Absorption, distribution and metabolic fate of 2,3-dihydro-9H-isoxazolo-[3,2-b]quinazolin-9-one (W2429).

After oral administration to rats, mice, beagle dogs and human volunteers, 2,3-dihydro-9H-isoxazolo [3,2-b]-quinazolin-9-one (W 2429) is readily absorbed. The initial half-lives for the elimination from the circulation of these four species are about 240, 20, 40 and 120 min, respectively. Studies in the rat, using 9-14C-W-2429 and 3a-14C-W-2429, showed that more than half of the radioactivity is excreted in the urine. The major urinary metabolite in the rat and dog is a conjugated form of W-2429. Metabolic cleavage of the pyrimidone ring of W-2429 yields 3-(o-carboxyphenylimino)isoxazolidine, which in turn is converted to anthranilic and malonic acids. Anthranilic acid is acetylated and hydroxylated, and these products are excreted partly in the form of their glycine and glucuronic acid conjugates. The isoxazole ring of W-2429 is also dehydrogenated during metabolism to yield 9H-isoxanzolo-[3,2-b]quinazolin-9-one.     

Toxicological investigation of 2,3-dihydro-9H-isoxazolo[3,2-b]quinazolin-9-one (W-2429). Acute and subacute toxicity in mice, rats and dogs.

The acute and subactue toxicity of 2,3-dihydro-9H-isoxazolo[3,2-b]quinazolin-9-one (W-2429), a non-narcotic analgesic agent, was investigated in mice, rats and dogs. The subacute toxicity study was conducted by repeated oral administration of the compound for 30 days. Treatment with W-2429 was well tolerated by rats as well as dogs. In the dog, the only signs of toxicity observed were decreased appetite and salivation at 100 mg/kg/day. No other significant evidence of physical, chemical, gross or histopathologic change was observed.     

Synthesis and anti-inflammatory activity of 3,3a-dihydro-2H,9H-isoxazolo [3,2-b] [1,3]benzoxazin-9-ones and related compounds.

A series of 3,3a-dihydro-2H,9H-isoxazolo[3,2-b]-[1,3]benzoxazin-9-ones was synthesized and evaluated for anti-inflammatory, antipyretic and analgesic activity. Since many of these compounds exhibited promising activity, particularly in the anti-inflammatory tests, a number of homologous 2,3,4,4a-tetrahydro-10H-1,2-oxazino[3,2-b]-[1,3]benzoxazin-10-ones and one 3,4,5,5a-tetrahydro-2H, 11H,-1,2-oxazepino [3,2-b][1,3]benzoxazin-11-one, the 9-chloro analog, were also prepared and evaluated. The expanded ring members were generally less active than the tricyclic compounds containing the isoxazolidine ring.     

Synthesis of 5-Aryl-12H-quinazolino[3,2-a]quinazolin-12-ones as Antiinflammatory Agents

Condensation of 4-aryl-2-chloroquinazolines with anthranilic acids leads to 5-aryl-12H-quinazolino[3,2-a]quinazolin-12-ones. Their mass-spectral fragmentations were studied. Some of these compounds were tested for analgesic and antiinflammatory activities.     

3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与乙酰胆碱酯酶抑制活性

目的初步探讨在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-3位苯环侧链中引入二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及其乙酰胆碱酯酶抑制活性。方法以取代的苯甲醛和乙酰甘氨酸为初始原料,经Erlenmeyer-Plchl反应、缩合反应、水解反应、缩合反应,生成6-芳甲基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮反应,得到6-芳甲基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物;以芳基乙烯为原料,经温和的氧化反应、缩合反应得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮类化合物,再与取代的α-氯代苯乙酮在乙酸中反应得到6-芳基-3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。两条合成路线得到的3-(羟基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物进一步经Williamson反应制备得到10个3-(烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。所有目标化合物结构均经质谱、红外光谱和核磁共振氢谱确证。采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选。结果根据前期已筛选化合物的活性数据和总结出的初步构效关系,设计并合成了10个C-3位苯环侧链中含有二乙胺基团的3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。体外乙酰胆碱酯酶抑制活性筛选表明,所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中7个化合物在10μmol.L-1浓度水平抑制活性超过了50%。结论根据体外重组人源AChE(rhAChE)抑制活性的测试结果,发现C-3位苯环侧链中含有二乙胺基团的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物均具有较好的rh-AChE抑制活性。在这一位置的侧链中引入二乙胺基团,可以增强化合物对rhAChE的抑制活性。     

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a]pyrimidone-(6) aus 2-Acetoacetylamino-imidazo[2,1-b]-1,3,4-thiadiazolen

Imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones by Cyclisation of 2-(Acetoacetylamino)-imidazo[2,1-b]-1,3,4-thiadiazoles The 2-acetoacetylamino-6-methyl- (or -aryl) imidazo[2,1-b]-1,3,4-thiadiazoles 1, 2a–f cyclise on heating in polyphosphoric acid (PPA) to yield the tricyclic 2,8-dimethyl- or 2-aryl-8-methyl-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-α]pyrimidin-6-ones 3, 4a–f . Only 4c inhibits the growth of vaccinia viruses. The other compounds have no antiviral activity.     

