Synthesis and anti-inflammatory activities of some thiazolo[3,2-a]pyrimidine derivatives.

Sixteen new 2-benzylidene-7-methyl-3-oxo-5-(substituted phenyl)-2, 3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl esters (1a-4d) have been synthesized by reacting 1,2,3,4-tetrahydropyrimidine-2-thiones (1-4) with chloroacetic acid and appropriate benzaldehydes in a single step. Their structures have been proved by IR, 1H NMR, mass spectra and elemental analysis. The compounds were tested for their anti-inflammatory activities. Test results revealed that compounds 1b, 1c, 4a and 4c exerted moderate anti-inflammatory activity at the 100 mg/kg dose level compared with indomethacin.     

Inhibitory effect of novel pyrimidines on ATP and ADP hydrolysis in synaptosomes from rat cerebral cortex

In this study, a new series of trihalomethyl-substituted pyrimidines and dihydropyrimidines were synthesized and tested as potential NTPDase inhibitors. For this purpose, synaptosomes from rat cerebral cortex were used as the enzyme source and ATP and ADP were used as the substrate. Among the new compounds, 4-methyl-2-methylsulfanyl-6-trichloromethylpyrimidine (2b) was found to be the most effective noncompetitive inhibitor, with an estimated K(i) value of 0.18 and 0.55 mM for ATP and ADP, respectively. Other pyrimidines inhibited NTPDase activity with the following rank order of inhibitory potency: 3,6-dimethyl-2-methylsulfanyl-4-trifluoromethyl-3,4-dihydro-pyrimidin-4-ol (3a) > 5-methyl-2-(4-methyl-6-trifluoromethyl-pyrimidin-2-yl)-3-trifluoromethyl-3,4-dihydro-2H-3-pyrazol-3-ol (6a) > 5-bromo-4,6-dimethoxy-4-trichloromethyl-1,2,3,4-tetrahydro-2-pyrimidin-2-one (9) for ATP and 6a > 9 > 3a for ADP. Our results demonstrate that a novel group of pyrimidines compounds can act as inhibitors of ATP and ADP hydrolysis in synaptosomes from rat cerebral cortex. These results can contribute for the understanding of the NTPDase activity and for further studies involving new compounds that can enlist as it inhibitors.     

Synthesis and pharmacological evaluation of newer thiazolo [3,2-a] pyrimidines for anti-inflammatory and antinociceptive activity

A new series of thiazolo [3,2-a] pyrimidine derivatives was designed and synthesized using 4-fluoroaniline and ethylacetoacetate as starting material. Anti-inflammatory activity was assessed by the rat paw edema method and antinociceptive activity was evaluated by thermal stimulus technique. The compounds 5-(4-chlorophenyl)-2-(4-fluorobenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3l) and 2-(4-chlorobenzylidene)-5-(4-fluorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3q) were found to possess significant anti-inflammatory and antinociceptive activities. These compounds also showed lower ulcerogenic activity and higher ALD₅₀ values. Compounds with an aryl ring substituted with a smaller electron withdrawing group at the fourth position displayed better activity than the other derivatives.     

Synthesis and anti-inflammatory activity of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives

The synthesis of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives and the results of anti-inflammatory activity in vivo are described. Most of the tested compounds exhibited anti-inflammatory activity and some of them were more active than acetylsalicylic acid.     

Benzoyl ring halogenated classical 2-amino-6-methyl-3,4-dihydro-4-oxo-5-substituted thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine antifolates as inhibitors of thymidylate synthase and as antitumor agents

In an attempt to circumvent resistance to and toxicity of clinically used folate-based thymidylate synthase (TS) inhibitors that require folylpoly-gamma-glutamate synthetase (FPGS) for their antitumor activity, we designed and synthesized two classical 6-5 ring-fused analogues, N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]-2'-fluorobenzoyl]-l-glutamic acid (4) and N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]-2'-chlorobenzoyl]-l-glutamic acid (5), as TS inhibitors and antitumor agents. The key intermediates in the synthesis of these classical analogues were the mercaptans 10 and 11, which were obtained from the corresponding nitro compounds 6 and 7 respectively, by reduction of the nitro groups followed by diazotization of the amines. The syntheses of analogues 4 and 5 were achieved via the oxidative addition of the sodium salt of ethyl 2-halo-substituted-4-mercaptobenzoate (16 or 17) to 2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine (18) in the presence of iodine. The esters obtained from the reaction were deprotected and coupled with diethyl-l-glutamate followed by saponification. Compounds 4 and 5 were both more potent inhibitors of human TS (IC(50) values of 54 and 51 nM, respectively) than were PDDF and the clinically used ZD1694 and LY231514. Compounds 4 and 5 were not substrates for human FPGS up to 250 muM. In addition, 4 and 5 were growth inhibitory against CCRF-CEM cells as well as a number of other tumor cell lines in culture, and protection studies established TS as the principal target of these analogues.     

