Synthesis,antiinflammatory, and analgesic activity of N-acylurea

Pharmaceutical Chemistry Journal -     

Synthesis,antiinflammatory and analgesic activity of new hexahydropyrimidine derivatives

A number of potentially active hexahydropyrimidine derivatives of pharmaceutical interest have been synthesized. Various diSchiff's bases prepared by reacting different aromatic aldehydes with 1,3-diaminopropane were suitably reduced to give their tetrahydro derivatives which were then condensed with appropriate aldehydes to give a series of hitherto unreported hexahydropyrimidines. The resulting products were evaluated by oral route for their antiinflammatory activity. The activity of compounds 11, 23 and 4 was excellent and comparable to indomethacin. In addition to oral route of administration, the antiinflammatory activity of hexahydropyrimidine derivatives was also studied topically through transdermal gels. Compounds 11, 23, 4 and 22 produced significant inhibition in edema and showed good antiinflammatory activity comparable to diclofenac sodium gel (Relaxyl gel). All these compounds were also tested for their analgesic activity and their LD50 determined. Compounds 11, 20 and 23 showed a comparable activity with aspirin. The MTD for all the compounds was found to be > 1800 mg/kg.     

Synthesis of carboxyalkylthio-triazoles and bicyclic derivatives with antiinflammatory and analgesic activity.

3-Carboxyalkylthio derivatives of 5-alkoxyphenyl-1,2,4-triazole were prepared, performing some substitutions both on carboxyalkyl chain, by lengthening it or introducing substituents with increasing molecular weight in alpha- at the carboxy group, and on N-4 atom in the triazole ring, by introducing an amino or methyl group, so that to vary steric conformation along with the lipophilicity of molecules. The corresponding bicyclic thiazolo-triazolone and triazolo-thiazinone derivatives, which represent the rigid models of carboxymethylthio- and carboxyethylthio- open structures, were also obtained. All the compounds show "in vivo" antiinflammatory activity, while only carboxyalkylthio derivatives of 4-amino- and 4-methyltriazole display an appreciable analgesic one. From the relief of some data on substituent present in the synthesized compounds, a structure-activity relationship is also suggested.     

Syntheses of N-substituted 2(3,4)-pyridylcarboxylic acid hydrazides with analgesic and antiinflammatory activity.

A group of N-substituted 2(3,4)-pyridylcarboxylic acid hydrazides were synthesized to investigate the effects that changes in functionality on the terminal hydrazide nitrogen have on analgesic and antiinflammatory activities. The most active analgesic-antiinflammatory compound was 1-(2-pyridylcarbonyl)-2-(2-pyridyl)hydrazine (10a), which was much more potent than dextropropoxyphene and caused a 100% inhibition of carrageenan-induced paw edema up to 5 h. Pyridylcarbonylhydrazides 5a, 8, and 10c exhibited analgesic activity similar to dextropropoxyphene. Although 10b was an inactive analgesic agent, it exhibited antiinflammatory activity similar to 10a.     

Synthesis and analgesic and antiinflammatory properties of new benzodiazepine derivatives

Several new N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides have been synthesized and characterized with respect to acute toxicity (LD₅₀), analgesic and antiinflammatory properties (formalin-and carrageenan-induced foot edema models), and interaction with morphine-induced antinociception in mice. The new compounds were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines followed by displacement of the benzotriazole ring with ammonia and cyclization of the resulting monoacyl aminals. The LD₅₀ of the synthesized compounds exceeds 1000 mg/kg. Three compounds produced significant analgesic action in doses 100–150 μg/kg in the early (painful) phase of the formalin test and potentiated the morphine-induced antinociception in this test. The synthesized drugs neither showed antinociception in the second (inflammatory) phase of the formalin test nor decreased the carrageenan-induced foot edema growth. Thus, the synthesized compounds produce analgesic action but do not possess antiinflammatory properties. The analgesic activity is probably due to the interaction with μ-and δ-opioid receptors. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 21–23, December, 2005.     