Synthesis of some 1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones with potential analgesic and antiinflammatory activities

Starting from 3-substituted-1,2,4-triazole-5-thiones (la-h), eight new 5-carbomethoxy-2-substituted-7H-1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones (2a-h) were synthesized and characterized by spectral and elementary analysis. The obtained compounds were submitted to preliminary pharmacological assay to evaluate their antiinflammatory and analgesic activities as well as gastrointestinal irritation liability and acute toxicity. Among the compounds studied, compounds 2c, 2d, 2e and 2h showed most remarkable antiinflammatory activity in the carrageenan and serotonin induced edema and in the inhibition of castor oil-induced diarrhea tests. The analgesic activity of these active compounds correlated with their antiinflammatory activities in the inhibition of acetic acid-induced writhing test. In gastric ulceration studies, the compounds were found safety at low dose levels (10 and 20 mg/kg).     

Design and synthesis of some new thiazolo [3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen as anti-inflammatory and analgesic agents

In the course of our ongoing studies, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen (CAS 5104-49-4) has been prepared. The compounds were synthesized by the cyclization of the 3-[(2-fluoro-4-biphenyl)ethyl]-5-mercapto-1,2,4-triazole (3) with chloroacetic acid and relevant benzaldehydes in the presence of acetic acid, acetic anhydride and anhydrous sodium acetate in one step. The product of this one-pot synthesis that precipitated on cooling of the reaction mixture was identified undoubtedly by X-ray crystallographic analysis as thiazolo[3,2-b]-1,2,4-triazole. In-vivo anti-inflammatory and analgesic activities of the compounds were assessed by carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic risks were evaluated. It is worthy of saying that the compounds which maintained analgesic/antiinflammatory activity of the starting compound were found to be safer with regard to gastric lesion risks at 100 mg/kg oral dose when compared with flurbiprofen. Among the synthesized compounds 3d showed the highest analgesic and antiinflammatory activity without inducing any gastric lesion and deserves further attention in order to develop new lead drug candidates.     

乙酰胆碱酯酶抑制剂3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性

目的 初步探讨乙酰胆碱酯酶(AChE)抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的合成及构效关系.方法 利用分子对接技术设计一些新的7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,采用化学方法合成这些目标化合物,采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选.首先由...     

Synthesis and biological evaluation of some 10-substituted 2,3-dihydroimidazo[2,1-b]quinazolin-5(10H)-ones, a new class of bronchodilators.

On treatment of N-substituted isatoic anhydrides with 2-methylmercaptoimidazolines, 10-substituted imidazo[2,1-b]quinazolin-5(10H)-ones are obtained. Several members of this class exhibited pronounced broncholytic activity. The structure-activity relationships (based on results obtained in the guinea pig histamine aerosol test) of these nonsympathomimetic bronchodilators are discussed. In addition, the detailed pharmacological evaluation of two analogs found to be five to ten times more active than theophyline as bronchodilators without having central nervous system or cardiovascular side effects is described.     

Synthesis and evaluation of anti-inflammatory activity of some thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones and their Michael addition products

Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (4-10) were obtained in a one step synthesis by heating 3-aryl-5-mercapto-1,2,4-triazoles (3a-d) with chloroacetic acid and appropriate aromatic aldehyde in acetic acid and acetic anhydride in the presence of anhydrous NaOAc. Michael type addition of cyclic secondary amines (N-methylpiperazine, piperidine) to 4-10 gave 2-phenyl-6-(alpha-aminoarylmethyl)thiazolo[3,2-b]-1,2,4-triazole-5 -ols (4a-10b). The structures of the compounds were confirmed by spectral and elementary analysis. The compounds synthesized in previous and present studies were investigated for their anti-inflammatory activities.     

New isomeric classes of topically active ocular hypotensive carbonic anhydrase inhibitors: 5-substituted thieno[2,3-b]thiophene-2-sulfonamides and 5-substituted thieno[3,2-b]thiophene-2-sulfonamides

A series of 5-substituted thieno[2,3-b]- and thieno[3,2-b)- and thieno[3,2-b)thiophene-2-sulfonamides was prepared and evaluated for topical ocular hypotensive activity in glaucoma models. The 5-substituents were varied to maximize both inhibitory potency against carbonic anhydrase and water solubility. At the same time, these substituents were varied in order to obtain compounds with the appropriate pKa to minimize pigment binding in the iris. All of these variables were optimized in the best compound, 5-[[(methoxyethyl)[(methoxyethyl)ethyl] amino]methyl]thieno[2,3-b]thiophene-2-sulfonamide hydrochloride (55).     

