A step forward in the field of drug design: 1,5-benzothiazepines and their nucleosides

(±)cis-2-(4-methoxyphenyl)-3-hydroxy/methoxy-6-methoxy/8-methoxy-2,3-dihydro-1,5-benzothiazepin-4-[5H/5-chloroacetyl/5-(4′-methylpiperazino-1′)acetyl]-ones and nucleosides viz; (±)cis-2-(4-methoxyphenyl)-3,6-dimethoxy-2,3-dihydro-1,5-benzothiazepin-4-[5-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)]-one and (±)cis-2-(4-methoxyphenyl)-3,8-dimethoxy-2,3-dihydro-1,5-benzothiazepin-4-[5-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)]-one have been synthesized by the condensation of substituted-2-aminobenzenethiols with methyl (±)trans-3-(4-methoxyphenyl)glycidate in xylene and by stirring the 3-methoxy derivative of 1,5-benzothiazepin-4(5H)-ones with sugar namely β-D-ribofuranosyl-1-acetate-2,3,5-tribenzoate at 155–160 °C in vacuo for 10 hours, respectively. The synthesized compounds have been characterized by the elemental analyses and spectral data and screened for their antimicrobial activity.     

Chlorination of 4-methyl-8-methoxy-2,3-dihydro-1H,1,5-benzodiazepin-2-one

The results of the chlorination of 4-methyl-8-methoxy-2,3-dihydro-1H,1,5-benzodiazepin-2-ones are compared with the results of quantum-chemical calculations of 4-methyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones with various substituents in the benzene ring in the case of homolytic halogenation. The chlorination of 4-methyl-8-methoxy-2,3-dihydro-1H-1,5-benzodiazepin-2-one (I) with N-chlorosuccinimide leads to 3-chloro- and 3,3-dichloro-4-methyl-8-methoxy-2,3-dihydro-1H-1,5-benzodiazepin-2-ones, whereas chlorination with sulfuryl chloride leads to 4-chloromethyl and 3,3-dichloro-4-methyl derivatives. The IR, PMR, and mass spectra of the synthesized compounds are presented.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1272–1274, September, 1981.     

Synthesis and antimicrobial activity of 2,4-diaryl-2,3-dihydrobenzo[b][1,4]thiazepines

A new series of structurally diverse 2,3-dihydrobenzo[b][1,4]thiazepines (2,3-dihydro-1,5-benzothiazepines) with substituted phenyl groups at C(2) and C(4) have been synthesized by reaction of 3-(5-bromo-2-methoxyphenyl)-1-arylpropen-1-ones with 2-aminobenzenethiols. The structures of all the synthesized compounds were confirmed by their analytical and spectral data (IR, ¹H NMR, ¹³C NMR). All the synthesized compounds were evaluated for antibacterial and antifungal activity against a variety of bacterial and fungal strains and interesting results were obtained. Some of the compounds had antibacterial and antifungal activity comparable to that of ciprofloxacin and fluconazole.     

Formylation of 4-aryl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones

The formylation of 8-chloro- and 8-methoxy-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones with the Vilsmeier reagent leads to 3-dimethylaminomethylene derivatives which, in the case of the 8-chloro derivative, have been converted by hydrolysis in acetic acid into 8-chloro-3-formyl-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones.Translated from Khimiya Geterotsiklicheskaya Soedinenii, No. 9, pp. 1262–1265, September, 1984.     

Reaction of 2,3-Dihydro-1,5-benzothiazepines and Phenylacetyl Chloride in the Presence of Triethylamine： A New Aspect on the Formation Mechanism of Dihydro-1,3-oxazin-4-one Derivatives

2a,4-Disubstituted 2,2a,3,4-tetrahydro-2-phenyl-1H-azeto[2,1-d][ 1,5]benzothiazepin-1-ones, as well as 2-substi-tuted 2,3-dihydro-3-phenylacetyl-2-styryl-benzothiazoles and 4a,6-disubstituted 3- .benzyl-4a,5-d/hydro-2-phenyl-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, were obtained from the reaction of 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines with phenylacetyl chloride in the presence of triethylamine. The mechanism for the formation of 4a,5-dihydro-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, 2,3-dihydro-1,3-oxazin-4-one derivatives, was suggested.     

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.     

