Tricyclic heteroaromatic systems. 5H-1,2,4-triazolo[5,1-c][1,4]benzodiazepine

The synthesis of the new tricyclic heteroaromatic system 5H-1,2,4-triazolo[5,1-c][1,4]benzodiazepine, diazaanalogue of 5H-pyrrolo[2,1-c][1,4]benzodiazepine, which is the common feature of some antitumor antibiotics, is reported. The structure of the new tricyclic system and of some of its key intermediates is assigned by means of nuclear magnetic resonance studies.     

Tricyclic heteroaromatic systems. 5H-1,2,3-triazolo[5,1-c][1,4]benzodiazepine

The synthesis of the new tricyclic system 5H-1,2,3-triazolo[5,1-c][1,4]benzodiazepine, diaza-analogue of 5H-pyrrolo[2,1-c][1,4]benzodiazepine, which is the common feature of some antitumor antibiotics, is reported. The structure of the new tricyclic system and of some of its key intermediates is assigned by means of a ¹³C nmr study.     

Synthesis of some 1,3,8-trisubstituted pyrimido[4,5-c][2,7]-naphthyridin-6-ones as potential antitumor agents

Condensation of three 2,4-disubstituted 6-aminopyrimidines with methyl 1-benzyl-4-oxo-3-piperidinecarboxylate afforded, in each case, new tricyclic, angular 1,3,8-trisubstituted pyrimido[4,5-c][2,7]naphthyridin-6-ones. 2,4,6-Triaminopyrimidine gave the 7,8,9,10-tetrahydrocyclo condensed product 5 as anticipated. However, the use of 2-amino-4-oxo- or 2,4-dioxo-6-aminopyrimidine afforded the dehydrogenated, 9,10-dihydrotricyclic products 11 and 12 . The growth of leukemia L1210 cells in culture were inhibited 50% by the 1,3-diamino analog 5 at 2 × 10⁻⁶M and by the 1,3-dioxo analog 12 at 10⁻⁵M.     

Benzimidazo[1,2-c]quinazoline dimers as potential antitumor agents

The 6-substituted benzimidazo[1,2-c]quinazoline 1 is a lead structure from our DNA intercalator program and is cytotoxic to the human colon cancer tumor line HT-29 with an inhibitory concentration 50, IC₅₀ of 4.00 μM. In order to try and improve the limited cytotoxicity of this class of compound we prepared a series consisting of two benzimidazo[1,2-c]quinazoline moieties linked by a polyalkylamino bridge, of different length and substitution. The compound with the -NH-(CH₂)₃-N(CH₃)-(CH₂)₃-NH-bridge had an inhibitory concentration 50, IC₅₀ of 0.5 μM. When tested in vivo, however, no clear anti-tumor activity was produced in the human breast cancer tumor line MX-1 or the human melanoma tumor line LOX, human tumor xenografts models.     

Tricyclic heteroaromatic ring systems II A convenient synthesis of 1H-pyrrolo[3,2-c]quinolines

Various quinol-4-yl hydrazones on heating in high boiling solvents undergo cyclizations to give lH-pyrrolo[3,2-c]quinolines in good yields. Some of these pyrroloquinolines were alkylated to provide their N-alkyl derivatives.     

Synthesis of 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones

The syntheses of the 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones 3, 4 , and 5 are described. The 7-phenyl group was introduced by phenylation of the lactam nitrogen in 10, 13 and 16 respectively. One of these compounds, 5 , showed moderate activity as a CNS agent.     

Tricyclic thiazolo[3,2-a]thiapyrano[4,3-d]pyrimidines and related analogs as potential anti-inflammatory agents

A series of novel tricyclic thiazolo[3,2-a]thiapyrano[4,3-d]pyrimidines and related oxa, aza and carbo analogs of general formula 1 were prepared by a convenient addition-cyclization reaction involving 2-amino-2-thiazoline ( 4 ) and bisarylidene ketones of formula 3. Some of these compounds demonstrated antiinflammatory activity.     

Cascade synthesis of polyoxygenated 6H,11H-[2]benzopyrano-[4,3-c][1]benzopyran-11-ones

2-(methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.     