Synthesis and anticonvulsant activity of pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d] pyrimidine derivatives and pyrimido[5′,4′:2,3]-thieno[2,3-c]isoquinoline derivatives

Methods for the synthesis of condensed thieno[3,2-d]pyrimidines based on pyrano[4,3-d]thieno[2,3-b]pyridines and thieno[2,3-b]isoquinolines have been developed and a series of new derivatives have been synthesized. The anticonvulsant activity of the synthesized compounds has been studied. Several compounds possessing specific anticonvulsant activity with respect to corazole-induced convulsions are revealed. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 9, pp. 14–16, September, 2007.     

Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones.

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.     

Cyclic guanidines. 17. Novel (N-substituted amino)imidazo[2,1-b]quinazolin-2 ones: water-soluble platelet aggregation inhibitors

A series of novel 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one derivatives substituted with a secondary amino group has been prepared and tested for the activities of inhibiting platelet aggregation in rats in vitro and ex vivo. Most of the compounds were found to be the potent inhibitors of platelet aggregation. Some of the active compounds were soluble in water and effective via iv infusion in rats. Structure-activity relationships have indicated that a lipophilic secondary amino group located at position 6 or 7 contributed to retention of potent activity. Among the compounds studied, 7-piperidino-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2- one (13 g,DN-9693) was the most favorable compound.     

Synthesis of new thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives as potent analgesic and anti-inflammatory agents

A series of thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones were synthesized and evaluated for their analgesic and anti-inflammatory activities. The structures of these compounds were supported by FT-IR, ¹HNMR, and Mass spectra. All of the final compounds showed potent analgesic activity and the best compound 9d was 2.4 times more potent than mefenamic acid as the reference drug. In addition, most of them showed comparable or better anti-inflammatory activity in comparison with mefenamic acid and indomethacin. Moreover, compounds 9d, 9e, 9g, 9h, 9i, 9k, 9n, and 9o did not exhibit any significant ulcerogenic activity.     

4-Cyclohexyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones: novel class of H1-antihistaminic agents

A series of novel 1-substituted-4-cyclohexyl-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones were synthesized by the cyclization of 3-cyclohexyl-2-hydrazino-3H-quinazolin-4-one with various one carbon donors. When tested for their in vivo H1-antihistaminic activity on guinea-pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. The compound 4-cyclohexyl-1-methyl-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.96% protection) when compared to the reference standard chlorpheniramine maleate (71.00% protection). The compound II shows negligible sedation (9%) when compared to chlorpheniramine maleate (30%). Hence, it could serve as prototype molecule for further development as a new class of H1-antihistamines.     

Structure-activity studies of 4,6-disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives with analgesic and antiinflammatory activities

4,6-Disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives showed analgesic and antiinflammatory activities when assayed by the acetic acid writhing test in mice and the carrageenin edema test in rats. To understand how the substituents affect the biological activities, the quantitative structure-activity relationships (QSAR) of 38 compounds were analyzed using the adaptive least-squares method (ALS method). The resulting QSAR suggested that some chemical modifications of 4,6-disubstituted furo[3,2-b]indole derivatives would improve their biological activities. Thus, 15 additional compounds were synthesized to reinforce and confirm the correlation. Among these compounds, particularly 4-(2-ethylhexanoyl)-2-(morpholinocarbonyl)-6-(trifluoromethy l) furo[3,2-b]indole showed pronounced biological activities. This compound gave a pharmacological activity spectrum similar to that of tiaramide but exhibited much higher potency.     

2H,5H-[1]benzothiopyrano [4,3-b]pyran derivatives with platelet antiaggregating activity

The synthesis of some N,N-disubstituted 4-amino-3-phenyl-2H,5H-[1]benzothiopyrano [4,3-b]pyran-2-ones by reaction of phenylchloroketene with a series of N,N-disubstituted 3-aminomethylene-2,3-dihydro-4H-1-benzothiopyran-4-ones, followed by dehydrochlorination of the primary adducts with DBN, is described. Some of these compounds showed a strong platelet antiaggregating activity in vitro, superior to that of acetylsalicylic acid.     

Synthesis, characterization and antiinflammatory-analgesic properties of 6-(alpha-amino-4-chlorobenzyl)thiazolo [3,2-b]-1,2,4-triazol-5-ols

A series of 6-(alpha-amino-4-chlorobenzyl)-thiazolo[3,2-b]-1,2,4-triazol-5-ols (2a-j) were synthesized from 6-(4-chlorobenzylidene) thiazolo[3,2-b]-1,2,4-triazolo-5(6H)-one (2) by applying Michael addition reaction. All the compounds were characterized by their melting points, elementary analysis, IR and 1H-NMR spectra and screened for their anti-inflammatory and analgesic activities. Among the derivatives compound 2i bearing 4-(4-acetylphenyl)piperazine showed the highest and dose-dependent analgesic and anti-inflammatory activity without inducing any gastric lesion.