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 of some new 2-(6-methoxy-2-naphthyl)- 5-aryl-1,3,4-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents

The synthesis of some new 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k) has been described. Ethyl-6-methoxy-2-naphthoate (1) yielded on treatment with hydrazine hydrate to 6-methoxy-2-naphthoic acid hydrazide (2). Compound 2 reacted with substituted aromatic carboxylic acids (3a-k) in phosphorus oxychloride yielded 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k). Newly synthesized compounds were characterized by IR, (1)H-NMR and mass spectral data. All the compounds were screened for their anti-inflammatory and analgesic activity. Compound 4j exhibited promising anti-inflammatory and analgesic activities.     

Synthesis of some 1-[(N, N-disubstituted thiocar bamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives and investigation of their antibacterial and antifungal activities

Fourteen new 1-[(N, N-disubstituted thiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (7a-n) were synthesised by reacting 1-(chloroacetyl)-3-(2-thienyl)-5-aryl-2-pyrazolines (5a-g) and appropriate sodium salts of N, N-disubstituted dithiocarbamoic acids (6a, b). The structures of the synthesised compounds were confirmed by elemental analyses, UV, IR, (1)H-NMR and FAB(+)-MS spectral data. Their antibacterial activities against Proteus vulgaris (NRRL B-123), Escherichia coli (NRRL B-3704), Aeromonas hydrophila (Ankara University, Faculty of Veterinary Sciences), Salmonella typhimurium (NRRL B-4420), Streptococcus feacalis (NRRL B-14617), Micrococcus luteus (NRLL B-4375) were investigated and in this investigation, a significant level of activity was illustrated. Antifungal activities of the compounds against Candida albicans and Candida globrata (isolates obtained from Osmangazi Uni. Fac. of Medicine) were found to be inactive. Compounds 7c-n were also evaluated for antituberculosis activity against Mycobacterium tuberculosis H(37)Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The preliminary results indicated that all of the tested compounds were inactive against the test organism.     

Synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyrans and related compounds, new potassium channel activators

The synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ols are described. The unsubstituted pyridone adduct lead compound 7e is highly active, with substituents on the pyridone ring leading to a decrease in activity. Strongly electron-withdrawing substituents at the C-6 position are required for optimal activity. When the 2-pyridone ring is replaced by other heterocycles such as 4-pyridone, pyrimidone, pyridazinone, pyrazinone, and 1,4-butanesultam, the activity is maintained. The removal of the 3-hydroxy function (----17a) does not significantly reduce the activity. The elimination of water from the chromanols leads to the formation of the chromenes, which are among the most potent antihypertensives known. The influence of diverse substituents, in particular heterocyclic C-6 substituents, was investigated in the 4-(2-oxo-1-pyrrolidinyl)chroman-3-ol series. Chromanols esterified at the 3-hydroxy group with short-chain acids, maintain their activity. The epoxidation of the chromene double bond also produces active compounds. The rearrangement of the epoxides 22 produces the 3-keto compounds 23 and the enol derivatives 25. The reduction of the ketone 23a produces cis-chromanol 7ab along with its trans isomer 7e. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats with a dose of 1 mg/kg; for selected compounds ED30 values as well as the duration of the antihypertensive effect were determined. 4-(1,2-Dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6- carbonitrile (18a) is under development as a coronary vasodilator and a drug for treating angina pectoris.     

Synthesis and anticonvulsant activity of 1-acetyl-5-arylidenyl-3-(2'-oxo/thiobarbiturinyl)-2-pyrazolines

1-(2'-Oxo/thiobarbiturinyl)-3-arylidenylchalcones (3-14) were synthesized by the condensation of different aromatic aldehydes with 5-acetyl-2-oxo/thiobarbituric acid (1 resp. 2) and various 1-acetyl-5-arylidenyl-3-(2'-oxo/thiobarbiturinyl)-2-pyrazolines (15-26) were synthesized by cyclisation of compounds 3-14 with hydrazine hydrate. The newly synthesized compounds showed anticonvulsant activity ranging from 40% to 90%. Compound 23 showed the maximum activity being more potent than the reference drug 1-acetyl-5-(P-methoxyphenyl)-3-(2'-thiobarbiturinyl)-2-pyrazoline.     

