Synthesis of new unsymmetrical 4,5-dihydroxy-2-imidazolidinones. Dynamic NMR spectroscopic study of the prototropic tautomerism in 1-(2-benzimidazolyl)-3-phenyl-4,5-dihydroxy-2-imidazolidinone

The acid-catalyzed cyclocondensation in refluxing acetonitrile of aqueous glyoxal with N-heteroaryl-N'-phenylureas 4a-f (heteroaryl = 2-thiazolyl, 2-pyrimidinyl,2-pyrazinyl, 2-pyridinyl, 3-pyridinyl and 2-benzimidazolyl) led to the formation of the corresponding 1-heteroaryl-3-phenyl-4,5-dihydroxy-2-imidazolidinones 5a-f. All the products were characterized by elemental and spectroscopic analyses. The free-energy barrier (Delta G not equal) for prototropic tautomerism in 1-(2-benzimidazolyl)-3-phenyl-4,5-dihydroxy-2-imidazolidinone (5f) was determined by dynamic NMR studies to be 81 +/- 2 KJ mol(-1).     

A new group of antischistosomal compounds

A number of compounds containing the 5-nitro-2-thiazolyl group are suitable for the treatment of schistosomiasis; 1-(5-nitro-2-thiazolyl)-2-imidazolidinone is particularly effective. The compounds are taken up selectively by the schistosomes causing the disease and by their eggs, and destroy both. – A review of earlier attempts to control this tropical disease is also presented in this communication.     

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.     

Nitroimidazoles. V . Synthesis of 1-methyl-2-(2-methyl-4-thiazolyl)nitroimidazoles

Reaction of readily available 2-methyl-4-formylthiazole ( 1 ) with glyoxal and ammonia gave 2-(2-methyl-4-thiazolyl)imidazole ( 2 ). Nitration of 2 with a mixture of nitric acid-sulfuric acid at 100° yielded 2-(2-methyl-4-thiazolyl)-4,5-dinitroimidazole ( 3 ) as the sole reaction product, while nitration at 65° afforded 2-(2-methyl-4-thiazolyl)-4-(or 5)-nitroimidazole ( 4 ). N-Methylation of compound 4 in the presence of base gave 1-methyl-2-(2-methyl-4-thiazolyl)4-nitroimidazole ( 6 ), whereas N-methylation with diazomethane afforded 1-methyl-2-(2-methyl-4-thiazolyl)-5-nitroimidazole ( 5 ). N-Methylation of compound 3 yielded 1-methyl-2-(2-methyl-4-thiazolyl)-3,5-dinitroimidazole ( 7 ) in high yield.     

Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides

A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.     

Reactions of 3-(4-Aryl-2-thiazolyl)- and 3-(2-Benzothiazolyl)-2-iminocoumarins with N-Nucleophiles

The reaction of 3-(4-aryl-2-thiazolyl)- and 3-(2-benzothiazolyl)-2-iminocoumarins with N-nucleophiles was studied. This reaction gives 2-N-substituted 3-(4-aryl-2-thiazolyl)- and 3-(2-benzothiazolyl)iminocourmarins. N-Nucleophiles such as arylamines, heterocyclic amines, and hydrazine derivatives undergo this reaction.     

Hantzsch reaction of 3-(2-bromoacetyl)tropolone. Synthesis of 3-(4-thiazolyl)tropolones

3-Acetyltropolone was brominated with phenyltrimethylammonium tribromide to afford 3-(2-bromoacetyl)-tropolone ( 2 ), whose reactions with thiourea, thioformamide, and ammonium dithiocarbamate gave respectively 3-(2-amino-4-thiazolyl)-, 3-(4-thiazolyl)-, and 3-(2-mercapto-4-thiazolyl)tropolone. In a similar manner, compound 2 was treated with six 1-substituted 2-thioureas and three thioamides to give the corresponding 3-(4-thiazolyl)tropolone derivatives.     

Studies on cardiotonic agents. III. Synthesis of 1-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3-substituted 2-imidazolidinone and 2-imidazolidinethione derivatives

A series of 1-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3-substituted 2-imidazolidinone and 2-imidazolidinethione derivatives was synthesized and examined for cardiotonic activity in anesthetized dogs. Alkylation of the 2-imidazolidinone (1) afforded the N-alkylated products, while alkylation of the 2-imidazolidinethione (12) afforded the S-alkylated derivatives accompanied with a small quantity of the N-alkylated products. The N-alkylated derivatives showed generally potent activity, and the S-alkylated ones exhibited weak activity. Insertion of an alkyl group between the piperidine and the imidazolidinone moiety generally resulted in a fall in activity.     

