Dibenzodiazepines in reactions of 2-acetyl-dimedone with 3,4-diaminobenzophenone

The reactions of 2-acetyldimedone and 2-acetyl-3-methoxy-5,5-dimethylcyclohex-2-en-1-one with 3,4-diaminobenzophenoneproduce2-[1-(2-amino-5-benzoylphenyl)amino]ethylidene-5,5-dimethyl-1,3-cyclohexanedioneand 2-acetyl-3-(2-amino-5-benzoylphenyl)amino-5,5-dimethylcyclohex-2-en-1-one, which are cyclized by the action of hydrochloric acid, yielding the respective hydrochlorides of 8-benzoyl- and 7-benzoyl-3,3,11-trimethyl-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepin-2-ones. Hydrolytic cleavage of the 8-benzoyl derivative leads to 2-acetyl-3-(2-amino-4-benzoylphenyl)amino-5,5-dimethylcyclohex-2-en-1-one. A similar cleavage to form 2-acetyl-3-(2-aminophenyl)amino-5,5-dimethylcyclohex-2-en-1-one is observed for the known hydrochloride of 3,3,11-trimethyl-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepin-2-one. The structures of the products were confirmed by PMR spectra and x-ray diffraction data.Riga Technical University, Riga LV-1658. Latvian Institute of Organic Chemistry, Riga LV-1006. University of Cincinnati, Ohio, USA. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 379–391, March, 1997.     

11-Aryl-3,3-dimethyl-7- and 7,8-Substituted 1,2,3,4,10,11-Hexahydro-5H-dibenzo[b,e]-1,4-diazepin-1-ones

In reactions of 3-(5- and 5,6-substituted 2-aminophenylamino)-5,5-dimethylcyclohex-2-en-ones with carbaldehydes of pyridine, thiophene, and furan and substituted benzaldehydes, we have obtained 21 novel 7H-7-methoxycarbonyl-, 7-benzoyl-, 7-trifluoromethyl-, 7-nitro- and 7,8-dichloro-11-aryl-3,3-dimethyl-1,2,3,4,10,11-hexahydro-5H-dibenzo[b,e]-1,4-diazepin-1-one.     

Dibenzo[b,e][1,4]diazepin-1-Ones,Synthesis and Derivatization

Several linearly fused tricyclic 6,7,6-systems were prepared. Reaction of 1,2-diamino-4-nitrobenzene with 5,5-dimethylcyclohexan-1,3-dione gave 3-(2-amino-5-nitroaniIino)-5,5-dimethylcyclohex-2-en-1-one (8) . Reaction of 8 and its analogue 6 with various aldehydes gave 2,3,4₎5,10,11-hexahydro-3,3-dimethyl-11-substituted-1H-dibenzo[b,e][1,4]diazepin-1-ones 9 and 10 . Acetylation of 9 and 10 gave the corresponding N-acetyl derivatives. Spectral data of the products are discussed.     

Reactions of 2-cyano-3-ethoxy-5,5-dimethyl-2-cyclohexen-1-one with 2-amino- and 2-hydrazionobenzimidazoles

The reactions of 2-cyano-3-ethoxy-5,5-dimethyl-2-cyclohexen-1-one with 2-amino- and 2-hydrazinobenzimidazoles gave 1-oxo-3,3-dimethyl-11-amino-1,2,3,4-tetrahydroquinazolino[3,2-a]benzimidazole and 2-(2-benzimidazolyl)-3-amino-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydroindazole, respectively.Riga Technical University, Riga LV-1658. Latvian Institute of Organic Synthesis, Riga LV-1006. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 235–240, Feburary, 1997.     

Conversion of acetamido- and nitro-substituted ortho-azidonitro derivatives of 2,3,4,5-tetrahydrobenzo [b][1,4]dioxocin to the corresponding furoxans and furazans in the gas phase