Triazolines. 14. 1,2,3-Triazolines and triazoles, a new class of anticonvulsants. Drug design and structure-activity relationships

Pioneering studies in our laboratories have led to the emergence of the delta 2-1,2,3-triazolines (4,5-dihydro-1H-1,2,3-triazoles) and the closely related 1H-1,2,3-triazoles as a unique family of anticonvulsant agents hitherto unknown. Unlike the traditional anticonvulsants, the dicarboximide moiety is absent from the traiazoline ring system. This paper examines the results of evaluation of several groups of 1-aryl-5-pyridyl-substituted triazolines and triazoles with particular reference to structure-activity relationships in each compound group as well as between compounds in the different groups and the 1,5-diaryl compounds. The Topliss manual approach for application fo the Hansch method is employed for the rational design of triazoline/triazole anticonvulsants. Anticonvulsant activity was determined, after intraperitoneal administration, in two standard seizure models in the mouse, the MES and scMet tests. Central nervous system toxicity was evaluated in the rotorod ataxia test. Analysis of structure-activity relationships using the Topliss scheme indicated a clear pi + sigma dependency in the 1-aryl-5-(4-pyridyl)triazolines while an adverse steric effect (Es) from 4-substitution appeared to be present in the 1-aryl-5-(3-pyridyl) compounds. A similar but strong steric effect dominated the structure-activity pattern of the 1-aryl-5-(4-pyridyl)triazoles, although a sigma dependency was more evident in the 1-aryl-5-(3-pyridyl)- and the 1,5-diaryltriazole series. No significant activity was observed among the 1-aryl-5-(2-pyridyl)triazolines, and although the respective triazoles were active, the parameter dependency was not clearly defined. Similarly, the 1,5-diaryltriazolines, as a group, showed no pronounced anticonvulsant activity. However, replacement of the 5-aryl with a pyridyl group, particularly a 4-pyridyl, led to highly enhanced anticonvulsant activity. In addition, oxidation of triazolines with no anticonvulsant activity yielded, as a rule, triazoles that were active, which could be linked to their chemistry or structural conformation. The triazolines and triazoles evince anticonvulsant activity as a class and compare very well with the prototype antiepileptic drugs--ethosuximide, phenytoin, phenobarbital, valproate--in their anticonvulsant potency and minimal neurotoxicity. They have emerged as a new generation of anticonvulsant agents that show great promise as potentially useful antiepileptic drugs.     

Synthesis and anti-HIV activity of N'-nicotinoyl--3-(4'-hydroxy-3'-methylphenyl)-5-[substituted phenyl]-2-pyrazolines

A series of N'-nicotinoyl-3-(4'-hydroxy-3'-methylphenyl)-5-(substituted phenyl)-2-pyrazolines were synthesized by the reaction between isoniazid (INH) and chalcones and were tested for their in vitro anti-HIV activity. Among them, compound (c) showed a promising anti-HIV activity in vitro against used strains (IIIB, ROD), with IC50 of both IIIB 5.7 microM and ROD 7.0 microM.     

Synthesis and antinociceptive activity of 2- and 3-methyl derivatives of 4-(pyridyl) isosteres of meperidine.

The respective cis- and trans-[3-Me,4-(pyridyl)] diastereoisomers of 4-(2-pyridyl)- (8a and 8b), 4-(3-pyridyl)- (8d and 8e) and 4-(4-pyridyl)-1,3-dimethyl-4-ethoxycarbonylpiperidines (8h and 8i) were synthesized for evaluation as 3-methyl substituted isosteres of meperidine. Alkylation of ethyl 2-, 3- or 4-pyridylacetate (7) with N-(2-chloroethyl)-N-(2-chloropropyl)methylamine (6) afforded the respective 3-methyl substituted compounds 8a and 8b, 8d and 8e or 8h and 8i, together with the corresponding 2-methyl substituted compounds 8c (only the trans-isomer was obtained), 8f and 8g, or 8j and 8k. Antinociceptive test results, acquired using the 4% sodium chloride assay in rats, indicated that a cis-3-methyl substituent usually enhanced antinociceptive potency slightly, whereas a trans-3-methyl substituent lowered activity 3-4 fold relative to the parent 3-unsubstituted compounds 3b-d, at a dose of 2 mg/kg sc. A trans-2-methyl substituent (8g and 8k), like a cis-methyl substituent (8a, 8d and 8h), also maintained or provided a small increase in antinociceptive activity. Trans-1,2-Dimethyl-4-ethoxycarbonyl-4-(3-pyridyl)piperidine (8g) and cis-1,3-dimethyl-4-ethoxycarbonyl-4-(4-pyridyl)piperidine (8h) were the most active antinociceptives producing a 66% inhibition of writhing at a dose of 2 mg/kg sc, relative to the reference drug meperidine (ED50 = 0.6 mg/kg sc).     

