Ring transformation of 1,5-benzoxazepines into spirobenzoxazoles. Synthesis of pyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines and spiro[benzoxazole-2′(3′H),4(1H)-pyrazolo[5,1-c][1,2,4]triazines]

The reactions of the 3-substituted 4-amino-8-ethoxycarbonyl[5,1-c][1,2,4]triazines 1 and 2 with o-amino-phenol hydrochloride gave the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5 and 8 . The alkylation of 5 with methyl iodide and isopropyl iodide afforded the 6-alkoxylpyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines 6a and 6b , respectively. Refluxing of 5, 6a, 6b and 8 in hydrochloric acid/acetic acid resulted in ring transformation to produce the spiro[benzoxazole-2′(3′H),4(1H)pyrazolo[5,1-c][1,2,4]-triazines] 7a, 7b and 9 . The screening data of the above compounds was described.     

A novel tetracyclic ring system. 10H-tetrazolo[5′,1′:3,4][1,2,4]triazino[5,6-b]indole

The reaction of 3-hydrazino-1,2,4-triazino[5,6-b]indole with nitrous acid affords a novel tetracyclic ring system: 10H-tetrazolo[5′,1′:3,4][1,2,4]triazino[5,6-b]indole. The mode of cyclization has been discussed.     

Facile synthesis and antifungal activity of 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

The reactions of the pyrazole-5-diazonium salt 3 with malononitrile and ethyl cyanoacetate gave 4-amino-3-cyano-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazine 7 and 4-amino-3,8-bisethoxycarbonylpyrazolo[5,1-c]-[1,2,4]triazine 8 , whose reactions with p-chloroaniline hydrochloride afforded 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)amidinopyrazolo[5,1-c][1,2,4]triazine 9 and 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)car-bamoylpyrazolo[5,1-c][1,2,4]triazine 10 , respectively. The reactions of 7 and 8 with o-phenylenediamine di-hydrochloride provided 9-ethoxycarbonyl-13H-spiro[benzimidazole-2′(3′H),6(5H)-pyrazolo[1,5′:3,4][1,2,4]tri-azino[5,6-b][1,5]benzodiazepine] hydrochloride 11a and 9-ethoxycarbonyl-6-oxo-13H-5,6-dihydropyrazolo-[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepine 12 , respectively. The antifungal activity of the above compounds was described.     

A new method for the synthesis of novel 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

Novel 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines 7,8 were synthesized by the reactions of malononitrile and ethyl cyanoacetate with the pyrazole-5-diazonium salt 3 . Moreover, compounds 7,8 were converted into the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines 9, 10 .     

On triazoles XLIV [1]. synthesis of new ring systems containing imidazo[2′,1′:3,4] [1,2,4] triazolo [1,5‐a]pyrimidine and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrimidine skeleton

Dedicated to Dr. János Császár on the occasion of his 70^th birthday Ring transformation of 2‐cyanoimido‐3‐methyl‐1,3‐oxazolidine ( 10 ) yielded 5‐amino‐3‐[N‐(2‐hydrox‐yethyl)‐N‐methyl]amino‐1H‐1,2,4‐triazole ( 6 ) that was ring closed with different β‐keto esters to 2‐[N‐(2‐hydroxyethyl)‐N‐methyl]amino‐1,2,4‐triazolo[1,5‐a]pyrimidinones ( 4 ). Cyclisation of derivatives 4 led to imidazo[2′,1′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines ( 2 ) and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrim‐idines ( 3 ) representing 10 novel ring systems. Besides spectroscopical evidence of structure of derivatives 2 and 3 X‐ray diffraction analysis of derivative 2b was also performed.     

Fused 1,2,4-triazole heterocycles. IV. Synthesis of four new heterocyclic ring systems of [1,2,4]triazolo[1,3]thiazinoquinolines

Syntheses of 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,4-c]quinolines 8, 5H-[1,2,4]triazolo[3′,4′:2)3][1,3]thiazino[5,4-c]quinolines 9, 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,6-c]quinolines 14 and 5H-[1,2,4]triazolo[3′,4′:2,3][1,3]thiazino[5,6-c]quinolines 15 are described starting from 4-chloro-3-chloromethylquinaldine (4) and 1,2,4-triazole-5-thiols 5 taking advantage of different reactivity of the chlorine atoms of 4 under different reaction conditions. The structures of products 8, 9, 14 and 15 and the intermediates leading to them were confirmed by desulfurization, unequivocal syntheses and nmr spectroscopy as well.     

