- The molecular structure of 4-amino 1-hydroxy butylidene-1 bisphosphonic acid (AHBBPA); an uncommon anhydrous hydroxybisphosphonic acid
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The molecular structure of an anhydrous hydroxybisphosphonic acid was determined by X-ray diffraction techniques and compared to the corresponding hydrated crystalline form. The hydrogen bond network and intermolecular interactions show that the polar bisphosphonic group undergoes a rotation to accomodate a different distribution in the hydrophobic/polar zones observed in the crystal packing, while the rest of the amino side chain connected to the functional carbon atom has identical conformation.
- Ohanessian, Jacqueline,Avenel, Daniele,El Manouni, Driss,Benramdane, Mounya
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Read Online
- Synthesis of silver nanoparticles for the dual delivery of doxorubicin and alendronate to cancer cells
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We present the synthesis of a silver nanoparticle (AgNP) based drug-delivery system that achieves the simultaneous intracellular delivery of doxorubicin (Dox) and alendronate (Ald) and improves the anticancer therapeutic indices of both drugs. Water, under microwave irradiation, was used as the sole reducing agent in the size-controlled, bisphosphonate-mediated synthesis of stabilized AgNPs. AgNPs were coated with the bisphosphonate Ald, which templated nanoparticle formation and served as a site for drug attachment. The unreacted primary ammonium group of Ald remained free and was subsequently functionalized with either Rhodamine B (RhB), through amide formation, or Dox, through imine formation. The RhB-conjugated NPs (RhB-Ald@AgNPs) were studied in HeLa cell culture. Experiments involving the selective inhibition of cell membrane receptors were monitored by confocal fluorescence microscopy and established that macropinocytosis and clathrin-mediated endocytosis were the main mechanisms of cellular uptake. The imine linker of the Dox-modified nanoparticles (Dox-Ald@AgNPs) was exploited for acid-mediated intracellular release of Dox. We found that Dox-Ald@AgNPs had significantly greater anti-cancer activity in vitro than either Ald or Dox alone. Ald@AgNPs can accommodate the attachment of other drugs as well as targeting agents and therefore constitute a general platform for drug delivery.
- Benyettou,Rezgui,Ravaux,Jaber,Blumer,Jouiad,Motte,Olsen,Platas-Iglesias,Magzoub,Trabolsi
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Read Online
- Systematic study of the physicochemical properties of a homologous series of aminobisphosphonates
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Aminobisphosphonates, e.g., alendronate and neridronate, are a well known class of molecules used as drugs for various bone diseases. Although these molecules have been available for decades, a detailed understanding of their most important physicochemical properties under comparable conditions is lacking. In this study, ten aminobisphosphonates, H2N(CH 2)nC(OH)[P(O)(OH)2]2, in which n = 2-5, 7-11 and 15 have been synthesized. Their aqueous solubility as a function of temperature and pH, pKa-values, thermal stability, IR absorptions, and NMR spectral data for both liquid (1H, 13C, 31P-NMR) and solid state (13C, 15N and 31P-CPMAS NMR) were determined.
- Alanne, Aino-Liisa,Ylisirnioe, Markku,Turhanen, Petri,Peraeniemi, Sirpa,Vepsaelaeinen, Jouko,Hyvoenen, Helena,Lahtinen, Manu,Kolehmainen, Erkki
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p. 10928 - 10945,18
(2012)
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Read Online
- Biocompatible organic coatings based on bisphosphonic acid RGD‐derivatives for PEO‐modified titanium implants
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Currently, significant attention is attracted to the problem of the development of the specific architecture and composition of the surface layer in order to control the biocompatibility of implants made of titanium and its alloys. The titanium surface properties can be tuned both by creating an inorganic sublayer with the desired morphology and by organic top coating contributing to bioactivity. In this work, we developed a composite biologically active coatings based on hybrid molecules obtained by chemical crosslinking of amino acid bisphosphonates with a linear tripeptide RGD, in combination with inorganic porous sublayer created on titanium by plasma electrolytic oxidation (PEO). After the addition of organic molecules, the PEO coated surface gets nobler, but corrosion currents increase. In vitro studies on proliferation and viability of fibroblasts, mesenchymal stem cells and osteoblastlike cells showed the significant dependence of the molecule bioactivity on the structure of bisphosphonate anchor and the linker. Several RGDmodified bisphosphonates of β–alanine, γ–aminobutyric and ε–aminocaproic acids with BMPS or SMCC linkers can be recommended as promising candidates for further in vivo research.
