Synthesis and biological activities of new 2-substituted 1,4-benzoxazine derivatives.

A series of new 1,4-benzoxazine derivatives (XI, XII) possessing (4-phenyl-1-piperazinyl)alkyl moieties at the 2-position and related compounds (XIII) were synthesized and tested for calcium antagonistic, calmodulin antagonistic and antihypertensive activities. Various compounds had in vitro calmodulin antagonistic activity superior or comparable to that of trifluoperazine. Among these compounds, tetrahydronaphtho[2,3-b] [1,4]oxazine derivatives such as 51, 53, 54, 58, 59, 60, 73 and 75 showed potent antihypertensive effects in spontaneously hypertensive rats. Optical isomers of 51 were also synthesized and evaluated biologically. No differences in biological activities were seen between the enantiomers.     

Utilisation of electrospray time-of-flight mass spectrometry for solving complex fragmentation patterns: application to benzoxazinone derivatives

In this paper we describe the application of electrospray time-of-flight mass spectrometry (ESI-TOFMS) to structural elucidation of the fragment ions formed from a range of natural and synthetic allelochemical derivatives. The extensive mass spectrometric characterisation of ten non-glucosylated benzoxazinone derivatives using this method is described here for the first time. The analytes include six naturally occurring 1,4-benzoxazin-3(4H)-one derivatives, including the hydroxamic acids DIMBOA [2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one] and DIBOA [2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one], lactams HBOA [2-hydroxy-2H-1,4-benzoxazin-3(4H)-one] and HMBOA [2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one], benzoxazolinones BOA [benzoxazolin-2(3H)-one] and MBOA [6-methoxy-benzoxazolin-2(3H)-one] and four synthetic variations, 2'H-DIBOA [4-hydroxy-2H-1,4-benzoxazin-3(4H)-one], 2'OMe-DIBOA [2-methoxy-4-hydroxy-2H-1,4-benzoxazin-3(4H)-one], 2'H-HBOA [2H-1,4-benzoxazin-3(4H)-one] and 2'OMe-HBOA [2-methoxy-2H-1,4-benzoxazin-3(4H)-one]. Assignments of the mass spectral fragments were aided by elemental composition calculation results, comparison of structural analogues and background literature, and acquired knowledge regarding feasible structures for the compounds. The influence of substituents on the chemical reactivity of the compounds with respect to the observed MS behaviour over varying nozzle potentials is addressed and, through comparison of the structural analogues, generic fragmentation patterns have also been identified.     

Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives

Novel 1,4-dihydropyridine derivatives bearing 3-[4-(substituted amino)phenylalkyl]ester side chains were prepared and tested for their antihypertensive activity in spontaneously hypertensive rats. Most compounds showed a more potent antihypertensive effect and a longer duration of action than nicardipine. The derivatives with a benzhydrylpiperazinyl and a benzhydrylpiperidinyl group were distinctive. 2-[4-(4-Benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (4e), its 4-(4-cyano-2-pyridyl) analogue (4f), its 3-[4-(4-benzhydryl-1-piperazinyl)phenyl]propyl ester analogue (4h), its 2-[4-(4-benzhydryl-1-piperidinyl)phenyl]ethyl ester analogue (4j), and its 2-[4-(1-benzhydryl-4-piperidinyl)phenyl]ethyl ester analogue (4k) were selected as candidates for further pharmacological investigations.     

A concise synthesis of a novel antiangiogenic tyrosine kinase inhibitor

An efficient synthesis of the potent KDR inhibitor 3-[5-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-1H-indole-2-yl]quinolin-2(1H)-one (1) is described. The process features a noncryogenic indole boronation and a dicyclohexylamine-mediated Suzuki coupling.     

Novel 1,4-benzothiazine derivatives: synthesis,crystal structure,and anti-bacterial properties

In order to develop relatively small molecules as pharmacologically active molecules, novel 1,4-benzothiazine derivatives with triazole and oxazolidinone were synthesized. In this study, a series of 1,2,3-triazolylmethyl-1,4-benzothiazine derivatives were developed by exploiting a click chemistry reaction using a CuI-catalyzed Huisgen [3 + 2] cycloaddition. Starting from 2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one, a number of 1,4-benzothiazine derivatives were also synthesized using different alkylating agents to give a 4-(substituted)-2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one in good yields. The crystal and molecular structure of compound oxazolidin-2-one in basic benzothiazine was established by single-crystal X-ray diffraction. The newly synthesized products were subjected to in vitro biological evaluation. The result indicated that the compounds show convincing antibacterial activities against different microorganisms. All structures of the synthesized compounds were elucidated on the basis of spectral analyses and chemical reactions.     

