Phosphonates bisphosphonates

Table XIX contains stability constants for complexes of Ca2+ and of several other M2+ ions with a selection of phosphonate and nucleotide ligands (681,687-695). There is considerably more published information, especially on ATP (and, to a lesser extent, ADP and AMP) complexes at various pHs, ionic strengths, and temperatures (229,696,697), and on phosphonates (688) and bisphosphonates (688,698). The metal-ion binding properties of cytidine have been considered in detail in relation to stability constant determinations for its Ca2+ complex and complexes of seven other M2+ cations (232), and for ternary M21 -cytidine-amino acid and -oxalate complexes (699). Stability constant data for Ca2+ complexes of the nucleosides cytidine and uridine, the nucleoside bases adenine, cytosine, uracil, and thymine, and the 5 -monophosphates of adenosine, cytidine, thymidine, and uridine, have been listed along with values for analogous complexes of a wide range of other metal ions (700). Unfortunately comparisons are sometimes precluded by significant differences in experimental conditions.

When methylene bisphosphonate (169) is reacted in a Horner reaction with an aromatic aldehyde, the alkenyl phosphonate 170 is produced (Scheme 5.25). By metalation with LDA in THF, this is converted to the vinyllithium intermediate 171 that, with the ketone 172, affords a Baylis-Hillman reaction-type product, 173 on base treatment, this is converted to the arylallene 174 [67]. 

Of interest in this section are phosphonates (R-P(=0)(-OR )(-OR")), including bisphosphonates (R-CH(P03H2)2) and phosphonoformates ((R0-)(R 0-)P(=0)(C00R")) phosphinates (RR P(=0)(-OR")) will also be mentioned briefly. In contrast to phosphates, alkyl phosphonates are not likely to be hydrolyzed by esterases due to lower acidity, a different shape, and, in some cases, the inability to undergo pseudorotation [118]. This increases the probability of alternative cleavage pathways, in particular oxidative ones, as documented below. 

Bisphosphonates are drugs of great interest in a number of metabolic bone diseases [119]. This therapeutic class comprises bis(phosphonic acids) and, more recently, bis(phosphonic acid) esters. The former are hydrophilic and poorly bioavailable, and they are generally not metabolized. In contrast, bis(phosphonic acid) esters may be more prone to biotransformation, as exemplified with the lead compound known as U-91502 (9.51 in Fig. 9.11). 

Huikko, K., and Kostiainen, R. (2000). Development and validation of a capillary zone electrophoretic method for the determination of bisphosphonate and phosphonate impurities in clodronate./. Chromatogr. A 893(2), 411-420. 

When the reaction is run using excess hydrogen phosphonate (3 equivalents), sequential addition of two molecules of the phosphonate takes place to form 1,2-bisphosphonate as shown in Scheme 21 [23]. As described above, the first addition affords the branched isomer with a trace of the linear byproduct. Only the former is reactive to undergo the second addition forming the bisphosphonate as illustrated in Scheme 22. 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroid use, poor oral hygiene). While on bis-phosphonate treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. 

A detailed account of the biochemistry of the bisphosphonates has recently appeared elsewhere170). Briefly, the bis-phosphonates inhibit soft tissue calcification. Bis-phospho-nates, such as HEBP inhibit the mineralization of cartilage, bone and dentine. Prolonged administration of HEBP to man at oral doses of 10 mg-1 kg-1 for more than one month affects the mineralization of hard tissues. Slight changes in the substituents on the gemi-... 

The reaction afforded the tandem cyclization product 170 as a mixture of two separable isomers together with an a,p-unsaturated cyclic bisphosphonate, which is formed by a direct deprotonation of the vinylic a-proton of 168 and subsequent intramolecular Michael cyclization. The authors described the formation of 170 by the conjugated addition of 168 to 2.2 equivalents of PhLi and subsequent intramolecular Michael reaction in the intermediate 169. It is likely that coordination of the lithium atom to the oxygens of the phosphonates favors formation of the /raw.v-isomer. As shown in Scheme 52, the reactions with bulky naphthyllithiums gave only the fraws-170 isomer. This novel methodology can provide a rapid entry into a variety of cyclic bisphosphonates in good stereoselectivity. 

The method has the added advantage in that it provides a route not only to nucleoside diphosphates (upon reaction with pyrophosphate) but also allows the preparation of phosphonate analogues by the use of methylene or difluoromethylene bisphosphonates.10 The latter analogues are both stable to hydrolysis. 

DISODIUM CLODRONATE DISODIUM (DICHLOROMETHYLENE)BISPHOSPHONATE LODRONATE PHOSPHONIC ACID, (DICHLORO-METHYLENE)BIS-, DISODIUM SALT PHOSPHONIC ACID, (DICHLOROMETHYLENE)DI-, DISODIUM SALT... 

The synthesis and evaluation of binding ability of new model host compounds, bis-phosphonates (396) triphosphonates (397) and (398), with guanidine have been reported. The introduction of electron donating or withdrawing sub-stitutents in the 5-position of the parent bisphosphonate (396, X,Y = H) revealed the presence of Jt-cation interactions which contribute at least 0.5 kcal/mol for a single benzene guanidinium interaction. Even more effective was the introduction of a third phosphonate functionality at the correct distance, as shown in... 

A simple procedure for the preparation of trifluoromethylated vinyl- and dienyl-phosphonates with y-alkoxycarbonyl moiety of exclusively or predominantly (Z)-configuration (201) has been described. It involves acylation of ethyl-1,1-bisphosphonate (202) with trifluoroacetic anhydride, addition of selected Reformatsky reagents to the resulting 1-trifluoroacetyl-1,1-ethyl bisphos-phonates (203) and finally spontaneous Horner-Wadsworth-Emmons (HWE) olefination of the adducts (Scheme 55). " ... 

Horner-Wadsworth-Emmons procedures are also commonplace in synthetic materials chemistry, recent examples including donor-acceptor substituted molecules with bicyclo-spacers, which require napthalene-, anthracene-, and pyrene-substituted phosphonates, (112), (113) and (114) respectively, well-defined, electroactive PPE/PPV copolymers through the condensation of dialdehydes and bisphosphonate (115), ° and triphenylamine-substituted PPV. ° ... 

Miscellaneous Reactions.- The phosphonate isostere (212) of (3 )-myo-inositol-1-phosphate has been prepared by olefination of the ketone (210) with the methylene bisphosphonate anion (211) followed by reduction and deprotection. 28 Further studies of the use of the phosphonate-based olefination of pyranoses in the synthesis of C-glycosides (e.g. 213)... 

Zhang, Y., Oldfield, E. Solid-state 31P NMR chemical shielding tensors in phosphonates and bisphosphonates A quantum chemical investigation. J. Phys. Chem. B 2004,108,19533 40. 

Page, P.C.B., McKenzie, M.J.. and Gallagher, J.A., Simple synthesis of oxiranylidene-2,2-6A(phosphonic acid). Tetrabenzyl geminal bisphosphonate esters as useful intermediates, Synth. Commun., 32, 211, 2002. 

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