Synthesis and analgesic and anti-inflammatory activity of some new (6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid residues

In this study for developing potent analgesic and anti-inflammatory compounds, we synthesized 6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid side chain, and performed preliminary screening of their in vivo analgesic and anti-inflammatory activities at a single dose of 100 mg/kg inmice by a p-benzoquinone-induced writhing test and a Carrageenaninduced hind paw edema model, respectively. We also determined their gastric ulceration effects in the tested animals. Propanoic acid derivatives were generally found to have higher analgesic and anti-inflammatory activities, and among them, 3-(6-benzoyl-2-benzothiazolinon-3-yl)propanoic acid (Compound 4 a) exhibited the highest analgesic and anti-inflammatory activity. However, all compounds showed lower anti-inflammatory effects than we observed for indomethacin at 10 mg/kg dose. Consequently, 6-acyl-2-benzoxazolinone/2-benzothiazolinones having propanoic acid side chain might lead to further studies for developing better candidates with potent analgesic and anti-inflammatory effects while acetic acid derivatives do not exhibit comparable satisfactory features.     

Anti-inflammatory and anti-ulcer properties of hypolaetin-8-glucoside, a novel plant flavonoid

The anti-inflammatory, analgesic and anti-ulcer activities of a novel flavonoid, hypolaetin-8-glucoside, obtained from Sideritis mugronensis, have been tested in the rat. The flavonoid was more potent than phenylbutazone in suppressing the acute phase of adjuvant-carrageenan-induced inflammation, but had less effect in the prolonged inflammatory phase. However, unlike phenylbutazone, it did not cause gastric erosions. Both compounds were equiactive in inhibiting the development of carrageenan-induced abscesses, whereas phenylbutazone had greater analgesic activity in tests on pressure pain threshold. The flavonoid and cimetidine both prevented the formation of cold-restraint induced gastric lesions, but cimetidine was more potent. These results show that hypolaetin-8-glucoside combines both anti-inflammatory and anti-ulcer properties and suggest that it may offer useful alternatives to anti-inflammatory drugs of the aspirin type.     

Comparative studies on the amino acid derivatives of indometacin

A series of amino acid derivatives of indometacin (IND) was investigated in regard to their protein binding and prostaglandin synthetase inhibition in vitro, and to acute toxicity, anti-inflammatory, antiedemic, analgesic actions, and the influence on the central nervous system in vivo. In biochemical tests the compounds were several times less potent than IND. They differed among themselves in the respect of toxicity, which was always much lower than that of IND. Out of eight compounds investigated N-IND-glycine (K1) and N-IND-epsilon-aminocaproic acid (K5) exerted more favorable antiedemic and analgesic action than IND did. Both the derivatives only weakly inhibited the cotton-pellet granuloma formation. K1 acted similarly to IND in the arthritis test. K1, K5 and IND similarly irritated the gastric mucosa. A modification of IND structure by introduction of glycine or epsilon-aminocaproic acid resulted in two new anti-inflammatory agents of more favorable therapeutic index in the antiedemic and analgesic action and of much lower toxicity than the reference compound.     

Synthesis of new Mannich bases of arylpyridazinones as analgesic and anti-inflammatory agents

A series of 2-[[4-(substituted-phenyl/ benzyl)-1-piperazinyllmethyl]-6-(4-methoxyphenyl)-3(2H)pyridazinone derivatives was prepared and examined for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and 1H-NMR spectra and elementary analysis. Among the compounds prepared, 2-[[4-(4-fluorophenyl)-1-piperazinyl]methyl]-6-(4-methoxyphenyl)-3(2H)pyridazinone IVe was found to be a most promising analgesic and anti-inflammatory agent. Compound IVe showed more potent analgesic activity than acetylsalicyclic acid in the phenylbenzoquinone-induced writhing test. Also IVe showed anti-inflammatory activity comparable to that of the standard compound indometacin against the carrageenan-induced paw edema. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed a gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. On the basis of the available data, the structure-activity relationship of the series of 2-[[4-(substituted-phenyl/benzyl)-1-piperazinyl]methyl]-6-(4-methoxyphenyl)-3(2H) pyridazinones is also discussed.     

