H NMR (CDCl3) δ 3.10 (s, 1H, SO2CH3), 3.89 (s, 1H, OCH3), 6.87
(s, 1H, pyrazole H-4), 7.01 (d, J = 8.0 Hz, 2H, methoxyphenyl H-3, H-5), 7.45 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-2, H-6), 7.58 (d, J = 8.0 Hz, 2H, methanesulphonylphenyl H-2, H-6), 7.68
(d, J = 8.0 Hz, 2H, methoxyphenyl H-2, H-6), 7.87 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3,
H-5), 7.96 (d, J = 8.0 Hz, 2H, methanesulphonylphenyl H-3, H-5); 13C NMR (CDCl3) δ 44.55
(SO2CH3), 55.37 (OCH3), 107.18 (pyrazole C-4) , 114.23 (methoxyphenyl C-3, C-5), 123.75 (q, J =
270 Hz, CF3), 124.71 (methoxyphenyl C-1), 125.01 (methanesulphonylphenyl C-2, C-6), 125.94
(trifluoromethylphenyl C-3, C-5), 127.21 (trifluoromethylphenyl C-2, C-6),
128.57
(methanesulphonylphenyl C-3, C-5), 129.04 (methoxyphenyl C-2, C-6), 130.94 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 133.63 (methanesulphonylphenyl C-4), , 138.76 trifluoromethylphenyl
C-1), 143.14 (methanesulphonylphenyl C-1), 143.96 (pyrazole C-5), 153.21 (pyrazole C-3), 160.12
(methoxyphenyl C-4); 19F NMR (CDCl3) δ -62.49; MS (m/z): 472 (M+., 54.7%), 107 (100%); Anal.
Calcd for C24H19F3N2O3S: C, 61.01; H, 4.05; N, 5.93; Found: C, 61.13; H, 4.17; N, 6.01.
4.1.5.4. 3-(4-Ethoxy)1-(4-methanesulfonylphenyl)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15d):
88% yield; orange powder; mp 150-151 °C; IR (KBr disk) 3069 (C-H aromatic), 2930 (C-H
1
aliphatic), 1321, 1155 (SO2); H NMR (CDCl3) δ 1.47 (t, J = 6.8 Hz, 3H, CH2CH3), 3.10 (s, 1H,
SO2CH3), 4.11 (q, J = 6.8 Hz, 2H, CH2CH3), 6.86 (s, 1H, pyrazole H-4), 7.00 (d, J = 8.0 Hz, 2H,
ethoxyphenyl H-3, H-5), 7.45 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.58 (d, J = 8.0
Hz, 2H, methanesulphonylphenyl H-2, H-6), 7.68 (d, J = 8.0 Hz, 2H, ethoxyphenyl H-2, H-6), 7.85
(d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.96 (d, J = 8.0 Hz, 2H,
13
methanesulphonylphenyl H-3, H-5); C NMR (CDCl3) δ 14.85 (CH2CH3), 44.55 (SO2CH3), 63.54
(CH2CH3) 107.17 (pyrazole C-4) , 114.74 (ethoxyphenyl C-3, C-5), 123.79 (q, J = 270 Hz, CF3),
124.53 (ethoxyphenyl C-1), 124.99
(methanesulphonylphenyl C-2, C-6), 125.94
128.57
(trifluoromethylphenyl C-3, C-5), 127.19 (trifluoromethylphenyl C-2, C-6),
(methanesulphonylphenyl C-3, C-5), 129.03 (ethoxyphenyl C-2, C-6), 130.74 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 133.64 (methanesulphonylphenyl C-4), , 138.73 trifluoromethylphenyl
C-1), 143.12 (methanesulphonylphenyl C-1), 143.97 (pyrazole C-5), 153.26 (pyrazole C-3), 159.52
(ethoxyphenyl C-4); 19F NMR (CDCl3) δ -62.33; MS (m/z): 486 (M+., 47.9%), 121 (100%); Anal.
Calcd for C25H21F3N2O3S: C, 61.72; H, 4.35; N, 5.76; Found: C, 61.83; H, 4.57; N, 5.88.