Parallel solution-phase synthesis of 4H-benzo[1,4]thiazin-3-one and 1,1-dioxo-1,4-dihydro-2H-1lambda6-benzo[1,4]thiazin-3-one derivatives from 1,5-difluoro-2,4-dinitrobenzene

This paper discusses the synthesis of privileged structures 4H-benzo[1,4]thiazin-3-one and 1,1-dioxo-1,4-dihydro-2H-1lambda6-benzo[1,4]thiazin-3-one derivatives in a parallel solution-phase manner using 1,5-difluoro-2,4-dinitrobenzene. Each scaffold possesses four diversity points. A cheap and efficient oxidant, urea-hydrogen peroxide (UHP), was applied for the introduction of the sulfone group. The intramolecular cyclization to 1,1-dioxo-1,4-dihydro-2H-1lambda6-benzo[1,4]thiazin-3-one was achieved by microwave assistance or the use of an inorganic base.     

A convenient approach to heterocyclic building blocks: synthesis of novel ring systems containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one moiety

Starting from commercially available educts, a straightforward synthetic route to new heterocyclic building blocks is exemplified with the one- or two-step synthesis of tri-, tetra-, or pentacyclic ring systems. Representatives of the following novel ring systems are prepared from 3-methyl-1-phenyl-2-pyrazolin-5-one and the corresponding o-halo-arenecarbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane: pyrimidino[4',5':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':5,6]pyrano[2,3c]pyrazol- 4-(1H)-one, thieno[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':4',5']thieno[2',3':5,6]-pyrano[2,3-c]pyrazol-4(1H)-one, [1,3]dioxolo[5',6'][1]benzothieno[2',3':5,6]pyrano-[2,3-c]- pyrazol-4(1H)-one, pyridazino[4',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one and pyrazolo-[4',3':5',6']pyrido[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one. While the latter two ring systems are directly obtained due to a spontaneous intramolecular substitution reaction, in the other reactions uncyclised 4-aroylpyrazol-5-ols are produced, which are cyclised into the target heterocycles in a subsequent synthetic step (i.e. treatment with NaH in DMF). Detailed NMR spectroscopic investigations ((1)H-, (13)C-, (15)N-) with the obtained compounds were undertaken to unambiguously prove the new structures.     

1H and 13C NMR spectral study of some 3,5-bis[(E)-thienylmethylene]piperidin-4-ones

(1)H and (13)C NMR spectra have been recorded for 3,5-bis[(E)-thienylmethylene]piperidin-4-one (1a), 3',3″-dimethyl-3,5-bis[(E)-thienylmethylene]piperidin-4-one (1b), 5',5″-dibromo-3,5-bis[(E)-thienylmethylene]piperidin-4-one (1c), their 1-methyl derivatives 2a-c and 3,5-bis[(E)-thienylmethylene]-2r,6c-diphenylpiperidin-4-one (3a). For selected compounds 2D spectra have been recorded. The spectral data are used to study the configuration and conformation of these molecules. The chemical shifts are discussed in light of steric, electronic and magnetic anisotropic effects. The magnetic anisotropic effects of thiophene ring and phenyl group are noteworthy. (1)H-(1)H COSY spectrum of 2b suggests that long-range (1)H-(1)H coupling, up to seven bonds, is possible in it. HMBC spectrum of 2b displays the magnetic nonequivalence of C-2 and C-6 and protons at these carbons.     

Phosphotungstic acid mediated,microwave assisted solvent-free green synthesis of highly functionalized 2ˈ-spiro and 2, 3-dihydro quinazolinone and 2-methylamino benzamide derivatives from aryl and heteroaryl 2-amino amides

Phosphotungstic acid has been found as green catalyst for the synthesis of spiro and cyclized quinazolinones and 2-amino substituted carboxamide under microwave irradiation and solvent-free condition has been developed. The scope of the reaction has been demonstrated for a variety of aldehydes and ketones with O-amino amides such as 2-amino-benzamide, 2-amino-5-iodo benzamide, 3-aminothiophene-2-carboxamide, 3-aminobenzofuran-2-carboxamide and 2-aminopyridine-3-carboxamides. The reaction afforded spiro-, cyclized quinazolinones and 2-amino substituted carboxamide derivatives within few minutes of irradiation in excellent yield. Plausible mechanism for the formation of products is provided. Synthetic utility of 1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one 3a has been demonstrated by synthesis of 1,4-di(1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one) buta-1,3-diyne 12, 1′-((1-benzyl-1H-1,2,3-triazol-4-yl) methyl)-1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one 13 and 1′-phenyl-1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one 14 under standard protocols.     

