Bis-phosphonates

CN (4-Amino-1-hydroxybutylidene)bis[phosphonic acid] monosodium salt trihydrate acid... 

RN 22560-50-5 MF CHzCljNaPsP MW 288.86 EINECS 245-078-9 CN (dichloromethylene)bis(phosphonic acid) disodium salt... 

The related hydantoin monophosphinate 19, bis-phosphonate 20, or bis-phosphinate 21 systems have also been reported using these milder Mannich methods (24). 

Addition of diaUcyl phosphites HP(0)(0R)2 to terminal alkynes led to the formation of bis-phosphonates in 47-90% yield. These products result from addition of two P-H bonds across the C=C triple bond. Interestingly, although diethyl phosphite gave good results, the isopropyl derivative gave lower yields, and only mono-... 

Large, well-designed trials have proven the benefits of bis-phosphonate therapy in preventing vertebral and nonvertebral fractures. Several studies have found decreases in vertebral fracture risk by as much as 40% to 50% with alendronate and risedronate.13,14,19-21 Data suggest a similar reduction with ibandronate on vertebral fractures.16,22 Alendronate and risedronate decrease the incidence of hip and nonvertebral fractures as well.14,19,23... 

Newly diagnosed, asymptomatic patients may be observed without treatment. This asymptomatic period may last for months to a couple years. All patients with multiple myeloma will become symptomatic, and once this occurs, treatment is required. First-line treatment may be one of several therapies, including VAD, thalidomide plus steroids, and autologous transplant. Nearly all patients will progress at some point, and second-line therapy usually will include bortezomib. All patients who have bone lesions should receive monthly bis-phosphonates, with the hope of reducing pain and fractures. 

General.—Pudovik et al.59 have re-examined some reactions between imines and dialkyl phosphonates reported initially in 1959 by N. Kreutzkamp and G. Gordes, and they have shown that the products of the reactions between dialkyl phosphonates and (70) or (71) are actually (72) and (73), and not the bis(phosphonic acids) (74 R2 = H, Ph) (Scheme 2). They were further able to show that, under milder conditions, the imino-ethers (70) will yield eventually (77), through (75) and (76). 

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). 

Example 57 the synthesis of 2-chloro-iV -methyladenine-9-(2-methyl-propyl)bis phosphonate, analogous to the corresponding bisphosphate, has been performed by Jacobson and associates [93]. The key step in this synthesis is the Arbuzov-Michaelis reaction. 

Fig. 9 Schematic representation of pillared a-zirconium phosphite-4,4 -(3,3 5,5 -tetram-ethylbiphenylene)bis(phosphonate) [64, 65]...

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. 

The following classes of phosphorus-containing compounds were not affected by large amounts of the enzyme with Mg2+, Mn2+, Zn2+, or Co2+ at either pH 9.1 or 7.5 (1) ribo- or deoxyribonucleoside mono-, di-, or triphosphates (2) ribo- or deoxyribopolynucleotides (3) nucleotide coenzymes (e.g., DPN+, UDP-glucose) (4) phosphomonoesters (e.g., glucose-6-P, p-nitrophenyl phosphate) (5) cyclic tri- or tetrametaphos-phates (6) phosphorofluoridates (inorganic phosphorofluoridate, adenosine 5 -phosphorofloridate) and (7) phosphonates (e.g., methylene-bis-phosphonate) (12, 57). 

Crude estimates of the affinities of the enzyme for other compounds have been made by study of their capacity to inhibit hydrolysis of PPi. If the observed inhibition is assumed to be competitive, a simplified kinetic treatment yields the inhibition constants (Ki" values) listed in Table VI (54). The data indicate that several of the compounds whose hydrolysis is not catalyzed (Section III,D) are nevertheless bound weakly to the enzyme (e.g., ADP, methylene-bis-phosphonate). There is also very weak binding of Pi( the product of the enzymic reaction [Eq. 

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-... 

To confirm that 5 has the expected 1,2-bis structure, we hydrolyzed and oxidized it to the bis-phosphonic acid. The 31p NMR spectra of this acid shows two doublets consistent for a 1,2-bis structure. The - P-NMR spectra reported for the 1,3-bis-(phosphonic acid) propane is a singlet. . 

In order to prepare these macrocycles it was necessary to synthesize the previously unknown o -bis(phosphino)benzene (IV). Lithium aluminum hydride reduction of the o-bis(phosphonate) III gave IV in 50% yield (31P NMR, 6 -123.8 ppm, Jpy = 207 Hz). The phosphonate III could be obtained in modest yields by the photo-activated nucleophilic aromatic substitution by sodium diethyl-phosphite on o-chloroiodobenzene in liquid ammonia solution (4). 

The synthesis of nucleoside diphosphates is best achieved using the Poulter reaction,9 which involves reaction of the tris(tetra-n-butylammonium) salt of pyrophosphate with a nucleoside 5 -tosylate in acetonitrile. A general procedure for the synthesis of nucleoside tosylates of thymidine and 2 -deoxyadenosine is included (Protocol 15), whilst the syntheses of the other tosylates (including ribonucleosides) have been described using related procedures. Simple modification of the protocol, whereby the tetra-n-butylammonium salt of pyrophosphoric acid is replaced by methylene or difluomethylene bis phosphonate, allows the synthesis of hydrolytically stable dNTP analogues.10... 

Earlier, Cava and co-workers had shown that EDOT 43 reacts with formaldehyde and dimethylamine to give the Mannich base 45 in 84% yield <1999T11745>. Subsequently, Cava and co-workers have converted the Mannich base 45 in two steps to the synthetically useful phosphonium salt 46. In an extension of this method, the diammonium salt 47 obtained from bis-EDOT has been treated with diethyl phosphite to give the bis-phosphonate 48 <2005T3045>. 

The sample studied was a cobalt bis(phosphonate) of composition C02(O3PC6H4OC6H4PO3)-2H2O. It is one of the series of first row transition element compounds with the same general formula, but different water contents. The Cu(ll) compound structure was solved from its powder pattern, unit cell dimensions a = 8 1012(5), b = 5.3109(3), c = 29.2595(5) A. It has a layered structure in which the layers are spaced at half the c-axis dimension. The reason for the doubling of the c-axis is that in one layer the rings are tilted around the ether oxygen to the left and in the next layer to the right. The Cu atoms are 5-coordinate with square pyramidal structure. 

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