118072-93-8 Usage
Description
Zoledronic acid is a white, crystalline powder that is available in vials for reconstitution for IV infusion over at
least 15 minutes. It does not undergo metabolic transformation and does not inhibit CYP450 enzymes.
Clearance of this agent is dependent on the patient's creatinine clearance, not on dose. Serum creatinine
levels should be evaluated before every treatment. Zolendronic acid is contraindicated in patients with severe
renal impairment.
Chemical Properties
White Solid
Originator
Zometa,Novartis Pharma,Switz
Uses
Different sources of media describe the Uses of 118072-93-8 differently. You can refer to the following data:
1. Bisphosphonate antiresorptive agent
2. bone resorption inhibitor
3. Zoledronic acid induces apoptosis in osteoclasts by inhibiting enzymes of the mevalonate pathway and preventing the isoprenylation of small GTP-binding proteins such as Ras and Rho.
Definition
ChEBI: An imidazole compound having a 2,2-bis(phosphono)-2-hydroxyethane-1-yl substituent at the 1-position.
Manufacturing Process
With stirring and under reflux, 8.6 g (0.053 mole) of imidazol-4-yl acetic acid
hydrochloride, 7.1 ml of 85% phosphoric acid and 25 ml of chlorobenzene are
heated to 100°C. Then 13.9 ml of phosphorus trichloride are added dropwise
at 100°C, whereupon evolution of gas occurs. Over the course of 30 min a
dense mass precipitates from the reaction mixture. The batch is heated for 3
hours to 100°C and the supernatant chlorobenzene is removed by
decantation. With stirring and under reflux, the residual viscous mass is
heated to the boil for 3 hours with 40 ml of 9 N hydrochloric acid. The batch
is filtered hot with the addition of carbon and the filtrate is diluted with
acetone, whereupon the crude 2-(imidazol-4-yl)-1-hydroxy-ethane-1,1-
diphosphonic acid precipitates. This product is recrystallised from water.
Melting point: 238-240°C (dec.).
Brand name
Zometa (Novartis).
Therapeutic Function
Bone calcium regulator
Biological Functions
Zoledronic acid, a bisphosphonate, was approved by the U.S. FDA in 2001 for the treatment of hypercalcemia
of malignancy, a metabolic complication that can be life-threatening. Hypercalcemia of malignancy
can occur in up to 50% of patients diagnosed with advanced breast cancer, multiple myeloma, and nonsmall
cell lung cancer. This condition arises when chemical moieties produced by the tumor cause overstimulation of
osteoclasts. When there is an increase in bone degradation, there is a concomitant release of calcium into the
plasma. When serum concentrations of calcium rapidly elevate, the kidneys are unable to handle the overload,
and hypercalcemia results. This can lead to dehydration, nausea, vomiting, fatigue, and confusion. Zoledronic
acid effectively decreases plasma calcium concentrations via inhibition of bone resorption (inhibition of
osteoclastic activity and induction of osteoclast apoptosis). It also prevents the increase in osteoclastic activity
caused by tumor-based stimulatory factors. Additionally zoledronic acid has been approved by the U.S. FDA for
the treatment of multiple myeloma and bone metastases associated with solid tumor–based cancers (e.g.,
prostrate and lung). This agent is currently in late-stage clinical trials for the treatment and prevention of
osteoporosis and, if approved, will be formulated as a 5-mg, once-yearly IV infusion.
Clinical Use
Zoledronic acid is most
commonly given to patients whose cancer is no longer responding to hormones, but it also may be
given to prevent the bone thinning and weakening that results from hormonal treatments.
Drug interactions
Potentially hazardous interactions with other drugs
Other nephrotoxic drugs: use with caution as can
enhance nephrotoxicity
Metabolism
Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue.
References
1) Green?et al. (1994),?Preclinical pharmacology of CGP 42446, a new, potent, heterocyclic bisphosphonate compound; J. Bone Miner. Res.,?9?745
2) Deeks and Perry (2008)?Zoledronic acid: a review of its use in the treatment of osteoporosis; Drugs Aging,?25?963
3) Perry and Figgitt (2004),?Zoledronic acid: a review of its use in patients with advanced cancer; Drugs,?64?1197
4) Koto?et al. (2010)?Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis and shows combined effects with other anticancer agents; Oncol. Rep.,?24?233
5) Tonyali?et al. (2010)?The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives; Expert Opin. Pharmacother.,?11?2715
Check Digit Verification of cas no
The CAS Registry Mumber 118072-93-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,8,0,7 and 2 respectively; the second part has 2 digits, 9 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 118072-93:
(8*1)+(7*1)+(6*8)+(5*0)+(4*7)+(3*2)+(2*9)+(1*3)=118
118 % 10 = 8
So 118072-93-8 is a valid CAS Registry Number.