4.1.5.5. 3-(4-Fluoro)-1-(4-methanesulfonylphenyl)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15e):
81% yield; pale yellow powder; mp 218-219 °C; IR (KBr disk) 3067 (C-H aromatic), 2924 (C-H
aliphatic), 1325, 1150 (SO2); 1H NMR (CDCl3) δ 3.10 (s, 3H, SO2CH3), 6.89 (s,1H, pyrazole H-4),
7.15-7.19 (m, 2H, fluorophenyl H-3, H-5), 7.45 (d, J = 7.6 Hz, 2H, trifluoromethylphenyl H-2, H-
18

6), 7.58 (d, J = 7.6 Hz, 2H, methanesulphonylphenyl H-2, H-6), 7.69 (d, J = 7.6 Hz, 2H,
trifluoromethylphenyl H-3, H-5), 7.89-7.93 (m, 2H, fluorophenyl H-2, H-6), 7.97 (d, J = 7.6 Hz,
2H, methanesulphonylphenyl H-3, H-5); 13C NMR (CDCl3) δ 44.53 (SO2CH3), 107.27 (pyrazole C-
4) , 115.84 (d, J = 22 Hz, fluorophenyl C-3, C-5), 123.79 (q, J = 270 Hz, CF3), 125.09
(methanesulphonylphenyl C-2, C-6), 125.98 (trifluoromethylphenyl C-3, C-5), 127.66 (d, J = 8 Hz,
fluorophenyl C-2, C-6), 128.27 (fluorophenyl C-1), 128.62 (trifluoromethylphenyl C-2, C-6),
129.05 (methanesulphonylphenyl C-3, C-5), 130.85 (q, J = 32 Hz, trifluoromethylphenyl C-4),
133.42 (methanesulphonylphenyl C-4),
,
139.07 (trifluoromethylphenyl C-1), 143.37
(methanesulphonylphenyl C-1), 143.82 (pyrazole C-5), 152.48 (pyrazole C-3), 163.14 (d, J = 247
Hz, fluorophenyl C-4); 19F NMR (CDCl3) δ -61.99, 112.79; MS (m/z): 460 (M+., 20.8%), 123
(100%); Anal. Calcd for C23H16F4N2O2S: C, 60.00; H, 3.50; N, 6.08; Found: C, 60.11; H, 3.87; N,
6.15.
4.1.5.6.
3-(3,4-Difluoro)-1-(4-methanesulfonylphenyl)-5-(4-trifluoromethylphenyl)-1H-pyrazole
(15f): 73% yield; pale yellow powder; mp 203-204 °C; IR (KBr disk) 3066 (C-H aromatic), 2925
1
(C-H aliphatic), 1324, 1157 (SO2); H NMR (DMSO-d6) δ 3.28 (s, 3H, SO2CH3), 7.45 (s,1H,
pyrazole H-4), 7.53-7.61 (m, 1H, difluorophenyl H-5), 7.58 (d, J = 8.0 Hz, 2H,
trifluoromethylphenyl H-2, H-6), 7.64 (d, J = 8.0 Hz, 2H, methanesulphonylphenyl H-2, H-6), 7.79-
7.81 (m, 1H, difluorophenyl H-2), 7.83 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.95-
7.99 (m, 1H, difluorophenyl H-6), 8.01 (d, J = 8.0 Hz, 2H, methanesulphonylphenyl H-3, H-5); 13C
NMR (DMSO-d6) δ 43.85 (SO2CH3), 108.23 (pyrazole C-4), 114.98 (d, J = 19 Hz, difluorophenyl
C-5), 118.63 (d, J = 17 Hz, difluorophenyl C-2), 122.90 (dd, J = 7, 4 Hz, difluorophenyl C-6),
124.44 (q, J = 270 Hz, CF3), 125.97 (methanesulphonylphenyl C-2, C-6), 126.30 (d, J = 4 Hz,
trifluoromethylphenyl C-3, C-5), 128.80 (trifluoromethylphenyl C-2, C-6), 129.55 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 129.87 (methanesulphonylphenyl C-3, C-5), 130.15 (difluorophenyl,
C-1),
133.82 (methanesulphonylphenyl C-4), 140.22 (trifluoromethylphenyl C-1), 143.36
(methanesulphonylphenyl C-1), 143.77 (pyrazole C-5), 149.64 (dd, J = 247, 13 Hz, difluorophenyl
C-3), 149.91 (dd, J = 247, 13 Hz, difluorophenyl C-4), 150.74 (pyrazole C-3); 19F NMR (DMSO-
d6) δ -61.10, -137.46, 138.80; MS (m/z): 478 (M+., 100%); Anal. Calcd for C23H15F5N2O2S: C,
57.74; H, 3.16; N, 5.86; Found: C, 57.71; H, 3.28; N, 6.00.