Complexation of uranium by 2-(2-thiazolylazo)-4-methoxyphenol and 2-(2-thiazolylazo)-5-methoxyphenol

A comparative study has been made of the complexation of uranium(VI) by 2-(2-thiazolyl)-4-methoxyphenol (TAMH) and 2-(2-thiazolylazo)-5-methoxyphenol(TAMR). The complexes are less stable and have lower molar absorptivities than the PAR and TAR complexes but are still useful for determination of uranium. The TAMH chelate can be extracted into isobutyl methyl ketone. Both complexes are 1:1 metal :ligand. For the TAMH complex log beta(1) = 8.8, = 1.4 x 10(4) at 610 mmu; for the TAMR complex log beta(1) = 8.1, = 2.0 x 10(4) at 530 mmu.     

Synthesis and Alkylation of Piperidinium 4,5-trans-3-Cyano-6-hydroxy-4-(2-iodophenyl)-6-methyl-5-(2-methylphenyl)carbamoyl-1,4,5,6-tetrahydropyridine-2-thiolate. Molecular and Crystal Structure of 3-(2-Iodophenyl)-2-(4-phenyl-2-thiazolyl)acrylonitrile

The reaction of o-iodobenzaldehyde, cyanothioacetamide, and N-acetoacetyl-o-toluidine in the presence of piperidine gave piperidinium 4,5-trans-3-cyano-6-hydroxy-4-(2-iodophenyl)-6-methyl-5-(2-methylphenyl)carbamoyl-1,4,5,6-tetrahydropyridine-2-thiolate used in the synthesis of substituted 4,5-trans-2-alkylthiotetrahydropyridines and 2-(2-thiazolyl)acrylonitriles. The structure of 3-(2-iodophenyl)-2-(4-phenyl-2-thiazolyl)acrylonitrile was studied using X-ray diffraction structural analysis.     

Synthesis of 5-Amino-4-(4-aryl-2-thiazolyl)-2,3-Dihydro-2-Pyrrolones

A method was developed for preparation of 5-amino-4-(4-aryl-2-thiazolyl)-2,3-dihydro-2-pyrrolones by alkylation of 4-aryl-2-thiazolylacetonitriles by N-substituted chloroacetamides in the presence of K₂CO₃. In 1-(1-naphthyl)-substituted pyrrolones atropoisomerism was observed.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 2, 2005, pp. 266–269.Original Russian Text Copyright © 2005 by Resnyanskaya, Tverdokhlebov, Tolmachev, Volovenko.     

A Convenient Preparation of 2-(2-Arylidene)- and 2-(2-Polyhydroxyalkylidene)hydrazono-4-imidazolidinones with Various Heterocyclic Side Chain Substituents at Position 5 as Potential Antiviral and Antitumor Agents

A variety of novel 5-[( Z )-arylidene]-2-[(2-( E )-arylidene)hydrazono]-4-imidazolidinones 1a-c to 4a , b and 5-[( Z )-arylidene]-2-[(2-( E )-polyhydroxyalkylidene)hydrazono]-4-imidazolidinones 5a-c to 7a-c were prepared from the reaction of 5-[( Z )-arylidene]-2-methylmercaptohydantoins 8a-c with 2-( E )-arylidene hydrazones 13a-d and/or 2-( E )-monosaccharides hydrazones 16a-c . The linear structure, and not that of the angular isomer, has been selected for the products. This structure has been confirmed from a model study of the condensation of 5-[( Z )-2-thienylidene]-2-hydrazono-4-imidazolidinone 9a with benzaldehyde and D -galactose, respectively. The acetylation and benzoylation reactions of compounds 1-7 have been studied. All the new compounds were tested for their potential antiviral and antitumor activities.     

Selenium heterocycles. XXXVII . Synthesis of 4-(thiazol-4-yl)-1,2,3-selenadiazoles and 4-(selenazol-4-yl)-1,2,3-selenadiazoles

Starting from readily available 2-substituted-4-formylthiazoles and selenazoles, a series of 4-(2-aryl-4-selenazolyl)-1,2,3-selenadiazoles I and 4-(2-substituted-4-thiazolyl)-1,2,3-selenadiazoles II were prepared. Pyrolysis of compound II afforded (2-substituted-4-thiazolyl) acetylenes VII. Addition of potassium hydroxide pellets to an alcoholic solution of II gave 2-substituted-1,4-diselenafulvenes VIII. Decomposition of compound II with base followed by the addition of carbon disulfide gave 5-substituted 2-thioxo-1,3-thiaselenoles XI.     

Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs 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

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 (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.     

Synthesis and herbicidal properties of 3-(2-oxo-1-imidazolidinyliminomethyl)indoles

The reaction of 1-substituted 2-chloroindole-3-carboxaldehydes with 1-amino-2-imidazolidinone gave a series of 1-substituted 2-chloro-3-(2-oxo-1-imidazolidinyliminomethyl)indoles which were evaluated as potential herbicides. The level of biological activity was not sufficient to warrant further investigation.     

New 7-substituted quinolone antibacterial agents. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl and 4-thiazolyl)-3-quinolinecarboxylic acids

A series of 1-ethyl-1,4-dihydro-4-oxo-7-(4-thiazolyl)-3-quinolinecarboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl)-3-quinolinecarboxylic acids were prepared. Also prepared was 10-[2-(aminomethyl)-4-thiazolyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. Analogs with basic amine substituents on the thiazole moiety were found to have antibacterial activity.     

Synthesis of thiazolotriazepinones

The synthesis of 4,5-dihydro-7-phenylthiazolo[2,3-c][1,2,4]triazepin-3(2H)-one ( 4 ) from 2-propenoic acid 2-(4-phenyl-2-thiazolyl)hydrazide ( 14 ), is reported. A synthesis of 4 which was reported earlier by Mahajan, Sondhi and Ralhan (9), from 3-chloropropanoic acid 2-(4-phenyl-2-thiazolyl)hydrazide ( 3 ), is erroneous. We were able to cyclize 3 to 1-(4-phenyl-2-thiazolyl)-3-pyrazolidinone ( 5 ). The cyclizations of 14 to 4 and 3 to 5 are consistent with the Baldwin Rules for Ring Closure.     

2-烷硫基-5-苯基亚甲基-4H-咪唑啉-4-酮的合成与表征

用2-硫代-3-正丁基-5-苯基亚甲基4-咪唑啉二酮的-S-烷基化反应合成了2-烷硫基-3-正丁基-5-苯基亚甲基-4H-咪唑啉-4-酮衍生物。探讨了S-烷基化反应的反应条件和所合成化合物的波谱性质。目标产物均为新的化合物，其结构经元素分析，IR，1H NMR和MS确正。     

1,4-Benzodiazepines III . Cyclization paths of hexaminium salts of 2-chioroacetamido-5-ehlorobenzophenone and its N-methyl derivative

This study reports the isolation and characterization of hexaminium salts of 2-chloroacetamido-5-chlorobenzophenone (I) and of 2-(N-methyl)chloroacetamido-5-chlorobenzophenone (II). The 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (VI) and 7-chloro-1,3-dihydro-1-meth-yI-5-phenyl-2H-1,4-benzodiazepin-2-one (VII), respectively are of pharmacodynamic importance. Based on chromatographic separation of some intermediates, and on spectrophotometric monitoring of cyclizations I → VI and II → VII, respectively, two different pathways for these reactions have been proposed. Since the slowest step in the reaction sequence II → VII follows the quasi first order rate law, intramolecular nucleophilic attack of the benzophenone carbonyl group on the hexamine moiety proved to be decisive for the cyclization (scheme II). However, cyclization I → VI seems to incorporate quite different solvolytic pathways in addition to one corresponding to the sequence II → VII. Isolated 4-imidazolidinone intermediates N,N' -methylene-bis[3-{2 -benzoyl-4-chIoro)phenyI]-4-imidazolidinone(III), and 3-(2 -benzoyl-4′-chlorophenyI)-4-imidazolidinone hydrochloride (IV) recyclize into the 1,4-benzodiazepine VI. The optimal reaction conditions have been found to be between pH 6-7.     

SYNTHESIS OF 3-(2-MERCAPTO-4-THIAZOLYL)-2H-1-BENZOPYRAN-2-ONE AND ITS DERIVATIVES

Abstract

Treatment of 3-(2-bromoacetyl)coumarins with ammonium dithiocarbamate provides 3-2-mercapto-4-thiazolyl)-2H-1-benzopyran-2-one (11) but not 4-hydroxy-4-(3-coumaririnyl) thiazolidine-2-thione (I). II undergoes smooth condensation with alkyl, aralkyl, phenacyl and acid halides to give corresponding thioethers and thioesters (III) respectively. The structures of the newly synthesized compounds were established on the basis of spectral data (IR, PMR and MS).