Tricyclic heteroaromatic systems. 1,2,4-triazolo[1,5-a]quinoxaline

The parent 1,2,4-triazolo[1,5-a]quinoxaline was prepared by a few-step reaction from ethyl N¹-(2-nitrophenyl)-N³-ethoxalyloxamidrazonate, which afforded the key intermediate diethyl 1-(2-nitrophenyl)-1,2,4-triazole-3,5-dicarboxylate in satisfactory yield. The latter was cyclized, hydrolyzed, decarboxylated, reduced and dehydrogenated to yield the title compound.     

Synthesis of some substituted triazolo[4,3-b][1,2,4]triazines as potential anticancer agents

The synthesis of some 3-substituted amino-6,7-diphenyl-1,2,4-triazolo[4,3-b][1,2,4]triazines (15) by cyclodesulfurisation of the corresponding N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-[substituted thio (carbamoyl)]hydrazines (3) using dicyclohexylcarbodiimid (DCC) and mercuric chloride is described. Moreover, trials to prepare 3-substituted amino-7-hydroxy-6-methyl-1,2,4-triazolo[4,3-b][1,2,4]triazines were not successful.

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Synthese einiger substituierter Triazolo[4,3-b][1,2,4]-triazine als potentielle Antikrebswirkstoffe

Zusammenfassung Es wird die Synthese einiger 3-substituierter Amino-6,7-diphenyl-1,2,4-triazolo[4,3-b][1,2,4]-triazine (15) mittels Cyclodesulfurisierung der entsprechenden N-(5,6-Diphenyl-1,2,4-triazin-3-yl)-N-[subst.thio(carbamoyl)]-hydrazine (3) unter Verwendung von Dicyclohexylcarbodiimid (DDQ) beschrieben. Versuche zur Herstellung von 3-substituierten Amino-7-hydroxy-6-methyl-triazolo[4,3-b][1,2,4]-triazinen schlugen fehl.

     

Thiazolo[4,3-c][1,4]benzodiazepines. I. Synthesis of amidine derivatives

Reactivity of 1,2,3,10,11,11a-hexahydro-5H-thiazolo[4,3-c][1,4]benzodiazepin-5-one-11-thione and 1,2,3,10,11,11a-hexahydro-5H-thiazolo[4,3-c][1,4]benzodiazepine-5,11-dithione was evaluated against various amines. The synthetic pathways involved in these reactions which led to new thiazolo[4,3-c]-[1,4]benzodiazepine amidines are described.     

Synthesis of some substituted tetrahydropyrimido[4,5-b][1,6]naphthyridines as potential antitumor agents

Cyclocondensation of two disubstituted 6-aminopyrimidines 11 and 12 with 1-benzyl-3-hydroxymethylene-4-piperidone afforded new tricyclic, linear disubstituted 6,7,8,9-tetrahydropyrimido[4,5-b][1,6]naphthyridines 4 and 5 respectively. Similar cyclocondensation of 11 with 1-benzoyl-1,2,3,6-tetrahydropyridine-5-carboxalde-hyde gave the corresponding benzoylated tetrahydropyrimido[4,5-b][1,6]naphthyridine 6 . Debenzoylation of 6 afforded 7 . 1-Benzyl-3-aminomethylene-4-piperidone when cyclocondensed with 11 also afforded 4 . The linear structures were established by ¹H nmr and ¹³C nmr. The growth of leukemia L1210 cells in culture was inhibited about 50% by 4,5,6 and 7 at 100 μM.     

Synthesis of substituted tetrahydropyrimido-[4, 5-b][1, 7]naphthyridines as potential antitumor agents

The synthesis of two linear trisubstituted 6, 7, 8, 9-tetrahydropyrimido[4, 5-b][1, 7]naphthyridines 1 and 3 were accomplished by the regiospecific cyclocondensation of two disubstituted 6-aminopyrimidines 10 and 11 with the ketoaldehyde 1-benzyl-4-hydroxymethylene-3-piperidone. Catalytic debenzylation of 1 afforded the disubstituted compound 2 . The linear structures of 1–3 were established by ¹H nmr and 13C nmr.     