Electron impact ionization of the five isomeric 2,3,4,5-tetrahydro-9-azido-7,8-dinitro-, 2,3,4,5-tetrahydro-8-azido-7,9-dinitro-, 2,3,4,5-tetrahydro-8-azido-7,10-dinitro-, 2,3,4,5-tetrahydro-7-azido-8,9-dinitro-, 2,3,4,5-tetrahydro-7-azido-8,10-dinitro- and the related 2,3,4,5-tetrahydro-7-acetamido-8-azido-9-nitro-, 2,3,4,5-tetrahydro-7-acetamido-9-azido-8-nitro-, 2,3,4,5-tetrahydro-9-acetamido-7-azido-8-nitro-, 2,3,4,5-tetrahydro-10-acetamido-7-azido-8-nitrobenzo[b] [1,4]dioxocin derivatives furnished, after elimination of nitrogen, the corresponding nitro and acetamido dioxocino-annelated benzofuroxans. Further loss of oxygen from the latter afforded the corresponding benzofurazans. It was shown in two cases that these processes occur primarily upon electron impact ionization, without excluding some small fraction undergoing a thermal degradation process. The proposed fragmentation patterns are supported by high-resolution and mass-analyzed ion kinetic energy spectroscopic data. Similar work on the unsubstituted 6,7-dihydro[1,4]dioxino[2,3-f]- and 7,8-dihydro-6H-[1,4]dioxepino[2,3-f]-2,1,3-benzoxa-diazole 1-oxide reveal that loss of oxygen from the molecular ion to furnish the corresponding benzofurazans is the result of electron impact ionization (at least in part).     

Reaction of 2-formyl-1,3-cyclanediones with N,N′-substituted 1,1-diamino-2-nitroethylenes

Reaction of 2-formyldimedone and 2-formyl-1,3-indanedione with 1,1-di(2-hydroxyethylamino)- and 1,1-di(4-morpholyl)-2-nitroethylenes produces 2-[3,3-di(2-hydroxyethylamino)-2-nitroprop-2-en-1-ylidene]- and 2-[3,3-di(4-morpholyl)-2-nitroprop-2-en-1-ylidene]-5,5-dimethyl-1,3-cyclohexanediones and the 1,3-indanediones, respectively. The reaction of the same 2-formyl-1,3-cyclanediones with 2-nitromethyleneimidazolidine yields 8,8-dimethyl-4-nitro-6-oxo-1,2,3,6,7,8-hexahydroimidazo[1,2-a]quinoline and 4-nitro-6-oxo-1,2-dihydro-6H-imidazo[1,2-c]-4-azafluorene.Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lanet.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 330–333, March, 1999.     

Hapten synthesis for (+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tet rahydro-8H-pyrido[4',3':4,5]thieno[3,2-f] triazolo[4,3-a][1,4]diazepine (E6123).

(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4, 5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f]triazolo[4,3-a] [1,4]diazepine (E6123) is a very potent platelet-activating factor (PAF) receptor antagonist and shows potent anti-PAF activities at the microgram level in a variety of animal models. In order to examine the pharmacokinetics of E6123 at low doses, establishment of a radioimmunoassay is required. On the basis of the metabolic pattern of E6123, we synthesized 6-[2-chloro-4-(3-carboxypropyl) phenyl]-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H -pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 22 as a potential hapten. In the synthesis of 22, we developed butynyl carbamate as a piperidine ring N-protecting group to prevent possible side reaction, namely oxidation of the methylene at position 2. This protecting group is stable under usual basic and acidic conditions.     

Synthesis and Biological Evaluation of Some Novel N,N ′-Bis-(1,2,4-Triazin-4-Yl)Dicarboxylic Acid Amides and Some Fused Rings with 1,2,4-Triazine Ring

Some of novel N , N '-bis-(1,2,4-triazin-4-yl)dicarboxylic acid amides ( 2-5 ) and thiadiazolo[2,3- b ][1,2,4]triazin-7-yl carboxylic acid derivatives ( 6 , 7 ) were prepared by heating 4-amino-6-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine ( 1 ) with different dicarboxylic acids (oxalic, malonic, fumaric, maleic, succinic, and phthalic acids respectively) in POCl 3 . Refluxing 1 with 1-chloro-2,4-dinitrobenzene in DMF yielded 3-methyl-6-nitro-10 H -benzo[1,2,4]thiadiazino[2,3- c ][1,2,4]triazin-4-one ( 8 ). Condensation of 1 with 2,4-pentandione in refluxing acetic acid furnished 6-methyl-4-(1-methyl-3-oxobut-1-enylamino)-3-thioxo-3,4-dihydro-2 H -[1,2,4]triazin-5-one ( 9 ). 3,8-D imethyl[1,2,4] triazino[3,4- b ][1,3,4]thiadiazine-4,7-dione ( 11 ) was prepared by refluxing 1 with 2-bromopropionyl bromide in anhydrous benzene to afford the corresponding N -acetylated derivative 10 , which was cyclized by using triethylamine. Also, some triazinylquinazolinones 13a , b were obtained by fusion of 1 with 6-bromo(and/or 6,8-dibromo)-2-methyl-3,1-benzoxazin-4 H -ones.     