The analgesic and antiinflammatory activity and pharmacologic properties of bromfenac

Bromfenac sodium (2-amino-3-(4-bromobenzoyl)benzeneacetic acid sodium salt sesquihydrate, AHR-10282B) is a potent long-acting, peripheral, analgesic compound possessing antiinflammatory, antipyretic, and prostaglandin synthetase-inhibiting properties. In the acetylcholine abdominal constriction assay in mice, bromfenac (bromfenac sodium) by the oral route at pretreatment times of 10, 20 and 300 min was respectively 3.7, 6.5 and 2.9 times more potent than zomepirac and 3.4, 6.6., and 44.2 times more potent than suprofen. In dogs bromfenac when given orally was 5.8 times more potent than zomepirac in blocking the nociceptive response to bradykinin. Naloxone did not alter the analgesic properties of bromfenac in mice; and after repeated administration, tolerance to analgesia did not develop. Bromfenac, given orally, was more potent than indometacin in suppressing acute (7.5-20 times) and chronic (3.8 times) inflammation. The gastric and intestinal toxicity potencies of bromfenac, given orally, were comparable with and 1.8 times more potent than indometacin, respectively. Bromfenac was 6.1 to 32.8 times more potent than indometacin in inhibiting the formation of prostaglandin E2 and F2 alpha from microsomes of bovine seminal vesicles, rabbit uteri, and rabbit renal medullae; but it did not block the direct action of prostaglandin E1 (abdominal constriction) and prostaglandin F2 alpha (contraction of the uterus). Bromfenac produced no unwanted central nervous system, cardiovascular, or autonomic effects.     

Synthesis and analgesic activity of new tricyclic pyrazolo[3,4-b]pyridines

The title compounds have been obtained in a two-step synthesis from 5-amino-4-(1-cycloalkenyl)pyrazoles. Among the synthetized compounds, the 6,7,8,9-tetrahydro-1,3-dimethyl-3H-pyrazolo[3,4-c]isoquinoline, showed interesting antiinflammatory and analgesic activity.     

Synthesis,antiinflammatory, and analgesic activity of 1,6-disubstituted pipecolinic and 6-substituted picolinic acids

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 22, No. 4, pp. 428–431, April, 1988.     

Synthesis and pharmacological study of a series of 3(2H)-pyridazinones as analgesic and antiinflammatory agents

The synthesis and the pharmacological evaluation of some 3(2H)-pyridazinone derivatives are reported. The compounds were screened for analgesic, antiinflammatory and antipyretic activities. All tested derivatives showed a higher analgesic activity than phenylbutazone, while being devoid of ulcerogenic action.     

Synthesis and evaluation of the analgesic and antiinflammatory activities ofO-Substituted salicylamides

The present investigation deals with the synthesis of some new salicylamidoacetyl sulfonamides 3a,b, salicylamido ethylacetate 4, salicylamido acetic acid hydrazide 5, which is considered as the key intermediate for the synthesis of several series of new compounds such as salicylamido pyrazol 6 and pyrazolone 7. N-imido-derivatives 9, 10, 11, thiadiazole 13, oxadiazole 14, 15, Schiffs bases 16a-f. Cyclocondensation of Schiffs bases with thioglycolic acid gave thiazolidinone 18a-c while with acetylchloride afforded azitidinones 19a-c and with acetic anhydride gave 1,4-benzoxazepine-3,5-dione. Some of the compounds were tested for their analgesic and antiinflammatory activities as well as ulcerogenic effects. Some derivatives were more effective than salicylamide and ulcerogenic activity was variably lowered.     

Synthesis and antitumour activity of a series of cyclic amidines of 2,3-dihydro-1H-1,5-benzodiazepines

2,3-Dihydro-1H-1,5-benzodiazepine amidines were prepared by nucleophilic substitution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-thiones. Evaluation of the 13 synthesised amidines as antitumour agents was carried out in vitro against 60 human tumour cell lines at the National Cancer Institute, Bethesda, USA. The screening revealed a moderate cell growth inhibition of two derivatives on all cell lines at concentrations ranging from 10(-5) to 10(-4) mol/l. Log P values were theoretically calculated. The more active derivatives were found to exhibit a higher lipophilicity.