Substituted imidazole compounds

Adams etal, US Patent 6,569,871 (May 27, 2003) Assignee SmithKline Beecham Corporation 

Utility CSBP/p38 Kinase Inhibitor in the Treatment of Inflammation 

The product from Step 1 (6.25 mmol) was dissolved in 32 ml ethylene glycol dimethylether, cooled to -10°C, POCI3 (16.3mmol) added followed by the dropwise addition of triethylamine (32.6 mmol) dissolved in 3 ml ethylene glycol dimethylether, and the reaction temperature kept below —5°C. The mixture was gradually warmed to ambient temperature over 1 hour, quenched with water, and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCOj, dried, and concentrated. The residue was triturated with petroleum ether, filtered, and the product isolated in 90% yield. NMR data supplied. 

A reactor was charged with N,N-dimethylformamide dimethyl acetal (700 mmol) and pyruvaldehyde dimethyl acetal (700 mmol), heated to 110°C 4 hours, cooled to 85 °C, and thiourea (636.4 mmol) and sodium methoxide (700 mmol) dissolved in 160 ml methyl alcohol added. Thereafter, the mixture stirred 4 hours. The mixture was cooled to 65 °C and 1-bromopropane (700mmol) added over 15 minutes. After 1 hour, 100ml EtOAc was added and the mixture heated to 95 °C. The solvents were distilled off, 120 ml water added, the mixture stirred 10 minutes at 50°C, cooled, concentrated, and the product isolated as a yellow oil. NMR data supplied. 

The product from Step 3 (105 mmol) was dissolved in 75 ml THE, 150 ml 3M HCl added, and heated to 50 °C 4 hours. THE was removed, the mixture cooled in an ice bath, and 300 ml EtOAc and NaHCOj added. The product was extracted with EtOAc and concentrated to give a brown oil. The residue was purified by flash chromatography on silica gel using 0-1% methyl alcohol/CH2Cl2 and the product isolated as a yellow oil. NMR data supplied. 

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A lithium-bromo exchange of 2,4,5-tribromoimidazole derivative 47 with 2 equiv of s-BuLi occurs regioselectively to give, after protonation, the 4-bromo-substituted imidazole compound 48 (eq 61). 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

We do not discuss in detail the cases of tautomerism of heterocycles embedded in supramolecular structures, such as crown ethers, cryptands, and heterophanes, because such tautomerism is similar in most aspects to that displayed by the analogous monocyclic heterocycles. We concentrate here on modifications that can be induced by the macrocyclic cavity. Tire so-called proton-ionizable crown ethers have been discussed in several comprehensive reviews by Bradshaw et al. [90H665 96CSC(1)35 97ACR338, 97JIP221J. Tire compounds considered include tautomerizable compounds such as 4(5)-substituted imidazoles 1///4//-1,2,4-triazoles 3-hydroxy-pyridines and 4-pyridones. 

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

Me Capra in particular proposed n> that the chemiluminescence reactions of a large number of organic compounds had this concerted dioxetane decomposition step as key reaction in the production of electronically excited products, namely acridinium salts 25,26,27) indolylperoxides 28>, activated oxalic esters 29>, diphenyl carbene 30>, tetrakis-dimethylamino-ethylene 31 32>, lucigenin 33>, and substituted imidazoles 23>. 

General procedures for the synthesis of the imidazole core have been published in 2000. Solvent-free microwave assisted synthesis of 2,4,5-substituted imidazoles 64 from aldehydes 62 and 1,2-dicarbonyl compounds 63 in the presence of ammonium acetate and alumina has been reported <00TL5031>. V-protected a-amino glyoxals 65 were utilized as potential chiral educts for the synthesis of amino acid-derived imidazoles 66 <00TL1275>. 

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

The first total syntheses of these compounds were by Hibino and coworkers [91,92] and utilized palladium(0)-catalyzed coupling of 135 and 136 to produce indole-substituted imidazole 137 in 82% yield (Fig. 39). (A similar approach to closely related compounds was reported by Achab and coworkers at about the same time as the first report by Hibino) [93]. Ester 137 was hydrolyzed in near quantitative yield by reaction with sodium car-... 

