Activated nitriles in heterocyclic synthesis: Syntheses of thiazole,pyrazole and 4H-1,4-benzothiazine derivatives

4-Arylazo-3-phenyl-5-aminopyrazoles (5a,b) and substituted hydroxythiazoles8a,b were synthesized from the reaction of4a,b with hydrazine hydrate and mercaptoacetic acid respectively. Compounds5a,b and8a,b were also obtained from coupling of2a,b with6 and7, respectively. 4H-1,4-Benzothiazine11 was prepared from1 and10. The reaction of the diazonium salts2a-c with diethyl 3-amino-2-cyanopent-2-en-1,5-dicarboxylate12 was also reported.     

Benzoin in heterocyclic synthesis: Synthesis and reactions of 2,3-Diphenyl-4-cyanopyrrole-5-thione

2,3-Diphenyl-4-cyano-pyrrole-5-thione (4) was prepared either by the reaction of benzoin (1) and cyanothioacetamide (3) followed by cyclization using AcOH/sodium acetate or by refluxing a mixture of benzoin (1) and cyanothioacetamide in pyridine to afford directly4. Several new pyrrole and pyrazole derivatives were synthesised using4 as synthon. The structure of the newly synthesised derivatives were based on celemental and spectral data studies. Methylation of the SH group in4 afforded5. Reaction of4 with ethyl bromo acetate afforded (6). Treatment of (5) and (6) with hydrazine hydrate afforded the same pyrazole derivative (10) through the intermediate (9). Treatment of6 with aniline and phenylhydrazine afforded the pyrrole derivatives8a,b respectively. Treatment of6 while dil HCl gave 2,3-diphenyl-4-cyano-pyrrole-5-one (7). Treatment of6 with NH₃/EtOH afforded the amidic derivatives (11) with treatment of6 with NH₃/heat then acidification it gave the carboxylic derivatives (12).     

Synthesis and pharmacological studies of some pyrone and benzodifuran derivatives

The michael adducts2a,b were obtained from the reaction of the phenylacetyl derivative1 with benzaldehyde and p-anisaldehyde respectively.2a and2b were subjected to react with cyanoethanoic acid hydrazide, malononitrile, cyanothioacetamide, cyanoacetamide and 1,1,3-tricyano-2-amino propene to yield4a-h and5a,b respectively. Hydrogen peroxide oxidation of2a,b gave the aurone derivative6a,b. The pyrone derivatives8a,b were obtained from2a,b by addition of chloroacetyl chloride followed by dehydrochlorination.     

Synthesis of several new isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,benzoxadiazine and benzothiazine derivatives from hydroximoyl halides

Furoylhydroximoyl chloride3 reacted with 2-aminopyridine, 2-aminopyrimidine,O-aminophenol,O-phenylenediamine and aminothiophenol to afford imidazo[1,2-a]pyridine6, imidazo[1,2-a]pyrimidine8, benzoxadiazine10, nitrosobenzopyrazine13a and nitrosobenzothiazine13b, respectively. Isoxazoline18 and pyrrolidino[3,4-d]isoxazolin-4,6-dione derivatives19a and19b obtained by the reaction of3 with acrylonitrile and N-arylmaleimide. Hydroximoyl chloride3 reacted with thiophenol and sodium benzenesulfinate to yield furylglyoxaloxime16a and16b, respectively. Hydroximoyl chloride3 reacted also with some active methylene compound to give isoxazole derivatives20–23, respectively.     

Synthesis and antifungal evaluation of 6-(N-arylamino)-7-methylthio-5,8-quinolinediones

A series of 6-(N-arylamino)-7-methylthio-5,8-quinolinedione derivatives4a-4l was newly synthesized for the evaluation of antifungal activity. 6-(N-Arylamino)-7-methylthio-5,8-quinolinediones were prepared by regioselective nucleophilic substitution of 6,7-dichloro-5,8-quinolinediones with arylamines in the presence of Ce³⁺, and Na₂S/dimethylsulfate. The MIC values of4a-4l were determined for antifungal susceptibilityin vitro againstCandida species by agar streak method. The derivatives4a-4l had generally potent antifungal activities against all human pathogenic fungi. Especially they had the most potent activity againstC. krusei at 12.5≈0.8 μg/ml. Compounds4d, 4g, 4h, 4j and4k had more potent antifungal activities than fluconazole. Compounds4g and4h completely inhibited the fungal growth at 0.8≈6.3 μg/ml against allCandida species, while fluconazole inhibited the growth at 25 μg/ml. The compounds such as4g and4h containing an N-(4-bromo-2-methylphenyl)- or N-(4-bromo-3-methylphenyl)amino substituent exhibited the most potent antifungal activities.     

