The Synthesis and Chemistry of Certain Anthelmintic Benzimidazoles LB
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Parasitology Today, vol. 6, no. 4. I990 107 The Synthesis and Chemistry of Certain Anthelmintic Benzimidazoles LB. Townsend and D.S. Wise A basis for interest in the benzimidazole ring system as a nucleus Benzimidazole, as the name implies, is a bicyclic ring system in from which to develop potential chemotherapeutic agents was which benzene has been fused to the 4- and 5-position of the established in the I95Os when it was found that 5,6-dimethyl- I - heterocycle (imidazole; Box I). Benzimidazole compounds in (a-D-ribofiranosyljbenzimidazole (I) was an integral part ofthe general, and benzimidazole carbamates in particular, are crys- talline materials, with fairly high melting points and are relatively insoluble in water. Compounds that are unsubstituted on either of the imidazole nitrogen atoms possess both acidic and basic characteristics. Modifications of the benzimidazole ring system that have been made during the search for anthelmintic activity are summarized in Box 2. Combinations of the modifications at positions 2- and 5- of the molecule has provided the most active drugs. The synthetic pathways to the various benzimi- structure of vitamin 6,~ As a result of these interests and dazoles usually proceeds through two steps, first the construc- extensive studies, one health related arena that has benefited tion of a benzene ring containing the desired substituents and a greatly has been the treatment ofparasitic diseases. The discovery I ,2-diamine grouping, followed by the ring closure of the of thiabendazole in I96 I further spurred chemists around the I ,2-diaminobenzene (o-phenylenediamine) derivative to con- world to design and synthesize several thousand benzimidazoles struct the imidazole ring. In many cases, this ring closure is the for screening for anthelmirltic activity but less than twenty ofthem have reached commercial use. Much ofthis work has been done RE 1;; - by pharmaceutical companies and is only reported in the patent 3: 2 3r literature. In this paper, Leroy Townsend and Dean Wise review d’ ’ FR the development ofsome cfthe synthetic methods that have been o - phenylenediamine critical to the preparation of the benzimidazoles ofanthelmintic R, R’ = ring substitution importance. On/y a few ,nolecules that demonstrate the pro- final step in the synthesis of the desired benzimidazole. How- cesses are discussed here, but numerous reviews of the synthesis ever, in other instances this ring closure is followed by exten- andchemistry ofother benzimidazoles are available’“. sive derivatization of the ring system or of the existing exocyclic substituents (Box 3). Box I. Tautomerism and isomerism The discovery4 in I96 I that 2-(4’-thiazolyl)benzimidazole The systematic numbering of the benzimidazole ring system is (thiabendazole) possessed a very potent broad spectrum of shown in structure 1. Although benzimidazole is depicted in I as activity against gastrointestinal parasites was the breakthrough pssessing the proton at N,, there actually exists a rapid that opened up a new era in the treatment of parasitic diseases. Exchange between the -NlH- and =N- nitrogen atoms, and two In the initial studies, a group of researchers at Merck prepared tautomers, I and II, may be drawn for the benzimidazole mol- thiabendazole by a condensation of o-phenylenediamine with thiazole-4-carboxamide in the presence of the dehydrating I < , $pW agent, polyphosphoric acid. This reaction was found to be quite ; I 9 a - a 7 H’ (acldlc) I II aNMJ ecule. Tautomerism occurs through either an intermolecular H” process involving two or more benzimidazole molecules or Thiabendazole through interactions witlh a protic solvent such as water. It renders the 5- and 6- positions, and any group at that position in general in nature and several hundred derivatives, including the the ring system, chemically equivalent. In N-substituted benzimi- 2-(2’-furyl)-,2-phenyl-,2-(2’-naphthyl)-, and 2-(S’-thiazoyl)- dazoles, tautomerism is no longer possible and two distinct congeners, were also prepared to determine the best candi- non-equivalent molecules or isomers may be isolated and charac- date for commercial development. Both the 2-phenyl- deriva- terized. For example, the two dimethylated benzimidazoles tive and thiabendazole were very active drugs, and were shown are an isomeric pair of non-equivalent molecules, while the mono-methylated molecules are tautomers and equivalent. QNH*+,,u aniline 2 @ 1990. Elsewr Science Publlshers Ltd. (LlK)OI 6947071901802.00 108 Parasitology Today, vol. 6, no. 4, I990 Box 2. Chemical Structures of Some Benzimidazole Anthelmintics Benzimidazoles Benzimidazole Carbamates NHCO&H, R = H Thiabendazole R = 1 \ i _ Mebendazole” crystals, mp 304°C