InChI:InChI=1/C5H10N2O7P2/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14)
118072-93-8Relevant articles and documents
Pharmacological evaluation of imidazole-derived bisphosphonates on receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation and function
Lin, Jianguo,Peng, Ying,Liu, Qingzhu,Li, Ke,Lv, Gaochao,Seimbille, Yann,Huang, Gang,Gao, Feng,Qiu, Ling
, p. 121 - 133 (2021)
Bisphosphonates (BPs) have been commonly used in the treatment of osteolytic bone lesions, such as osteoporosis and osteogenesis imperfecta. However, serious side-effects can occur during the therapy. To search for novel potent BPs with lower side-effects, a series of imidazole-containing BPs (zoledronic acid [ZOL]; ZOL derivatives by substitution of the hydrogen at the 2-position on the imidazole ring with a methyl [MIDP], ethyl [EIDP], n-propyl [PIDP], or n-butyl group [BIDP]) were developed and the effects on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation were investigated using the murine macrophage RAW 264.7 cells at the protein, gene, and morphological and functional levels. Influences of these BPs on the cell growth and proliferation of RAW 264.7 were also studied in order to determine cytotoxicity. The results showed that PIDP significantly inhibited the RANKL-induced osteoclast formation in a dose-dependent fashion without inducing cytotoxicity under the concentration of 12.5?μM. It exerted remarkable suppressive effects on the development of actin rings, the bone resorption, and the expressions of osteoclastogenesis-related gene and protein markers. The down-regulation of c-Jun N-terminal kinase (JNK), protein kinase B (Akt), and inhibitor of nuclear factor kappa-B (IκB) phosphorylation in the early signaling event and subsequent inhibition of the expression of c-Fos and nuclear factor of activated T cells (NFATc1) might be involved in these effects. All these results indicated that PIDP might be a promising drug to treat bone-related disorders.
Zoledronic acid: Monoclinic and triclinic polymorphs from powder diffraction data
Chernyshev, Vladimir V.,Shkavrov, Sergey V.,Paseshnichenko, Ksenia A.,Puryaeva, Tamara P.,Velikodny, Yurii A.
, p. 263 - 266 (2013)
The crystal structures of the monoclinic and triclinic polymorphs of zoledronic acid, C5H10N2O7P 2, have been established from laboratory powder X-ray diffraction data. The molecules in both polymorphs are described as zwitterions, namely 1-(2-hydroxy-2-phosphonato-2-phosphonoethyl)-1H-imidazol-3-ium. Strong intermolecular hydrogen bonds (with donor-acceptor distances of 2.60 A or less) link the molecules into layers, parallel to the (100) plane in the monoclinic polymorph and to the (1 0) plane in the triclinic polymorph. The phosphonic acid groups form the inner side of each layer, while the imidazolium groups lie to the outside of the layer, protruding in opposite directions. In both polymorphs, layers related by translation along [100] interact through weak hydrogen bonds (with donor-acceptor distances greater than 2.70 A), forming three-dimensional layered structures. In the monoclinic polymorph, there are hydrogen-bonded centrosymmetric dimers linked by four strong O - H...O hydrogen bonds, which are not present in the triclinic polymorph. Copyright
“Greener” Synthesis of Zoledronic Acid from Imidazol-1-yl-acetic Acid and P-Reagents Using Diethyl Carbonate as the Solvent Component
Grün, Alajos,Keglevich, Gy?rgy,Szalai, Zsuzsanna
, p. 8 - 12 (2021/03/19)
The synthesis of a third generation dronic acid, zoledronic acid by the reaction of imidazol-1-yl-acetic acid with phosphorus trichloride/phosphorous acid in diethyl carbonate (DEC) as a “green” solvent, and in DEC – methanesulfonic acid (MSA) solvent mixtures is described. The earlier not “green” and expensive MSA and sulfolane solvents may be replaced by DEC.
Rational synthesis of α-hydroxyphosphonic derivatives including dronic acids
Grün, Alajos,Rádai, Zita,S?regi-Nagy, Dávid Illés,Greiner, István,Keglevich, Gy?rgy
, p. 386 - 387 (2019/01/18)
New, green methods have been elaborated for the syntheses of α-hydroxyphosphonates and α-hydroxymethylenebisphosphonic derivatives (HMBPs, dronates). α-Hydroxyphosphonates were prepared via the Pudovik reaction, while the synthesis of HMBPs has been performed in the three-component reaction of carboxylic acids, phosphorus trichloride and phosphorus acid.
