Reactions of 3-(1-arylhydrazono-L-threo-2,3,4-trihydroxybutyl)-1-methyl-2-Quinoxalinones

The 1-methyl derivatives (3 and 4) of 3-(1-phenyl- (1) and 3-(1-p-bromophenylhydrazono-L-threo-2,3,4-trihydroxybutyl)-2-quinoxalinone (2) were prepared by methylation. Periodate oxidation of 3 gave 1-methyl-3-[1-(phenylhydrazono)glyoxal-1-yl]-2-quinoxalinone (5), which, on reduction with sodium borohydride, gave the corresponding 3-[2-hydroxy-1-(phenylhydrazono)ethyl] derivative (8). Reaction of 5 with hydroxylamine or benzoylhydrazine gave the corresponding 2-oxime (6) and 2-(benzoylhydrazone) (7), respectively. Acetic anhydride causes one molecule of 3 or 4 to undergo elimination of two molecules of water, with simultaneous acetylation and ring closure to afford pyrazoles 9 and 10, respectively. Pyrolysis of the triacetate of 3 led to the elimination of acetic acid from the sugar and the hydrazone residue, to give the 3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl] derivatives (9). Acetic acid was found to effect the same rearrangement, but without acetylation, of 1, 2, and 3 to give the 3-[5-(hydroxymethyl)] derivatives 11, 12, and 13, respectively. The structure of these pyrazoles was confirmed by a series of reactions, including methylation and acetylation. The n.m.r. and i.r. spectra of the compounds were investigated.     

Isolation and identification of the intermediates during pyrazole formation of some carbohydrate hydrazone derivatives

Reaction of the oxidation product of L-ascorbic acid, dehydro-L-ascorbic acid, with o-phenylenediamine, followed by 2,4,6-trichlorophenylhydrazine (3) afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (4), whose structure was deduced from studying its periodate oxidation, which gave the glyoxal derivative 3-[1-(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one (5) that upon reduction afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-2-hydroxyethy-1-yl]quinoxalin-2(1H)one (6). The reaction of 5 with 3 afforded the bishydrazone 3-[1,2-bis(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one. The reaction of 5 with acetic anhydride in pyridine afforded the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-acetoxy-3-[2-acetyl-2-(2,4,6-trichlorophenyl)hydrazono)]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 4 with acetic anhydride in pyridine afforded the acyclic diacetate intermediate 3-[3,4-di-O-acetyl-2-deoxy-1-(2,4,6-trichlorophenylhydra-zono)but-2-en-1-yl]quinoxalin-2(1H)one (12), which was also obtained from the reaction of 4 with boiling acetic anhydride. Compound 12 rearranged under the reaction conditions to give the pyrazole derivatives 3-[5-(ace-toxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (14) and 2-acetoxy-3-[5-(acetoxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl)]quinoxaline (15), as well as the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-(2-acetoxyethen-2-yl)-3-[2-(2,4,6-trichlorophenyl)hydrazono]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 3-[5-(hydroxymethyl)-l-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (16) with acetic anhydride in pyridine or 12 with boiling acetic anhydride afforded 15 and 16, respectively. Treatment of 4 with diluted sodium hydroxide afforded the pyrazolo[2,3-b]quinoxaline (flavazole) derivative 1-(2,4,6-trichlorophenyl)-3-(L-threo-glycerol-1-yl)pyrazolo[2,3-b]quinoxaline whose acetylation afforded the acetyl derivative 3-(2,3,4-tri-O-acetyl-L-threo-glycerol-1-yl)-1-(2,4,6-trichlorophenyl)pyrazolo[2,3-b]quinoxaline. The assigned structures were based on spectral analysis. The activity of compound 4 against hepatitis B virus has been studied.     

