Benzimidazole carbamate derivatives

Q90 Mebendazole is not suitable for v/omen knov/n to be pregnant. Mebendazole, v/hich is a benzimidazole carbamate derivative, has shov/n toxicity in rats. 

Mebendazole is a benzimidazole carbamate derivative that is used for the treatment of threadworm, roundworm, whipworm and hookworm infections. It is not recommended for women who are pregnant and in children under 2 years because the manufacturer reports that toxicity in animal studies has been reported. 

Kus, C. 2003. Synthesis of some new benzimidazole carbamate derivatives for evaluation of antifungal activity. Turk. J. Chem. 27(l) 35-39. 

The benzimidazole group of anthelminthics is derived from the simple benzimidazole nucleus and includes the thiabendazole analogues and the benzimidazole carbamates. Substitution of side chains and radicals on the benzimidazole nucleus gives rise to the individual members of this group (Fig. 4.1). 

In 1971, the first benzimidazole derivative (1, HOE 33258) was reported to be an active microfilaricidal agent in L. carinii and D. immitis models [30]. After this report, very little effort was dedicated to this important problem for a decade. Recently, however, there has been renewed interest and activity which has shown some benzimidazole carbamates such as mebendazole (2), fluben-dazole (3), albendazole (4) and oxibendazole (5) to have significant macrofilari-... 

In general, benzimidazole-2-methyl carbamate derivatives (28) can be synthesized by the reaction of an appropriate diamine (26) with 1,3-dicarbo-methoxy-5-methylisothiourea (27) [43], This is the most general and economic synthesis for benzimidazole carbamates. However, the same reaction was less than satisfactory when the aza analogues of o-phenylenediamines (29) were used. In order to synthesize the aza analogues of mebendazole (2) or flubendazole (3), the reactions of methoxycarbonyl isothiocyanate (30) with a wide variety of diamines such as 3,4-diaminopyridines, 4,5-diaminopyrimi-dines, o-phenylenediamines have been investigated in the presence of dicyclo-hexylcarbodiimide [44, 45] and were found to be quite successful in the synthesis of carbamates (31). 

Chem. Descrip. Benzimidazole carbamate, 2-N-octyl-4-isothiazolin-3-one, and a urea deriv. 

Chem. Descrip. Aq. disp. of benzimidazole carbamate and triazine deriv. Uses Biocide for dry film protection of interior/exterior coatings from surf, fungal and algal growth Acticide EPO [Thor UK]... 

An impressive range of nucleophiles was successful for arylboronic acids in the presence of Cu(OAc)2 and base, which included amine, anilines, amides, imines, ureas, carbamates, sulfonamides, and aromatic heterocycles (e.g., imidazoles, pyrazoles, triazoles, tetrazoles, benzimidazoles, and indazoles) (Equation (226)) 996 997 1000-1011 For all the reactions investigated with A-nucleophiles, the use of Et3N resulted in yields superior to those obtained with pyridine, but pyridine was the base of choice for the preparation of imidazole derivatives from heteroarenes. For the tetrazole, NMO and DBU were studied as alternative bases. There are mechanistic studies.999,1002-1013... 

The discovery of parbendazole stimulated a vigorous search for better benzimidazole anthelmintics in different pharmaceutical companies of the world. Soon a number of drugs (14-22) were introduced in veterinary and humans medicine. All these benzimidazole anthelmintics may be regarded as the 5(6)-derivatives of car-bendazim (10) which per se is an effective pesticide rather than an anthelmintic [12]. A novel non-carbamate benzimidazole fasciolicide, triclabendazole (23) [13] and a benzimidazole-2-carbamate anthelmintic, ricobendazole (24) [14] have been introduced recently (Table 1). 

After it was established that the 2-alkoxycarbonylamino function is an essential requirement for obtaining anthelmintic activity in benzimidazoles, a series of 5(6)-alkyl/arylbenzimidazole-2-carbamates (37) and 5-(2-substituted ethenyl)benzi-midazole-2-carbamates (38) were prepared [5,54,55]. The most effective derivative was found to be methyl 5(6)-butylbenzimidazole-2-carbamate (13 parbendazole) [10], which finds wide usage in management of intestinal roundworm infections in domestic animals [14]. 

All of these derivatives are 1,2-disubstituted benzenes, which are converted by chemical reaction, for example, in aqueous medium with sodium hydroxide or with dimethyl sulfate, into alkyl N-benzimidazol-2-yl-carbamates (Koyamada et ai, 1969 Adams and Wommack, 1970). Thiophanate derivatives themselves are inactive (Nogutsi et al., 1971), but in plants they are converted into benzimidazole derivatives, exerting their effect in this form (Selling et ai, 1970 Vonk and Kaars Sijpesteijn, 1971 Soeda et al., 1972). The lack of activity of 1,3- and l,4-bis(3-alkoxycarbonyl-l-thioureido)benzenescan be explained by their inability to cyclise the benzimidazole ring. Thioallophanic acid derivatives are thus the precursors of alkyl N-benzimidazol-2-yl-carbamates. Further substitutions on the benzene ring decrease the fungitoxicity of the compounds. 

Fig. (4). Synthetic antimitotic fungicides benzimidazoles derivatives (11-14, 16) and an isopropyl carbamate (15).

Recently, the carbamate fungicide diethofencarb (15) which takes advantage of a negatively-correlated cross-resistance phenomenon, has been developed as a potent fungicide against benzimidazole-resistant fungi [45, 46]. Studies on the mode of action of 15 have revealed that P-tubulin in the benzimidazole-resistant strain F914 of N. crassa has an affinity for diethofencarb (15) rather than for benzimidazole derivatives, whilst in a wild-type strain of N. crassa there was an inverse affinity [46, 47]. 

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