The synthesis of [1]benzothieno[2,3-c]quinolines, [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline,and [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline

Photocyclization of 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamide 10 afforded [1]benzothieno[2,3-c]-quinolin-6(5H)-one 11 which was chlorinated to 6-chloro[1]benzothieno[2,3-c]quinoline 12 followed by dechlorination to give [1]benzothieno[2,3-c]quinoline 5 . A series of 6-substituted alkoxy and thioalkoxy[1]benzothieno[2,3-c]quinoline derivatives were prepared along with the N-methyl quaternary salt 13 of 5 . 6-Chloro[1]-benzothieno[2,3-c]quinoline 12 was converted into 6-hydrazino[1]benzothieno[2,3-c]quinoline 23 which upon treatment with formic acid yielded [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline 6 . Treatment of 23 with nitrous acid resulted in [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline 7 . Compounds 6 and 7 are novel heterocyclic ring systems.     

[1,3]Dioxolo[5,6][1]benzothieno[2,3-c]-quinolin-6(5H)-ones

Summary The reaction of 3,4-methylenedioxycinnamic acid (1) with thionyl chloride resulted in the formation of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) and cinnamoyl chloride (3). Subsequent reaction of the former withp-substituted anilines led to the formation of 7-chloro-N-(p-substituted phenyl)-thieno[2,3-f]-1,3-benzodioxole-6-carboxamides (4a–c) which on photocyclization afforded 2-substituted [1,3]dioxolo[5,6][1]benzothieno[2,3-c]quinolin-6(5H)-ones (5a–c) in fairly good yields and high purity. The structures have been confirmed by IR,¹H NMR, and analytical methods.Accepted for presentation at the Hong Kong International Symposium on Heterocyclic Chemistry (August 13–16, 1995)     

New polyazaheterocycles. 9-Methyl-di-s-triazolo[4,3-a:4,3-c]pyrimidine and 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-a]pyrimidine

9-Methyl-di-s-triazolo[4,3-a:4,3-c]pyrimidine and 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-a]pyrimidine have been synthetized from 4-hydrazino-7-methyl-s-triazolo[4,3-c]pyrimidine. Structural assignments based on nmr, ir and chemical manipulations are discussed.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 7. [1]Benzothieno[2,3-c]naphtho[2,1-h]quinoline and [1]benzothieno[2,3-c]naphtho[2,1-h][1,2,4]triazolo[4,3-a]quinoline

The synthesis of two novel polycyclic heterocyclic ring systems via photocyclization is described. These are [1]benzothieno[2,3-c]naphtho[2,1-h]quinoline and [1]benzothieno[2,3-c]naphtho[2,1-h][1,2,4]triazolo[4,3-α]-quinoline. In the ¹H nmr spectrum the proton at position 6 is strongly deshielded in the first ring system while the proton at position 6 in the second ring system is shifted considerably upfield while the proton at position 8 in the second ring system is the most deshielded proton in that ring system. The bay regions in both ring systems are severely congested.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 8 . [1]Benzothieno[2,3-c]naphtho[1,2-h]quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline

The previously unknown polycyclic heterocyclic ring systems, namely, [1]benzothieno[2,3-c]naphtho[1,2-h]-quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline were synthesized via photocyclization of 3-chloro-N-(1′-phenanthryl)benzo[b]thiophene-2-carboxamide.     

A new derivative of 1,5-dihydropyrazolo[4,3-c][1,2,5]benzotriazepine

A new compound, 1,5-dihydro-3-methyl-7-nitro-propylpyrazolo[4,3-c][1,2,5]benzotriazepine, was synthesized by intramolecular cyclization of 5-amino-4-[(2-bromo-5-nitrophenyl) azo]-3-methyl-1-isopropylpyrazole, and it was established on the basis of the spectral data that the triazepine ring in the synthesized compound exists in two tautomeric forms — amino-azo- and hydrazone. The structure of the compound synthesized was confirmed by the data of the PMR, IR, electronic, and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1136–1139, August, 1984.