Reactions with acetoacetanilide: Synthesis and antibacterial activity of some new pyran,pyrano[2,3-c]pyrazole and pyrano[2,3-c]-pyridine derivatives

The reaction of acetoacetanilide (1) with the α-cyanocinnamonitrile derivatives2 yielded the Michael adducts4 which could be converted into the pyrano[2,3-c] pyrazole derivatives5 via their reaction with hydrazine hydrate. Cyclisation of4 afforded the cyanoaminopyrans9 which could in turn be converted into the corresponding pyridine derivatives10. The pyranopyrazoles9 reacted with different activated nitrile derivatives (3a-c) to give the pyrano[2,3-c]pyridine derivatives13, 16 and19 respectively. The biological activity of the synthesised heterocyclic derivatives was investigated and discussed.     

Reactions with activated nitriles: A new route for the synthesis of new pyridine and pyrazolopyridine derivatives

It has been found that α, β-unsaturated nitrile derivatives1–3 reacted with S-methylisothiourea to give the propene derivatives4–6 respectively. Cyclisation of4–6 using ethanolic hydrochloric acid afforded the pyridine derivatives7–9 in good yields. On the other hand, the reactions of hydrazine hydrate and of phenylhydrazine with each of7–9 gave the corresponding pyrazolopyridine derivatives10–15. The structures of the newly synthesised derivatives were assigned on the basis of elemental analyses, IR and¹H-NMR spectral data studies.     

Further derivatives of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid and their antibacterial activities

Compound 4, 5, 6, 7, and 8 were synthesized from 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid 1 as a starting material. The pyrazolo[4,3-d]oxazinone 4 was obtained from direct reaction of the acid 1 with hydroxylamine hydrochloride. Acid chloride 2 was converted easily into the new derivatives consisting of 1-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-oyl)-sulfamide 5 and 3,4-dibenzoyl-1,5-diphenyl-1H-pyrazole 6. The nitrile derivative 7 was obtained by dehydration of the amide 3 in a mixture of SOCl₂ and Dimethylformamide (DMF). Cyclocondensation reaction of 7 with anhydrous hydrazine led to the formation of 7-aminopyrazolo[3,4-d]pyridazine 8 derivative. These new synthesized compounds evaluated for their antibacterial activities against Gram-positive and Gram-negative bacteria using the tube dilution method. The finding of antibacterial activity study showed that the sulfamide derivative 5 was the best compound of the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria.     

Synthesis of 1,4-dihydropyridine derivatives with vasodilating activities (I)

□Asymmetric 2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylate with [N-(3,4-methylenedioxybenzyl)-N-methyl] aminoethyl group as the ester moiety and related 1,4-dihydropyridine derivatives were prepared and tested for the effects on vascular smooth muscles. 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[N-(3′, 4′-methylenedioxybenzyl)-N-methyl] aminoethyl ester 5-methyl ester (11) and 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[N-2′,3′-methylenedioxybenzyl)-N-methyl] aminoethyl ester 5-ethyl ester (15) showed potent vasodilating activities. IC₅₀ (10⁻⁸ M) was 2.6 and 2.7 for11 and15, compared with 3.5 for nicardipine.     

Synthesis of C-(2-furyl)-N-(4-nitrophenyl)methanohydrazonyl bromide. Reactions with nucleophiles and active methylene compounds

Synthesis of C-(2-furyl)-N-(4-nitrophenyl)methanohydrazonyl bromide2 is described. Treatment of2 with nucleophiles affords the corresponding substitution products3–7. Also, compound2 reacts with selenocyanate anion and thiocyanate anion and give the corresponding selenadiazoline and thiadiazoline8 and9, respectively. Moreover, reaction of2 with enolates of various active methylene compounds afforded the pyrazole derivatives17–20.     

Synthesis of 6-[1-[4-(benzoxazol-2-yl)thiobuthyl]-1,2,3-triazole-4-yl]methylenepenam as β-lactamase inhibitors

The 6,6-dibromopenam6 was treated with CH₃MgBr and carbaldehyde5 to afford the 6-bromo-6-(1-hydroxy-1-methyl)penicillanate7, which was reacted with acetic anhydride to give acetoxy compound8. The deacetobromination of8 with zinc and acetic acid gave 6-exomethylenpenams, Z-isomer9 and E-isomer10, which were oxidized to sulfones11 and12 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl₃ and neutralized to give the sodium salts13, 14, and15.     

New synthesis of chromonopyrroloimidazolinones and arylidene thioxoimidazolinones

6-Formyl-5-methoxy-2-methyl chromone derivatives condensed with 2-thiox-4-imidazolinone derivatives to form the corresponding “10-methoxy-7-methyl-3-thioxochromono [6,7-b]pyrrolo[1,2-a-]-imidazolin-1-one derivatives(IIIa-f) or the 5-arylidene-2-thioxo-4-imidazolinone derivatives(IVa-f). The activity of the NH in the imidazol moiety of(IIIa) was confirmed by formation of the Mannich bases(Va, b). Moreover, alkylation of(IIIa) was undertaken to give the alkylmercapto derivatives(VIa, b). The antimicrobial activities of compoundsIIIb-e, IVa, IVd andIVe were studied.     

