Uses of the Aza-crown Macrocycles

There are important new applications of the aza-crown macrocycles for medicinal purposes. The perturbation of metabolic processes based on biological metal ion-ligand coordination can produce a disease or even death. Conversely, undesirable biological processes can be prevented by using certain metal ion-ligand interactions. For example, the weak complexing ability of chlorine to the central platinum ion of ds-platin (61) allows cw-platin to have antitumor activity (Haiduc and Silvestru, 1989). When applied in a biological 

A novel method to localize and treat tumors by means of a ligand-radioisotope complex attached to an antibody is now being tested. The cyclic polyamines are ideal ligands for this purpose because they can be attached to an antibody and form strong complexes with the appropriate radioactive metal ions (Cox et al., 1989 Craig et al., 1989 Kaden et al., 1989 Moi et al., 1987, 1988 Morphy et al., 1988, 1989 Parker et al., 1989 Riesen et al., 

The cyclic amines form complexes with radioactive metal ions that are kinetically inert with respect to dissociation either by the pH of body fluids or reaction with the common metal ions in body fluids. 

Derivatives of [14]N4(10) (cyclam) even in low doses have a good efficiency in reducing the lethal response to nickel. These macrocycles significantly enhance the urinary and biliary excretion of Nr and restore the altered levels of other trace metal ions such as Cu-+, Zn-, and Fe They are more efficient in this application than linear chelating agents such as EDTA or triethylenetetraamine (Athar et al., 1987 Misra et al., 1988). 

There have only been a few preclinical studies using the aza-crown macrocycles. The toxicity of the crowns has been somewhat studied. Crown ethers are more toxic than the aza-crown macrocycles because toxicity arises from the slow leakage of potassium ions out of and sodium ions into cells (Gokel, 1991). Dibenzo-18-crown-6 is much less toxic than the other crown ethers because it is much less soluble in water. Complexed ligands are much less toxic than the uncomplexed ligand. For example, complexes of [12]N4-tetraacetate are not toxic while the uncomplexed ligand will remove metal ions from cells (Lauffer, 1987). Thus, it is important to have stable complexes when the macrocycles are used for medicinal purposes. 

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This chapter contains information on the nomenclature of the aza-crown macrocycles and a brief review of their complexing abilities and selectivities for various eations, anions, and neutral organie molecules. Some information on important medicinal uses for these compounds is also included. The last section gives a few general comments about the compounds that are covered in this book. 

Other high molecular weight amines to have been successfully used for adduct purification include the aza-crown macrocycles Me4-14-ane-N4 and Me6-18-ane-N6.48 These reversibly form adducts with indium and gallium alkyls, such as [(Et3Ga)4(Me6-18-ane-N6)], [(Et3Ga)6(Me6-18-ane-N6)], [(Pr13Ga)4(Me6-18-ane-N6)], and [(Pr13Ga)4(Me4-14-ane-N4)].49 Formation of... 

Unfortunately, only a few aza- and peraza-crowns can be purchased. On the other hand, many polyamines and diaminoethers are available and can be used for the synthesis of the desired aza-crown macrocycles. A most useful starting material, 4-oxa-l,7-heptanediamine, is very expensive ( 50 per gram in 1992). Even so, this material was used in the ring closure step to prepare triaza-18-crown-6 as shown in the following sequence (Graf and Lehn, 1981 Miller et al., 1989). 

The condensation of 2,3-diaminobenzo-15-crown-5 2a with s-trans-chloroethanedial dioxime proceeds with the formation of the (15-crown-5)eno[g]quinoxaline-2(lfJ)-one oxime 11a, which when heated in absolute ethanol at 60 °C in the presence of C0CI2 for 4h results in 2,2 -azobis[(15-crown-5-eno[g]quinoxaline)] 12 (1986CB3870).The use of cyanogen-di-AT-oxide and (E,fr)-dichloroglyoxime instead of the s-twns-chloroethanedial dioxime in the reaction with 2,3-diamino-benzo-15-crown-5 2a and 12,13-diamino-4,7-bis(ferrocenylmethyl)-2,3,4,5,6,7,8,9-octahydrobenzo[k]-4,7-di-aza-l,10-dithiacyclo do decine (2b) makes it possible to synthesize the macrocyclic dioximes 11b,c (1986JCR(S)90, 2007JCOC2509). 

Chirality derived from the readily accessible a-amino acids has been incorporated into the side chains of aza and diaza macrocyclic polyethers. A number of procedures suitable for peptide synthesis have proved (178) to be unsuitable for acylating the relatively unreactive secondary amine groups of aza crown ethers. Eventually, it was discovered that mixed anhydrides of diphenylphos-phinic acid and alkoxycarbonyl-L-alanine derivatives do yield amides, which can be reduced to the corresponding amines, e.g., l-172. By contrast, the corresponding bisamides of diaza-15-crown-S derivatives could not be reduced and so an alternative approach, involving the use of chiral A-chloroacetamido alcohols derived from a-amino acids, has been employed (178) in the synthesis of chiral receptors, such as ll-173 to ll-175, based on this constitution. 

The saturated aza-oxa crown ethers were first synthesised as intermediates in the synthesis of the nitrogen cryptands.1 The reaction conditions used for the formation of these macrocycles involved the high-dilution technique. In this versatile method, a diamine and a diacid chloride are simultaneously added in the presence of triethylamine to a large volume of solvent, usually toluene, over an extended period of time. The major product from such a reaction is the [1+1] cyclised product, although the [2+2] adduct can often be isolated as well, in low yield. Whilst this method is still sometimes used,2,3 particularly for cryptand synthesis (Chapter 5), it has been superseded by methods that are more convenient and which proceed under medium dilution. 

For the synthesis of aza-thia macrocycles, many of the methods that are available for the synthesis of aza cycles (Chapter 2) or aza-oxa crowns (Chapter 3) are also applicable. Thus the Richman-Atkins co-cyclisation of the ditoluenesulfonamide with an alkylditoluenesulfonate may be used for the synthesis of the [18]-N4S2 ring (Scheme 3.6). In this case, desulfonylation to afford the tetraamine 23 is best carried out with lithium in liquid ammonia.12... 

Macrocyclization under high dilution conditions has been used to prepare different liquid crystals composed of 2-phenylpyrimidine or 5-phenylpyrimidine connected by PEG units <03JOC597>. Treatment of polyoxypropylenediamine (Jeffamine) with 1,4-benzoquinones afforded low but variable yields of the 2,5-bridged quinoid(aza)crown ethers not utilizing high dilution conditions <03TL5531>. 

Macrocyclic reagents, such as chromogenic crown ethers of the type 14-crown-4 (extraction to 1,2-dichloroethane in the presence of picrate) were used for determination of Li [53]. The 14-crown-4 type derivatives have been applied for determination of Li in blood by a continuous FIA method [54,55]. The use of chromogenic reagents aza-12 (-13 or -14)-crown-4 has also been proposed [56,57]. The effect of substituents on the selectivity of separation of Li (and Na) by means of benzo-14-crown-4 and 13-crown-4 ethers was studied [58]. A review of chromogenic macrocyclic reagents used for determination of lithium (and other alkali metals) has been published [32]. 

Agents used as PT catalysts are onium salts (ammonium and phosphonium salts), macrocyclic polyethers (crown ethers), aza-macrobicyclic ethers (ciyptands), open chain polyethers (polyethylene glycols, PEGs, and their dimethyl ethers, glymes). Table 1 summarizes some of the properties of commonly used PT catalysts. 

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