Amidines activity requirements

Antibacterial activity is retained when the relatively complex amide side chains are replaced by a simple heterocycle amidine. The required reagent (7-2) is prepared by reaction of azepine formamide (7-1) with oxalyl chloride. Condensation of the product with 6-APA (2-4) leads to the formation of the amidine and thus amdinocillin (7-3) [11]. 

The essential structure-activity requirements were the same as for the HI receptor except that the heteroaromatic ring had to contain an amidine unit (HN-CH-N ). These results are summarized in Fig. 13.7. 

The Vilsmeier cyclisation of acetanilides by the conventional methods described above often requires long reaction times and elevated temperatures. Moreover, only activated acetanilides react efficiently to afford 2-chloro-3-substituted-quinolines strongly deactivated systems afford mainly amidine 5 or acrylamide 6. ... 

Neither the oxide nor the amidine function are in fact required for activity. Treatment of the oxime, 7, with chloro-acetyl chloride in the presence of sodium hydroxide proceeds directly to the benzodiazepine ring system (14)(the hydroxyl ion presumably fulfills a role analogous to methylamine in the above rearrangement). Reduction of the N-oxide function of 14 leads to diazepam (15). ... 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

We found 192 unique structures, with 252 recorded activities on 46 targets (see also Figure 2.3). A vast majority of them (176 structures) are likely to be charged at pH 7.4, as they are aliphatic amines, amidines or guanidines, and sometimes carboxylic acids. This indicates that low MW compounds are likely to require salt bridge interactions... 

The apparently quite broad structural requirements for anticonvulsant activity, noted earlier in this chapter, extend to yet another class of five-membered heterocycles that include an imide function. Imidazo-2,4-diones, better known as hydan-toins, have comprised some of the most widely used drugs for treating severe motor and psychomotor epileptic seizures. The general reaction used to prepare this heterocyclic system involves the treatment of a carbonyl compound with ammonium carbonate and potassium cyanide. The first step in the complex sequence can be visualized as the addition of the elements of ammonia and hydrogen cyanide to give an a-aminonitrile (88-2). Addition of ammonia to the cyano group would then lead to an amidine (88-3). Carbon dioxide or carbonate ion present in the reaction... 

Several 3-aryl-2-methylimidazo[4,5-b]pyridines (36 X = H, R = H, 4-F, 4-Et X = Cl, R = H, 4-F, 3-CF3, 2,4-Me2, 2,4-Ch, 2-Me-6-Et, 3-CF3-4-C1) with pesticidal activity have been prepared in moderate yields by the reaction of /V-(2-chloro-3-pyridyl)acetamides (37) with aromatic amines in the presence of P2O5 and Et3N-HCl at 150 C.140 With X = H the cyclized products were isolated directly, whereas with X = Cl treatment of the intermediate amidines (38) with K2CO3 in DMF was required to arrive at the final cyclized product. 

Pyrido[2,3-d]pyrimidines 70 were synthesized in a one-pot three-component cyclocondensation of os/i-unsalurated esters 67, CH-active nitriles 68 and amidines 69 [122], While reflux in THF or MeOH for 24 hours was required... 

The reaction of A-acylimidates 17 or A-cyanoimidates 18 with amidines at room temperature also provides a route to 2,4,6-trisuhstituted 1,3,5-triazines with three different substituents.325,422,423 In the case of A-cyanoimidates 18, 4,6-disubstituted l,3,5-lriazin-2-amines 19 are obtained.422,423 Activated imidates 17 and 18 react with amidines under mild conditions in alcoholic solution to provide the 1,3,5-triazines.325,422,423 ln a similar reaction, A-cyano-carboximidamides condense with amidines to form 1,3,5-triazines however, more vigorous conditions are required.424... 

Catalytic hydrogenation of oximes to amines requires conditions resembling those for catalytic hydrogenation of nitro compounds and nitriles.20d The catalyst should be as active as possible, e.g., Raney nickel101 (if necessary, platinized), platinum oxide,102 palladium-charcoal,103 palladium-barium sulfate,104 or rhodium-alumina.105 This rhodium catalyst also serves for reduction of an amidoxime to the amidine.106 Hydrogenation may be effected under pressure, but the temperature should be kept as low as possible to avoid formation of secondary amines. 

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