- Danilko, Ksenia V.,Dyakonov, Grigory S.,Farrakhov, Ruzil G.,Galimshina, Zulfia R.,Gil'fanova, Guzel U.,Lukina, Elena S.,Mukaeva, Veta R.,Parfenov, Evgeny V.,Parfenova, Lyudmila V.
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- "water soluble" palladium nanoparticle engineering for C-C coupling, reduction and cyclization catalysis
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The use of Pd nanoparticles (Pd-NPs) to realize several important organic reactions allows efficient catalysis with low metal loading (1000 ppm), hence providing a greener catalytic system. However, to be truly green Pd-NPs need to be synthesized in a sustainable manner and be able to react in aqueous media in order to avoid the use of organic solvents. Here we describe an original and eco-friendly synthesis of Pd-NPs (using benign reactants and simple conditions) perfectly stable in water. Remarkably, this synthesis allows for control over their size and morphology by simply tuning the pH of the stabilizer. We then evaluate the catalytic efficiency of these Pd-NPs on six different model reactions (Suzuki Miyaura, Sonogashira, Heck, nitrophenol reduction and pentynoic cycloisomerization) in aqueous media. We show that the stabilizer structure influences the activity owing to its ability to promote the mass transfer of the organic substrates towards the NP surface in the aqueous environment. Finally, catalytic evaluations show that our nano-catalysts prepared in an eco-friendly manner are among the best catalysts described so far in the literature in each case, with high turnover frequencies reached with a low loading of palladium.
- Iben Ayad,Belda Marín,Colaco,Lefevre,Méthivier,Ould Driss,Landoulsi,Guénin
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supporting information
p. 6646 - 6657
(2019/12/26)
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- Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis
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Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
- Savino, Salvatore,Toscano, Annamaria,Purgatorio, Rosa,Profilo, Emanuela,Laghezza, Antonio,Tortorella, Paolo,Angelelli, Mariacristina,Cellamarea, Saverio,Scala, Rosa,Tricarico, Domenico,Thomas Marobbio, Carlo Marya,Perna, Filippo,Vitale, Paola,Agamennone, Mariangela,Dimiccoli, Vincenzo,Tolomeo, Anna,Scilimati, Antonio
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p. 184 - 200
(2018/09/18)
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- Copolymers having gem-bisphosphonate groupings
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A copolymer includes a main hydrocarbon chain and side groups including carboxylic groups and polyoxyalkylate groups. The copolymer further includes gem-bisphosphonate groups. A composition, such as n admixture for suspensions of mineral particles, includes the copolymer. The copolymer can be used for fluidifying suspensions of mineral particles and maintaining the fluidity of such suspensions. The copolymer can also be used for reducing the sensitivity of hydraulic compositions to clays and alkaline sulfates.
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(2018/10/15)
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- Functional Micelles for Hard Tissue Targeted Delivery of Chemicals
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Compositions and methods for targeting agents to hard tissue are provided.
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- Microwave-assisted efficient synthesis of bisphosphonate libraries: A useful procedure for the preparation of bisphosphonates containing nitrogen and sulfur
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Microwave-assisted rapid and efficient procedure for the synthesis of bisphosphonate and their libraries is described in solvent-free medium. Bisphosphonates having nitrogen and sulfur are synthesized following this new procedure. This procedure is simple and can be useful for the generation of compound libraries of a class of bone-resorptive inhibitors such as N- and N-, S- containing bisphosphonates.
- Lenin, Racha,Raju, Rallabandi Madusudan,Rao, Divvela V. N. Srinivasa,Ray, Uttam Kumar
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p. 1624 - 1629
(2013/07/26)
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- A practical synthesis of alendronate sodium through counterattack reaction
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An efficient synthesis of alendronate sodium, an osteoporosis drug, has been developed through counterattack reaction' involving treatment of the respective acyl phosphonate with (MeO) and TMSBr followed by deblocking with aqueous HCl.