Diastereoselective Pictet-Spengler approach for the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-one peptide turn mimics

Sixteen pyrrolo[3,2- e][1,4]diazepin-2-ones 1 were synthesized in 4-5 steps and 5-48% overall yields from 4-oxoproline 8 by a route featuring a diastereoselective Pictet-Spengler reaction to close the seven-membered diazepinone ring. Crystallographic analysis of pyrrolo[3,2- e][1,4]diazepin-2-one 1b by X-ray diffraction demonstrated that the alpha-amino acid residue adopted dihedral angle geometry similar to an ideal gamma-turn, illustrating the potential for employing these novel heterocycles as peptide turn mimics.     

Synthesis of 6-acetylhomopterin. A naturally occurring pyrimido[4,5-b][1,4]diazepine

2-amino-4-oxo-6-acetyl-3,4,7,8-tetrahydro-3H,9H-pyrimido- [4,5-b][1,4]diazepine (or 6-acetylhomopterin), has been synthesised from 1-amino-4,4-diethoxy-3-pentanol and 2-amino-4-chloro-5-nitro-6(1H)-pyrimidinone.     

10-Aryl-7,7-dimethyl-5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones

In reactions of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one with aromatic aldehydes (2- and 4-hydroxy-, 2-hydroxy-3-methoxy-, 4-dimethylamino-, 4-methoxy-, 2,4- and 3,4-dimethoxy-, 3,4-methylenedioxy-, 4-bromo-, 4-fluoro-, 4-chloro-, 2-nitro- and 3-nitrobenzaldehydes, furfural, and 2-thiophenecarbaldehyde), we have obtained the corresponding 10-aryl-7,7-dimethyl-5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones.     

A CONVENIENT SYNTHESIS OF 2-AMINO-5,6,7,8,-TETRAHYDRO-5-OXO-4-ARYL-7,7-DIMETHYL-4H-BENZO-[b]-PYRAN-3-ETHYLCARBOXYLATES UNDER MICROWAVE IRRADIATION

A series of 2-amino-5,6,7,8-tetrahydro-5-oxo-4-aryl-7,7-dimethyl-4H-benzo-[b]-pyran-3-ethylcarboxylates were synthesized by reaction of β-cyano-β-carbothoxy styrene and 5,5-dimethyl-1,3-cyclo-hexanedione under microwave irradiation without catalyst and solvent.     

Electron Ionization Mass Spectra of Organophosphorus Compounds Part I: The Mass Fragmentation Pathways of Cyclic α-Aminophosphonates Monoester Containing 1,2,4-Triazinone Moiety

Abstract

The electron impact induced fragmentation reactions of 3-(4-chlorophenyl)-3,4- dihydro-2-ethoxy-2-oxido-7-methyl-2H,6H-[1,2,4]triazino[4,3-e][1,4,5,2]thiadiazaphosphin in-6-one (1), 3,7-dimethyl-2-ethoxy-2-oxido-1,2,3,4-tetrahydro-6H-[1,2,4]triazino[4,3-b][1,2,4,5]triazaphosphinin-6-one (2), and 9-amino-3,7-dimethyl-4-ethoxy-4-oxido-2,3,4,9-tetrahydro-8H-[1,2,4]triazino[3,2-c][1,2,4,5]triazaphosphinin-8-one (3) are presented and compared. The 1,2,4-triazine rings have almost identical fragmentation routes. The 1,2,4-triazine rings are rather stable relative to the phosphorus rings. Therefore, fragmentation of the phosphorus rings is more favorable for the compounds than the stable 1,2,4-triazine rings.     