4.1.5.7. 1-(4-Aminosulfonylphenyl)-3-(4-hydroxyphenyl)-5-(4-trifluoromethylphenyl)-1H-pyrazole
(15g): 65% yield; pale yellow powder; mp 229-230 °C; IR (KBr disk) 3391, 3250 (NH2), 3075 (C-
H aromatic), 1325, 1159 (SO2); 1H NMR (DMSO-d6) δ 6.86 (d, J = 8.4 Hz, 2H, hydroxyphenyl H-
3, H-5), 7.21 (s,1H, pyrazole H-4), 7.48 (s, 2H, NH2, D2O exchangeable), 7.53 (d, J = 8.4 Hz, 2H,
19

trifluoromethylphenyl H-2, H-6), 7.56 (d, J = 8.4 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.76 (d,
J = 8.8 Hz, 2H, aminosulphonylphenyl H-2, H-6), 7.81 (d, J = 8.4 Hz, 2H, hydrxyphenyl H-2, H-6),
7.86 (d, J = 8.8 Hz, 2H, aminosulphonylphenyl H-3, H-5), 9.69 (s, 1H, OH, D2O exchangeable); 13C
NMR (DMSO-d6) δ 107.16 (pyrazole C-4) , 116.03 (hydroxyphenyl C-3, C-5), 123.51
(hydroxyphenyl C-1), 124.48 (q, J = 270 Hz, CF3), 125.52 (aminosulphonylphenyl C-2, C-6),
126.21 (trifluoromethylphenyl C-3, C-5), 127.27 (trifluoromethylphenyl C-2, C-6), 127.43
(aminosulphonylphenyl C-3, C-5), 129.34 (q, J = 32 Hz, trifluoromethylphenyl C-4), 129.79
(hydroxyphenyl C-2, C-6), 134.34 (aminosulphonylphenyl C-4), , 139.66 (trifluoromethylphenyl C-
1), 142.24 (aminosulphonylphenyl C-1), 143.12 (pyrazole C-5), 152.67 (pyrazole C-3), 158.30
(hydroxyphenyl C-4); 19F NMR (DMSO-d6) δ -61.10; MS (m/z): 459 (M+., 33.4%), 93 (100%);
Anal. Calcd for C22H16F3N3O3S: C, 57.51; H, 3.51; N, 9.15; Found: C, 57.79; H, 3.63; N, 9.08.