Synthesis, cytotoxicity, and anti-inflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4

A number of 2-(furan-2-yl)-4-phenoxyquinoline derivatives have been synthesized and evaluated for anti-inflammatory evaluation. 4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde (8), with an IC(50) value of 5.0 microM against beta-glucuronidase release, was more potent than its tricyclic furo[2,3-b]quinoline isomer 3a (>30 microM), its 4'-COMe counterpart 7 (7.5 microM), and its oxime derivative 13a (11.4 microM) and methyloxime derivative 13b (>30 microM). For the inhibition of lysozyme release, however, oxime derivative 12a (8.9 microM) and methyloxime derivative 12b (10.4 microM) are more potent than their ketone precursor 7 and their respective tricyclic furo[2,3-b]quinoline counterparts 4a and 4b. Among them, 4-[4-[(2-furan-2-yl)-quinolin-4-yloxy]phenyl]but-3-en-2-one (10) is the most active against lysozyme release with an IC(50) value of 4.6 microM, while 8 is the most active against beta-glucuronidase release with an IC(50) value of 5.0 microM. (E)-1-[3-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl] ethanone oxime (11a) is capable of inhibiting both lysozyme and beta-glucuronidase release with IC(50) values of 7.1 and 9.5 microM, respectively. For the inhibition of TNF-alpha formation, 1-[3-[(2-furan-2-yl)quinolin-4-yloxy]phenyl]ethanone (6) is the most potent with an IC(50) value of 2.3 microM which is more potent than genistein (9.1 microM). For the inhibitory activity of fMLP-induced superoxide anion generation, 11a (2.7 microM), 11b (2.8 microM), and 13b (2.2 microM) are three of the most active. None of above compounds exhibited significant cytotoxicity.     

Reaction of dehydro-d-erythorbic acid and its aryl analogs with ortho-diamines

Condensation of 3-(d-erythro -2,3,4-trihydroxy-l-oxobutyl)-2-quinoxalinone and its 6-chloro derivative (obtained by the reaction of d-erythro-2,3-hexodiulosono-1,4-lactone with ortho-diamines) with aryl- or aroyl-hydrazines gave 3-[l-(phenylhydrazono)-d-erythro-2,3,4-trihydroxybutyl]-2-quinoxalinone (5) and relatives. Whereas boiling acetic anhydride causes the loss of two molecules of water per molecule of such hydrazones, affording, the 3-[5-(acetoxymethyl)-l-arylpyrazol-3-yl]-2-quinoxalinones, identical with those obtained from the l-threo isomer, alkali causes the loss of only one molecule, affording, the corresponding flavazoles. Periodate oxidation of 5 gave 3-[l-(phenylhydrazono)glyoxal-l-yl]-2-quinoxalinone, which afforded the corresponding mixed bis(hydrazones). A similar sequence of reactions was conducted with the aryl analogs, 4-phenyl-2,3-dioxobutano-1,4-lactone and its p-chlorophenyl derivative, whereby the 3-[2-aryl-l-(arylhydrazono)-2-hydroxyethyl]2-quinoxalinones, were prepared; these were transformed into 3-(α-hydroxybenzyl)-flavazoles that gave monoacetyl derivatives.     

Transformation of the hydrazones of 6-chloro-3-(l-threo-2,3,4-trihydroxy-1-oxobutyl)-2-quinoxalinone into other heterocyclic compounds

The difference in reactivity of the two amino groups in 4-chloro-o-phenylene-diamine allowed it to react with l-threo-2,3-hexodiulosono-1,4-lactone to give, after further reaction with various hydrazines, 6-chloro-3-(1-substituted-hydrazono-l-threo-2,3,4-trihydroxybutyl)-2-quinoxalinones (5-14), whose structures were deduced from their reactions, as well as from mass spectrometry of the (p-nitrophenyl)-hydrazone. Elimination of one mole of water per mole from these hydrazones gave the 1-aryl-6-chloro-3-(l-threo-glycerol-1-yl)flavazoles; the mass spectrum of one of these flavazoles is discussed. Elimination of two moles of water per mole from the hydrazones (5, 7, and 8) occurred with simultaneous cyclization to give 3-[l-aryl-5- (hydroxymethyl)pyrazol-3-yl]-6-chloro-2-quinoxalinones. whose acetylation gave the corresponding- monoacetyl derivatives (that could also be obtained by the action of boiling acetic anhydride on the starting hydrazones). Periodate oxidation of the hydrazones and the flavazole derivatives afforded the corresponding aldehydes (that could react with hydrazines).     