Chemoselective synthesis and cytotoxic activity of a series of novel benzo[1,4]oxazin-3-one derivatives

That tetraacetonitrile copper perchlorate catalyzes intramolecular amidation of arenes was found to be a new strategy for construction of nitrogen-containing heterocycles and resulted in the formation of a series of novel benzo[1,4]oxazin-3-one derivatives from N-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)-2-phenoxyacetamides.This approach of heterocyclic construction proceeds in a chemoselective manner in which only benzo[1,4]oxazin-3-one derivatives were obtained by C—N bonds formation with cheap and simple copper salt catalyst under mild conditions in moderate to good yields.The biological assay of some of benzo[1,4]oxazin-3-one derivatives showed that they had moderate antiproliferative activity toward MDA-MB231 and HeLa cancer cell lines.     

Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione, the B,C,D ring core of the shermilamine alkaloids

Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione (4), from N-(4-bromo-2,5-dimethoxyphenyl)acetamide (23) is described. Oxidative cyclisation of 2,2'-disulfanediylbis[N-(2,5-dimethoxyphenyl)acetamide] (19) to 5,8-dimethoxy-2H-1,4-benzothiazin-3(4H)-one (7b) is also reported.     

Studies on organophosphorus compounds—XXVII: Synthesis of thiono-, thiolo- and dithiolactones

Unsubstituted and alkyl- or cyanosubstituted lactones such as dihydro-2(3 H)-furanone, dihydro-5-methyl-2(3 H)-furanone, dihydro-5,5-dimethyl-4-propyl-2(3 H)-furanone and tetrahydro-2,2-dimethyl-5-oxo-3furan-carbonitrile react with the dimer of p-methoxyphenylthionophosphine sulfide, 1, in anhydrous xylene or toluene to give the corresponding thionolactones, 3a-d, in good yields. Dihydro-2(3 H)-thiophenone and 1 produce dihydro-2(3 H)-thiophenthione. Aromatic lactones such as 2 H-1-benzopyran-2-one give the corresponding 2-thione. 1-Oxa-4-thiaspiro[4,5]decan-2-one, when treated with 1 at 120-125°, gave 1,4-dithiaspiro[4,5]decan-2-one and 1,4-dithias-piro[4,5]decan-2-thione. Tetrahydro-5,5-dimethyl-2-oxo-4-propyl-3-furancarboxylic acid ethyl ester reacted with 1 at 110° giving the corresponding 2-thione and 5,5-dimethyl-4-propyl-4,5-dihydrothieno[2,3-c]-1,2-dithiole-3-thione.     

The use of umbelliferone in the synthesis of new heterocyclic compounds

New coumarin derivatives, namely 7-[(5-amino-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one, 5-[(2-oxo-2H-chromen-7-yloxy)methyl]-1,3,4-thiadiazol-2(3H)-one, 2-[2-(2-oxo-2H-chromen-7-yloxy)acetyl]-N-phenylhydrazinecarbothioamide, 7-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one and 7-[(5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy]-2H-chromen-2-one were prepared starting from the natural compound umbelliferone. The newly synthesized compounds were characterized by elemental analysis and spectral studies (IR, 1H-NMR and 13C-NMR).     

A structure-activity relationship study of compounds with antihistamine activity

A structure-activity relationship (SAR) analysis of H(1)-, H(2)- and H(3)-antihistamine activity was carried out and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine, 2-(2-benzyl-4-thiazolyl)ethanamine, 2-(2-benzhydrylthiazol4-yl)ethanamine, 2-(1-piperazinyl- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole, 2-(1-piperazinyl)benzothiazole, 2-[4-(1-alkyl)piperidinyl]benzothiazole, 2-(N,N',N'-dimethylalkyl-1,2-ethanediamino)benzothiazole, 2[1-(4-aminopiperidinyl)]benzothiazole, 2-[2-phenyl-4-thiazolyl]ethanamine derivatives and selected H(1)- and H(2)-antihistamine drugs were obtained. NP TLC and RP2 TLC plates (silica gel NP 60F(254) and silica gel RP2 60F(254) silanized precoated), impregnated with a solution of aspartic acid (L-Asp) and a solution of an analogue of aspartic acid (propionic acid), were used in two developing solvents as H(1)-, H(2)- and H(3)-antihistaminic interaction models. The lipophilicity data of the examined compounds were obtained and used in the SAR assay. Biochromatographic tests using TLC plates impregnated with solutions of asparic acid or propionic acid were found to be a source of useful data for the qualitative analysis of compounds with different structures, demonstrating activity to histamine H(1)-, H(2)- and H(3)-receptors. The four presented discriminant models based on biochromatographic studies are an efficient tool in the SAR analysis for initial prediction of compound activity direction within histamine receptors.     