4.1.5.8. 1-(4-Aminosulfonylphenyl)-3-(p-tolyl)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15h): 74%
yield; off-white crystals; mp 194-195 °C; IR (KBr disk) 3355, 3260 (NH2), 3085 (C-H aromatic),
1
2930 (C-H aliphatic), 1322, 1164 (SO2); H NMR (DMSO-d6) δ 2.51 (s, 3H, CH3), 7.28 (s, 1H,
pyrazole H-4), 7.29 (d, J = 8.0 Hz, 2H, tolyl H-3, H-5), 7.51 (s, 2H, NH2, D2O exchangeable), 7.55
(d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.57 (d, J = 8.0 Hz, 2H, aminosulphonylphenyl
H-2, H-6), 7.81 (d, J = 8.0 Hz, 2H, tolyl H-2, H-6), 7.85 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl
H-3, H-5), 7.89 (d, J = 8.0 Hz, 2H, aminosulphonylphenyl H-3, H-5); 13C NMR (DMSO-d6) δ 21.31
(CH3), 107.59 (pyrazole C-4), 124.48 (q, J = 270 Hz, CF3), 125.64 (methanesulphonylphenyl C-2,
C-6), 125.92 (methanesulphonylphenyl C-3, C-5), 126.20 (trifluoromethylphenyl C-3, C-5), 127.29
(trifluoromethylphenyl C-2, C-6), 129.03 (q, J = 32 Hz, trifluoromethylphenyl C-4), 129.27 (tolyl
C-1), 129.83 (tolyl C-2, C-6), 129.89 (tolyl C-3, C-5), 134.22 (methanesulphonylphenyl C-4),
138.34 (tolyl C-4), , 142.18 trifluoromethylphenyl C-1), 143.29 (methanesulphonylphenyl C-1),
143.39 (pyrazole C-5), 152.44 (pyrazole C-3); 19F NMR (DMSO-d6) δ -60.74; MS (m/z): 457 (M+.,
100%); Anal. Calcd for C23H18F3N3O2S: C, 60.39; H, 3.97; N, 9.19; Found: C, 60.67; H, 3.84; N,
9.08.
4.1.5.9. 1-(4-Aminosulfonylphenyl)-3-(4-methoxy)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15i):
83% yield; orange powder; mp 163-164 °C; IR (KBr disk) 3358, 3262 (NH2), 3061 (C-H aromatic),
1
2924 (C-H aliphatic), 1325, 1158 (SO2); H NMR (DMSO-d6) δ 3.82 (s, 1H, OCH3), 7.05 (d, J =
8.8 Hz, 2H, methoxyphenyl H-3, H-5), 7.28 (s, 1H, pyrazole H-4), 7.48 (s, 2H, NH2, D2O
exchangeable), 7.54 (d, J = 8.8 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.56 (d, J = 8.8 Hz, 2H,
aminosulphonylphenyl H-2, H-6), 7.83 (d, J = 8.8 Hz, 2H, methoxyphenyl H-2, H-6), 7.87 (d, J =
8.8 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.89 (d, J = 8.8 Hz, 2H, aminosulphonylphenyl H-3,
20

13
H-5); C NMR (DMSO-d6) δ 55.66 (OCH3), 107.32 (pyrazole C-4) , 114.73 (methoxyphenyl C-3,
C-5), 123.75 (q, J = 270 Hz, CF3), 125.12 (methoxyphenyl C-1), 125.60 (aminosulphonylphenyl C-
2, C-6), 126.17 (trifluoromethylphenyl C-3, C-5), 127.28 (trifluoromethylphenyl C-2, C-6), 127.39
(aminosulphonylphenyl C-3, C-5), 129.82 (methoxyphenyl C-2, C-6), 130.94 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 134.29 (aminosulphonylphenyl C-4), 142.23 (trifluoromethylphenyl
C-1), 143.28 (aminosulphonylphenyl C-1), 143.32 (pyrazole C-5), 152.33 (pyrazole C-3), 160.01
(methoxyphenyl C-4); 19F NMR (DMSO-d6) δ -60.89; MS (m/z): 473 (M+., 53.2%), 107 (100%);
Anal. Calcd for C23H18F3N3O3S: C, 58.35; H, 3.83; N, 8.87; Found: C, 58.41; H, 3.87; N, 8.64.
