Benzimidazolone compounds

Caci E, Folli C, Zegarra-Moran O, Ma T, Springsteel MF, Sammelson RE, Nantz MH, Kurth MJ, Yerkman AS, Galietta LJ. 2003. CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds. Am J Physiol... 

BenZimidaZolones. This class of pigments derives its name from 5-aminobenzimidazolone/Pj5 -2J-< 7 which upon reaction with diketene or 2-hydtoxy-3-naphthoyl chloride leads to compounds which can be coupled with a variety of diazotized amines. 

A series of benzimidazole and benzimidazolone derivatives from the Janssen laboratories has provided an unusually large number of biologically active compounds, particularly in the area of the central nervous system. Reaction of imidazolone itself with isopropenyl acetate leads to the singly protected imidazolone derivative 51. Alkylation of this with 3-chloro-l-bromopropane affords the functionalized derivative Use of this... 

In addition to the imidazole-based compounds detailed earlier, more recently the Schering-Plough group reported on several new series of H3 antagonists including oximes (47) [121], benzimidazoles (48) [122], benzimidazolones (49) [123], and indoles (50) [124]. All of the compounds shown have K] of less than 10 nM in guinea-pig brain. 

Although, strictly speaking, it would be more precise to refer to such compounds as benzimidazolone azo pigments, the convention of listing them as benzimidazolone pigments will be followed. 

Compounds of structures (14)-(16) are in general less studied than all other classes of (oxa/thia)-2-azoles, either because of difficulty in their preparation or their thermal instability. Some of them are stable, but others are nonisolable reactive intermediates <75S205). The dioxazolidine (137) is reversibly dissociated to the nitrone and pivalaldehyde <80JCR(S)122> (Equation (2)) the dioxazolidine (138) is more stable, but decomposes on heating at 300°C to yield the pivalaldehyde (Bu CH=0) and the benzimidazolone (139) (Equation (3)) <86JOC732). 

D.M. Smith, Dihydrobenzimidazoles, Benzimidazolones, Benzimidazolethiones and Related Compounds, in P. N. Preston, Benzimidazoles and Congeneric Tricyclic Compounds, Chemistry of Heterocyclic Compounds, Bd.l, Kap.3, S. 331 -344, John Wiley Sons, Inc. New York 1981. 

Nausea that accompanies the administration of cancer chemotherapy agents was resistant to drug intervention until the introduction of the serotonin receptor antagonist odansetron (see Chapter 13). The benzimidazolone-based compound itasetron (57-6) has much the same activity as its tricylcic predecessor. Condensation of 2-nitrophenyl-isocyanate (57-1) with the bridged bycyclic diamine (57-2) leads to the addition... 

PlCN may be used to introduce this group by nucleophilic substitution. This reaction has been used e.g. to prepare the di-cyanophosphino derivatives of heterocyclic cations, which in turn may be reduced by phosphite again. The resulting compounds are benzimidazolones and quinolones in which the PCN group as a novel pseudochalcogen takes the place of oxygen. 

The effect of a Lewis acid on the o-nitro-(-aniline system is well illustrated by the unexpected result from the attempted Friedel-Crafts acetylation of these compounds. In 1926, van Romburgh and co-workers51,52 observed that the action of acetic anhydride and zinc chloride on the o-nitrodimethylaniline (111) did not give the acetylated product (112), but instead the benzimidazolone (113). Even more surprising was their alleged observation that the same reagents converted the diethyl compound (114) into the quinoxaline... 

Thus, for example, Kym and Ratner [77] found that benzimidazolone (XX) is readily nitrated to the 5,6-dinitro derivative (XXI). According to the experiments of Efros and Yeltsov [78] the compound obtained may undergo further nitration to the tetranitro derivative (XXII) having all nitro groups placed adjacent to one another (see also p. 552) ... 

The introduction of the nitro group does not affect much the tautomeric equilibrium in the series of benzimidazolones studied. However, the position and number of nitro groups in the compounds influence markedly the values of chemical shifts and coupling constants of 13C and 15N nuclei [562],... 

Dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds 81HC(40,1)331. 

In view of the observation that A-o-nitrophenyl derivatives of glycine and other a-amino acids could be converted into benzimidazolones by the action of heat, and the assumption that iV-oxides were intermediates in the thermolysis [156], it was thought tliat flash vacuum pyrolysis with a very short reaction time might allow isolation of the IV-oxides. This approach, however, did not turn out to be as synthetically efficient as the base treatment method [97]. Indeed, heating such compounds in sand at 200° C is probably of more use for making benzimidazoles or benzimidazolones [156]. Benzimidazole iV-oxides can be made from acid-catalysed thermal or photochemical reactions of AyV-dialkyl-o-nitroanilincs, but not from purely thermal reactions. 