- Seki, Masahiko
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experimental part
p. 1556 - 1558
(2012/07/14)
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- Non-hydrolysable analogues of inorganic pyrophosphate as inhibitors of hepatitis C virus RNA-dependent RNA-polymerase
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Inorganic pyrophosphate (PPi) is the product of the polymerization reaction catalyzed by DNA-and RNA-polymerases. A number of novel non-hydrolsable PPi analogues was synthesized; some of them inhibited the polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore based on a non-hydrolysable methylenediphosphonate backbone has been developed. The structure-activity relationship analysis of 12 bisphosphonates is presented and the structural features crucial for NS5B polymerase activity inhibition are stated. Pleiades Publishing, Ltd., 2012.
- Yanvarev,Korovina,Usanov,Kochetkov
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experimental part
p. 224 - 229
(2012/08/27)
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- MODIFIED HYDROXYPOLYMER CONJUGATES WITH BONE SEEKING AND TUMOR KILLING MOIETIES
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The present invention is related to a modified hydroxypolymer conjugate, preferably a dextran-guanidine-biphosphonate conjugate for treating not only skeletal tumors i.e. bone metastasis, particularly bone metastasis related to hormone refractory prostate cancer HRPC and breast cancer, but also osteoporosis. A method for producing and using said hydroxypolymer conjugate is also disclosed.
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- A one-pot synthesis of 1-hydroxy-1,1-bis(phosphonic acid)s starting from the corresponding carboxylic acids
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By starting with various carboxylic acids, a one-pot procedure for the synthesis of the corresponding 1-hydroxy-1,1-bis(phosphonic acid)s is reported. The efficiency of this simple methodology is illustrated by synthesizing well-known marketable amino hydroxy bis(phosphonate)s such as alendronate or N-methyl pamidronate without additional steps for the protection/deprotection of the amine function.
- Egorov, Maxim,Aoun, Sameh,Padrines, Marc,Redini, Francoise,Heymann, Dominique,Lebreton, Jacques,Mathe-Allainmat, Monique
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supporting information; experimental part
p. 7148 - 7154
(2012/01/06)
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- Fragmentation pathways of eight nitrogen-containing bisphosphonates (BPs) investigated by ESI-MSn in negative ion mode
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Fragmentation pathways of eight nitrogen-containing bisphosphonates (BPs), including Pamidronate, Alendronate, and five corresponding acylated derivatives, and Risedronate, were investigated by electrospray ionization mass spectrometry (ESI-MS) in conjunction with tandem mass spectrometry in negative ion mode. Characteristic fragment ions involved were formed by successive loss of water molecules, including α, β-unsaturated product ions formed by dehydration of the α-hydroxyl group and β-hydrogen, cyclic ions with P-O-P four-membered rings formed by dehydration of the two -OH groups attached to two phosphorus atoms, and cyclic phosphoramide ions with five- or six-membered rings formed by loss of water via an intramolecular nucleophilic substitution reaction, in which -NH2 (or -NH-) group on γ or δ carbon acted as the nucleophile to attack phosphorus atom of PO group at the initial stage. Another notable characteristic product ion [HP2O5]- at m/z 143, shown by all eight ESI-MS2 spectra, is a diagnostic ion of bisphosphonate group, formed from the four-membered ring ion containing P-O-P. Some additional fragmentation ions were produced from chloroacetyl Alendronate, chloroacetyl Pamidronate, and Risedronate containing triple bond ions, formed by loss of water from the corresponding enol anions. The hydrogen/deuterium (H/D) exchange experiment, theoretical calculations, and the high-resolution mass spectrometry were appropriately employed to rationalize the proposed fragmentation pathways.
- Qu, Zhibo,Chen, Xiaolan,Qu, Chen,Qu, Lingbo,Yuan, Jinwei,Wei, Donghui,Li, Huina,Huang, Xiaoying,Jiang, Yuqin,Zhao, Yufen
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experimental part
p. 85 - 93
(2011/11/04)
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- Process for producing biphosphonic acids and forms thereof
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Disclosed herein is a process for producing bisphosphonic acids and salts thereof. The process comprising reacting a carboxylic acid of Formula [I] with phosphorous acid and halophosphorus compound in the presence of a solvent selected from aliphatic hydrocarbon or water miscible cyclic ether. Further, the present invention also provides novel forms of bisphosphonic acids and process for preparation thereof.
