Prodrugs Mannich bases

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

Cogan, P. S., Fowler, C. R.,Post, G. C., and Koch, T. H. Doxsaliform A novel A-Mannich base prodrug of a doxorubicin formaldehyde conjugate (letter). Drug Des. Discov. 1 247-255, 2004. 

Mannich Bases Mannich base prodrugs could enhance the delivery of their parent drugs through the skin because of their enhanced water solubility as well as enhanced lipid solubility. A -.Vlannich bases, or A -acyl gem-diamines (67), are generally formed, as shown in Scheme 9, by reaction of an acidic NH com-... 

Mannich base prodrugs are regenerated by chemical hydrolysis (Section 2.8) without enzymatic catalysis (30). Various other chemical approaches can be used to achieve increased skin permeability by enhancing both water solubility and lipid solubility (31). 

The toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

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. 

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. 

First, we examine the hydrolytic opening of cyclic Mannich bases, i.e., rings that contain N-CH2-0, N-CH2-S, or N-CH2-N fragments. The mechanism of hydrolytic fragmentation of linear Mannich bases was discussed in Sect. 11.5, and, in this section, we demonstrate that cyclic Mannich bases can also be of interest in prodrug design. 

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

Some cyclic AT-Mannich bases have also been reported, for example, the imidazolidin-4-ones (11.116) that were investigated as potential prodrugs of peptides (11.117) [141], The imidazolidin-4-ones, prepared by allowing the peptide to react with acetone under dehydrating conditions, are bases with pKa values of 3 - 4. For most of the derivatives, hydrolysis is spontaneous the protonated form (i.e., at pH < 2) reacts ca. 10 - 30 times slower than does the neutral form (pH > 6). Very large differences in reactivity were noted,... 

Labeled Mannich bases of natural compounds or of compounds capable of interacting with biomolecules in the course, for example, of metabolism, such as drugs, prodrugs, etc., are usefully employed as tracers in biological and pharmacological investigations. Table 36 summarizes Mannich bases labeled with isotopes other than the commonly used deuterium, which are reported in the literature. 

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,... 

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. 

A second challenge is the toxitity potential of some prodrugs, namely, a toxic metabolite formed from the promoiety or a reactive metabolic intermediate generated during the activation of some bioprecursors. The former case is illustrated by the liberation of formaldehyde, as seen with Mannich bases or some double esters [1,4]. The latter case involves a very few known examples of failed bioprecursors whose activation was via a reactive and toxic intermediate. Thus, arylacetylenes were examined as potential bioprecursors of nonsteroidal anti-inflammatory agents [1]. Although the nature of the final (and stable) metabolite (an arylacetic add) was known, researchers at the time were not aware that the metabolic pathway involved an intermediate and highly reactive ketene. 

Acidic compounds with N—H bonds such as amides, carbamates, and hydan-toins, may be transformed to /V-rnannich bases to form oral prodrugs [2], These prodrugs are generally made by reacting an amide, carbamate, or hydantoin with formaldehyde and a primary or secondary aliphatic or aromatic amine (Fig. 4). The (V-mannich prodrugs tend to have better physicochemical properties than the parent compounds. The derivatives may have increased water solubility, dissolution rate, and/or lipophilicity. 

Another example of a prodrug-based molecular design is the Mannich adduct (27) of nitromethylene compound (7) with amine and formaldehyde, which were prepared independently by Kishida et al. [30] and Krtlger et al. (Fig. 9) [31]. Nauen et al. reported that these adducts are hydrolyzed to the original material in acidic milieu [2]. 

Even though any modification of C-2 leads to inferior activity, or none at all, the pyrro-lidinomethyl derivative of the 2-carboxamide (rolitetracycline) appears to be an exception. However, on closer scrutiny this Mannich reaction product (Eq. 6.12) will be seen as a prodrug of TC. The compound is 2,500 times more water soluble than the parent TC compound (comparing free bases), to which it hydrolyzes in vivo. Thus its activity is essentially that of the parent compound. 

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