4.1.5.10. 1-(4-Aminosulfonylphenyl)-3-(4-ethoxy)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15j):
86% yield; off-white powder; mp 178-179 °C; IR (KBr disk) 3353, 3258 (NH2), 3071 (C-H
aromatic), 2934 (C-H aliphatic), 1325, 1169 (SO2); 1H NMR (DMSO-d6) δ 1.37 (t, J = 6.8 Hz, 3H,
CH2CH3), 4.02 (q, J = 6.8 Hz, 2H, CH2CH3), 6.82 (d, J = 8.0 Hz, 2H, ethoxyphenyl H-3, H-5), 6.89
(d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.06 (s, 1H, pyrazole H-4), 7.38 (s, 2H, NH2,
D2O exchangeable), 7.45 (d, J = 8.0 Hz, 2H, aminosulphonylphenyl H-2, H-6), 7.57 (d, J = 8.0 Hz,
2H, ethoxyphenyl H-2, H-6), 7.75 (d, J = 8.0 Hz, 2H, trifluoromethylphenyl H-3, H-5), 7.87 (d, J =
8.0 Hz, 2H, aminosulphonylphenyl H-3, H-5); 13C NMR (DMSO-d6)δ 14.83 (CH2CH3), 63.44
(CH2CH3) 106.62 (pyrazole C-4) , 114.66 (ethoxyphenyl C-3, C-5), 123.75 (q, J = 270 Hz, CF3),
124.67
(methanesulphonylphenyl C-2, C-6), 124.78 (ethoxyphenyl C-1), 125.71
127.09
(trifluoromethylphenyl C-3, C-5), 125.74 (trifluoromethylphenyl C-2, C-6),
(methanesulphonylphenyl C-3, C-5), 129.15 (ethoxyphenyl C-2, C-6), 130.71 (q, J = 32 Hz,
trifluoromethylphenyl C-4), 133.86 (methanesulphonylphenyl C-4), , 138.73 trifluoromethylphenyl
C-1), 142.14 (methanesulphonylphenyl C-1), 142.89 (pyrazole C-5), 152.52 (pyrazole C-3), 159.25
(ethoxyphenyl C-4); 19F NMR (DMSO-d6) δ -60.71; MS (m/z): 487 (M+., 28.7%), 121 (100%);
Anal. Calcd for C24H20F3N3O3S: C, 59.13; H, 4.14; N, 8.62; Found: C, 59.31; H, 4.27; N, 8.53.
4.1.5.11. 1-(4-Aminosulfonylphenyl)-3-(4-fluoro)-5-(4-trifluoromethylphenyl)-1H-pyrazole (15k):
73% yield; yellow powder; mp 233-234 °C; IR (KBr disk) 3391, 3262 (NH2), 3066 (C-H aromatic),
1
1325, 1160 (SO2); H NMR (DMSO-d6) δ 7.31-7.36 (m, 2H, fluorophenyl H-3, H-5), 7.33 (s,1H,
pyrazole H-4), 7.49 (s, 2H, NH2, D2O exchangeable), 7.53-7.62 (m, 4H, aminosulphonylphenyl H-
2, H-6 , trifluoromethylphenyl H-2, H-6), 7.82 (d, J = 7.6 Hz, 2H, trifluoromethylphenyl H-3, H-5),
7.88 (d, J = 7.6 Hz, 2H, aminosulphonylphenyl H-3, H-5), 7.97-8.03 (m, 2H, fluorophenyl H-2, H-
13
6); C NMR (DMSO-d6) δ 107.67 (pyrazole C-4) , 116.28 (d, J = 21 Hz, fluorophenyl C-3, C-5),
123.79 (q, J = 270 Hz, CF3), 125.74 (aminosulphonylphenyl C-2, C-6), 126.22 (d, J = 4 Hz,
trifluoromethylphenyl C-3, C-5), 127.31 (trifluoromethylphenyl C-2, C-6), 128.07 (d, J = 8 Hz,
21

fluorophenyl C-2, C-6), 129.13 (fluorophenyl C-1), 129.40 (q, J = 32 Hz, trifluoromethylphenyl C-
4), 129.86 (aminosulphonylphenyl C-3, C-5), 134.10 (aminosulphonylphenyl C-4), 139.07
(trifluoromethylphenyl C-1), 142.07 (aminosulphonylphenyl C-1), 143.50 (pyrazole C-5), 151.50
(pyrazole C-3), 162.73 (d, J = 243 Hz, fluorophenyl C-4) ; 19F NMR (DMSO-d6) δ -61.11, -112.14;
MS (m/z): 461 (M+., 42.3%), 64 (100%); Anal. Calcd for C22H15F4N3O2S: C, 57.27; H, 3.28; N,
9.11; Found: C, 57.33; H, 3.40; N, 9.08.
