Synthesis of fused sulfonamide (1,1-dioxoisothiazole)substituted 1,5-diarylpyrazoles as cyclooxygenase inhibitors (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 1999
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.A series of novel sulfone substituted 4,5-diarylthiazoles were synthesized and shown to display exceptionally selective COX-2 inhibition.
Synthesis of 1-P-SULF Am Ylphen YL-3 Trifluoromethylpyrazoles Class of CYCLOOXYGENASE-2 Inhibitors
Heterocyclic Communications, 2003
Condensation of p-sulfamylphenylhydrazine with diketones 1 afforded pyrazoles 2. Reaction of 2 with isocyanate and isothiocyanate derivatives gave the corresponding ureas 3 and thioureas 4 respectively. Cyclization of the thioureido group of compounds 4 by treating with ethyl bromoacetate, ethyl ß-bromopropionate and abromoacetophenone afforded the corresponding thiazolidinone, thiazinone and thiazoline derivatives 5 , 6 and 1 respectively. Introduction: A number of selective inhibitors of cyclooxygenase-2 (COX-2) were shown to possess anti-inflammatory activity with little or no gastric side effects 1 ' 2. To date, two distinct structural classes of molecules have been reported as selective 3 4 inhibitors of COX-2, NS-398 and L-745, 337 are members of methanes sulfonamide class of inhibitors, and DUF 647 , SC-57666, (SC-58125) I are few of the many examples of the tricyclic inhibitors class (Figure 1). 14 Recently, it was found that within the 1,5-diarylpyrazole class of COX-2 inhibitors, the p-sulfamylphenyl group was essential for good COX-2 inhibitors potency and in vivo efficacy. Also, although there was substantial flexibility in functionality allowed at the 3-position of the pyrazole, trifluoromethyl and difluoromethyl were optimal in terms of potency and selectivity. In addition, substituents on the phenyl moiety at 5-position of the pyrazole ring had profound effects on both in vitro potency and selectivity. Morover, CELEBRX Π is a nonsteroided anti-inflammatory drug that exhibits antiflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2) and at therapeutic concentrations in humans. In continuation of our previous work 15 20 in the synthesis of trisubstituted pyrazoles containing trifluoromethyl and/or sulfonamide moieties, many new 1,5-diarylpyrazoles of selective COX-2 inhibitors related to the previously reported I and II were synthesised as a class of COX-2 inhbitors. Results and Discussion: Condensation of the key intermediate, p-sulfamylphenylhydrazine hydrochloride with fluorodiketones ! afforded 5-substituted-3-trifIuoromethyl-l-(p-sulfamylphenyl)pyrazoles (2; Table 1). The IR spectra of this pyrazoline displayed two absoption bands at 3225 cm' 1 and 3347 cm" 1 indicative of the NH2 group, in addition to two strong bands at 1335-1345 and 1152-1150 cm" 1 for the SO2N group. Their 'h NMR spectra exhibited the aromatic and the NH2 protons as multipiets at δ 6.52-8.14 (Tabel 2). Condensation of pyrazole derivatives 2 with the appropriate isocyanate and isothiocyanate in dry acetone yielded the corresponding benzenesulfonylurea 3 and thiourea 4 derivatives respectively (Table 1). The IR spectra of these compounds exhibited two bands at 1330-1350 cm 1 and 1150-1165 cm 1 due to SO2N group as well as a urea carbonyl band at 1650-1656 cm 1 in the case of compounds 3 and a thiourea carbonyl absorption at 1136-1140 cm 1 in the case of compounds 4. The structure of the above compounds 3 and 4 were further supported by their elemental analyses as well as 'h NMR spectra (Table 2).
Journal of Medicinal Chemistry, 2003
A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.
Bioorganic & Medicinal Chemistry Letters, 1999
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors.
Journal of Medicinal Chemistry, 1997
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structureactivity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
Journal of Heterocyclic Chemistry, 2002
A group of 1,2-diphenyl-3,5-dioxopyrazolidines possessing a methylsulfonyl (11) or sulfonamide (15) substituent at the para position of the N 1-phenyl ring, in conjunction with a hydrogen, methyl or fluoro substituent at the para position of the N 2-phenyl ring, and a C-4 n-butyl, methyl or spiro-cyclopropyl substituent were synthesized for evaluation as potential cyclooxygenase-2 (COX-2) selective inhibitor antiinflammatory agents. The title compounds 11 and 15 were synthesized using a four-step and a three-step reaction sequence, respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative (6, 12) gave the corresponding azobenzene product (8, 13) which was reduced with zinc dust in the presence of ammonium chloride to yield the corresponding hydrazobenzene (9, 14). Base-catalyzed condensation of 9 and 14 with a malonyl dichloride (10) afforded the target 3,5-dioxopyrazolidine product (11, 15). 4-n-Butyl-1-(4-methylsulfonylphenyl)-2-phenyl-3,5-dioxopyrazolidine (11a) was a selective COX-1 inhibitor (COX-1 IC 50 = 8.48 µM). In contrast, 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyrazolidine (11b, COX-2 IC 50 = 11.45 µM) and 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-dioxopyrazolidine (11c, COX-2 IC 50 = 9.86 µM) were about 46-fold and 20-fold less selective COX-2 inhibitors respectively, relative to the reference drug celecoxib.
Oriental journal of chemistry, 2015
A new series of thiadiazole linked pyrazole benzenesulfonamide derivatives were synthesized by the condensation of aldehydic pyrazole with aryl substituted thiadiazole amine followed by Schiff base reaction. The synthesized compounds (6a-o) were characterized by IR, NMR, and Mass spectral data, further evaluated their in-vivo anti-inflammatory, analgesic and invitro COX-II inhibition assay. The compounds 6b and 6m showed most significant in-vivo antiinflammatory with 72.33 &71.17% inhibition along analgesic activity having 67.89% and 71.37 % respectively. Their selectivity against COX-II enzyme with selectivity index 67.81 and 66.38 was established for 6b and 6m, which is compared with Celecoxib. During the gastric ulceration study, selected compounds couldn’t observed any ulcerogenic effect on gastric mucosa.The in-silico pharmacokinetic profile and molecular docking study exposed very good binding affinity towards the Cyclooxygenase (COX-II) enzyme (PDB Id: 3PGH), therefore the co...
MedChemComm, 2018
With the aim of achieving new compounds possessing both anti-inflammatory and antiplatelet activities, we synthesized (E)-3-[3-(pyridin-3/4-yl)-1-(phenyl/sulfonylmethylphenyl)-1H-pyrazol-4-yl]acrylamides, and evaluated their COX-1 and COX-2 inhibitory and antiplatelet activities. Since COX-2 inhibitory and antiplatelet compounds have anticancer potential, we also screened their antiproliferative effects against three human cancer cell lines. Compounds 5n, 5p, 5s, 10d, 10g and 10i were determined as dual COX-2 inhibitor/antiplatelet compounds. Compound 10h appeared to be a compound that exhibited antiplatelet activity without inhibiting the COX enzyme. Compounds 5h, 10a and 10i were the most effective derivatives which displayed antiproliferative activity against Huh7, MCF7 and HCT116 cells. Particularly, compound 10i, as the compound exhibiting the highest cytotoxic, antiplatelet and COX-2 inhibitory activity, was remarkable.