The modes of anti-inflammatory and analgesic actions of 2-[4-(3-methyl-2-butenyl) phenyl] propionic acid (TA-60) and 2-[4-(2,2-dichlorovinyl) phenyl] propionic acid (TA-668) and effect of TA-60 on the gastrointestinal tract

TA-668 and TA-60, potent anti-inflammatory compounds, showed no inhibition against the dextran-, the serotonin- and the carrageenin + prostaglandin E2 (PGE2)-induced hind paw edemas in rats and neither did typical acidic non-steroidal anti-inflammatory drugs (ANSAIDs) such as indomethacin. On the other hand, salicylic acid, mepirizole and tiaramide X HCl inhibited the hind paw edema induced by carrageenin + PGE2 in rats. TA-668 and TA-60 as well as other ANSAIDs inhibited the arachidonic acid (AA)-induced erythema, but did not inhibit the PGE2-induced erythema. Mepirizole and tiaramide X HCl showed no inhibition against both the AA- and the PGE2-induced erythemas. TA-668 and TA-60 showed analgesic activities in the adjuvant-induced hind paw edematous rats. The analgesic activities of these compounds disappeared when PGE2 was injected into the inflamed paw as well as indomethacin and ibuprofen. It is concluded that anti-inflammatory and analgesic activities of both TA-668 and TA-60 were based on the inhibition of cyclo-oxygenase. TA-60 showed a protective effect against gastric necrosis induced by necrotizing agents such as HCl, NaOH or NaOH + EtOH. TA-60 showed about a 4 times less potent activity than ibuprofen in delay of occurring time of castor oil-induced diarrhea in rats. These results suggest that the slight ulcerating effect of TA-60 on the gastrointestinal tract might be attributed to its gastric protective effect and slight decreasing effect on the gastrointestinal level of PGE2.     

Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and anti-inflammatory agents

In this study, a series of (7-acyl-5-chloro-2-oxo-3H-benzoxazol-3-yl)alkanoic acid derivatives were synthesized and evaluated for their analgesic and anti-inflammatory activities by using the p-benzoquinone-induced writhing test and the carrageenan hind paw edema model, respectively. Acetic acid-induced peritoneal capillary permeability test and serotonin-induced hind paw edema test were also employed for the most active compounds. The test results indicated that (7-acyl-2-oxo-3H-benzoxazol-3-yl)alkanoic acids (Compounds 6 a-c, 8 a-c, 10 a-c) were equally or more potent analgesic and anti-inflammatory agents than aspirin and indomethacin respectively. The compounds 8a and 8c, but not 8b have the longest carbon chain on alkanoic acid moiety did not induce gastric lesion in mice.     

Amide derivatives of [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, we have explored the prevention of gastric side effects such as gastric lesions and bleeding while maintaining the high analgesic and anti-inflammatory activities by the derivatization of the carboxylate moiety into amides in [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids. We have tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Compounds 3a, 3d, 3e, 3j and 3k potent analgesic and anti-inflammatory activities without gastric lesions in the tested animals. Therefore, conversion of the carboxylate moiety into certain amide derivatives generated potent analgesic and anti-inflammatory compounds while eliminating the gastrointestinal side effects. Cyclooxygenase (COX)-selectivity of the active compounds was also investigated by using in vitro human whole blood assay. Compounds 3a, 3e, 3h and 3k selective inhibition of COX-2 to some extent although the inhibitory activity was not very potent.     

Synthesis and anti-inflammatory and analgesic activities of 2,4-di-n-butyl-3,5-diarylimino-1,2,4-thiadiazolidines

Ten 1,2,4-thiadiazolidines were synthesized and screened for their anti-inflammatory and analgesic activities. Butyl isothiocyanate was used as a starting material. Several compounds showed significant anti-inflammatory and analgesic activities. The unsubstituted and o-methyl, p-acetoxy and o-chloro substituted compounds were found to be more potent anti-inflammatory and analgesic agents than the other compounds.     

Synthesis of some floctafenine derivatives of expected anti-inflammatory/analgesic activity

New derivatives related to floctafenine were synthesized and representative examples were screened for their anti-inflammatory and analgesic activities. All compounds tested were found to exhibit anti-inflammatory and analgesic activities and some were more potent than the references, floctafenine and indomethacin, in carragenan-induced rat's paw edema. None of the tested compounds showed an ulcerogenic effect on the p-benzoquinone-induced writhing test in mice.     

Amide derivatives of [6-(5-methyl-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, amide derivatives of [6-(5-methyl-3-phenyl-pyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were synthesized and tested for their in vivo analgesic and anti-inflammatory activity by using the p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a, 6d, 6e, 6g, 6h and 6m were more potent than that of aspirin as an analgesic and indomethacin as an anti-inflammatory drug, respectively. The other derivatives generally resulted in comparable activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro human whole blood assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and other mechanisms might be involved.     