Two independent papers have reported the synthesis of nitrogen-heterocycle complexes of the type [RhCl3(py-X)3] (py-X = 3-Etpy, 3-CNpy, 4-Etpy, or 4-CNpy) and rr(ans-[RhY2L4] (Y = Cl or Br L = several substituted pyridines, isoquinoline, pyrimidine, pyrazole, thiazole, and substituted imidazoles). All the compounds were prepared catalytically by boiling RhCl3.3H20 with ethanolic solutions of L. It is interesting that 2-substituted... 

The Hi-receptor antagonists for the most part are substituted ethylamine compounds. In comparison with histamine, the Hi-antagonists contain no imidazole ring and have substituents on the side chain amino group. 

This benzilic acid type of rearrangement is the result of the action of alkali on the dicarbonyl compound, and is accelerated by calcium ions. The formation of saccharinic acids by the action of aqueous alkali on sugars is very well known 82,84,92 however, if ammonia is present, very little8 or no production of saccharinic acid has been reported. The reaction of the intermediate carbonyl compounds with ammonia is faster than the benzilic acid type of rearrangement to give saccharinic acid, and, hence, substituted imidazoles are formed, as illustrated in Scheme 9. 

Oxazoles resemble 1-substituted imidazoles in their positional reactivity order for electrophilic substitution, 5 > 4 > 2 [59LA(626)83, 59LA(626)92 74AHC(17)99 84MI29]. The compounds can be regarded as hybrids of... 

Generally speaking, 2-aminothiazoles, -oxazoles, and N-substituted imidazoles react with or-halogenoketones more easily than NH compounds, though 2-amino-4,5-dimethyloxazole and 3-amino-l-methyl-4-phenylpyrazole are reported214 not to undergo the Tschitschibabin reaction. 

Chelation sometimes does not take place automatically, as illustrated by the coordination of histamine, 4-(2-aminoethyl)imidazole (19 R = H). It appears to tautomerize and coordinates with the non-chelating nitrogen, whereas the NH2 group is protonated, so that a monodentate ligand (in fact a 4-substituted imidazole) coordinates to the metal, in this case Ni with NCS- anions in the compound [Ni(NCS)4(hamH)2] (hamH = histaminium cation).70... 

Substituted imidazoles are an example of a pharmaceutically important class of heterocyclic compounds, several of which have been incorporated in drugs that have reached the market, e.g. cimetidine, ondansetron and losartan (figure 1). 

The isolated yields of the Bredereck method are satifactory for the synthesis of di-substituted compounds (figure 5) but are generally lower for 4(5)-mono-substituted imidazoles. 

Allthough this SPS route averted some of the problems inherent to the synthesis of substituted imidazoles via condensation approaches, the value of the synthesized libraries of compounds is of a limited interest for the histamine receptor research field. First, there is only a limited number of glyoxals, one of the four reaction components, available as precursor. Secondly, only tri- and tetra-substituted imidazoles can be prepared via this method. And finally, the linker (H0-C(=0)-(CH2)2-), a pharmacophore not common to histaminergic ligands, remains present in the final product. 

Carboximidoyl chlorides may be reacted with oximes to give 30-65% yield of amidines, which may then be used to form imidazoles in good yields, by treatment with TsOH (equation 201)716. Highly substituted imidazoles may be prepared in a simple one-pot synthesis by treating vicinal tricarbonyl compounds with an aldehyde and ammonium acetate (equation 202)717. The reaction occurs in 66-90% yield and seems to be general in scope. 

Substituted imidazole 1-oxides 228 can be prepared by N-oxidation of imidazoles 248, by N-alkylation of 1-hydroxyimidazoles 249, or by cycliza-tion using suitable starting materials derived from a 1,2-dicarbonyl compound, an aldehyde, an amine, and hydroxyamine. The substituents at the three first starting materials are transferred to the product and make control over the substituents in the imidazole 1-oxide 228 possible depending on the protocol used by the synthesis. The synthesis of 3-hydroxyimidazole 1-oxides is presented in Section 3.1.6. 

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