Synthesis and antimicrobial activity of some 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-4-bromo-2-pyrazolines and 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones

A series of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones (4a-e) have been synthesized by the oxidation of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-4-bromo-2-pyrazolines (3a-e) with dimethylsulfoxide. The structure has been established on the basis of spectral data (IR,1H NMR). The synthesized compounds have been screened in vitro for their possible antimicrobial activity.     

Synthesis of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives of potential anti-inflammatory activity

A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.     

Synthesis and antimicrobial activity of some (3-phenyl-5-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanones: new derivatives of 1,3,5-trisubstituted pyrazolines

A series of (3-phenyl-5-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanones was synthesized by condensing suitably substituted chalcones, i.e., 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-ones, and isoniazid in acetic acid. The structure of newly synthesized compounds has been established on the basis of analytical and spectral data. The new compounds were screened for antimicrobial activity and most of them showed good activity comparable with that of standard drugs ciprofloxacin and fluconazole. Compounds containing methoxy group showed high antimicrobial activity.     

Structural influences upon antihistamine activity; 3-amino-1-aryl-1-(2-pyridyl)propenes and related compounds

A series of 3-amino-1-aryl-1-(2-pyridyl)propenes and related compounds have been prepared by the dehydration of corresponding tertiary alcohols, and the configurations of geometrical isomeric derivatives established from spectroscopic data. The ability of the aminopropenes to antagonize histamine-induced contractions of the guinea-pig ileum is reported. These data allow various structure-activity relations to be discussed including stereochemistry (cis 2-pyridyl/H geometry is superior to cis substituted phenyl/H but not necessarily to cis phenyl/H), nature of the basic function (1-pyrrolidino is markedly superior to either dimethylamino or 1-piperidino) and the importance of the vinylic hydrogen atom (sharp falls in potency follow its replacement by methyl).     

Synthesis and antihypertensive activity of 5-thio-2-pyridinecarboxylic acid derivatives.

Synthesis of various substituted 5-thio-2-pyridinecarboxylic acids and their derivatives is described by three methods, i.e., displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate (10) by a thiol anion, alkylation of methyl 5-thio-2-pyridinecarboxylate derived from reaction of the diazotized methyl-5-amino-2-pyridinecarboxylate (5) with thiocyanate followed by borohydride reduction of the product, and alkylation of 5-thio-2-pyridinecarbonitrile followed by hydrolysis. 5-Thio-2-pyridinecarbonitrile was obtained from butyl 6-methyl-3-pyridyl sulfoxide (2) by nitrosation and dehydration of the oxime. Many of these 5-thio-2-pyridinecarboxylic acid derivatives were orally active antihypertensive agents in the spontaneously hypertensive rat. Optimization of the structural parameters for this activity yiedled 5-[m-trifluorobenzyl) thio]-2-pyridinecarboxylic acid (41) and its sulfoxide, 42. Further biological studies with these compounds are described.     

Eco-friendly synthesis and antimicrobial activities of some 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines

Background

Green catalyst fly ash: H₂SO₄ was prepared by mixing fly ash and sulphuric acid. Microwave irradiations are applied for solid phase cyclization of 5-bromo-2-thienyl chalcones and phenyl hydrazine hydrate in the presence of fly ash: H₂SO₄ yields, 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines. These pyrazolines were characterized by their physical constants and spectral data. The antimicrobial activities of all synthesized pyrazolines have been studied.

Results

Scanning electron microscopy (SEM) analysis shows the morphology changes between fly ash and the catalyst fly ash: H₂SO₄. The SEM photographs with the scale of 1 and 50 μm show the fly-ash particle is corroded by H₂SO₄ (indicated by arrow mark), and this may be due to dissolution of fly ash by H₂SO₄. The yields of 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines is more than 75% using this catalyst under microwave heating. All pyrazolines showed moderate activities against antimicrobial strains.

Conclusion

We have developed an efficient catalytic method for synthesis of 1-phenyl-3(5-bromothiophen-2-yl)-5-(substituted phenyl)-2-pyrazolines by solid phase cyclization using a solvent-free environmentally greener catalyst fly ash: H₂SO₄ under microwave irradiation between aryl chalcones and hydrazine hydrate. This reaction protocol offers a simple, economical, environment friendly, non-hazardous, easier work-up procedure, and good yields. All synthesized pyrazoline derivatives showed moderate antimicrobial activities against bacterial and fungal strains.     

Synthesis and biological activity of trans(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogues: a new class of potassium channel opener.