4.1.5.12.
1-(4-Aminosulfonylphenyl)-3-(3,4-difluoro)-5-(4-trifluoromethylphenyl)-1H-pyrazole
(15l): 75% yield; pale yellow powder; mp 111-112 °C; IR (KBr disk) 3389, 3252 (NH2), 3076 (C-H
aromatic), 1324, 1162 (SO2); 1H NMR (DMSO-d6) δ 7.42 (s,1H, pyrazole H-4), 7.50-7.55 (m, 1H,
difluorophenyl H-5), 7.57 (d, J = 7.6 Hz, 2H, trifluoromethylphenyl H-2, H-6), 7.63 (d, J = 8.0 Hz,
2H, aminosulphonylphenyl H-2, H-6), 7.73-7.81 (m, 1H, difluorophenyl H-2), 7.82 (d, J = 7.6 Hz,
2H, trifluoromethylphenyl H-3, H-5), 7.94-7.98 (m, 1H, difluorophenyl H-6), 8.01 (d, J = 8.0 Hz,
2H, aminosulphonylphenyl H-3, H-5); 13C NMR (DMSO-d6) δ 108.18 (pyrazole C-4), 114.98 (d, J
= 19 Hz, difluorophenyl C-5), 118.60 (d, J = 17 Hz, difluorophenyl C-2), 122.90 (dd, J = 7, 4 Hz,
difluorophenyl C-6), 124.43 (q, J = 270 Hz, CF3), 126.25 (aminosulphonylphenyl C-2, C-6),
126.67 (d, J = 4 Hz, trifluoromethylphenyl C-3, C-5), 128.78 (trifluoromethylphenyl C-2, C-6),
129.30 (q, J = 32 Hz, trifluoromethylphenyl C-4), 129.86 (aminosulphonylphenyl C-3, C-5),
130.20 (difluorophenyl, C-1), 133.81 (aminosulphonylphenyl C-4), 140.23 (trifluoromethylphenyl
C-1), 143.38 (aminosulphonylphenyl C-1), 143.78 (pyrazole C-5), 150.02 (dd, J = 247, 13 Hz,
difluorophenyl C-3), 150.29 (dd, J = 247, 13 Hz, difluorophenyl C-4), 150.76 (pyrazole C-3); 19F
NMR (DMSO-d6) δ -60.52, -136.37, -138.80; MS (m/z): 479 (M+., 93.7%), 64 (100%); Anal. Calcd
for C22H14F5N3O2S: C, 55.12; H, 2.94; N, 8.76; Found: C, 55.20; H, 3.11; N, 8.58.
4.2. Pharmacological screening
4.2.1. In vitro cyclooxygenase (COX) inhibition assay
The ability of the test compounds listed in Table 1 to inhibit ovine COX-1 and human recombinant
COX-2 (IC50 value, µM) was determined using an enzyme immuno assay (EIA) kit (catalog no.
560131, Cayman Chemical, Ann Arbor, MI, USA) according to previously reported method [19].
4.2.2. In vivo anti-inflammatory activity
The test compounds 14a-l, 15a-l, and the reference drugs celecoxib, aspirin and ibuprofen were
evaluated using the in vivo carrageenan-induced rat foot paw edema model reported previously [20]
22

Acknowledgements
We are grateful to the Beni-Suef Funding Unit, Beni-Suef University, Egypt for financial support of
this research.
Declaration of interest
The authors have declared no conflict of interest.
References
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B.J. Al-Hourani, S.K. Sharma, J.Y. Mane, J. Tuszynski, V. Baracos, T. Kniess, M. Suresh, J.
Pietzsch, F. Wuest, Bioorg. Med. Chem. Lett. 21 (2011) 1823.