Synthesis of imidazo[4,5-e][1,4]diazepine-8-one

We have developed a method for synthesis of 1-methyl-4,5,7, 8-tetrahydro-6H-imidazo[4,5-e][1,4]diazepin-8-one. We have shown that in intramolecular cyclization of N-(2-hydroxyethyl)- or N-(2-chloroethyl)amides of 1-methyl-4-aminoimidazolyl-5-carboxylic acids it is not the corresponding tetrahydroimidazo[4,5-e][1,4]diazepin-8-ones which are formed but rather the isomeric 4-amino-5-(oxazolin-2-yl)imidazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1203–1206, September, 1993.     

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.     

无外加催化剂条件下2-氨基-3-腈基-4-芳基-7,7-二甲基-5-氧 代-4H-5,6,7,8- 四氢苯并-[b]-吡喃-3-羧酸乙酯的合成

亚苄基氰基乙酸乙酯(1)与5,5-二甲基-1,3-环已二酮在乙二醇中不加任何催化剂于80℃反应2～3h得2-氨基-4-芳基-7,7-二甲基-5-氧化-4H-5,6,7,8-四氢苯并-[b]-吡喃-3-羧酸乙酯(3),产率75%～93%。     

Derivatives of condensed pyrimidine,pyrazine, and pyridine systems

Reaction of 2-mercapto-3-amino-5,6-dimethyl- and 2-mercapto-3-amino-5,6-diphenylpyrazines withα-halo acid esters gave 2-carbethoxy-3-aminopyrazines, which are converted by the action of sodium ethoxide to 5,6-dimethyl- and 5,6-diphenylpyrazino[2,3-b]-[1,4]thiazin-6-ones. The latter are more conveniently obtained from 2-chloro-3-amino-5,6-dimethyl- and 2-chloro-3-amino-5,6-diphenylpyrazines and thioglycolic acid. 5,6-Dihydropyrazinothiazine is formed by reduction of 5,6-dimethyl pyrazino[2,3-b][1,4]thiazin-6-one, whereas the 2,3-dimethyl-5-amino-6-sulfonic acid and its N-oxide are formed by oxidation.     

Synthesis of 4-Amino-6-R-4,5-dihydro-3-phenacylthio-1,2,4-triazin-5-ones and 8H-3-R-7-Aryl-1,2,4-triazino[3,4-b][1,3,4]thiadiazin-4-ones

A study was carried out on the reaction of 4-amino-6-R-2,3,4,5-tetrahydro-3-thioxo-1,2,4-triazin-5-ones with halo ketones in alkaline media to yield 4-amino-6-R-4,5-dihydro-3-phenacylthio-1,2,4-triazin-5-ones, which then convert to 8H-3-R-7-aryl-1,2,4-triazino[3,4-b][1,3,4]thiadiazin-4-ones.     

Structure-activity studies on triazolothienodiazepine derivatives as platelet-activating factor antagonists.

A series of triazolodiazepines was synthesized and evaluated for anti-platelet activating factor (PAF) activities. Structure-activity relationship (SAR) studies on this series revealed that the introduction of a methyl group into the 8-position of the thienodiazepine nucleus can lead to a lengthening of the duration of action. Introduction of a methyl group produced an asymmetric center and the enantiomers so formed were separated with an optical resolving column. In the in vitro assay system, the (+)-isomers displayed 50-200 times more potent anti-PAF activity than the (-)-isomers. After comparison of toxicology and pharmacokinetics, (+)-6-(2-chlorophenyl)-3- cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4' ,3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (35(+)-isomer, E6123) was selected from among the compounds synthesized as a candidate for clinical study.     

Investigation of the products of interaction of cyclic diketones with nitrogen-containing 1,4-binucleophiles

The interaction of arylbis(5,5-dimethylcyclohexane-1,3-dion-2-yl)methanes with o-phenylenediamine and o-aminophenol leads to the preparation of 3,3-dimethyl-11-aryl-2,3,4,5,10,11-hexahydrobenzo[b,e]-1,4-diazepin-1-ones and 3,3,6,6-tetramethyl-9-aryl-10-(2-hydroxyphenyl)-2,4,5,7,9-decahydroacridine-1,8-diones respectively. A one-pot method is proposed for the synthesis of derivatives of hexahydrodibenzo[b,e]-1,4-diazepin-1-ones. The structure of the first member of this series was confirmed by X-ray diffraction analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1798–1808, December, 2004.