The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed. A 3-pyridyl or 3-quinolyl group, a small N-alkyl thioamide function, and a thiane oxide ring, in which the sulfoxide is in a trans relationship to the thioamide, are preferred for activity. Selected compounds were tested intravenously in the normotensive anaesthetized rat for hypotensive effects, and the activities reflect their in vitro K(+)-channel opening activity. This led to further evaluation of compound 8a and the selection of the (-)-enantiomer 8b (RP 52891) for development as an antihypertensive and antianginal agent.     

Microwave-assisted synthesis and anti-bacterial activity of some 2-amino-6-aryl-4-(2-thienyl)pyrimidines

Some novel 2-amino-6-aryl-4-(2-thienyl)pyrimidines were synthesized from 3-aryl-1-thien-2-ylprop-2-en-1-ones and guanidine hydrochloride in presence of alkali by conventional heating in alcoholic medium and microwave heating in solvent-free conditions. The compounds were evaluated for in vitro anti-bacterial activity. The anti-bacterial data revealed that compounds 5a-e had better activity against tested gram-positive organisms than the reference ciprofloxacin and norfloxacin. However, the compounds were nearly inactive against gram-negative bacteria. Compounds 5c and e were the most active compounds against gram-positive bacteria.     

Synthesis and biological activity of substituted 4-aryl-2-methylenehydrazino-4-oxobut-2-enoic acids and their derivatives

Aseries of substituted 2-methylenehydrazino-4-aryl-4-oxobut-2-enoic acids and their anilides and esters were obtained using reactions of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and their amides and esters with benzophenone hydrazone, benzyl monohydrazone, and triphenylphosphazines. The methyl ester of 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-chlorophenyl)-4-oxobut-2-enoic acid was also synthesized by decyclization of 3-(1,2-diphenyl-2-oxoethylidenehydrazino)-5-(4-chlorophenyl)-3H-furan-2-one using methanol. The synthesized compounds exhibit moderate anti-inflammatory, analgesic, and antimicrobial activity.     

Synthesis and Antiinflammatory and Analgesic Activity of the Products of 3-Imino-(3H)-Furan-2-One Recyclization under the Action of Substituted Hydrazines

A series of 6-aryl-4-(1,5-dimetyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-1,4-dihydro-2H-pyridazin-3-ones and 4-[2-aryl-1-(2,4-dinitrophenylamino)-2-oxo-1,2-dihydropyrrol-3-ylidenamino]-1,5-dimetyl-2-phenyl-1,2-dihydropyrazol-3-ones were synthesized via recyclization of 1,5-dimethyl-4-(5-aryl-2-oxo-furan-3-ylidenamino)-2-phenyl-1,2-dihydropyrazol-3-ones under the action of substituted hydrazines. Most compounds exhibit weak antiinflammatory and analgesic activity.__________Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 1, pp. 13 – 16, January, 2005.     

Synthesis of 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents.

Thirty new 1,2-dihydropyridine derivatives of the general formula 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones (1-15) and 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-iminopyridines (16-30) were synthesized using one-pot multicomponent reactions of the properly substituted acetophenone, appropriate aldehyde, ammonium acetate and ethyl cyanoacetate (1-15) or malononitrile (16-30) in ethanol. These target compounds (1-30) were evaluated for their cardiotonic activity using the spontaneously beating atria model, from reserpine-treated guinea pigs. The best pharmacological profile was obtained with 3-cyano-6-(3,4-dimethoxyphenyl)-4-(4-hydroxyphenyl)-2(1H)-pyridinone (9) which displaced selectivity for increasing the force of contraction (108.7 +/- 6.7,% change over control) rather than the frequency rate (40.8 +/- 5.3,% change over control) at a 5 x 10(-4) M concentration. The effects of structural changes upon activity are reported.     

Anti-inflammatory activity of some novel alpha-amino naphthalene derivatives

alpha-Acetylamino naphthalene (1) was reacted with different aromatic aldehydes and with primary or secondary amines to give alpha-aminonaphthylsubstitutedaryl chalkones (2-5) and alpha-(substituted aminoethyl)-amidonaphthalenes (14-25), respectively. These substituted chalkones were treated with hydrazinehydrate and hydroxylamine hydrochloride to give 1-acetyl-5-substitutedaryl-3-(alpha-aminonaphthyl)-2-pyrazolines (6-9) and alpha-(2-substitutedaryl-isoxazolin-4-yl)-aminonaphthalenes (10-13), respectively. Their chemical structures were confirmed by IR and 1H-NMR spectral data and elemental analysis. Studies of the anti-inflammatory and ulcerogenic activities and acute toxicity of these newly synthesized compounds were performed in vivo and compared with the standard drug, phenylbutazone (CAS 50-33-9). Some of these compounds showed potent anti-inflammatory activity and less ulcerogenic effects than phenylbutazone.