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A.J. Scheen, Rev Med Liege 59 (2004) 565.
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K.R. A. Abdellatif, M.A. Chowdhury, Y. Dong, E.E. Knaus, Bioorg. Med. Chem. 16 (2008)
6528.
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[11] K.R. A. Abdellatif, M.A. Chowdhury, Y. Dong, D. Das, G. Yu, C. Velázquez, M.R. Suresh,
E.E. Knaus, Bioorg. Med. Chem. 17 (2009) 5182.
[12] M.A. Chowdhury, K.R. A. Abdellatif, Y. Dong, D. Das, M.R. Suresh, E.E. Knaus, Bioorg.
Med. Chem. Lett. 18 (2008) 6138.
[13] K.R. A. Abdellatif, M.A. Chowdhury, Y. Dong, C. Velázquez, D. Das, M.R. Suresh, E.E.
Knaus, Bioorg. Med. Chem. 16 (2008) 9694.
[14] K.R.A. Abdellatif, M.A. Chowdhury, E.E. Knaus, J Heterocyclic Chem. 45 (2008) 1707.
23

[15] M. Abdur Rahim, P.N. Praveen Rao, A. Bhardwaj, J. Kaur, Z. Huang, E.E. Knaus, Bioorg.
Med. Chem. Lett. 21 (2011) 6074.
[16] S. Padhye, A. Ahmad, N. Oswal, P. Dandawate, R. a Rub, J. Deshpande, K.V. Swamy, F.H.
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Tables, Figures and Schemes Legends:
Table 1: In vitro COX-1 and COX-2 inhibition, and anti-inflammatory (AI) data for 1-(4-
amino(methane)sulfonylphenyl)-3-substituted-phenyl-5-(4-trifluoromethylphenyl)-4,5-dihydro-1H-
pyrazoles (14a-l), 1-(4-amino(methane)sulfonylphenyl)-3-substituted-phenyl-5-(4-trifluoromethyl-
phenyl)-1H-pyrazoles (15a-l), and the reference drugs celecoxib, aspirin and ibuprofen.
Figure 1: Chemical structures of the selective cyclooxygenase-2 (COX-2) inhibitors celecoxib (1),
rofecoxib (2), and valdecoxib (3), and celecoxib analogs (4-8).
Figure 2: Chemical structures of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (1),
the designed dihydropyrazoles (pyrazolines) 14a-f, 14g-l and the designed pyrazoles 15a-f, 15g-l.
Scheme 1: Synthetic protocol for compounds 11a-f, 12, 14a-l, 15a-l.
24

Me
SO2NH2
SO2Me
SO2NH2
N
O
N
O
O
N
Me
Rofecoxib (2)
NHR1
Celecoxib (1)
F3C
Valdecoxib (3)
R
H
N
SO2Me
SO2R2
SO2R
N
N
N
N
N
HOOC
N
R = H, F, Me
4
R1 = Me, Et; R2 = Me, NH2
F3C
F3C
R = Me, NH2
5
6
R1
OH
N
O
SO2R2
SO2R
N
N
N
N
F3C
F3C
R1 = OH, COOH; R2 = Me, NH2
7
R = Me, NH2
8
Figure 1.
25

CF3
CF3
R2
R2
R1
R1
N
N
N
N
SO2CH3
SO2NH2
14a-f
14g-l
CH3
4
5
3
F3C
1
N
N
2
SO2NH2
Celecoxib (1)
CF3
CF3
R2
R2
R1
R1
N
N
N
N
15g-l
SO2NH2
15a-f
SO2CH3
R1 = OH, CH3, OCH3, OCH2CH3, F; R2 = H, F
Figure 2.
