Synthesis and analgesic and anti-inflammatory activities of (2Z,5Z)-1-aryl-3-hydroxy-5-(3,3-dialkyl-3,4-dihydroisoquinolin-1(2<Emphasis Type="Italic">H</Emphasis>)-yliden)pent-2-en-1,4-diones

5-Arylfuran-2,3-diones and (Z)-alkyl-4-aryl-2-hydroxy-4-oxobut-2-enoates react with 3,3-dialkyl-1-methyl-3,4-dihydroxyisoquinolines to form (2Z,5Z)-1-aryl-3-hydroxy-5-(3,3-dialkyl-3,4-dihydroxyisoquinolin-1(2H)-yliden)pent-2-en-1,4-diones which have analgesic and anti-inflammatory activities.     

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.     

Synthesis of new 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole derivatives as potential antimicrobial agents

New (E)-1-aryl-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 6 (pyrazolic chalcones) were synthesized from Claisen–Schmidt reaction of 3-aryl-1-phenylpyrazol-4-carboxaldehydes 4 with several acetophenone derivatives 5. Subsequently, the cyclocondensation reaction of chalcones 6 with phenylhydrazine in acetic acid medium afforded the new 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazoles 7. The synthesized compounds were characterized by spectral studies and evaluated for their in vitro antibacterial activity against three pathogenic bacterial strains, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and in vitro antifungal activity against three pathogenic fungal strains Aspergillus flavus, Chrysosporium keratinophilum, and Candida albicans.     

Non-Steroidal Anti-inflammatory Agents: Novel Pyrazolyl-, 1,2-Oxazolyl-, and 1,3-Diazinyl Derivatives of 4(3H)-Quinazolinones

Four novel series of 4(3H)-quinazolinone derivatives have been prepared by cyclization of the key intermediates 3-aryl-2-(3-aryl-3-oxopropenyl)-4-(3H)-quinazolinones with different reagents: 3-aryl-1-iminocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones, 3-aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones, 3-aryl-2-(3-aryl-4,5-dihydro-1,2-oxazol-5-yl)-4(3H)-quinazolinones, and 3-aryl-2-(4-aryl-2-thioxo-1,2,5,6-tetrahydro-1,3-diazin-6-yl)-4(3H)-quinazolinones. The anti-inflammatory activity of representatives of these compounds is comparable to or higher than that of proquazone.     

Darstellung,Kristallstruktur und Wirkung von 2-Methyl-3-(4-oxo-3-phenyl-thiazolidin-2-ylidenamino)-4-(3H)-chinazolinon

Quinazolinones, I: Preparation, Crystal Structure, and Activity of 2-Methyl-3-(4-oxo-3-phenylthiazolidine-2-ylidenamino)-4(3H)-quinazolinone The cyclisation of 1-(3,4-dihydro-2-methyl-4-oxo-3H-quinazoline-3-yl)-3-phenylthiourea (2) with chloroacetic acid leads to 2-methyl-3-(4-oxo-3-phenyl-thiazolidine-2-ylidenamino)-4(3H)-quinazolinone (3) and not to the isomer 4 . The crystal structure of 3 has been determined and refined until R = 0.0715. Compound 3 possesses good hypnotic and anticonvulsant activities.     

Synthesis and analgesic, anti-inflammatory activities of 3-(3-methoxyphenyl)-2-substituted amino-quinazolin-4(3H)-ones

A variety of novel 3-(3-methoxyphenyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(3-methoxyphenyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(3-methoxyphenyl)-quinazolin-4(3H)-one was synthesized from 3-methoxy aniline. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic behavior. Among these the compound 2-(1-methyl butylidene-hydrazino)-3-(3-methoxyphenyl)-3H-quinazolin-4-one (AS3) emerged as the most active compound for the analgesic activity, while the compound 2-(1-ethyl propylidene-hydrazino)-3-(3-methyoxyphenyl)-3H-quinazolin-4-one (AS2) showed most potent anti-inflammatory activity of the series and these compounds are moderately more potent when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid.     

Pyrazolodiazepines. 2. 4-Aryl-1,3-dialkyl-6,8-dihydropyrazolo[3,4-e] [1,4]diazepin-7(1H)-ones as antianxiety and anticonvulsant agents.

A series of 4-aryl-1,3-dialkyl-6,8-dihydropyrazolo[3,4-e] [1,4]diazepin-7(1H)-ones was synthesized and screened for psychotropic activity. In animals, a number of these pyrazolodiazepinones had strong CNS effects similar to diazepam. One compound, 4-(2-fluorophenyl)-6,8-dihydro-1,3,8-trimethylpyrazolo[3,4-e] [1,4]diazepin-7(1H)-one (54), is being studied in the clinic as a component of a new animal anesthetic, Tilazol.     