Oxazepines ano Thiazepines,XVII New Procedures for the Preparation of 2,3-Oihydro-1,5-Benzothiazepin-4(5H)-Ones Substituted in Position 2

Abstract

2,3-Dihydro-2-aryl-1,5-benzothiazepin-4(5)-ones and 2,3-disubstituted 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones have hitherto been synthesized by heating the mixture of 2-aminothiophenol and appropriately sub-stituted acrylic acids without solvent.^2–7 This is a very simple and convenient method, but because of the accompanying decompositions, the yield of the reaction is generally quite poor (20 ? 40%). For this reason, it seemed expedient to work out new procedures for the synthesis of these biologically important benzothiaze-pines. Preparation of 2,3-dihydro-2-phenyl-1,5-benzothia-zepin-4(5H)-one (20) was achieved by the ring enlargement of 1-thioflavanone⁸ but, because of the difficulties in the synthesis of the 1-thiochromanone deriva-tives in some cases, this procedure could hardly be generalized.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XX. Synthesis of 2H-pyrano[2,3-f]quinazoline derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-6-aminomethylene-7,8-dihydro-(2-methyl)(2-phenyl)quinazolin-5(6H)-ones III , prepared in good yields from 7,8-dihydro-(2-methyl)-(2-phenyl)quinazolin-5(6H)-ones via their 6-hydroxymethylene derivatives I and II , gave in satisfactory to excellent yields N-N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-(8-methyl)(8-phenyl)-2H-pyrano- [2,3,-f]quinazolin-2-ones IV , which are derivatives of the new heterocyclic system pyrano[2,3-f]quinazoline. This cycloaddition occurred both in the case of aliphatic and aromatic N-substitution only with 2-phenyl-enaminones III , whereas with 2-methyl derivatives III the reaction took place only in the case of aromatic N-monosubstitution. Dehydrochlorination of IV with DBN afforded, generally in excellent yields, N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-y]quinazolin-2-ones, which were dehydrogenated with DDQ to give N,N-disubstituted 4-amino-3-chloro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-f]quinazolin-2-ones in excellent yields.     

Solution-phase parallel synthesis of 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones

Practical and efficient parallel methods have been developed for the synthesis of 7,8-disubstituted 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones and 3,7,8-trisubstituted 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones. This benzothiazepin-4(5H)-one skeleton possesses three or four diversity points. Furthermore, three novel tricycles integrating a benzothiazepin-4(5H)-one scaffold with other privileged structures, such as benzimidazole, benzimidazolone, and thio-benzimidazole, were also developed. The synthetic strategy provides an efficient way to access the benzothiazepinone core, starting from commercially available 1,5-difluoro-2,4-dinitrobenzene (DFDNB), and also allows further derivation of the strategically anchored functionalities.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones VII. Synthesis of 2H,5H-[1]benzothiopyrano[4,3-b]pyran and 2H,5H-thiopyrano[4,3-b]pyran derivatives

The dipolar 1,4-cycloaddition of dichloroketerie to N,N-disubslituled 3-aminomethylene-2,3-dihydro-4-thiochromanones and 3-aminomethylenetelrahydro-4-thiopyranones gave N,N-disubstituted 4-amino-3,3-diehloro-3,4-dihydro-2H,5H-[1]benzolhiopyrano[4,3-b]pyran-2-ones and 4-amino-3,3-dichloro-3,4,7,8-tetrahydro-2H,5H-thiopyrano[4,3-b]pyran-2-ones, respectively, only in the ease of aromatic or strong hindering aliphatic N-substitution. The adducts gave N,N′-disubstituted 4-amino-3-chloro-2H,5H-[1]benzothiopyrano[4,3-b]pyran-2-ones and 4-amino-3-chloro-7,8-dihydro-2H,5H-thiopyrano[4,3-b]pyran-2-ones, respectively, by dehydro-chlorination with DBN. By chromatography on neutral alumina, 3-(2,2-dichloroethylidene)-2,3-dihydro-4-thiochromanone was isolated as an unstable liquid from the reaction between dichloroketerie and 3-diethylaminornethylene-2,3-dihydro-4-thiochromanone.     

Electron impact mass spectral fragmentation patterns of 2a,4-disubstituted 5-benzoyl-2-chloro-2a,3,4,5-tetrahydroazeto[1,2-a][1,5]benzodiazepin-1( 2H)-ones