Design and synthesis of certain mesoionic sydnonyl styrylketones as potential nonsteroidal antiinflammatory agents

In an attempt to develop effective and safer analgesic anti-inflammatory agents, nine compounds belonging to 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(4-methoxyphenyl) sydnones, containing the structural features of mesoionic sydnone and styrylketone, have been designed and synthesized by condensing 4-acetyl-3-(4-methoxyphenyl) sydnone with various substituted aryl aldehydes and characterized by spectral studies. They have been tested for analgesic activity by acetic acid induced writhing in mice and for anti-inflammatory activity by carrageenan induced rat paw edema at 100 mg/kg body weight p.o. The compounds containing furyl and chloro substituents showed highly significant analgesic effect, while those with dimethylamino, chloro and nitro substituents exhibited highly significant anti-inflammatory effect at the end of 3 h. The compounds that showed good analgesic and anti-inflammatory activities were evaluated for ulcerogenicity in rats to assess their gastric side effects at 100 mg/kg body weight p.o. They were found to be less ulcerogenic than the standard drug.     

Synthesis of amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl] acetic acid and their analgesic and anti-inflammatory properties

A series of structurally different amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were prepared and tested for their analgesic and anti-inflammatory activity in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a and 6b were equipotent, and 6m was more potent than acetyl salicylic acid (CAS 50-78-2) as an analgesic and indometacin (CAS 53-86-1) as an anti-inflammatory drug, respectively. The other amide derivatives and parent carboxylic acid molecule generally resulted in lower activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro COX inhibitor screening assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and that other mechanisms might be involved.     

吡里酮二甲醇酯类化合物的合成及其抗炎镇痛活性

目的为探讨吡里酮类化合物抗炎镇痛作用的构效关系,设计合成了吡里酮二甲醇的单酯和二酯类化合物,并进行抗炎及镇痛活性试验.方法采用羟醛缩合反应和酯化反应合成目标化合物,以小鼠耳肿胀法和醋酸扭体法分别测定目标化合物的抗炎和镇痛活性.结果与结论合成得到了10个目标化合物(均未见文献报道),其结构经IR、1H-NMR、MS确定.药理实验表明,目标化合物均具有一定的抗炎或镇痛作用.     

Synthesis and analgesic and anti-inflammatory activity of ethyl (6-substituted-3 (2H)-pyridazinone-2-yl)acetate derivatives

A number of 6-substituted-3(2H)-pyridazinones and the corresponding methyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives carrying the arylpiperazinyl structure present in potent antinociceptive agents reported in the literature were synthesized. As part of a programme a series of diverse arylpiperazine derivatives of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference non-steroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship in the series of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives was also discussed. When compared to parent 6-substituted-3(2H)-pyridazinones, the new ester derivatives, for example ethyl (6-4-[(2-fluoro)phenyl]piperazine-3(2H)-pyridazinone-2-yl)acetate exhibited better analgesic and anti-inflammatory activity and a lower ulcerogenic effect.     

Synthesis and evaluation of novel prodrugs of naproxen

A series of novel prodrugs of naproxen has been synthesized. Naproxen (1) was reacted with thionyl chloride to yield acid chloride (2) which was further reacted with glucose to form the glucosyl naproxen (3). Tetra-acetate of glucosyl naproxen was prepared and finally reacted with different amino acids to yield the title compounds. These compounds were evaluated for analgesic, anti-inflammatory activities, and for possible GI toxicity. Compound 5b depicted most potent analgesic activity with percentage inhibition of 98.15%. Compound 5a was found to be most potent anti-inflammatory agent with 76% inhibition. Compound 5n was second most active analgesic (92.26%) and anti-inflammatory (73%) agent. In vitro hydrolysis pattern of synthesized prodrugs was studied in phosphate buffer of pH 7.4 and acetate buffers of pH 3.0, 4.0, and 5.0, respectively. Selected compounds were evaluated for their ulcerogenic potential and all the tested derivatives were significantly less irritating to gastric mucosa than the parent drug.     

Synthesis and analgesic and antiinflammatory activity of methyl 6-substituted-3(2h)-pyridazinone-2-ylacetate derivatives

A series of methyl 6-substituted-3(2H)-pyridazinone-2-ylacetates 9 were synthesized and their analgesic and anti-inflammatory effects were evaluated in the phenylbenzoquinone-induced writhing test (PBQ test) and carrageenan-induced paw edema method, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. Methyl 6-(4-(4-fluorophenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9e was found to be more active than acetylsalicylic acid (ASA). Methyl 6-(4-(2-ethoxyphenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9c has shown an anti-inflammatory activity as compared to the standard compound indometacin at the carrageenan-induced paw edema method.A significant dependence of the anti-inflammatory effect on the substituents has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at the position 6 of the 3(2H)-pyridazinone system influences analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and (1)H-NMR spectra and elemental analysis.     