Benzofused tricycles based on 2-quinoxalinol

This paper describes our recent efforts to synthesize novel compound scaffolds integrating 2-quinoxalinol with privileged structures of 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-benzoimidazole-2-thione, 3-hydroxy-1H-quinoxalin-2-one, 2H-benzo[1,4]oxazin-3-ol, 2H-benzo[1,4]thiazin-3-ol, and 1,3,4,5-tetrahydro-benzo[1,4]diazepin-2-one, respectively. Eight novel benzofused tricycles and their substituent diversity points were developed. These include pyrazino[2,3-g]quinoxaline-2,8-diol (I), 3-hydroxy-6,8,9,10-tetrahydro-1,4,6,10-tetraaza-cyclohepta[b]naphthalen-7-one (II), 6-hydroxy-4H-1-oxa-4,5,8-triaza-anthracen-3-one (III), 6-hydroxy-4H-1-thia-4,5,8-triaza-anthracen-3-one (IV), 6-hydroxy-1,1-dioxo-1,4-dihydro-2H-1lambda(6)-thia-4,5,8-triaza-anthracen-3-one (V), 6-hydroxy-1,3-dihydro-imidazo[4,5-g]quinoxalin-2-one (VI), 6-hydroxy-1,3-dihydro-imidazo[4,5-g]quinoxaline-2-thione (VII), and 7-hydroxy-1,4-dihydro-pyrazino[2,3-g]quinoxaline-2,3-dione (VIII). This strategy of integrating two benzofused privileged structures into one molecule may provide a greater chance for the discovery of novel lead compounds.     

Acanmontanoside, a new phenylethanoid diglycoside from Acanthus montanus

A new phenylethanoid glycoside acylated with syringic acid, namely acanmontanoside, was isolated from the aerial portions of Acanthus montanus (Nees). T. Anderson, along with decaffeoylverbascoside, verbascoside, isoverbascoside, leucosceptoside A, (2R)-2-O-?-D-glucopyranosyl-2H-1,4-benzoxazin-3(4H)-one (HBOA-Glc), (2R)-2-O-?-D-glucopyranosyl-4-hydroxy-2H-1,4-benzoxazin-3(4H)-one (DIBOA-Glc), (3R)-1-octen-3-ol-3-O-?-D-xylopyranosyl-(1→6)-O-?-D-glucopyranoside and ebracteatoside B. The structure elucidations were based on physical data and spectroscopic analyses including 1D- and 2D-NMR.     

Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity

A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthesized and evaluated as alpha 1 adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potently exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)piperidino]butyl group at the 1-position exhibited both activities, and varied significantly in terms of the substituents at the 4-position of the pyrroloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7- methyl-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha 1-adrenergic antagonistic activity (pA2 = 8.89 +/- 0.21) and 5-HT2 antagonistic activity (pA2 = 8.74 +/- 0.22) in isolated guinea pig arteries. This compound exhibited antihypertensive activity and a duration of action equivalent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spontaneously hypertensive rats, as well as potent antiplatelet aggregation activity.     

液质联用同时测定大鼠尿液中6种苯二氮卓类药物

建立高效液相色谱串联质谱法同时测定大鼠尿液中的6种苯二氮卓类药物(BZDs).以乙酸乙酯为萃取溶剂,经液-液萃取前处理后检测.以地西泮为内标,流动相为甲醇-0.01％甲酸+5 mmol/L甲酸铵,梯度洗脱,柱温为40℃;流速为0.3 mL/min;进样量为2 μL,质谱采用电喷雾离子源正离子模式(ESI+).8-溴-1...     

A facile synthetic approach to novel spiro-oxindoles/acenaphthylen-1-ones containing benzo[1,4]thiazin-3-one ring via 1,3-dipolar cycloaddition

A series of spiro-oxindole derivatives containing spirobenzo[1,4]thiazin-3-one ring were synthesized regioselectively via a multicomponent 1,3-dipolar cycloaddition of isatin, 2-(4-methyl-benzylidene)-4H-benzo[1,4]thiazin-3-one and sarcosine or l-proline in toluene under reflux condition. Also spiro-acenaphthylen-1-ones containing spirobenzo[1,4]thiazin-3-one ring have been synthesized using 2-(4-methyl-benzylidene)-4H-benzo[1,4]thiazin-3-one as dipolarophile. The methodology affords high yields of products in short reaction time.     

Studies on antibacterial agents. I. Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids

A series of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids was synthesized and tested for antibacterial activities. Among them, 9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7241) exhibited potent antibacterial activity against gram-positive and -negative bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251) showed potent activity characteristically against Propionibacterium acnes.