Synthesis and antibacterial activity of 2-substituted 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.

A series of 2-substituted 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was prepared and evaluated for antibacterial activity. The 6-fluoro-2-methyl-1-prenyl-1,4-dihydro-7-(3,5-dimethylpiperazinyl)-4-oxo-3-quinolinecarboxylic acid (14f) exhibited the most potent antibacterial activity against gram-positive bacteria among the total 32 derivatives. The synthetic strategies involve the use of well known keto ester condensation of benzoyl chloride and reductive cyclization of intermediates (4a-d) to afford 4-hydroxy-1,2-dihydro-2-oxo-quinoline derivatives (5a,b) or 1-hydroxy-1,4-dihydro-4-oxo-quinoline derivatives (6a,b).     

Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines

As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.     

2-Oxo-1,8-naphthyridine-3-carboxylic acid derivatives with potent gastric antisecretory properties

The syntheses of 2-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having potent gastric antisecretory properties in the pyloric-ligated (Shay) rat model are described. Two of the more potent compounds tested that were selected for more detailed dose-response evaluation were 4-amino-1-ethyl-1,2-dihydro-2-oxonaphthyridine-3-carboxylic acid ethyl ester (35) and 1-ethyl-1,2-dihydro-7-methyl-4-(4-methyl-1-piperazinyl)-2- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (77). These compounds lowered total acid output in the rat in a dose-related fashion. Both compounds were more potent than cimetidine when tested in the rat. Both 35 and 77 showed inhibitory activity in food-stimulated acid secretion in the Pavlov-pouch, conscious dog. The mechanism of action for this series is not known. Details of structure-activity relationships are described.     

4-Heterocyclyloxy-2H-1-benzopyran potassium channel activators

The reaction of 2,4-dihydroxypyridine (2) with 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1) yielded the 4-[(1,2-dihydro-2-oxo-4-pyridyl)oxy] compound 3a, accompanied by small amounts of the isomeric 4-(1,2-dihydro-4-hydroxy-2-oxo-1-pyridyl) compound 4. This could also be prepared by hydrogenation of the benzyloxy derivative 5. Reaction of 3,6-pyridazinediol (10) with 1 (R = CN) gave the 4-[(1,6-dihydro-6-oxo-3-pyridazinyl)oxy] compound 11a, which in turn rearranged on heating with NaH in DMSO into the 4-(1,6-dihydro-3-hydroxy-6-oxo-1-pyridazinyl) compound 12. A series of 6-substituted analogues (R = CO2Me, CSNH2, NO2, Br) of 3a and 11a were synthesized. N-Alkylation led to compounds 14a-c (R = Me, Et, CHMe2). The 4-heterocyclyloxychromenes 9 and 16a were obtained by alkaline hydrolysis of their 3-camphorsulfonates. The racemic pyridazinyloxy compounds 11a and 14a could be resolved via their diastereomeric camphorsulfonates or camphanates. The differences between the 4-heterocyclyloxychromanols and the isomeric N-substituted compounds 4 and 12 were elucidated in the course of extensive NMR investigations. While in DMSO the former appeared to be conformationally flexible molecules the latter were rigid. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats, using doses of 1 mg/kg. High and long lasting activities were found for the pyridyloxy compounds 3a and 3d, the pyridazinyloxy compound 11a, and its N-alkylation products, as well as for the 3S,4R-enantiomers 20a and 22a. (-)-(3S,4R)-3,4-Dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3- pyridazinyl)oxy]-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (22a) was selected for further development.     