Indole alkoloids from Nauclea officinalis with weak antimalarial activity

Five indole alkaloids (naucleofficines A-E) were isolated from the stems (with bark) of Nauclea officinalis: (E)-2-(1-beta-d-glucopyranosyloxybut-2-en-2-yl)-3-(hydroxymethyl)-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (1), (E)-1-propenyl-12-beta-d-glucopyranosyloxy-2,7,8-trihydro-indolo[2,3-a]pyran[3,4-g]quinolizin-4,5(13H)-dione (2), (E)-2-(1-hydroxybut-2-en-2-yl)-11-beta-d-glucopyranosyloxy-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (3), (E)-1-propenyl-4-hydroxy-2,4a,7,8,13b,14,14a-hepthydro-(4alpha,4abeta,13balpha,14abeta)indolo[2,3-a]pyran[3,4-g]quinolizin-5(13H)-one (4) and 1-(1-hydroxyethyl)-10-hydroxy-7,8-dihydro-indolo[2,3-a]pirydine[3,4-g]quinolizin-5(13H)-one (10-hydroxyangustoline) (5), together with two known compounds, naucleidinal (6) and angustoline (7). All of the structures of the seven compounds above were elucidated by spectroscopic methods including use of 1D- and 2D-NMR spectroscopic analyses. Compounds 2 and 3 are rare examples of monoterpene indole alkaloids with a glucopyranosyloxy group attached to position C-12. In vitro activity screening of the above seven compounds showed weak to moderate inhibitory activity against Plasmodium falciparum.     

Discovery of novel antitubercular 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues

In search of potential therapeutics for tuberculosis, we describe herewith the synthesis, characterization and antimycobacterial activity of 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. Among the synthesized compounds, 4-[(5-[(4-fluorophenylamino]-1,3,4-oxadiazol-2-yl)methylamino]-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one (4a) was found to be the most promising compound active against Mycobacterium tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentrations, 0.78 and 3.12μg/mL, respectively, free from any cytotoxicity (>62.5μg/mL).     

Synthesis of AZT analogues: 7-(3-azido-2-hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-,7-(3-triazolyl-2-hydroxypropyl)theophylline

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Synthesis and biological evaluation of 1,3-oxathiolane 5-azapyrimidine, 6-azapyrimidine, and fluorosubstituted 3-deazapyrimidine nucleosides

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4-tr iazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3, 5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-[2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-yl] cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

Synthesis of 2',3'-dideoxy-3'-C-(hydroxymethyl)-4'-thiopentofuranosyl nucleosides as potential antiviral agent.

1-O-Acetyl-2,3-dideoxy-3-C-(hydroxymethyl)-4-thiofuranose derivative was synthesized from (S,S)-1,4-bis(benzyloxy)-2,3-epoxybutane derived from (+)-diethyl L-tartrate and the enantiomerically pure (E)-5-(2-bromovinyl)-1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-4'- thiopentofuranosyl]uracil 4 was obtained via coupling of silylated uracil followed by palladium-mediated coupling of methyl acrylate.     

A facile synthesis and anti-avian influenza virus (H5N1) screening of some novel pyrazolopyrimidine nucleoside derivatives

Treatment of 5-amino-1-(9-methyl-5,6-dihydronaphtho[1',2':4,5]thieno[2,3-d]pyrimidin-11-yl)-1H-pyrazole-4-carbonitrile (1) with formic acid afforded pyrazolo[3,4-d]pyrimidin-4-one derivative 2. The sodium salt of the latter compound (generated in situ) was treated with some alkyl halides to afford the corresponding N-substituted compounds 3-7. The siloxy derivative 8 (generated also in situ from 2) was ribosylated and glycosylated to yield compounds 9 and 11, respectively. Deprotection of compounds 9 and 11 in methanolic ammonia produced the free nucleosides 10 and 12, respectively. Moreover, the prepared compounds were tested for antiviral activity against H5N1 virus [A/chicken/Egypt/1/2006] and some of them revealed moderate results compared with the other tested compounds.     