The mass spectrometric behaviour of six 2a,4-disubstituted 5-benzoyl-2-chloro-2a,3,4,5-tetrahydroazeto[1,2-a][1,5]benzodia zepin-1(2H)-ones has been studied with the aid of mass-analysed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization. All compounds show a tendency to eliminate a chlorine atom, a chlorine atom plus benzaldehyde, benzoyl radical, chloroketene or chlorine atom plus CO and H2O molecules to yield, respectively, [M-Cl]+ ions, 2a,4-disubstituted 2a,3-dihydroazeto[1,2-a][1,5]benzodiazepin-1(2H)-one ions, [M-PhCO]+ ions, 2,4-disubstituted 1-benzoyl-2,3-dihydro-1H-1,5-benzodiazepine ions, or 1,2,4-trisubstituted 1H-1,7-benzodiazonine ions, which could also be formed from [M-Cl]+ ions by loss of CO and H2O molecules simultaneously. The [M-Cl]+ ions could further lose benzoyl radical to form [M-Cl-PhCO]+ ions, or lose benzoyl amide and undergo a rearrangement to form 4,6-disubstituted 1-benzoazocine-2(1H)-one ions. The [M-PhCO]+ ions could eliminate NH to produce 2a,4-disubstituted 2,2a,3,4-tetrahydroazeto[1,2,-a]quinolin-1-one ions, which could further eliminate chloroketene, CO and/or HCl to produce some important ions, respectively. 2,4-Disubstituted 1-benzoyl-2,3-dihydro-1H-1,5-benzodiazepine ions could lose benzoyl radical to yield 2,4-disubstituted 2,3-dihydro-1H-1,5-benzodiazepine ions, which could further yield other small fragment ions by loss of propene/styrene or small fragments.     

SYNTHESIS AND ANTIMICROBIAL SCREENING OF SOME NEW 4-IMINO-3,5,7-TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES AND THEIR RIBOFURANOSIDES AS POTENTIAL CHEMOTHERAPEUTIC AGENTS

Some new nucleosides, viz. 4-imino-3,5,7-trisubstituted-1-(2′,3′,5′-tri-O-kbenzyl–β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin/e–2(1H)-ones/ thiones(VII/VIII), have been synthesized by condensation of trimethylsilyl derivatives of 4-imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin/e-2(1H)-ones/thiones (III/IV) with β-D-ribofuranosyl1-acetate-2,3,5-tribenzoate. Compounds III/IV have been synthesized by refluxing 2-amino-3-cyano-4,6-disubstituted pyridine (II) with substituted an arylisocyanate or an isothiocyanate respectively. The structure of all the synthesized compounds have been established by IR and ¹H NMR studies. These compounds have been screened for antimicrobial activities in order evaluate. The possibility of the derivatives to be used as potential chemotherapeutic agents.     

Synthesis of functionalized 2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones and their recyclization to 2,3-dihydrothieno[3,4-d]pyrimidin-4(1H)-ones

By the reaction of 6-aryl(alkyl)amino-5-cyano-2,3-dihydro-1,3-thiazin-4(10)-ones with α-halogenoketones in the presence of triethylamine, 2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones have been synthesized and their acid-catalyzed recyclization to 2,3-dihydrothieno[3,4-d]pyrimidin-4(1H)-ones has been found and studied. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:104–111, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20181     

Reaction of 2,3-tetramethylen-3,4-dihydroquinazol-4-one and its derivatives with aromatic aldehydes and furfurol

α-Aryliden-6H(nitro)- and 6,8-dibromo-2,3-tetramethylen-3,4-dihydroquinazol-4-ones were synthesized by condensation of 6H(nitro)- and 6,8-dibromo-2,3-tetramethylen-3,4-dihydroquinazol-4-ones with aromatic aldehydes, furfurol, and of α-formyl-2,3-tetramethylen-3,4-dihydroquinazol-4-one with benzaldehyde and 4-nitrobenzaldehyde in glacial acetic acid. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 342-347, May-June 2009.     

Studies on the syntheses of analgesics. Part XXXIX . Synthesis of 1,2,3,4,5,6- Hexahydro-8-hydroxy -2,6-methane-3,6,1 1-trimethyl-2,3-benzo|g| diazocine and 1,2,3,4,5,10,11,12-Octahydro-7-hydroxy-1,5-dimethylpyridazino|2,3-b| isoquinoline |studies on the syntheses of heterocyclic compounds. Part LXI |

1,2,3,4,5,6-Hexahydro-8-hydroxy-2,6-methano-3,6,1 1-trimethyl-2,3-benzo |g| diazocine (IV) and 1,2,3,4,5,10,11,12-octahydro-7-hydroxy-1,5-dimethylpyridazino |2,3-b| isoquinoline (VI) were synthesized from a common intermediate, 3-(3-methoxyphenyl)-2-butanone (VII), through several steps. Reaction of VII with ethyl bromoacetate gave the mixture of ethyl 4-keto-3-(3-methoxyphenyl)-3-methylpentanoate (XIV) and ethyl 4-keto-5-(3-methoxyphenyl)hexanoate (XV) which were hydrolyzed and condensed with methylhydrazine to give the 4,5-dihydro-5-(3-methoxyphenyl)-2,5,6-trimethyl- (XVIII) and 4,5-dihydro-6-(3-methoxy-α-methylbenzyl)-2-methylpyridazine-3(2H)one (XIX). Reduction of XVIII and XIX followed hy cyclization afforded the 2,3-benzo |g| diazocine (XXII) and the pyridazino |2,3-b| isoquinoline (XXIII) which on treatment with 47% hydrobromine acid afforded the phenolic bases (IV and VI), respectively. The mass spectrum of IV, VI, XXII and XXIII was also discussed.     