Synthesis of pyrazolo [4,5]pyridazine and isoxazolo [3,4d]pyridazine derivatives

Arylhydrazones of diethylacetondicarboxylate3 was treated with formaldehyde to give 1-aryl-4,5,6-trihydropyridaine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4d] 1,3,4,5-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave 1-amidopyrazolo-5-one-1-aryl-3-carboxypyridazine6. On the other hand compound3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-2,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbazide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Potential antitumor α-methylene-ψ-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans

Ten, heretofore unreported, 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)]-2′-oxo-3′-methylenetetrahydrofurans (H, F, Cl, Br, I, CH₃, CH₃, CH₂CH₃, CH=CH₂, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K₂CO₃ (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC₅₀) ranging from 0.69 to 2.9 μg/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC₅₀:0.4∼2.8 μg/ml).     

Synthesis and antitumor evaluation ofcis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and-uridine analogues

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), {[N-(2′,3′,5′-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine}dichloroplatinum (II) (6a), {[N-(2′,3′,5′-tri-O-acetyl) uridine-6-yl-methyl]ethane-1,2-diamine}dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl- methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatiate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4a) and 6-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2′,3′,5′-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2′,3′,5′-tri-O-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.     

Synthesis of imidazole derivatives containing biologically active units

Reaction of oxazolin-5-ones1 withp-amino-diphenylamine was resulted in the formation of the corresponding imidazolin-5-ones2 which on treatment with sulphur afforded phenothiazines3. Acridine derivatives5 were obtained from acetylaminodiphenylamines derivatives6 on heating with ZnCl₂ at 200°C.3 reacted with chloroacetyl chloride to give7 which reacted in turn with different amines to give8. Antibacterial activity of the obtained products was studied.     

A New Larvicidal Lignan from Piper fimbriulatum.

Abstract

A new lignan, 3,4,5′-trimethoxy-3′,4′-methylenedioxy-7,9′:7′,9 diepoxylignan (1) (6-[4-(3,4-dimethoxy-phenyl)-tetrahydro-furo[3,4-c.]furan-1-yl]-4-methoxy-benzo[] dioxole) together with two known lignans, 7′-epi.-sesartemin (2) and diayangambin (3), and a known flavonoid, 5-hydroxy-7,4′-dimethoxyflavone (4), were isolated from the leaves of Piper fimbriulatum. C. DC. Their structures were assigned by a combination of one- and two-dimensional NMR techniques. 7′-epi.-Sesartemin (2) showed the highest larvicidal activity against Aedes aegypti. (LC₁₀₀ 17.6 µg/ml) and weak antiplasmodial (IC₅₀ 7.0 µg/ml) and antitrypanosomal (IC₅₀ 39.0 µg/ml) activities. None of the compounds was active against Leishmania mexicana..     

Synthesis of pyrazolo [4,3-c] pyridazine and isoxazolo [3,4-d] pyridazine derivatives

Arylhydrazones of diethyl acetonedicarboxylate3 was treated with formaldehyde to give 1-aryl-1,4,5,6-tetrahyeheypyridazine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4-d] 1,4,5,6-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave pyrazolote [4,3-c] pyridazine6. On the other hand compound 3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-3,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbzide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Synthesis and antimicrobial activities of 2-azetidinyl-4-quinazolinone derivatives of diclofenac analogue

A new class of 2-azetidinyl-4-quinazolinones 6a–k was synthesized by multi-step process, starting from 2-[2-(2,6-dichlorophenyl)amino]phenyl acetic acid 1. Acid 1 was easily converted to acid chloride 2, which on cyclization reaction with 5-bromo anthranilic acid yielded benzoxazinone 3. The condensation reaction of 3 with benzene-1,4-diamine afforded 4-quinazolinone 4. Finally the title compound 6a–k was synthesized from 4-quinazolinone 4 by Schiff base formation 5a–k with aromatic aldehyde and then cyclization reaction with chloroacetylchloride. The in vitro antimicrobial activity of compounds 5a–k and 6a–k were tested. These compounds showed pronounced antimicrobial activity when 4-Cl and 4-OCH ₃ groups were present.     

Synthesis of sulphonic acids and sultam derivatives

Reaction of propane-1,3-sultone with amines gave N-substituted aminosulphonic acids2a?i. Dehydration of2a?c with POCl₃ gave the corresponding sultams3a?c. Propane-1,3-sultone1 reacted with tertury amines to give the betaiene salts4–11. 2,4-Dimethyl-1,3-butadiene-1,4-sultone12 condensed with amines to give N-substituted-2,4-dimethyl-1,3-butadiene-1,4-sultams13a and13b. The reaction of3a, 13a with hydrazine hydrate gave acid hydrazides3d or13c. Compounds3d, 13c reacted with isocyanates to yield urea derivatives14a?c, 15a?c.