Syntheses of 19-[O-(carboxymethyl)oxime] haptens of epipregnanolone and pregnanolone

O-(Carboxymethyl)oximes 1 and 2 derived from two epimeric 5beta-pregnanolones (3beta-hydroxy-5beta-pregnan-20-one and 3alpha-hydroxy-5beta-pregnan-20-one) in position 19 were prepared. Two synthetic routes were employed, both using protection of the 20-keto group after reduction into the (20R)-alcohol in the form of acetate. In the first route, (20R)-19-hydroxy-5beta-pregnan-3beta,20-diyl diacetate (3) was transformed into the corresponding 19-[O-(carboxymethyl)oxime] methyl ester 6, then deacetylated by acid and partially silylated with tert-butyldimethylsilyl chloride. The desired 3-O-silylated derivative 8 was separated, oxidized to the 20-ketone and protecting groups were sequentially removed to give the first title hapten 1. The second route started from (20R)-19-hydroxy-3-oxopregn-4-en-20-yl acetate (11), which was hydrogenated in the presence of base to the 5beta-pregnan-3-one derivative 12, protected in position 19 with tert-butyldimethylsilyl group and reduced with borohydride. The prevailing 3alpha-alcohol 15 was separated, protected in position 3 with a methoxymethyl group, deprotected in position 19 and transformed into the 19-[O-(carboxymethyl)oxime] 19. After deacetylation, esterification with diazomethane and oxidation in position 20, the pregnanolone skeleton was regenerated. Final deprotection steps gave the second title hapten 2. Both haptens, i.e., (19E)-3beta- and -3alpha-hydroxy-20-oxo-5beta-pregnan-19-al 19-[O-(carboxymethyl)oxime], were designed for the development of immunoassays of the corresponding parent neuroactive steroids.     

Study of 1-deoxy-1-(indol-3-yl)-L-sorbose, 1-deoxy-1-(indol-3-yl)-L-tagatose,and their analogs

Alkaline degradation of the ascorbigen 2-C-[(indol-3-yl)methyl]-alpha-L-xylo-hex-3-ulofuranosono-1,4-lactone (1a) led to a mixture of 1-deoxy-1-(indol-3-yl)-L-sorbose (2a) and 1-deoxy-1-(indol-3-yl)-L-tagatose (3a). The mixture of diastereomeric ketoses underwent acetylation and pyranose ring opening under the action of acetic anhydride in pyridine in the presence of 4-dimethylaminopyridine (DMAP) with the formation of a mixture of (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-xylo-hex-1-enitol (4a) and (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-lyxo-hex-1-enitol (5a), which were separated chromatographically. Deacetylation of 4a or 5a afforded cyclised tetrols, tosylation of which in admixture resulted in 1-deoxy-1-(indol-3-yl)-3,5-di-O-tosyl-alpha-L-sorbopyranose (12a) and 1-deoxy-1-(indol-3-yl)-4,5-di-O-tosyl-alpha-L-tagatopyranose (13a). Under alkaline conditions 13a readily formed 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)cyclopenten-2-one (15a) in 90% yield. Similar transformations were performed for N-methyl- and N-methoxyindole derivatives.     

Synthesis and cytotoxic evaluation of certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives

Certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCIs 60 cancer cell lines. The preliminary results indicated these tricyclic 4-(phenylamino)furo[2,3-b]quinolines were more cytotoxic than their corresponding 2-(furan-2-yl)-4-(phenylamino)quinoline isomers. For the 4-(phenylamino)furo[2,3-b]quinolines, compounds 2a and 3d are two of the most potent with a mean GI50 value of 0.025 microM in each case. Inactivity of 2b and 2c (positional isomers of 2a) indicated that both electronic environment, and the distance between intercalating pharmacophore and H-bond-donating MeO group are important. For the 2-(furan-2-yl)-4-(phenylamino)quinoline isomers, compound 12 (a mean GI50 of 4.36 microM), which bears a para-COMe substituent, is more active than its meta-substituted counterpart 13 (10.5 microM). However, the electron-donating MeO substituent is preferred at the meta-position, and the cytotoxicity for the meta-substituted derivatives decreased in the order: MeO derivative 14b (3.05 microM) > oxime 16 (6.85 microM) > ketone 13 (10.5 microM) > methyl oxime 18 (20.6 microM).     

