67293-68-9

Upstream product

• 109425-46-9 [1-(Dimethoxy-phosphoryl)-2-methoxy-ethyl]-phosphonic acid dimethyl ester 
• 34162-79-3 vinylidene-1,1-diphosphonic acid 
• 149-73-5 trimethyl orthoformate 
• 16001-93-7 tetramethyl methylenediphosphonate 
• 109-89-7 diethylamine 
• 50-00-0 formaldehyd 

Downstream Products

• 115178-17-1 Tetramethyl 2-benzylthioethane-1,1-diphosphonate 

Relevant academic research and scientific papers

α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates.

Targeting Cancer Cells with a Bisphosphonate Prodrug

Nitrogen-containing bisphosphonates have antitumor activity in certain breast cancer and myeloma patients. However, these drugs have limited oral absorption, tumor cell entry and activity, and cause bone side effects. The potencies of phosphorylated antiviral drugs have been increased by administering them as prodrugs, in which the negative charges on the phosphate moieties are masked to make them lipophilic. We synthesized heterocyclic bisphosphonate (BP) prodrugs in which the phosphonate moieties are derivatized with pivaloyloxymethyl (pivoxil) groups and that lack the hydroxy “bone hook” on the geminal carbon. When the lipophilic BP prodrugs enter tumor cells, they are converted into their active forms by intracellular esterases. The most active BP prodrug, tetrakispivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (7), was found to potently inhibit the in vitro growth of a variety of tumor cell lines, especially hematopoietic cells, at nanomolar concentrations. Consistent with this fact, compound 7 inhibited the prenylation of the RAP1A small GTPase signaling protein at concentrations as low as 1–10 nm. In preclinical studies, 7 slowed the growth of human bladder cancer cells in an immunodeficient mouse model. Thus, 7 is significantly more active than zoledronic acid, the most active FDA-approved BP, and a potential anticancer therapeutic.

Challenging synthesis of bisphosphonate derivatives with reduced steric hindrance

An alternative approach is reported for the synthesis of methyl ester protected bisphosphonate building blocks, such as methylene bisphosphonate, vinylidenebisphosphonate and aryl substituted prochiral vinylidenebisphosphonates, that cannot be obtained directly from dimethyl phosphite and dichloromethane.

NOVEL BISPHOSPHONIC ACID DERIVATIVE AND APPLICATION FOR SAME

The novel bisphosphonic acid ester derivatives represented by the following formula (1): ????????Y-Cy-(NH)m-(CH2)n-C(X)(PO(OR1)(OR2))2?????(1) wherein each symbol is as defined in the DESCRIPTION, which has an amino group substituted by a heterocyclic group or a heterocyclic group containing a nitrogen atom, and the acid moiety is esterified with a POM group, an n-butanoyloxymethyl (BuOM) group and the like, exhibit a superior direct or indirect cytotoxicity effect on tumor cells and virus infected cells.

Synthesis of novel bisphosphonate polyamine conjugates and their affinity to hydroxyapatite

Bisphosphonates are negatively charged molecules, widely used as bone drugs since they have high affinity to bone surface. Polyamines are small organic bases that are positively charged under the physiological conditions and they participate in the regulation of important cellular functions. In this study, we report a general synthesis strategy for bisphosphonate-polyamine conjugates starting from ethenylidene bisphosphonates and N-Boc protected polyamines. Four novel conjugates were prepared and characterized with spectroscopic methods. The affinity of these novel compounds to hydroxyapatite was also determined by using 99mTc procedure. ARKAT-USA, Inc.

Phosphonated Fluoroquinolones, Antibacterial Analogs Thereof, and Methods for the Prevention and Treatment of Bone and Joint Infections

The present invention relates to phosphonated fluoroquinolones, antibacterial analogs thereof, and methods of using such compounds. These compounds are useful as antibiotics for prevention and/or the treatment of bone and joint infections, especially for the prevention and/or treatment of osteomyelitis.

ETUDE PAR RMN DES REACTIONS D'ADDITION DES SPIROPHOSPHORANES A LIAISON P-H SUR LE TETRA ETHYLE ET LE TETRA METHYLE ETHYLIDENE BIS PHOSPHONATE

The spirophosphoranes 1 to 4,6 and 7 bearing a P-H bond have been condensed with tetraethyl (z) or tetra methyl (x) ethenylidene bis phosphonate by a Michael type addition reaction.The resulting compounds: Spirophosphoranes-bis phosphonates 1x, 3x, 4x, 5x, 6x, 7x and 2z, 4z, 5z, 7z havd been studied by NMR 1H, 31P and 13C.With the spirophosphorane 7 that contain 90percent of its tricoordinated form 7' the formation of an intermediate 7ax or 7az has been observed: 7ax or 7az give rise to a slow transposition at 20 deg C or a fast rearrangement at 60 deg C into phosphorane 7x or 7z.Key words: Ethenylidene bis phosphonate, spirophosphorane, phosphorane-bis phosphonate, stereomutation, tautomeric equilibrium PIII-PV, diastereotopy.

Antimicrobial agents and process for their manufacture

Disclosed are tetraalkyl enthenylidenebisphosphonates and a method for their manufacture. These compounds are suitable for use as antimicrobial agents in combating a number of pathogenic microorganisms, such as bacteria, yeasts, viruses, fungi and protozoa, when used together with a pharmaceutically-acceptable carrier. Also disclosed is a method for treating infectious diseases by administering a safe and effective amount of these tetraalkyl ethenylidenebisphosphonates.

Synthesis of Ethenylidenebis(phosphonic acid) and Its Tetraalkyl Esters

A new method for the preparation of tetraalkyl ethenylidenebis(phosphonates) has been developed.This two-step procedure involves the base-catalyzed reaction of a methylenebis(phosphonate) ester with paraformaldehyde followed by acid-catalyzed elimination of methanol.The effects of variations in the reaction conditions of the first step of this process are described.Ethenylidenebis(phosphonate) esters can be converted to the free acid by reaction with bromotrimethylsilane.