Benzimidazole-4, 7-diones

Bayatah et al. [36] efficiently synthesized the 2-substituted benzimidazole-4, 7-diones (xxx). The intermediate 2-chloromethyl-l,5,6-trimethylbenzimidazole-4,7-dione (xxix) served as a point of departure for the synthesis of desired products. 

Garuti L, Robert M, Malagoli M et al (2000) Synthesis and antiproliferative activity of some benzimidazole-4, 7-dione derivatives. Bioorg Med Chem Lett 10 2193-2195... 

Gellis A, Kovacic H, Boufatah N et al (2008) Synthesis and cytotoxicity evaluation of some benzimidazole-4, 7-diones as bioreductive anticancer agents. Eur J Med Chem 43 1858-1864... 

Several benzimidazole-4,7-diones were synthesized and tested for antitumor activity (88JMC260). There is also a report on oxidation of 4-amino-or 4-aikoxybenzo-2,l,3-thiadiazoles with hydrogen peroxide in concentrated hydrochloric acid to give 5-chlorobenzo-2,l,3-thiadiazole-4,7-dione (88KGS114). 

In addition, the alkyl-linked bisbenzimidazole 135 [115] and thiazolyl-benzimidazole-4,7-diones 136 [116] exhibited cytotoxic activity against tumor cell lines (Fig. 12). 

Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[l,2-a]pyrimidin-5-(l//)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[l,2-c]quinazolin-2(3//)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g ]quinoline-4,9-dione derivatives <05EJ01903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-l,3-dihydro-2//-imidazol-2-one provided a one-pot synthesis of 5//-imidazo[2,l-ft][l,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-ary 1-3-acetyl-1,4,5,6-... 

Quantum chemical standard state 4 Quasi Equilibrium Theory 326, 340 Quinones, addition of thiols 769 from thiols and 4,7-benzimidazole-dione 775... 

Quinoxaline-2,3-dione is converted into 2,3-dichloroquinoxaline by phosphoryl chloride142 or phosphorus pentachloride.143 2,3-Dibromo-quinoxaline is similarly obtained using phosphoryl bromide in dimethyl-aniline.144 Quinoxalin-2-one undergoes ring contraction to 2-methyl-benzimidazole (134) with hydrazine145 however, quinoxaline-2,3-dione gives 3-hydrazino-2-quinoxalinone.145 Quinoxalin-2-one yields a 3-p-dimethylaminophenyl derivative with 7V,N-dimethylaniline (in AcOH, with NH4N03), and a 3-(indol-3-yl) derivative with indole.146... 

OHDPAT, 8-hydroxy-2(di- -propylamino)tetralin ACPD, trans-1 -amino-cyclopenty 1 -1,3 -dicarboxylate AMP A, DL-cr-amino-3-hydroxy-5-methylisoxazole-4-propionate BIMU8, [endo-A-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2,3-dihydro-3-isopropyl-2-oxo-177-benzimidazol-l-carboxamide hydrochloride CGP 35348, 3-aminopropyl(diethoxymethyl)phosphinic acid CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione CP 99994, (+)-(2 , 3A)-3-(2-methoxybenzylamino)-2- ... 

Diaminobenzimidazole reacts with 5-phenyl-2,3-dihydrofuran-2,3-dione in sulfuric acid conditions to give 2-phenylfuro[3,2-< ]-1,2,4-triazino[2,3-a] benzimidazole (38) <87KGS444>. If the reaction is carried out in acetic acid, then both compound (38) and its isomer 2-phenylfuro[2,3-e -l,2,4-triazino[2,3-a]benzimidazole are formed (Scheme 10). 

Preparation of R-(—)-3-amino-6-azindinyl-2,3-dihydro-7-methyl-lH-pyrrolo[l,2-a]benzimidazole 5,8-dione... 

An interesting approach for the synthesis of some fused pyrimidines has been reported by Shaaban [102] via reaction of 4,4,4-trifluoro-l-(thien-2-yl)butane-1,3-dione in the presence of triethylorthoformate with 5-aminopyrazole or 1,2,4-aminotriazole or 2-aminobenzimidazole under microwave irradiation. The resulting trifluoromethyl derivatives of pyrazolo[l,5-a]pyrimidine 56, l,2,4-triazolo[l,5-a] pyrimidine 57 and pyrimido[l,2-a]benzimidazoles 58 were obtained in excellent yields and purity (Scheme 42). 

Various new benzimidazole-4,1-diones (xv) substituted at 2-position were synthesized via a microwave assisted reaction by Gellis et al. [24], Their cytotoxicity has been evaluated on the colon, breast and lung cancer cell lines and good results were observed comparable to that of mitomycin C. 

Treatment of phthalic acid (145) with sodium azide under acidic conditions has been reported" to give various products anthranilic acid (147) and a trace of o-phenylenediamine (148) in concentrated sulfuric acid and anthranilazide (149) and benzimidazol-2-one (150) in 90% sulfuric acid. Analogously, phthalic anhydride (146) gives the following products anthranilic acid (147), benzimidazol-2-one (150) and some 3,l-benzoxazine-2,4(l//)-dione (isatoic anhydride) (151) in sulfuric acid and benzimidazol-2-one (150) in acetic acid. A recent report" has revealed that Ae Schmidt reaction of phthalic acid (145) in 90-98% sulfuric acid gives anthranilic acid (147) and anthranilazide (149) (major products) by a process thought to involve 3,l-benzoxazine-2,4(l//)-dione (151) as an intermediate. Benzimidazol-2-one (150) is produced in this reaction by a secondary process from anthranilazide (149). Photolysis of (149) also produces (150). 

The bioactive benzimidazolequinone 131 has been synthesized by demethylation of the dimethoxybenzimidazole 129 followed by facile oxidation of the intermediate dihydroxy compoimd 130 by ferric chloride to yield the quinone 131 in excellent yield (Scheme 23). Synthesis of the related ben-zimidazolequinones 134 was achieved by dinitration of 132 followed by the reduction of 133 and oxidation as above. The benzimidazole-6,9-dione 134 has been found to be 300 times more cytotoxic towards the human skin fibroblast cell line in the MTT assay than the clinically used bioreductive drug, mitomycin C. Attaching methyl substituents onto the quinone moiety increased reductive potential and decreased cytotoxicity and selectivity towards hypoxia [67]. 

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