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(2009/12/27)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF BISPHOSPHONIC ACID
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The present invention is to relate an improved process using anisole as solvent for the preparation of compound of formula (I) and its pharmaceutically acceptable salts thereof. wherein R represents-NR1R2, or formula (II), a group n = 1,2,3,4 and 5, where R1 and R2 may be same or different and independently represents hydrogen, or C1-6 alkyl;
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(2008/06/13)
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- Syntheses of phosphonic esters of alendronate, pamidronate and neridronate
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Several synthetic pathways for obtaining phosphonic esters of the amino bisphosphonic acids (NBPs) pamidronate, alendronate and neridronate were investigated. The general guideline was to react N-protected amino acids activated as phthalimide esters or as acyl chlorides. Succinimide esters were found less reactive and quickly abandoned. γ-Lactam formation arises when starting from Boc- or Cbz-protected amino acids. The phthalimide N-protecting group allowed access to alkyl or aryl mono-, di- (symmetric or not) and triesters of these three NBPs in high yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Guenin, Erwann,Monteil, Maelle,Bouchemal, Nadia,Prange, Thierry,Lecouvey, Marc
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p. 3380 - 3391
(2008/02/10)
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- Process for the preparation of bisphosphonic acid
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The present invention is to relate an improved process using anisole as solvent for the preparation of compound of formula (I) and its pharmaceutically acceptable salts thereof. wherein R represents —NR1R2, or a group n=1, 2, 3, 4 and 5, where R1 and R2 may be same or different and independently represents hydrogen, or C1-6 alkyl;
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(2008/06/13)
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- Aminoalkylbis(phosphonates): Their complexation properties in solution and in the solid state
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Five geminal bis(phosphonates) containing an amino group in the α, γ or δ position of the carbon chain have been synthesised and their acid-base and complexation properties with Cu2+, Zn2+, Ca2+, Mg2+ and Na+ ions studied by potentiometry. Determination of the stability constants of the complexes with divalent metal ions is complicated by the formation of precipitates. The results of these studies show a negligible effect of the hydroxo group in the α position on the acid-base and complexation properties of the ligands. The presence of an amino group in the α position, however, decreases the basicity, which results in a lower complexation ability of the bis(phosphonates). The crystal structures of the three ligands with different degrees of protonation have also been determined. The structure of the triammonium salt of aminomethylbis(phosphonic acid) shows that the proton is bound to the nitrogen atom in monoprotonated species. The structure of the Cu2+ complex of pamidronate [(Cu2(H2pam) 2}·H2O]n shows the presence of dimeric units with a relatively short distance (2.99 A) between the metal centres. These units form a coordination polymeric chain. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Kubicek, Vojtech,Kotek, Jan,Hermann, Petr,Lukes, Ivan
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p. 333 - 344
(2007/10/03)
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- Novel procedure for the synthesis of 1-hydroxy-1,1-bisphosphonic acids using phenols as medium
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A facile synthetic route for the synthesis of bisphosphonates in phenols is described. Preparations of some of bisphosphonates, which are presently in clinical use such as risedronic acid and alendronate sodium, are synthesized following this new, simple method. This procedure can be useful for the synthesis of this class of bone-resorptive inhibitors in bulk quantities. Copyright Taylor & Francis Group, LLC.
- Rao, Divvela V. N. Srinivasa,Dandala, Ramesh,Narayanan, Garimella K. A. S. S.,Lenin, Racha,Sivakumaran,Naidu, Andra
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p. 4359 - 4365
(2008/03/13)
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- Process for the preparation of biphosphonic acids
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An improved process for bisphosphonylation of acids, substituted acids to obtain compounds with the formula using phosphorus trihalide, phosphorus acid, in presence of phenolic compounds as diluent/solvent.
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(2008/06/13)
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- Process for the preparation of biphosphonic derivatives
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The present invention provides a novel process for preparation of bisphosphonic acid derivatives or pharmaceutical acceptable salt thereof, by reacting carboxylic acid having structural formula (II) with phosphorous acid and a halophosphorous compound, wherein halophosphorous compound is selected from the group comprising of PCl3, PCl5, POCl3, PBr3, POBr3, and PBr5 in presence of diphenyl ether.
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(2008/06/13)
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- PROCESS FOR PRODUCING BISPHOSPHONIC ACIDS AND FORMS THEREOF
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Disclosed herein is a process for producing bisphosphonic acids and salts thereof. The process comprising reacting a carboxylic acid of Formula [I] with phosphorous acid and halophosphorus compound in the presence of a solvent selected from aliphatic hydrocarbon or water miscible cyclic ether. Further, the present invention also provides novel forms of bisphosphonic acids and process for preparation thereof.