An efficient alternative route to 3,6-disubstituted-furo[2,3-d]pyrimidin-2-one analogues

Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2,3-d]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2,3-d]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrinmidin-2-one analogues.     

Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives

A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one (4a–k) were synthesized by reaction of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4h and 4i displayed an encouraging antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.     

In Vitro antifungal activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones

The in vitro antifungal activity of several N2-phenyl-3(2H)-isothiazolones substituted at C4 of the phenyl moiety with heterocyclic nucleus or groups of different physico-chemical properties against four human pathogenic fungi was determined by broth macrodilution method; results were compared with those obtained with itraconazole and ketoconazole. These isothiazolones showed moderate to high activity against some or all tested strains and in comparison with the reference drugs, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g), 5-chloro-2-phenylisothiazol-3-one (1c), 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]-1,4-dihydrotriazol-5-one (1s) and 2-(4-nitrophenyl)isothiazol-3-one (2g) against Aspergillus niger, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g) and 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]piperazine-1-carboxamide (1q) against Trichophyton mentagrophytes had comparable activity, compounds 1g and 2g showing higher activity against Microsporum canis. Antifungal activity was favored by the presence of chlorine at C5 of the isothiazolone and/or the presence of nitro group or heterocyclic nucleus at C4 of the phenyl ring and proper hydrophilicity of the molecule.     

Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists

1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.     

Synthesis of 5-hydroxy-2-(beta-D-ribofuranosyl)pyran-4-one from a pyranulose glycoside.

The synthesis of 5-hydroxy-2-(beta-D-ribofuranosyl)pyran-4-one (9) is described. Treatment of pyranulose glycoside with bromine in carbon tetrachloride afforded brompyranulose glycoside in 90% yield. The reaction of (6S)- and (6R)-4-bromo-6-hydroxy-6-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-6H- pyran-3-one (2) in acidic media was examined with the following results: the reaction of 2 with trifluoroacetic acid (TFA) in dioxane afforded a mixture of 5-hydroxy-2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyran-4-one (3) and its furan derivative 5-hydroxy-2-{5-(benzoyloxy)methyl]furan-2-yl}pyran-4-one (4), but the use of hydrochloric acid formed the bromofurfural, 3-bromo-5-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-2-furancarboxyal dehyde only. Acetylation of a mixture (3 and 4) with acetic anhydride facilitated product separation to give the corresponding acetates 5-acetoxy-2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyran-4-one (5) and 5-acetoxy-2-{5-[(benzoyloxy)methyl]furan-2-yl}pyran-4-one (6). Treatment of 5 with hydrazine afforded 3-hydroxymethyl-6-(beta-D-ribofuranosyl)-1H-pyridazin-4-one in 43% yield. Debenzoylation of 5 with aq ammonia gave 9 in 50% yield.     

Three isoflavanones with cannabinoid-like moieties from Desmodium canum

Three further derivatives of 5,7,2',4'-tetrahydroxy-6-methyl isoflavanone have been isolated from the root extract of Desmodium canum and assigned the structures 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(1a,2,3,3a,8b,8c-hexahydro-6-hydroxy-1,1,3a-trimethyl-1H-4-oxabenzo[f]cyclobut[c,d]inden-7-yl)-4H-1-benzopyran-4-one (1) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(6a,7,8,10a-tetrahydro-3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl)-4H-1-benzopyran-4-one (2) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl) 4H-1-benzopyran-4-one (3). The three compounds and the previously isolated chromene 4 all derive from the geranylated precursor 5 by a series of cannabinoid-like oxidative rearrangements.