Pharmacological investigations of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M 73101), a new analgesic and anti-inflammatory drug

Analgesic, anti-inflammatory and other related actions of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101) were investigated in experimental animals, and the following results were obtained: Analgesic activity of M73101 was more potent than that of other anti-inflammatory drugs except for aminopyrine in phenylquinone test in mice. M73101 showed the most potent analgesic activity among the drugs tested in Randall-Selitto test in rats. The mode of analgesic action of M73101 resembled that of aminopyrine. M73101 possessed potent inhibitory activities on acute inflammatory edema and suppressed the permeability of capillary vessels. M73101 inhibited histamine release from isolated rat mast cells (in vitro) and rat skin (in vivo) by the condensation product of N-methyl-homoanisylamine formaldehyde (compound 48/80), and leucocyte emigration in carrageenin rat pleurisy. M73101 was much less active than phenylbutazone and other anti-inflammatory drugs in causing gastric lesion. Considering from therapeutic index, M73101 was found to be much superior to mepirizole, tiaramide, benzydamine, phenylbutazone and acetylsalicylic acid.     

Pharmacological studies of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101). (2). Anti-inflammatory activity (author's transl)]

The anti-inflammatory activity and the mode of action of M73101, a new non-steroid analgesic anti-inflammatory agent, were investigated in experimental animals and compared with those of reference drugs. M73101 inhibited the increase in vascular permeability induced by acetic acid and its activity was more potent than that of phenylbutazone. M73101 showed a marked inhibitory effect against rat paw edema induced by various phlogistic agents (carrageenin, dextran, histamine, serotonin and bradykinin) and the activities were equal to or more potent than those of aminopyrine, mepirizole and tiaramide HCl. M73101 also inhibited the edema induced by mustard, scalding and anti-rat rabbit serum in rats. In addition, the anti-edematous effect of M73101 on carrageenin-induced rat paw edema was not influenced by spinalectomy or adrenalectomy, indicating that the anti-inflammatory action of M73101 was not mediated by the central nervous system and the adrenals. Local and oral administration of M73101 inhibited significantly the leucocyte migration into the fluid of CMC pouch in rats and the activity was more potent than phenylbutazone, suggesting that the anti-inflammatory effect of M73101 was due to the direct action at the inflamed site. On the other hand, M73101 did not show any marked activities on the experimental chronic inflammatory models. From these results, it is suggested that M73101 may be useful for clinical application as a basic analgesic, anti-inflammatory drug with remarkable anti-inflammatory activity in acute and subacute cases. The mechanism of the anti-inflammatory action of M73101 probably involves inhibition of an increase in vascular permeability and leucocyte migration.     

水杨酸-g-壳聚糖衍生物的合成及药效研究

制备水杨酸-g-壳聚糖载体衍生物，观察两者在药效上的协同和互补作用。通过二甲苯致小鼠耳肿胀实验观察水杨酸与壳聚糖抗炎的协同作用；通过小鼠扭体实验和热板痛实验观察衍生物的镇痛作用；通过胃黏膜形态学变化评价壳聚糖与水杨酸的互补作用。实验结果表明，水杨酸-g-壳聚糖衍生物外用抗炎作用优于水杨酸、壳聚糖和皮炎平，内服优于阿司匹林；即时镇痛作用低于阿司匹林，长效镇痛作用与阿司匹林相近；对胃黏膜的刺激性远远低于阿司匹林；水杨酸-g-壳聚糖衍生物具有抗炎协同作用和药效互补作用。     

Synthesis and anti-inflammatory activity of novel pyridazine and pyridazinone derivatives as non-ulcerogenic agents

Herein, we report the synthesis and pharmacological properties of several series of pyridazine and pyridazinone derivatives. All the synthesized compounds were tested, in vivo, for their anti-inflammatory and ulcerogenic properties against indomethacin, as a reference compound. Compounds 4a and 9d have shown a potent anti-inflammatory activity more than indomethacin with rapid onset of action and safe gastric profile. The latter compounds were then selected for further investigation. In the MTT assay in vitro, both compounds were identified as potent and selective COX-2 inhibitors.