Polyazasteroids II.. 1,2,4-Triazolol[3′,4′:2,3]pyrimido[4,5-c]quinolin- 11(12H)ones,imidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3] pyrimido[4,5-c]quinolin-11(12H)ones

Starting with 2-substituted quinoline-3,4-dicarboxylic acids, a series of substituted 1,2,3,4-tetrahydropyrimido[4,5-c]quinolinone-3-thiones were obtained. The latter compounds were converted to the three novel polyazasteroid series: 1,2,4-Triazolo[3′,4′:2,3]pyrimido[4,5-c]-quinolin-11(12H)ones, imidazo[2′,1′:2,3]pyrimido[4,5c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones. The intermediate 3-hydrazino-1,2-dihydropyrimido[4,5-c]quinolinones and nitrous acid gave the 3-azido derivatives rather than the tetrazolo compounds.     

Synthesis of representative 10-aryl-, 10-aralkyl- and 10-heteraryl-9H-naphtho[1′,2′:4,5]thiazolo[3,2-b]- [1,2,4]triazin-9-ones as potential anti-HIV agents

To prepare the title compounds, cyclocondensation of 1-amino-2-iminonaphtho[1,2-d]thiazole ( 2 ) with some representative glyoxylic acid derivatives was investigated. Heating 2 with methyl phenylglyoxylate ( 3a ) in methanol afforded only the open chain intermediates 4a,b . However, when this reaction was performed in re-fluxing glacial acetic acid, the expected compound, 10-phenyl-9H-naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]- triazin-9-one ( 5a ) was produced in 27% yield. Similar treatment of 2 with benzyl-, 2-furyl- and 2-thienylgly-oxylic acids 3b-d gave the corresponding 10-benzyl-, 10-(2-furyl)- and 10-(2-thienyl)-9H-naphtho[1′,2′:4,5]thi-azolo[3,2-b][1,2,4]triazin-9-ones 5b-d in 48–67% yields. As by-products, 9-benzoyl- and 9-(2-thenoyl)naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazoles 6a,d were also isolated. Compound 5a was selected for in vitro anti-HIV evaluation but found to be inactive.     

Synthesis of diimidazo[1,2-a:2′,1′-c]pyrazines and diimidazo[1,2-a:2′,1′-c] [1,4]diazepines

Two new heterocyclic compounds, diimidazo[1,2-a:2′,1-c]pyrazine and 5H-diimidazo[1,2-a: 2,1′-c][1,4]diazepine have been synthesized by various routes from 2,2′-biimidazole (1) (2) together with some hydro, hydroxy and alkyl derivatives.     

Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

Research on nitrogen containing heterocyclic compounds. XVII. Synthesis of 8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine,a novel tetracyclic ring of pharmaceutical interest

The synthesis of 8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine 6 , a novel nitrogen-containing tetracyclic ring, is reported starting from 5H-imidazo[2,1-c][1,4]benzodiazepine 7. Reaction of this compound with nitromethane and subsequent reduction of the obtained nitromethyl derivative 8 afforded 11-aminomethyl-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine 9. Treatment of the latter compound with formaldehyde led to 1,2,3,3a-tetrahydro-8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine 10 , which was then oxidized to the title compound.     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

Synthesis,structure and some reactions of 4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]‐quinazolines]

2′‐Substituted 5′,6′,7′,8′‐tetrahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 3a‐d were synthesized by condensation of 3‐substituted 5‐amino‐1,2,4‐triazoles 1a‐d with 2‐cyclohexylidene cyclohexanone 2 in DMF. The compounds 3 were hydrogenated with sodium borohydride in ethanol to give 2′‐substituted cis‐4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 4a‐d in high yields. The reactions of alkylation, acylation and sulfonylation of the compounds 4 were studied. The structure of the synthesized compounds was determined on the basis of NMR measurements including HSQC, HMBC, NOESY techniques and confirmed by the X‐ray analysis of 6 and 11b . The described synthetic protocols provide rapid access to novel and diversely substituted hydrogenated [1,2,4]triazolo[5,1‐b]quinazolines.     

Synthesis of novel 3-carboethoxy-6-methyl-4-oxo-4H-pyrimido[1′,2′:5,6]-[1,3,5]triazino[1,2-a]benzimidazoles

Reaction of 4-amino-2-methylbenzimidazo[1,2-a][1,3,5]triazines 2 with diethyl ethoxymethylenemalonate afforded 3-carboethoxy-6-methyl-4-oxo-4H-pyrimido[1′,2′:5,6][1,3,5]triazino[1,2-a]benzimidazoles 3 , a new ring system.     

[1,3]Thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines – A New Heterocyclic System Accessed via Bromocyclization

A facile access to novel condensed system of [1,3]thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5‐a]pyrimidine is presented. This protocol consists of bromine‐assisted direct electrophilic heterocyclization of 3‐N‐allylamine‐5,6‐dihydro[1,3]thiazolo[2,3‐c][1,2,4]triazole. The bromination took place in acetic acid and gave a good yield of the target product, which was dehydrobrominated by sodium acetate action.     