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(2008/06/13)
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- ANTIRESORPTIVE MUTUAL SALT OF RALOXIFENE AND BISPHOSPHONIC ACID
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The mutual salt of raloxifene and bisphosphonic acid exhibits unexpectedly synergistic effects of two components to enhance bone mineral density (BMD), control blood-calcium density, and lower the serum cholesterol level.
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(2008/06/13)
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- A PROCESS FOR PREPARATION OF BISPHOSPHONIC ACID COMPOUNDS
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The present invention provides a novel process for preparation of bisphosphonic acids or salts thereof, e.g. alendronic acid, by reacting a carboxylic acid, phosphorous acid and a halophosphorous compound in a water miscible neutral solvent.
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Page/Page column 11
(2008/06/13)
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- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a bisphosphonate
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The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and a bisphosphonate. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-1α, 25-dihydroxyvitamin D3and a bisphosphonate.
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(2010/02/11)
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- Enteric coated formulation for bisphosphonic acids and salts thereof
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Pharmaceutical compositions, processes for preparing the compositions and methods of using the composition are provided. The pharmaceutical composition comprises an inert core surrounded by an active coating containing one or more bisphosphonic acids or salts thereof, a seal coating surrounding the active coating and an enteric coating surrounding the seal coating. Alendronic acid and alendronate sodium trihydrate are the preferred active ingredients. The composition may be provided in the form of pellets in a capsule or Peltabs. The invention further provides methods for the treatment of disorders caused by the abnormal dissolution or deposition of calcium salts using the inventive compositions.
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- INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 2-SUBSTITUTED 1-(HYDROXY-ETHYLIDENE)-1,1-BISPHOSPHONIC ACIDS OF HIGH PURITY AND THE SALTS THEREOF
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Process for the synthesis of high purity 2-substituted-1-(hydroxy-ethylidene)-1,1-bisphosphonic acid of formula (I), the salts and hydrates thereof - wherein the meaning of R is 3'-pyridyl or 2'-amino-ethylidene group - from compounds of formula (II) - wherein the meaning of R is as described above - or salts and hydrates thereof with phosphorous acid in the presence of methanesulfonic acid using phosphorus pentoxide as reagent and in given case the obtained acid is converted into a salt with base.
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- Effects of Bisphosphonates on the Growth of Entamoeba histolytica and Plasmodium Species in Vitro and in Vivo
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The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC50 50 ～ 4-9 μM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC50 ～ 10-20 μM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pKa values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC50 values 50 values around 1 μM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.
- Ghosh, Subhash,Chan, Julian M. W.,Lea, Christopher R.,Meints, Gary A.,Lewis, Jared C.,Tovian, Zev S.,Flessner, Ryan M.,Loftus, Timothy C.,Bruchhaus, Iris,Kendrick, Howard,Croft, Simon L.,Kemp, Robert G.,Kobayashi, Seike,Nozaki, Tomoyoshi,Oldfield, Eric
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p. 175 - 187
(2007/10/03)
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- Radiolabelled bisphosphonates and method
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The present invention relates to 32P or 33P-labelled bisphosphonates as radiotherapeutic radiopharmaceuticals. The 32P- or 33P-labelled bisphosphonates, which are chemically identical to the unlabelled agent, are expected to target the lesion site in an identical manner, but also deliver a significant radiocytotoxic effect to the surrounding cells. This should result, given the favorable energetics of the β particle emission from the 33P nuclide, in a loss of proliferative capacity of cells associated with the tumor lesion. The relative stability and in vivo localisation of bisphosphonates makes them good candidates as 32P/33P delivery vehicles.
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- Process for the preparation of solid oral dosage forms comprising alendronic acid
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The present invention relates to a process for preparing solid oral dosage forms e.g. tablets,capsules,coated tablets/capsules, etc. comprising as active ingredient 4-amino-1-hydroxybutylidene-1, 1-biphosphonic acid or one of its pharmaceutically acceptable salts (“Alendronic acid”). It comprises the free acid or one of its pharmaceutically acceptable salts. The process is characterized by granulating pharmaceutical carriers with an aqueous solution of Alendronic acid which is solubilized with the aid of alkaline hydroxides or alkaline salts. The oral dosage forms obtained by this process are less irritating to the digestive system than oral dosage forms obtained by conventional processes. The present invention also relates to tablets and to capsules prepared by said process.
