Syntheses of monocyclic and bicyclic 2,4(1H,3H)-pyrimidinediones and their serotonin 2 antagonist activities

New serotonine 2 (5-HT2) antagonists with a monocyclic or bicyclic 2,4(1H,3H)-pyrimidinedione have been prepared and their activities evaluated. In a series of monocyclic compounds, 1-substituted 5-phenyl-2,4(1H,3H)-pyrimidinedione 14 showed potent in vitro activity, and the corresponding 3-substituted 5-phenyl and 6-phenyl derivatives 3, 8 and 20a also showed moderate activity. In the bicyclic compounds, 3-substituted 5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione 33 exhibited the most potent activity among the compounds prepared in this paper. The in vivo antagonist activity of 33 was comparable to that of ketanserin, a typical peripheral 5-HT2 antagonist.     

Formation and structure elucidation of two novel spiro[2H-indol]-3(1H)-ones

The molecular structures of two byproducts 1,1'-diphenyl-3',4'-dihydrodispiro[indole-2,2'-furan-5',2'-indole]-3,3'(1H, 1'H)-dione (3) and 1,5'-diphenyl-4',5'-dihydro-3'H-spiro[indole-2,2'-pyrano[3,2-b]indol]-3(1H)-one (4), which accompanied the rearrangement of 3-hydroxy-3-methyl-1-phenylquinoline-2,4(1H,3H)-dione (1) to 2-hydroxy-2-methyl-1-phenyl-1,2-dihydro-3H-indol-3-one (2), have been elucidated by NMR, MS, and X-ray diffraction.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

462—Indirect electrochemical oxidation of benzylamine using 5-amino-6-hydroxy-2,4(1H, 3H)-pyrimidinedione as a current mediator

In the electrochemical oxidation of benzylamine on a Pt electrode at 15–35°C and pH 9.2, 5-amino-6-hydroxy-2,4(1H, 3H)-pyrimidinedione (uramil) was found to be utilized as a current mediator. The oxidized forms of uramil, which attack benzylamine to give N-benzylidene benzylamine. were assumed to be alloxane ketimine and/or a neutral radical of uramil on the basis of the results of coulometric and kinetic experiments.     

Synthesis and Crystal Structure of 1-Phenyl-3-methyl-4-（4-bromophenyl）-6-（2-chlorophenyl）-pyrazolo[3,4-b] Pyridine under Microwave Irradiation

1INTRODUCTIONThepyrazolo[3,4-b]pyridineclassofcompoundspossessmanybiologicalandpharmacologicalactivi-ties[1],suchasactiveanti-concretionmedicaments[2]aswellasactiveanti-gramnegativeandpositivebacteriaagents[3].Thereforethesynthesesofsuchcompoundshavearousedgreatattentionofalargenumberofchemists.Themostimportantsyntheticrouteisthecondensationreaction[4～11]ofamino-pyrazoleandα,β-unsaturatedcompounds.Theorganicreactionundermicrowaveirradia-tionhastheadvantagesoffastreactionspeed,shorttime…     

Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (emivirine)

Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7- hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4- dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4- dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated emivirine analogues 7-(3,5-dimethylphenyl)-1- ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline- 2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locaTed analogues of emivirine. However, the compounds 4 6 showed lower activities against HIV-1 than emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.     

Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.     

The preparation and aqueous basic oxidation of diethyl 1-methyl-3-hydroxy-5-phenylpyrrole-2,4-dicarboxylate

Diethyl 1-methyl-3-hydroxy-5-phenylpyrrole-2,4-dicarboxylate has been synthesized in good yield from readily available materials, diethyl benzylidenemalonate and ethyl sarcosinate. It was found to react with oxygen in aqueous base to give two oxidation products, ethyl 1-methyl-2-oxo-3-hydroxy-5-phenyl-3-pyrroline-4-carboxylate ( 9 ) and ethyl 1-methyl-2,3-dioxo-5-phenyl-4-pyrroline-4-carboxylate ( 10 ). These two oxidation products are postulated to arise from the decomposition of a common intermediate, diethyl 1-methyl-2-hydroperoxy-3-oxo-5-phenyl-4-pyrroline-2,4-dicarboxylate. Reaction of the title compound with oxygen in pyridine containing Triton B again produced two products, the dioxo compound ( 10 ) and diethyl 1-methyl-2-hydroxy-3-oxo-5-phenyl-4-pyrroline-2,4-dicarboxylate ( 12 ). Compound 12 was shown to react in aqueous base to give exclusively 9 . The hydration of 10 in acidic and basic media is also discussed.     