crystals, acetic acid, mp 288°C insoluble in water, slightly soluble in alcohol insoluble in water o- - R = (CH,),CHOCONH- Cambendazole i _ FIubendazole’” crystals, mp 238°C crystals, mp 280°C insoluble in water, soluble in alcohol insoluble in water Prodrugs 0 Ciclobendazole” R= t- , NHCO,Me crystals, mp 250°C ’ 1 N=C<NHCWe e&$;lmp ,29”c Albendazole” R I CH3CHfiHaS- a\ NHCOCH,OCH, crystals, mp 208°C R = CHsCH$H20 - ;;i$ia;;t;&C practically insoluble in water Netobimin crystals, water soluble ; NHC-NHCO,Me Thiophanate (methyl) ‘I crystals, soluble in alcohol a\ NHCNHCO,Me k! Parbendazoleg crystals, R = CH,CH&H,CH,- mp 225°C. insoluble in water studied further. A new, efficient procedure for the conversion Since hydroxylation was occurring at the 5-position, analogs of N-arylamidines with hypochlorite and a base to form of thiabendazole with different groups at this position were benzimidazoles was devised by the Merck group5, and this developed. As a potential candidate, 5-aminothiabendazole (9) discovery made it economically practical to market the was prepared by a condensation of 4-nitrophenylenediamine 2-phenyl derivative and thiabendazole. In this procedure it is (7) with (2) to furnish 5-nitrothiabendazole (8). The nitro unnecessary to prepare the o-phenylenediamine compound group of compound (8) was then reduced to furnish 5- because aniline is used as a starting material. Thus, to prepare aminothiabendazole (9). Compound (9) was nearly (80%) as thiabendazole (4) aniline is reacted with 4-cyanothiazole (2) in active as the parent thiabendazole. Acylation of the 5-amino the presence of aluminium trichloride (a Lewis acid), to give the intermediate N-arylamidine hydrochloride (3). The critical NH, oxidative cyclization to give (4) is then carried out by treating + (3) with sodium hypochlorite in the presence of a base. The NH, latter reaction has been accomplished commercially in one step, but it may also be performed stepwise through the intermediate (5). 7 ltwas later found that both thiabendazoleand 2-phenylbenz A8* imidazole suffer from an enzymatic hydroxylation at the S-position to give (a), which inactivates the drug and therefore i!zzzFHOW;menzymatic 9 H ~~‘:‘, thiabendazole 6 limits its effectiveness. To overcome this problem, investi- gators began to prepare second generation benzimidazoles H with structural modifications that might prevent metabolic IO cambendazole inactivation. These studies led to an abundance of potential functional portion of (9) with isopropyl chloroformate pro- anthelmintic benzimidazoles, and many methods of prep- duced the 5-isoproxycarbonylamino derivative (I 0), which aration. was marketed under the name cambendazole’. Later, Parasitology Today, vol. 6, no 4, I990 109 effective. Several compounds were prepared that possessed thisgroupatthe2-position.Oneofthesecompounds,prepared by the reaction of 4-but+o-phenylenediamine (I 3) with car- bomethoxycyanamide (14) in boiling propanol, was methyl 5-butyl-2-benzimidazolylcarbamate (I 5; parbendazole). thiabendazole Following the introduction of this compound, additional IO II drugs were produced by several pharmaceutical companies. cambendazole was prepared directly from thiabendazole by Janssen Pharmaceutics produced mebendazole, flubendazole, an electrophilic substitution of a nitrene or nitrene-like and ciclobendazole” among others; Smith Kline and French intermediate derived from isopropyl azidoformate, initiated discovered al bendazole ’ ’ , oxibendazole ’ 2, and fenbenda- by heat or UV light7. Another unique synthesis of cambenda- zole13; and Syntex developed oxfendazole’4. To prepare zole involves a reduction of the 3-(4-thiazolyl)benzotriazine these benzimidazoles, several new ring closing reagents were I -oxide ( I I)‘. Through a systematic study involving a modification of the thiazole ring at the 2-position of thiabendazole, workers at Smith Kline and French found that the thiocarbonate com- pound (I 2a) possessed anthelmintic activity’. This led to the H preparation of 2-acylarninobenzimidazoles (I Zb), 2-benz- I3 I4 15 parbendazole ’ ONpNH!,, = employed or invented and these 2-methoxycarbamate .N a H synthons are shown in Table I. To prepare mebendazole, flubendazole, ciclobendazole, 12a IL = S,R E CC&Is 12b :Y=O,R=akyl and a variety of benzimidazoles containing a group attached to 12~ .K=O,R-akoxy the 5-position of the benzimidazole by a carbonyl (C=O) 124 :K=O,R=akylan-im linkage, a general reaction scheme was developed by re- imidazolylcarbamates (I I!c)and 2-benzimidazolylureas (I 2d). searchers at Janssen (see Box 3). In this synthetic sequence, the All of these compounds ‘possessed anthelmintic activity, how- initial step is to append to ring A, the group which becomes the ever, the 2-methylcarbamate derivative stood out as the most 5-carbonyl linked substituent. This