N-Mannich base

These moieties are found mainly in compounds that are potential prodrugs and generally undergo rapid nonenzymatic hydrolysis, as exemplified by the following overall reaction of an N-Mannich base ... 

As with the O-Mannich bases discussed above, the rate of nonenzymatic hydrolysis of N-Mannich bases depends on factors such as steric hindrance and electrophilicity of the sp3 C-atom. A rather large number of studies have been published on the value and properties of N-Mannich bases as potential prodrugs for amines, amides, and imides [80] [82] [88] [89], Here, we first review available reactivity data and then discuss selected examples of medicinal relevance. 

For some N-Mannich bases of benzamides and various amines, the rate constant increased with the size of the alkylamino group and with the pKa of the free amine. The reactivity also increased strongly with increasing acidity of the parent amide. Thus, N-Mannich bases of toluenesulfonamide or suc-cinimide had tm values of 1 min or less. 

A few N-Mannich bases of the anti-inflammatory drug salicylamide are reported in Table 11.1. The pharmacokinetic behavior of one of these, N-(morpholinomethyl)salicylamide (11.54), was examined in the rabbit [90], Plasma concentration curves showed that the oral bioavailability of salicylamide was increased two- to sixfold by administration of the prodrug. 

N-Mannich derivatization has also been documented to improve skin delivery [91][92], In the case of theophylline (11.56) and 5-fluorouracil (11.58), a much improved solubility in water of the various N-Mannich bases examined was observed. To avoid breakdown, however, the prodrugs had to be dissolved in a polar nonaqueous solvent (isopropyl myristate) for pharmaceutical use. The delivery of theophylline and 5-fluorouracil through hairless mouse skin was, thus, accelerated approximately sixfold through use of the prodrugs 11.57 and 11.59, respectively. 

R-CONH2+ CI-I20+ HNR,R2 = R-CONH-CH2-NR1R2+ H,0 FIGURE 16.2 Schematic for preparation N-Mannich base prodrugs. 

Boron-11 NMR spectroscopy can be used for structural elucidation of complex boron containing heterocycles. Hydrolytic stabilities of dioxazabora heterocycles (19) and their corresponding N Mannich bases with different carboxamides have been determined by nB NMR studies (82M1025). 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

C -Mannich bases, unless otherwise staled N-Mannich bases... 

C-Mannich derivatives of uridine 467 and thymidine s or N-Mannich bases of cy-tidinc iododcrivatives arc yielded from nucleosides subjected to aminomethyla-(X = 0. NAIkyl) iof, presence of the glycoside moiety may favor the reaction at C-5 (arrow in 468) through the formation of a polycyclic structure bearing an electron-attracting group inserted at the adjacent position, C-6. ... 

In addition to the studies of molecules with similarities to natural vitamins, such as the models of tetrahydrofolic acid or the analogs of vitamin K (Refs. 512 and 914 for Chaps. I and II), aminomethylation has been performed on the nicotinamide group of vitamin P, with the formation in good yields of the corresponding N-Mannich base." Improved conversion is obtained, starting from the palladium complex of the vitamin (Fig. 6, Chap. I). 

Pharmaceuticals made from Mannich bases are reported in Table 43, where almost the whole range of the different classes is represented. C-Mannich bases, in particular cyclic and acyclic P-aminoketones, predominate, although N-Mannich bases, especially amide derivatives, are also well represented. 

Herbicides are mainly aminomethylphosphonic acids (593) amidic N-Mannich bases are also represented.- - - ... 

Johansen. M. and Bundgaard, H., lYodrugs as drug delivery systems. XXIV. N-Mannich bases as bioreversible lipophilic transport forms for cphedrinc, phenethylaminc and other amines. Arch. Plutnn. Chemi Sci. Ed., 10, 111, 1982. 

Saab, A. N Sloan, K. B Beall, H. D and Villanueva, R Effect of aminomethyl (N-Mannich base) derivatization on the ability of S -acctyloxymethyl-6-mercaptopurine prodrug to deliver 6-mercaptopurine through hairless mouse skin. / Pharm. Sci.. 79, 1099,... 

Arylamines 79 are allowed to react under acidic conditions, in the presence of acetic acid, which affects even Ihe chemosclectivity of the reaction with formation of N-Mannich base when the molar ratio acid/sub.strate is very low (1 25). " ... 

C -Mannich bases, unless otherwise stated See also SO derivatives ° S-Mannich bases N-Mannich bases F used ring derivatives included... 

Tertiary Mannich bases having a halogen atom in position 4 with respect to the amino group (Fig. 127) can give cyclic products by intramolecular N-alkylation, with formation of the heterocyclic quaternary salts 330, as shown by the N-Mannich bases of chloroacctohydrazidc and by some brominated O-Mannich bases. ... 

Bundgaard, H. and Johansen, M., Prodrugs as drug delivery systems. IV. N-Mannich bases as potential prodrugs for amide, ureidc and other NH-acidic compounds, J. Pham Sci., 69,44, 1980. 

Johansen, M. and Bundgaard, H., Pro-dmgs as drug delivery systems. XIII. Kinetics of decomposition of N-Mannich bases of salicy-lamidc and assessment of their suitability as possible pro-drugs for amines, Int. J. Pharm., 7,119,1980 Chem. Abstr.. 94, 162641, 1981. 

Polymeric N-Mannich bases derived, in particular, from aminumcthylalion of polyacrylamide - and its copolymers are the most investigated. The reaction mechanism has also been studied (Chap. 1, 6.2)." ... 

Tramontini, M., Angiolini, L., and Ghcdini, N Mannich bases in polymer chemistry. Polymer. 29, 771. 1988. 

C.1,2) C- and N-Mannich bases,. starting, respectively, from uraciF and 5-fluorocyto-sine, - adenine or other purines, - can result. Multiple aminomethylation may also occur with purines, the synthesis of monoaminomethylated derivatives, such as 466, being possible only with weakly basic amines. 

Koch, S. A. M. and Sloan, K. B., N-Mannich base dcrivates of 5-fluoro-cytosine a pro-drug approach to improve topical delivery, Inl. J. Pham, 35, 243, 1987 Chem. Absir., 106.219506, 1987. 

Among N-Mannich bases, derivatives of polyacrylamide (517) are investigated particularly for their flocculant properties in water treatment. The corresponding quaternary ammonium salts are also used. Benzimidazolic and bcnzotriazolic Mannich bases 518, usually with the bulky alkyl group linked to the amine moiety, are used effectively against corrosion in a manner similar to alkylphenols 513, which have the apolar group linked to the substrate moiety. 

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