Pyrimidine derivatives. VII. Nucleophilic reactions of 5-bromo-1-(bromoalkyl)-6-bromomethyl-2,4(1H,3H)-pyrimidinediones

The reactions of 1-(bromoalkyl)-5-bromo-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1) with several nucleophiles were examined as follows: by reaction with sodium methoxide, 6-(bismethoxy)methyl-5-debrominated derivatives 2, 3 , and 4 were prepared; the corresponding di-substituted compounds (side chains in 1-and 6-positions) 5, 6, 7 , and 9 were obtained by treatment with silver nitrate, silver acetate, potassium thiocyanate, and potassium thioacetate; the reaction with thioacetamide and iso-butylamine gave bicyclic compounds [1,4]thiazino[4,3-c]- 11 , pyrazino[1,2-c]- 12 , and [1,4]diazepino[1,2-c]pyrimidinedione 13 , respectively; pyrrolidine, morpholine, and sodium azide afforded the corresponding 6-substituted compounds 14, 15 , and 16 .     

4(3H)-Quinazolinones containing heterocyclic group in position 3

The corresponding 2,3-substituted 4(3H)-quinazolinones were obtained in the reactions of 2-methyl- and 2-phenyl-4-oxo-3,1-benzoxazines with 1-amino-1,2,4-triazole, 4-amino-2,3-dimethyl-1-phenyl-5-pyrazolone, 2-amino-5-ethyl-1,3,4-thiadiazole, 3-amino-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole, 1-amino-3-cyano-4,6-dimethyl-2-pyridone, and 1-amino-3-cyano-6-phenyl-4-trifluoromethyl-2-pyridone. The formation of N-benzolyanthranilamides in the reactions of 2-phenyl-4-oxo-3,1-benzoxazine with 2-amino-5-ethyl-1,3,4-thiadiazole and 1-amino-3-cyano-6-phenyl-4-trifluoromethyl-2-pyridones was exceptional. The structures of two of the products have been confirmed by X-ray crystallography.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 936–943, July, 2000.     

Unequivocal syntheses of 6-methyl- and 6-phenylisoxanthopterin

Although 6-methyl- ( 1 ) and 6-phenylisoxanthopterin ( 2 ) have previously been synthesized, the requirement of high purity necessary for immunological testing has necessitated our development of the first reported synthesis of these compounds by unequivocal methods. In the process of so doing four new pyrazines, ethyl 3-amino-5-chloro-6-methyl-2-pyrazinecarboxylate ( 11 ), N,N-dimethyl-N'-(6-chloro-3-cyano-5-phenylpyrazin-2-yl)methanimidamide ( 16 ), 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide ( 19 ), and ethyl 3-amino-5-chloro-6-phenyl-2-pyrazinecarboxylate ( 20 ) were synthesized. Four new pteridines, 7-methoxy-6-methyl-2,4-pteridinediamine ( 7 ), 7-methoxy-6-phenyl-2,4-pteridinediamine ( 17 ), 2-amino-7-ethoxy-6-methyl-4(3H)-pteridinone ( 12 ), and 2-amino-7-ethoxy-6-phenyl-4(3H)-pteridinone ( 21 ) have also been synthesized enroute to these isoxanthopterins.     

Aminomethylation of 6-methyl-1-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione

Mannich reactions of 6-methyl-1-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione with formaldehyde and morpholine, piperidine, N-methylpiperazine, and diethylamine gave the corresponding 5-aminomethylsubstituted pyrimidine derivatives. The title compound reacted with excess piperazine to form 3,5-bis-(piperazin-1-yl) derivative, while its reaction with an equimolar amount of piperazine afforded 5,5′-(piperazin-1,4-diylbismethylene)bis[6-methyl-1-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione].     

Synthesis of 1H-pyrazolo[3,4-c]isoquinolin-1-ones by the condensation of cyclohexanone derivatives with 3-amino-1-phenyl-1H-pyrazol-5(4H)-one

The synthesis of 1H-pyrazolo[3,4-c]isoquinolin-1-ones was carried out by reacting 3-aryl(heteryl)-2,4-diacetyl-5-hydroxy-5-methylcyclohexanones with 3-amino-1-phenyl-1H-pyrazol-5(4H)-one. The structure of the 7-acetyl-2,4,6,7,8,9-hexahydro-8-hydroxy-5,8-dimethyl-2-phenyl-6-(fur-2-yl)-1H-pyrazolo[3,4-c]isoquinolin-1-one obtained was proved by X-ray diffraction analysis.     

Facile synthesis of [1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin derivatives by a one-pot reactions using 4-amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5 (4H)-one

<正>4-Amino-3-mercapto-6-methyl-l,2,4-triazin-5(4H)-one 1 converted to 4-amino-6-methy-3-(methylthio)-1,2,4-triazin-5(4H)-one by methylation with methyl iodide.Controlled hydrazination of the resulting compound afforded 4-amino-3-hydrazinyl-6- methyl-l,2,4-triazin-5(4H)-one 2 as a building block,to the synthesis of some novel derivatives of[1,2,4]triazino- [4,3,b][1,2,4,5]tetrazepine 3-6,by the reaction with 3-chloropentane-2,4-dione,chloro acetonitrile,1,3-dichloroacetone,and methyl bromoacetate.This general synthetic procedure can be extended to the preparation of wide variety of tetrazepines using 1,2- bielectrophiles derivatives.     

Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.     

Reactions of 2-Amino-4-methyl-6-(2-pyridyl)- and 2-Amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazoles with Aldehydes

The reaction of 2-amino-4-methyl-6-(2-pyridyl)-7,8-dihydroindazolo[4,5-d]thiazole, obtained by treating 3-methyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with pyridinium bromide perbromide and then with thiourea, and 2-amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazole with 4-bromo-, 4-fluoro-, 4-dimethylamino-, 4-methoxy-, 3,4-dimethoxy-, and 3,4-methylenedioxybenzaldehydes, furfural, pyridinecarbaldehyde, and thiophenecarbaldehyde gave the corresponding Schiff bases. The products of the condensation of these aminothiazoles with cinnamaldehyde, 1-(2-pyridyl)- and 4-chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, 2-formyl-dimedone, and 2-formyl-1,3-indanedione were also obtained.     

Synthesis and Crystal Structure of 3-（ 2- Hydroxybenzly ）-4-（ 4- Hydro xybenzylideneamino ）-（1H） - 1,2,4- Triazole-5-Thione and Its Antibacterial Activities

1 INTRODUCTION 2. 1 Physical measurements Azole derivatives, such as pyrazole, imidazole, All solvent and chemicals were commercial rea- triazole(including benzotriazole), tetrazole and indole, gents and used without further purification. Ele- have extensive biological activities. They have be- mental analyses were performed on a PE 1700 CHN come the central focus of studies for agricultural che- auto elemental analyzer. IR spectra were recorded on micals, medicines, plant growth regul…     

Synthesis and chemical properties of 8-aryl-7-acyl-1-6-dimethyl-6-hydroxy-4-cyano-5,6,7,8-tetrahydro-3(2H)-isoquinolinones and isoquinolinethiones

8-Aryl-7-acetyl-1, 6-dimethyl-6-hydroxy-4-cyano-5, 6, 7, 8-tetrahydro-3(2H)-isoquinolinones and -isoquinolinethiones and their sodium salts were obtained by the reaction of cyanoacetamide and cyanothioacetamide with 3-aryl-2, 4-diacetyl-5-methyl-5-hydroxycyclohexanonesinbasicrnedium. 8-Aryl-7-acetyl-6-methoxycarbonyl-1, 6-dimethyl-4-cyano-5, 6, 7, 8-tetrahydro-3(2H)-isoquinolinones were obtained by the reaction of acetyl chloride and the above isoquinolinone sodium salts. The reaction of iodoacetamide and the above isoquinolinethione sodium salts yielded 8-aryl-7-acetyl-3-carbamoylmethylthio-1, 6-dimethyl-4-cyano-5, 6, 7, 8-tetra-hydroisoquinolines, which were cyclized into 1-amino-6-aryl-7-acetyl-2-carbamoyl-5, 8-dimethyl-8-hydroxy-6, 7, 8, 9-tetrahydrothiophene[2,3-c]isoquinolines in basic medium.     

Novel,Simple, and Efficient Synthesis of 3-(2-(5-(Benzylideneamino)-3-phenyl-1H-pyrazol-1-yl)thiazol-4-yl)-4-hydroxy-6-methyl-2H-pyran-2-one Derivatives via a One-Pot,Four-Component Condensation Reaction

The synthesis of 3-(2-(5-(benzylideneamino)-3-phenyl-1H-pyrazol-1-yl)thiazol-4-yl)-4-hydroxy-6-methyl-2H-pyran-2-one derivatives was achieved through a one-pot, four-component reaction involving condensation of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, thiosemicarbazide, phenacylcyanaide, and various aryl aldehydes in dry alcohol and few drops of acetic acid under reflux condition. This four-component reaction has some advantages such as ease of handling, good yields, and easy workup. All structures of newly prepared compounds were confirmed by analytical and spectral data.     

5-二乙氨甲基-6-甲基嘧啶-2,4-二酮的合成及抗炎活性

经由6-甲基嘧啶-2,4-二酮(6-甲基尿嘧啶)在无水乙醇中与甲醛和二乙胺反应,得到5-二乙氨甲基-6-甲基嘧啶-2,4-二酮;研究了影响反应收率的各种因素;利用质谱和核磁共振谱对产品进行了结构鉴定;同时利用小鼠耳肿胀试验测定了产物的抗炎活性.结果表明,所制备的5-二乙氨甲基-6-甲基嘧啶-2,4-二酮具有显著的抗炎活性.