Polycyclic N-heterocyclic compounds. XLI. Synthesis of 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines, 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines and their related compounds as a series of potential blood platelet aggregation inhibitors

As a series of polyheterocyclic compounds for exploitation as anti-platelet agents, tricyclic heterocyclic compounds, 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines 3–6, 9, 12–14 , and 16–26 , having nitrogen, oxygen, or sulfur containing functional groups at the 4-position, were prepared. In addition, tetra-cyclic heterocyclic compounds, 3-methyl-1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzaze-pinium chloride ( 7 ), 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines 10a-e , 2,3,6,7-tetrahydro-1H 5H-pyrimido[1′,2′:1,6]pyrimido[5,4-d][1]benzazepine ( 11 ), and 1,2,5,6-tetrahydro-4H-thiazolo-[3′,2′:1,6]pyrimido[5,4-d][1]benzazepinium chloride ( 15 ) via ring closure of 4-(hydroxyalkylamino)- 6, 9a-e , and 3c , and 4-(2-hydroxyethylthio)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine ( 14 ) with phosphoryl chloride or thionyl chloride, respectively, were also prepared. Their inhibitory activities against collagen-induced aggregation of rabbit blood platelets in vitro were investigated. Among them, compound 5 having a morpholino group at the 4-position on the tricyclic nucleus, which enhanced the activity more than 14-fold as compared with aspirin, was found to have the most satisfactory in inhibitory activity.     

Cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]-thiazole with α-ketocarboxylic acid derivatives: Synthesis of 2-substituted 3-Oxo-3H-naphtho[1′,2′:4,5]thiazolo-[3,2-b][1,2,4]triazines as potential anti-HIV agents

The cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]thiazole ( 1 ) with a series of α-keto mono- and dicarboxylic acid derivatives 5a-i under different conditions was investigated. When the experiments were performed by refluxing in glacial acetic acid, the corresponding cyclized products, 2-substituted 3-oxo-3H-naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazines 4 were obtained in fair to good yields. On the other hand, when the reaction was conducted in boiling ethanol, it gave only the open chain condensates 6 , or in rare cases, together with minor amount of 4 . Since the intermediates 6 exist as mixture of both E- and Z-isomers, cyclization through heating was found insufficient. In any event representative compounds 4b,g,i have been evaluated for anti-HIV activity, but none of them were active.     

A facile synthesis of novel pyrazolo[5′,1′:3, 4]-[1, 2, 4]triazino[6, 5-f][1, 3, 4]thiadiazepines

The reaction of the 3-substituted 4-aminopyrazolo[5, 1-c][1, 2, 4]triazines 1a-d with thiosemicarbazide hydrochloride in acetic acid gave new pyrazolo[5′,1′:3, 4][1, 2, 4]triazino[6, 5-f][1, 3, 4]thiadiazepines 3, 4 and 6 , which were converted into the 5-oxo derivatives 5 and 7 by hydrolysis in hydrochloric acid/acetic acid.     

Synthesis and 13C-NMR study of novel pyrazolo[5′,1′:3, 4][1, 2, 4]triazino[5, 6-d]pyrimidines

The pyrazolo[5′, 1′:3, 4][1, 2, 4]triazino[5, 6-d]pyrimidines 5a-c, 6 were synthesized from the pyrazolo[5, 1-c]-[1, 2, 4]triazines 1a, c and the ring carbon signals of 5a-c, 6 were assigned by the aid of coupling constant [J( 13 C-¹H)] data.     

New heterocyclic structures. [1,2,5]Thiadiazolo[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazine and thiazolo[3,2a][1,2,5]thiadiazolo[3,4-d]pyrimidine

Derivatives of two new molecular structures, namely, 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one and 6,7-dihydro-9H-thiazolo[3,2-a][1,2,5]thiadiazolo[3,4-d][pyrimidin-9-one, and derivatives of N-substituted sulfamic acid, namely, (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-on-7-yl)sulfamic acid and (7-amino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-on-6-yl)sulfamic acid, were separated out as by-products in the reduction reaction of 8-amino-3,4-dihydro-7-nitroso-2H,6H-pyrimido[2,1- b][1,3]thiazin-6-one and 7-amino-2,3-dihydro-6-nitroso-5H-thiazolo[3,2-a]pyrimidin-5-one derivatives, respectively, with sodium hydrosulfite. A mechanism of reaction, which hypothesizes the action of sodium hydrosulfite in an asymmetic form, is proposed. The results of single-crystal X-ray investigation on 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one (R = 0.032 for 863 reflections) and (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b]- [1,3]thiazin-6-on-7-yl)sulfamic acid, sodium salt (R = 0.028 for 3507 reflections) are reported.