4394-00-7Relevant articles and documents
1,2-dihydro-3,1-benzoxazin-4-one and 4-H-1,2-dihydro-pyrido-[2,3-d]-[1,3]-oxazin-4-one derivatives as potential prodrugs. Part II: Hydrolysis
Schwenker,Chen
, p. 887 - 890 (1991)
-
Design and synthesis of niflumic acid-based N-acylhydrazone derivatives as novel anti-inflammatory and analgesic agents
Kheradmand, Amin,Navidpour, Latifeh,Shafaroodi, Hamed,Saeedi-Motahar, Ghazaleh,Shafiee, Abbas
, p. 2411 - 2420 (2013/07/26)
A new series of niflumic acid-based N-acylhydrazone derivatives 5a-p were synthesized and evaluated for their anti-inflammatory and analgesic activities. Most of the compounds have shown anti-inflammatory activity with a moderate-to-excellent activity range (20-80 % reduction in inflammation). Among them, 3-chlorophenyl 5d and 3-pyridyl derivatives 5o exhibited the most potent anti-inflammatory activity relative to niflumic acid as the reference drug (77, 76, and 70 % reduction in inflammation at 1-h postdrug administration, respectively). Also, molecular simplification of niflumic acid through replacing the N-aryl group with N-methyl group produced compounds 6a-f with anti-inflammatory activity in a quite similar manner to those of their parent derivatives. In this subgroup, 4-pyridyl derivative 6f showed the most potent anti-inflammatory activity relative to niflumic acid (80 % reduction in inflammation at 1-h postdrug administration). The compounds with highest anti-inflammatory activity were subjected to analgesic assays and showed moderate-to-excellent analgesic activities. The compound 5j, 4-methoxy derivative, exhibited the highest analgesic activity relative to niflumic acid (97 and 68 % activity, respectively).
Synthesis, stability studies, anti-inflammatory activity and ulcerogenicity of morpholinoalkyl ester prodrugs of niflumic acid
Talath, Sirajunisa,Gadad, Andanappa K.
, p. 744 - 752 (2007/10/03)
In search for potential prodrugs for anti-inflammatory drug candidates in the niflumate series, novel morpholinoalkyl ester prodrugs of niflumic acid (CAS 4394-00-7) 5a-b were prepared by esterification of appropriate morpholinylalkyl alcohols 3a-b with niflumic acid 4 in the presence of dicyclohexyl carbodiimide (DCC) and catalyst dimethylamino pyridine (DMAP) at 0-5°C. The structures were confirmed by elemental and spectral data (UV, IR, 1H-NMR, 13C-NMR, and EI-MS). The ester prodrugs 5a-b showed better solubility than the parent drug niflumic acid 4 in simulated gastric fluid (SGF) and phosphate buffer (pH 7.4). The in vitro hydrolysis studies were conducted at pH 1.3 (SGF), phosphate buffer (pH 7.4) and in human plasma diluted with phosphate buffer (pH 7.4) at 37 ± 0.5°C using HPLC with UV detection. The ester prodrugs 5a-b were quantitatively hydrolyzed to the parent drug niflumic acid 4 by enzymatic and/or chemical means. It is observed that an increase in the carbon chain length rendered the prodrugs 5a-b more stable in phosphate buffer (pH 7.4) than in pH 1.3 (SGF), but they were rapidly hydrolyzed in human plasma at 37 ± 0.5°C. They exhibited longer hydrolytic half-lives of 16.11-53.30 h in aqueous buffer solutions (pH 1.3 and 7.4) and 1.63-2.73 min in human plasma, respectively. The title compounds were evaluated in vivo for anti-inflammatory activity in carrageenan induced rat paw oedema model in rats at the doses 45, 90, 150 mg/kg b.w. The test compounds exhibited good anti-inflammatory activity (46.6-53.2 % at the dose of 150 mg/kg b. w.) with respect to niflumic acid (78.7 % at the dose of 90 mg/kg b.w.). The compounds were also screened for in vivo ulcerogenicity, it was observed that the prodrug 5b was significantly less irritating to gastric mucosa than compound 5a and the parent drug niflumic acid 4 following single and chronic oral administration in rats. ECV. Editio Cantor Verlag.