Synthesis and structure-activity relationships of anti-inflammatory 9,10-dihydro-9-oxo-2-acridine-alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids

Eighteen test compounds, in three chemical series, were prepared as potential anti-inflammatory agents and evaluated by the rat hindpaw carrageenan-induced edema assay. The compounds, isosteric with known anti-inflammatory and antiallergic cyclo-oxygenase and lipoxygenase inhibitors, are 10-methyl-9,10-dihydro-9-oxo-2-acridinealkanoic acids, 9,10-dihydro-9-oxo-2-acridinealkanoic acids, and 4-(2-carboxyphenyl)aminobenzenealkanoic acids. Compounds within each of these series differ in the structure of the alkanoic acid side chain. Compounds containing the acetic acid and the branched 2-propionic acid side chain showed inhibition of carrageenan-induced edema. The activity of compounds with these side chains and the inactivity of those with carboxy, oxyacetic, thioacetic, and 3-propionic acid side chains is in accordance with the proposed template model of Appleton and Brown for the active site of cyclo-oxygenase, rather than with the alternative active site model proposed by Gund and Shen. One compound, (+-)-2-[N-(2-carboxyphenyl)-4-aminophenyl]propionic acid (3c), showed edema inhibition at 50 mg/kg po, comparable to that of an equivalent dose level of (+)-naproxen. Compounds 4a and 5a, which contain a carboxylic acid side chain, exhibited inhibition of soybean 12-lipoxygenase with IC50 values of 17.2 and 8.4 microM, respectively. The inhibition observed for the control drug, naproxen, was 24 microM.     

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.     

3-Methyl-2H-1-benzopyran potassium channel activators

By aldol condensation of 4-chromanones with paraformaldehyde, 3-alkylenechromanones 10 were obtained which gave 3-alkylchromenes following reduction and dehydration. Subsequent 3-chloroperbenzoic acid oxidation produced the versatile epoxide intermediates 15, from which 3,4-epoxy-3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile (15a) was resolved into its enantiomers by entrainment. In addition to the methyl group, the benzyl, alkyloxymethyl, and 2-nitroethyl residues could be introduced in the 3-position. Treatment of 15a with 2-pyridone simultaneously gave N- and O-substituted products 19a and 20. 19a easily gave 4-(1,2-dihydro-2-oxo-1-pyridyl)chromene 21 by treatment with base. The corresponding pyrrolidinone compounds 26 and 27 were obtained by a slightly modified procedure. Reaction with 2,4-dihydroxypyridine or 3,6-pyridazinediol resulted in the exclusive formation of 4-(heterocyclyloxy)chromanols (31 and 32). Treatment of 15a with 3-amino-6-pyridazinol gave 4-(3-amino-1,6-dihydro-6-oxo-1-pyridazinyl)chromanol derivative 34 lacking an NH bridge. This could be established after methylation of the ring-nitrogen atom (----35). Trans-configurated 3-methyl-4-pyridone compound 36 was obtained by addition of methyllithium to chromene 3. Hyperpolarizing and antispasmodic or relaxing effects of the compounds were determined in organ bath studies using pig coronary arteries precontracted with acetylcholine or rabbit main pulmonary arteries precontracted with noradrenaline. In the 3-methyl series the classical pyridone and pyrrolidinone structures (9, 21, 26, 27) were only weakly active or inactive, but the corresponding 4-(heterocyclyloxy) and 4-(heterocyclylamino) derivatives (31, 32, 35) were even more potent than the demethyl analogues. In conformation/activity investigations it was found that the activity of the 4-substituted benzopyran derivatives seems to be dependent on the relative orientation of their ring systems.     

Novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents

A novel series of 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole substituted at the 2-position were synthesized. The reaction of 2, 6-bis-benzylidenecyclohexanone (1) with thiosemicarbazide in the presence of NaOH afforded a mixture of the 3-H, 3a-H trans 2 and cis 2a diastereoisomers which have been separated by fractional recrystallization. Interaction of the first intermediate 2 with substituted phenacyl bromides, aromatic aldehydes and chloroacetic acid in presence of a mixture of acetic acid and acetic anhydride, and 2, 3-dichloroquinoxaline yielded the corresponding 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole derivatives substituted at the 2-position with 4-aryl-2-thiazolyl 3a, b, 5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl 4a, b and thiazolo[4, 5-b]quinoxalin-2-yl 5, respectively. Moreover, the other intermediates 3, 5-diaryl-1-thiocarbamoyl-2-pyrazolines 7a-d were reacted with the previously-mentioned reagents and gave the corresponding 3, 5-diaryl-1-(4-aryl-2-thiazolyl)-2-pyrazolines 8a-h, 3, 5-diaryl-1-(5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl)-2-pyrazolines 9a-d and 3, 5-diaryl-1-(thiazolo[4, 5-b]quinoxalin-2-yl)-2-pyrazoline derivatives 10a, b, respectively. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity. The structures of the new compounds were confirmed by elemental analyses as well as (1)H-NMR, IR, and MS data.     

Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-methyl-3-substituted quinazolin-4-(3H)-ones

A series of novel 2-methyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by treating (2-methyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with different amines, the starting material dithiocarbamate was synthesized from anthranilic acid. The compounds synthesized were investigated for analgesic, anti-inflammatory and antibacterial activities. All the test compounds exhibited significant activity, the compounds VA2, VA3 and VA4 shown more potent analgesic activity, and the compounds VA3 and VA4 shown more potent anti-inflammatory activity than the reference compound diclofinac sodium.     

Sydnone derivatives. Part VII: Synthesis of some novel thiazoles and their pharmacological properties.

The synthesis of some 4-(arylsydnonyl)-2-(4-arylhydrazono-3-methyl-5-oxo-2-pyrazolin-1-yl)- thiazoles by reacting 1-thiocarboxamido-3-methyl-4-(aryihydrazono)-2-pyrazolin-5-ones with different 4-bromoacetyl-3-arylsydnones is described. A few compounds from this series were screened for their anti-inflammatory, analgesic, and CNS depressant activities. Among the tested compounds 6s, 6d, 6n, and 6u showed significant anti-inflammatory activity comparable with that of standard drug Ibuprofen. Compounds containing chlorine and carboxylic substituents are more active. 6f, 6r, and 6u showed marked analgesic activity and most of the compounds tested showed promising CNS depressant activity comparable with that of standard drug pentobarbitone.     

Pyridonecarboxylic acids as antibacterial agents. 4. Synthesis and antibacterial activity of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4 -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its analogues

The title compounds (28-56) with an amino- and/or hydroxy-substituted cyclic amino group at C-7 were prepared with 1-substituted 7-chloro-, 7-(ethylsulfonyl)-, and 7-(tosyloxy)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acids and their ethyl esters (3-7) with cyclic amines such as 3-aminopyrrolidine. The N-1 substituent includes ethyl, vinyl, and 2-fluoroethyl groups. As a result of in vitro and in vivo antibacterial screenings, three compounds, 1-ethyl- and 1-vinyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids (33a and 33b) and 1-vinyl-7-[3-(methylamino)-1-pyrrolidinyl] analogue 34b, were found to be more active than enoxacin (2) and to be worthy of further biological study. Structure-activity relationships are discussed.     

Novel potent and selective thrombin inhibitors based on a central 1,4-benzoxazin-3(4H)-one scaffold

Novel thrombin inhibitors with the central 1,4-benzoxazine-3(4 H)-one scaffold, benzamidine P1 arginine side chain mimetic and various P3 moieties are described. 3-(Benzyl(2-(4-carbamimidoylbenzyl)-4-methyl-3-oxo-3,4-dihydro-2 H-1,4-benzoxazin-7-yl)amino)-3-oxopropanoic acid (7b), the most potent compound in the series, exhibited a K i of 2.6 nM in vitro for thrombin and high selectivity against trypsin and factor Xa.     

Synthesis and calcium antagonistic activities of fecal metabolites of a new calcium antagonist (+)-(R)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N- [2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4- methyl-3-oxo-2H-1,4-benzothiazine (SD-3211) in rats

In order to confirm the structure of three fecal metabolites, M-I, M-II and M-III, of a new calcium antagonist, (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4- benzothiazine (SD-3211), in rats, (+)-3,4-dihydro-2-[5-hydroxy-2-[3-[N-methyl-N-[2- [(3,4-methylenedioxy)-phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl- 3-oxo-2H-1,4-benzothiazine((+)-I), (+)-3,4-dihydro-2-[5-hydroxy-2-[3-[N- [2-[(3,4-methylenedioxy) phenoxy]ethyl]amino] propoxy]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine((+)-II) and (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4- benzothiazine((+)-III) were synthesized. Compounds (+)-I, (+)-II and (+)-III were identified with the fecal metabolites M-I, M-II and M-III, respectively. The calcium antagonistic activities of (+)-I, (+)-II and (+)-III were examined.     

Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

Isolation and identification of metabolites of ofloxacin in rats, dogs and monkeys

Metabolites of (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid (ofloxacin) in excreta of rats, dogs and monkeys after oral administration of 14C-ofloxacin (20 mg/kg) were isolated and identified. Three metabolites of ofloxacin were detected in the excreta of all three species, and identified by t.l.c., u.v., n.m.r. and mass spectrometry as follows: M-1, ester glucuronide of ofloxacin; M-2, unchanged ofloxacin; M-3, (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid (desmethyl ofloxacin); M-4, (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid piperazine-4-oxide (ofloxacin N-oxide). It is concluded that ofloxacin is metabolized by O-acyl glucuronidation, N-demethylation and N-oxidation.