Synthesis and in vitro anti-HIV Activity of Certain 2-(1H-Benzimidazol-2-ylamino)pyrimidin-4(3H)-ones and Related Derivatives

In an ongoing effort to develop novel non-nucleoside human immunodeficiency virus inhibitors, a series of substituted 2-(1H-benzimidazol-2-ylamino)pyrimidin-4(3H)-ones and related derivatives were synthesized via cyclocondensation of 2-guanidino-1H-benzimidazole with diethyl ethoxymethylenemalonate, substituted diethyl malonates, some β-keto esters and 2-acetylbutyrolactone. From these series of compounds, 2-(1H-benzimidazol-2-ylamino)-6-hydroxy-5-phenylpyrimidin-4(3H)-ones ( 5f , NSC 666286) was confirmed to have a moderate in vitro anti-HIV activity.     

Untersuchungen an 1,3-Thiazinen, 28. Mitt. Reaktionen von 3-Amino-2-thioxo-tetrahydro-(4H)-1,3-thiazin-4-onen mit Nucleophilen

1,3-Thiazines, XXVIII⁽¹⁾: Reactions of 3-Amino-2-thioxotetrahydro-(4H)-1,3-thiazin-4-ones with Nucleophiles 3-Amino-2-thioxotetrahydro-(4H)-1,3-thiazin-4-ones 1 are cleaved by nucleophiles preferentially at the N-3-C-4-bond. With some nitrogen bases under forced conditions cleavage of the S-1-C-2-bond also occurs yielding thiosemicarbazides.     

Syntheses with Unsaturated Nitriles,IX: 3(2H)-Pyridazinones from Alkylidenemalononitrile Dimers

The coupling of 1-amino-2,6,6-tricyanocyclohexadiene derivatives 1 - 3 with a variety of aryldiazonium salts produces the hydrazones 5 - 7 which in the presence of weak base in ethanol at elevated temperature furnish 2-aryl-4-cyanopyridazin-3(2H)-ones 8 - 10 . In boiling toluene, however, the tautomeric hydrazones 11 - 13 are being formed.     

Synthesis of (Z)-1,3-diaryl-2-(4-aryl-1H-1,2,3-triazol-1-yl)prop-2-en-1-ones and their antibacterial studies

The cyclization of 1,3-diaryl-2-azido-2-propen-1-ones with various alkynes in the presence of a catalytic amount of copper sulfate–sodium ascorbate in DMSO–water mixture under microwave irradiation led to the formation of (Z)-1,3-diaryl-2-(4-substituted-1H-1,2,3-triazol-1-yl)prop-2-en-1-ones. The structure and stereochemistry of the products have been elucidated by spectroscopic and single crystal X-ray analyses. All the newly synthesized compounds have been tested for their antibacterial activity against four strains of bacteria and found to have moderate to good inhibition.     

Synthesis and evaluation of antibacterial and antifungal activities of new (Z)-3-bromo-4-(1,3-diaryl-1H-pyrazol-4-yl)but-3-en-2-ones and 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1,3-diaryl-1H-pyrazoles

Bromination of 4-(1, 3-diaryl-1H-pyrazol-4-yl) but-3-en-2-ones, triggered by a combination of potassium bromide and cerium(IV) ammonium nitrate in a biphasic system consisting of water and dichloromethane furnishes the corresponding monobromo compounds 2 directly, instead of the expected dibromo compounds. The α-bromo compounds 2 were utilized as efficient precursors for the synthesis of several bipyrazolyl derivatives, 4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1, 3-diaryl-1H-pyrazoles (3). All the α-bromoenones 2 and bipyrazoles 3 are new compounds and their identity was established by m.p., spectral and analytical data. The new products 2 and 3 were tested for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis (Gram positive), Escherichia coli, and Pseudomonas aeruginosa (Gram negative) and antifungal activity against Aspergilus flavus and Aspergillus niger. The antimicrobial activity of the tested compounds is compared with the commercially available antibiotic, ciprofloxacin and antifungal agent, fluconazole.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Synthesis and evaluation of the biological activities of some 3-{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl]-imino}-1,3-dihydro-2H-indol-2-one derivatives

Reaction of ethyl-6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidin-5-carboxylates (1a-i) with hydrazine hydrate yielded 6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidin-5-carbohydrazides (2a-i). These products, on reaction with cyanogen bromide, gave 5-(5-amino-1,3,4-oxadiazol-2-yl)-6-methyl-4-aryl-3,4-dihydropyrimidin-2 (1H)-ones (3a-i). The resultant aminooxadiazolylpyrimidinones were condensed with isatin to obtain various 3-{[5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3,4-oxadiazol-2-yl]-imino}-1,3-dihydro-2H-indol-2-ones (4a-i). These products were characterized by IR, 1H NMR, mass spectra and elemental analysis. Products (4a-i) revealed promising antibacterial, antifungal and antioxidant activity.     