26

R2
R1
CF3
CH3
H
9a-f
+
10
O
R1
R2
O
b, for 9e
a
b
c
d
e
f
OH
CH3
OCH3
OCH2CH3
F
F
H
H
H
H
H
F
CF3
a
F
R2
R1
CF3
O
O
O
11a-f
R2
12
F
R1
c, 13a-b
R1
R2
R3
CF3
N
a
b
c
d
e
f
OH
CH3
OCH3
OCH2CH3
F
F
H
H
H
H
H
F
CH3
CH3
CH3
CH3
CH3
CH3
N
e, 13a-b
for 11b and 11d
g
h
i
j
k
l
OH
CH3
OCH3
OCH2CH3
F
F
H
H
H
H
H
F
NH2
NH2
NH2
NH2
NH2
NH2
14a-l
SO2R3
R2
d
R1
NHNH2.HCl
CF3
N
N
SO2R3
13a-b
13a, R3 = CH3; 13b, R3 = NH2
15a-l
SO2R3
Scheme 1. Reagents and conditions: (a) EtOH, 10% NaOH, RT, 2 h for 9a-d, 0.5 h for 9e-f; (b)
EtOH, 10% NaOH, RT, 2 h for 9e; (c) EtOH, reflux, 24 h; (d) glacial AcOH , reflux, 24 h; (e)
AcOH (96%), reflux, 36 h.
27

Table 1. In vitro COX-1 and COX-2 inhibition, and anti-inflammatory (AI) data for 1-(4-
amino(methane)sulfonylphenyl)-3-substituted-phenyl-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-
1H-pyrazoles
(14a-l),
1-(4-amino(methane)sulfonylphenyl)-3-substituted-phenyl-5-(4-
trifluoromethylphenyl)-1H-pyrazoles (15a-l), and the reference drugs celecoxib, aspirin and
ibuprofen.
R2
R2
R1
R1
CF3
CF3
N
N
N
N
SO2R3
14a-l
SO2R3
15a-l
Compd
R1
R2
R3
IC50 (uM)a
COX-2
S.I.b
AI activityc
% ED50
COX-1
COX-2
inhibition (umol/kg)
(50 mg/kg)
14a
14b
14c
14d
14e
14f
OH
Me
OMe
OEt
F
H
H
H
H
H
F
Me
Me
Me
Me
Me
Me
NH2
17.3
6.6
6.7
1.11
10.8
0.97
4.8
2.58
5.95
2.23
5.77
3.42
2.46
3.05
25.0
16.3
—
—
24.1
5.6
30.0
—
38.8
296.0
16.4
23.1
5.8
31.3
—
F
9.4
Inactive
41.3
—
14g
OH
H
1.9
190.5
28

14h
14i
Me
OMe
OEt
F
H
H
H
H
F
NH2
NH2
NH2
NH2
NH2
Me
22.5
8.9
8.7
1.5
2.59
5.93
2.51
4.47
3.35
6.08
4.07
2.80
5.03
3.49
5.27
3.10
3.18
2.54
3.70
2.85
4.78
7.70
0.017
1.05
5.0
41.3
33.8
38.8
25.0
2.5
—
160.1
14j
11.3
9.7
4.5
279.8
312.0
14k
2.17
3.7
14l
F
12.4
5.9
—
—
—
15a
OH
Me
OMe
OEt
F
H
H
H
H
H
F
0.97
2.9
15b
Me
11.8
15.1
8.6
30.0
32.5
31.3
16.3
15.0
Inactive
Inactive
8.8
15c
Me
5.4
—
15d
Me
1.71
4.1
268.3
15e
Me
14.3
7.9
—
—
—
—
15f
F
Me
1.5
15g
OH
Me
OMe
OEt
F
H
H
H
H
H
F
NH2
NH2
NH2
NH2
NH2
NH2
9.6
3.1
15h
18.1
21.3
10.7
19.4
6.4
5.7
15i
8.4
—
15j
2.9
42.5
15.0
22.5
239.6
15k
6.8
—
15l
F
1.34
0.87
> 100
7.2
—
Celecoxib
Asprin
Ibuprofen
30.9
6.7
—
—
—
—
—
—
—
—
—
—
—
—
714.0
327.0
1.7
7.6
a The in vitro test compound concentration required to produce 50% inhibition of ovine COX-1 or
human recombinant COX-2. The result (IC50, μM) is the mean of two determinations acquired using
29