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- Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa)
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Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED50 of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
- Widler, Leo,Jaeggi, Knut A.,Glatt, Markus,Müller, Klaus,Bachmann, Rolf,Bisping, Michael,Born, Anne-Ruth,Cortesi, Reto,Guiglia, Gabriela,Jeker, Heidi,Klein, Rémy,Ramseier, Ueli,Schmid, Johann,Schreiber, Gerard,Seltenmeyer, Yves,Green, Jonathan R.
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p. 3721 - 3738
(2007/10/03)
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- Pharmaceutical tablets
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The present invention relates to novel pharmaceutical tablets useful for administering pharmaceutical active ingredients, such as bisphosphonates. These tablets have improved surface properties which can aid esophageal transit, thereby reducing the potential for adverse gesture intestinal effects. The present invention also relates to processes for making said novel pharmaceutical tablets.
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- Process for preparing alendronic acid
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A novel process for the preparation of alendronic acid is disclosed. The method comprises the steps of reacting a compound of formula I with H3PO3 wherein R is an imido group and R1is selected from the group consisting of chloro, bromo, iodo, fluoro, hydroxy, amino, —OR2or —OC(O)R2, wherein R2is C1-C12alkyl, C1-C12cycloalkyl or C1-C12aryl; and then reacting the product of the first step with a deprotecting agent. Alendronic acid is then recovered. The method is safe, efficient and suitable for use on a large scale.
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- Hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof
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New hydrate forms of alendronate sodium, having water content of between about one and about twelve percent, and processes for their manufacture, are disclosed. New crystalline forms of alendronate sodium B, D, E, F, G and H, and processes for manufacturing them, are also disclosed. These new forms of alendronate sodium are suitable for incorporation into pharmaceutical compositions for combating bone resorption in bone diseases.
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- Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A potential route to chemotherapy
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We have investigated the effects in vitro of a series of bisphosphonates on the proliferation of Trypanosoma cruzi, Trypanosoma brucei rhodesiense, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum. The results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar IC50 activity values against parasite replication (e.g. o-risedronate, I50 = 220 nM for T. brucei rhodesiense; risedronate, IC50 = 490 nM for T. gondii). In T. cruzi, the nitrogen-containing bisphosphonate risedronate is shown to inhibit sterol biosynthesis at a pre-squalene level, most likely by inhibiting farnesylpyrophosphate synthase. Bisphosphonates therefore appear to have potential in treating parasitic protozoan diseases.
- Martin,Grimley,Lewis,Heath III,Bailey,Kendrick,Yardley,Caldera,Lira,Urbina,Moreno,Docampo,Croft,Oldfield
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p. 909 - 916
(2007/10/03)
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- Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
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A process is provided for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof which comprises of: a) reacting 4-aminobutyric acid with phosphorous acid and phosphorus trichloride in the presence of a polyalkylene(glycol); and b) recovering said 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof.
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- Therapeutic derivatives of diphosphonates
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Novel chemotherapeutic agents having utility in treating infectious diseases such as periodontal disease, certain urinary tract infections, infectious urinary tract stones, and bone cancer, are obtained by combining chemically a diphosphonate compound with a therapeutic agent effective against the foregoing diseases.
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- Regimen for treatment or prophylaxis of osteoporosis
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Methods for treating or preventing osteoporosis, including regimens for intermittent dosing of bone resorption inhibiting polyphosphonate compound or a pharmaceutically acceptable salt or ester of any such compound.
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- ETUDE STRUCTURALE DE L'ACIDE BUTANE HYDROXY-1 AMINO-4 DIPHOSPHONIQUE-1,1'
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Structural study using X-Ray Crystallography of the amino hydroxy diphosphonic acid of the title has been done.The final objective is to use this functionalized hydroxy diphosphonic acid in complexation study and in organic synthesis of biological derivatives by the way of the amino group.Results are discussed on the basis of the environment of phosphorus atoms and on the molecular geometry around the central carbon atom.Key words: X-ray crystallography; structure; hydroxydiphosphonic acid derivative; amino group; molecular geometry
- Leroux, Y.,El Manouni, D.,Safsaf, A.,Neuman, A.,Gillier, H.
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p. 181 - 192
(2007/10/02)
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- Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
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A process for the preparation of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid or salts thereof which comprises: (a) reacting 4-aminobutyric acid with a mixture of phosphorous acid and PC13 in the presence of methanesulfonic acid; and (b) recovering said 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid or salts thereof.
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