Novel syntheses of 2,3-dihydro-1,5-benzothiazepin-4(5h)-ones and 2h-1,4-benzothiazin-3(4h)-ones

Nucleophilic additions of alpha-mercaptoalkanoate esters and beta-mercaptoalkanoate acids to benzoquinone diimines, followed by cyclization with trifluoroacetic acid or 1,3-dicyclohexylcarbodiimide (DCC), provide novel, high-yielding syntheses of 2H-1,4-benzothiazin-3(4H)-ones (3a-f) and 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones (5a-c), respectively.     

Reactions of 4-acyl-1-alkoxyaryl-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones with nucleophilic reagents

4-Acetyl-1-alkoxyaryl-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones reacted with amines to give 1-alkoxyaryl-5-aryl-4-(1-R-aminoethylidene)pyrrolidine-2,3-diones. Reactions of amines with 4-benzoyl-substituted analogs involve nucleophilic attack on the C³ atom in the heteroring to produce the corresponding 3-R-amino-1-alkoxyaryl-5-aryl-4-benzoyl-2,5-dihydro-1H-pyrrol-2-ones. Reactions of the title compounds with hydrazine hydrate, regardless on the substituent on C₄, afforded 4-aryl-3-methyl(phenyl)-5-[2(4)-methoxyphenyl]-4,6-dihydropyrrolo[3,4-c]pyrazol-6-ones.     

Halogenation of Imidazo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-2-one Derivatives

Chlorination and bromination of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one and its N-methyl-substituted derivatives in acetic acid at 90–95°C leads to formation of the corresponding 5,6-dichloro(dibromo)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones. Iodination of the same substrates with ICl under analogous conditions yields 6-iodo derivatives. Chlorination of 6-iodo-1,3-dimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one is accompanied by replacement of the iodine atom by chlorine with formation of 5,6-dichloro-1,3-dimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one. Bromination of 6-bromo- and 6-chloro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones gives 5,6-dibromo- and 5-bromo-6-chloro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, respectively.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005, pp. 586–589.Original Russian Text Copyright © 2005 by Yutilov, Lopatinskaya, Smolyar, Gres’ko.     

Syntheses of some new 1,5‐benzothiazepine derivatives and their ribofuranosides as antimicrobial agents

(±)‐cis‐2‐(4‐Methoxyphenyl)‐3‐hydroxy/methoxy‐6‐ethoxy/phenoxy‐2,3‐dihydro‐1,5‐benzothiazepin‐4‐[5H/5‐chloroacetyl/5‐(4′‐methylpiperazino‐1′)acetyl]‐ones have been synthesized by the condensation of 2‐amino‐3‐ethoxy/phenoxybenzenethiol with methyl‐(±)‐trans‐3‐(4‐methoxyphenyl)glycidate in xylene. Ribofuranosides, viz. (±)‐cis‐2‐(4‐methoxyphenyl)‐3‐methoxy‐6‐ethoxy/phenoxy‐2,3‐dihydro‐1,5‐benzothiazepin‐4‐[5‐(2′,3′,5′‐tri‐O‐benzoyl‐β‐D ‐ribofuranosyl)]‐ones, have been synthesized by the treatment of 3‐methoxy derivatives of 1,5‐benzothiazepines with a derivative, sugar, viz. β‐D ‐ribofuranose‐1‐acetate‐2,3,5‐tribenzoate, in toluene in vacuo. The structures of all the synthesized ribofuranosides and their precursors have been characterized on the basis of elemental analyses and IR, ¹H NMR, and ¹³C NMR spectral data. These compounds were screened for their antimicrobial activity. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:620–625, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10051     

Chemistry of Acyl(imidoyl)ketenes: IX. Synthesis and Thermolysis of 3-Aroyl-8-chloro-1,2-dihydro-4<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones

Reactions of 3-Z-aroylmethylene-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-ones with oxalyl chloride afford 3-aroyl-8-chloro-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones and Z-3-(2-aryl-2-chlorovinyl)-6-chloro-2H-1,4-benzoxazine-2-ones. Aroyl(imidoyl)ketenes generated by decarbonylation of pyrrolobenzoxazinetriones undergo dimerization through [4+2]-cycloaddition to form 4-aroyl-3-aroyloxy-2-(2-oxo-2H-1,4-benzoxazin-3-yl)-1H, 5H-pyrido[2,1-c][1,4]benzoxazine-1,5-diones.