Synthesis of 2-[2-(1-Imidazolyl)ethyl]-4-phenylcycloalka[g]phthalazin-1(2H)-ones as Thromboxane A2 Synthase Inhibitors

A series of 2-[2-(1-imidazolyl)ethyl]-4-phenylcycloalka[g]phthal-azin-1(2H)-ones ( 3a—d ) with variable cycloalkene ring size was prepared and tested in vitro for thromboxane A₂ synthase inhibitory activity.     

Verbindungen mit potentiell positiv inotroper Wirkung, 2. Mitt. Synthese von 3,4-Dihydro-2-[(3-oxo-1-cyclopenten-1-yl)amino]-1(2H)-phenanthron und 3-(1,2,3,4-Tetrahydro-1-hydroxy-2-phenanthrylamino)-2-cyclopentenon

Compounds with Potentially Positive Inotropic Activity, II: Synthesis of 3,4-Dihydro-2-[(3-oxo-1-cyclopenten-1-yl)amino]-1(2H)-phenanthrone and 3-(1,2,3,4-Tetrahydro-1-hydroxy-2-phenanthrylamino)-2-cyclopentenone The synthesis of the title compounds from 1,3-cyclopentanedione and 2-amino-3,4-dihydro-1(2H)-phenanthrone and 2-amino-1,2,3,4-tetrahydro-1-phenanthrole is described.     

Synthesis of deuterium-labeled CCR2 antagonist JNJ-26131300, [4-(1H-indol- 3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid

Synthesis of multiple deuterium-labeled CCR2 antagonist JNJ-26131300, that is, [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid, is described. First, condensation of indole-D₇ with 4-piperidone produced 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-D₅, which subsequently underwent catalytic hydrogenation to give 3-piperidin-4-yl-1H-indole-D₅. Next, bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid was prepared through multiple steps from 3-(3,4,5-trifluoro-phenyl)-acrylic acid and bromo-piperidin-4-yl-acetic acid ethyl ester. Nucleophilic coupling of 3-piperidin-4-yl-1H-indole-D₅ with bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid afforded the desired compound [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid-D₅.     

Design and synthesis of 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one as antihistamine agents

A series of novel 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one was synthesized by the reaction of 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride with various amines. The starting material, (3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride was synthesized from 4-chloroaniline by a multistep synthesis. All the title compounds were tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs at the dose level of 10 mg/kg using chlorpheniramine maleate as the reference standard. The results of the biological activity indicate that the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-2-oxoethylthio)quinazolin-4(3H)-one (1) emerged as the most potent compound of the series (71.13 % protection) when compared to the reference standard chlorpheniramine maleate (70.09 % protection). Interestingly, compound A1 shows negligible sedation (12 %) compared to chlorpheniramine maleate (32 %). Therefore, compound A1 can serve as the lead molecule for further development.     

Synthesis of Z- and E-1-Methyl-2-(1-hydroximinoethyl)-6-methoxy-3,4-dihydronaphthalene and Evaluation as Inhibitors of 17α-Hydroxylase-C17,20-Lyase (P450 17)

The synthesis and biological evaluation of Z- and E-1-methyl-2-(1-hydroximinoethyl)-6-methoxy-3,4-dihydro-naphthalene ( Z-1 and E-1 ) as nonsteroidal inhibitors of 17α-hydroxylase-C17,20-lyase (P450 17, CYP17) is described. Z-1 and E-1 were separated by column chromatography and identified by ¹H NMR. The synthesis of the key compound 3 was accomplished by a new reaction acetylating the 1-methyl-6-methoxy-3,4-dihydronaphthalene compound 2 under Friedel-Crafts conditions. Compound 2 was obtained from the 1-tetralone via Wittig reaction. Using a microsomal fraction of human testicular enzyme, Z-1 and E-1 inhibited the target enzyme only marginally.     

Synthesis and CNS Activity of N,N-Disubstituted 1-(Aminomethyl)-5-alkyl-3-(aryloxyacetylhydrazono)indolin-2-ones

Isatin and 5-methylisatin were condensed with various aryloxyacetylhydrazides to furnish the 3-(aryloxyacetylhydrazono)-5-alkylindolin-2-ones 1–4 . When 1–4 were subjected to Mannich reaction, the N,N-disubstituted 1-(aminomethyl)-5-alkyl-3-(aryloxyacetylhydrazono)indolin-2-ones 5–8 were obtained. The compounds were CNS active and relatively non-toxic (albino mice).