The difficulty of monobrominating benzimidazole and its 1-substituted derivatives mirrors the state of affairs with the uncondensed imidazoles. Electrophilic bromination occurs at first in the 5-position, then at C-7, but excess brominating agent often substitutes all available positions on the fused benzene ring [23]. It has been found, though, that NBS supported on silica gel forms the 2-bromobenzimidazole (67%) in the first instance [32]. The same compound can also be made from 2-benzimidazolone, and it should be readily available via the 2-anion formed by reaction of an Al-protected benzimidazole with LDA, n-butyllithium or t-butyllithium. Hydroxymethyl and A -(dialkylamino)methyl protecting groups would appear to be the best choices [24, 25]. 

A side-chain methylenamino group reacts with a nitroso group (introduced in situ) when the compound is heated with mineral acid [2466]. An unusual reaction occurred when the nitro-t-amine (103.4) was refluxed with acetic anhydride and zinc chloride the course of this reaction may involve an A -oxide [2039]. When an o-nitroalkylamine is heated with ethoxide, the two functions are converted into a 1-hydroxyimidazole ring [3004]. Nitrosation of the pyrim-idinone (103.5) involves several steps including a Fischer-Hepp rearrangement of an iV-nitroso to a ring-C-nitroso the final product is a 6-(4 -nitrophenyl-amino)purin-2-one [2667]. In a weakly basic medium, the nitroamine (103.6) is cyclized to either the benzimidazole (when R == H), or the benzimidazolone (when R H). 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

Replacement of the imidazolidinone ring by a benzimidazolone or quinazolinedione results in potent, non-selective 5-HT2A ligands. Striking is the rather low 5-HT2A receptor affinity of the compound bearing the ritanserin side chain (Table 16). 

Derivatives of three main classes of chemical compounds have been found to be agonists at 5-HT4-RS indoles, benzamides, benzimidazolones. Other classes are represented by a quinoline, a naphthalimide, a benzoate and a ketone. 

As mentioned above, three main families of 5-HT4 compounds have been described based on the nature of their aromatic nucleus (indole, benzamide or/and benzoate and benzimidazolone). In addition to these observations, we can note that the structural characteristics of both aromatic nucleus and side chain are required for the selectivity of the 5-HT4 ligands. 

In Table VI a and b the results of 56 oxatomide analogues (36 benzimidazolones and 20 benzimidazoles) are summarized. All compounds were tested at a standard dose of 10 mg/kg. In particular those compounds are active which showed the highest activity in guinea-pig anaphylaxis and histamine oedema, e. g. the benzimidazolones 8, 9, 10, 13, 14, 23, 24 and 25 and the benzimidazoles 48, 61 and 62. However, no linear correlation was found. 

Oxatomide has been selected from a new chemical series of benzimidazolones and benzimidazoles on the basis of its activity on hypersensitivity and histamine-induced reactions in three species, the guinea-pig, the rat and the dog. In a well-known model, the guinea-pig anaphylaxis, oxatomide was at least as effective on the anaphylactic shock as on the histamine oedema induced in the same animals. In the rat, the new compound was an orally active inhibitor of PCA-reactions. Compound 48/80-induced lethal shock was prevented at doses of the same order as those required to inhibit histamine skin reactions. In the dog inhibition of allergic reactions, induced by Ascaris allergens in the skin of hypersensitive dogs, inhibition of histamine skin reactions and reduction of circulating histamine released by Cremophor EL were obtained by virtually the same oral doses. 

Dihydrobenzimidazoles, Benzimidazolones, Benzimidazolethiones, and Related Compounds Condensed Benzimidazoles of Type 5-6-5 Condensed Benzimidazoles of Type 6-6-5... 

Moriarty and coworkers have developed a convenient synthetic approach to 2-benzimidazolones, 2-benzoxazolones and related compounds based on the Hofmann-type rearrangement in the reaction of anthranilamides, salicylamides and some P-substituted amides with (diacetoxyiodo)benzene [501]. For example, various 2-benzimidazolones (401, X = NR) and 2-benzoxazolones (401, X = O) were prepared by the treatment of amides 400 with (diacetoxyiodo)benzene in a basic methanolic solution (Scheme 3.160). This reaction probably occurs via initial Hofmann-type rearrangement followed by intramolecular cyclization of the intermediate isocyanate [501]. 

Conversion to benzimidazolones is a reported strategy for analoging catechol structures. For examples, see Menichincheri, M. et al.,J. Med. Chem. 47, 6466-6475 (2004). The catechol is compound 2c with IC o> 40 pM. The benzimidazolone is compound 4f with IC50 = 19 pM. Note that the benzimidazolone is drawn as a hydroxy tautomer in this paper. 

---