- 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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- AMIDE-LINKED EP4 AGONIST-BISPHOSPHONATE COMPOUNDS AND USES THEREOF
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The present invention relates to EP4 agonist-bisphosphonate conjugates or related compounds and uses thereof. Said conjugates or related compounds may be used to provide delivery of an EP4 agonist or related compound to a desired site of action, such as a bone. Bisphosphonate moieties, linked to the EP4 agonists via amide linkers, have been implicated in the inhibition of bone resorption and bone targeting.
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Paragraph 00140-00141
(2017/01/31)
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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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- 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
(2020/09/09)
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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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Page/Page column 4
(2009/12/27)
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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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- 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 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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Page/Page column 12
(2008/06/13)
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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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- Solvent systems
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In a method for making bisphosphonates by reacting a carbonyl compound with a phosphorus halide, the reaction is carried out in a solvent/carrier system which is a mixture of an amine hydrochloride, phosphorous acid and optionally phosphoric acid.
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- Solvent systems for the production of bisphosphonates
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In a method for making bisphosphonates by reacting a carbonyl compound with a phosphorus halide, the reaction is carried out in a solvent/carrier system comprising an amine hydrochloride, phosphorous acid and optionally phosphoric acid.
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- Novel bisphosphonates and uses thereof
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Glycosides and orthoester glyco side derivatives of bisphosphonate compounds useful for treating and/or preventing hypercalcaemia of malignancy, Paget's disease, osteoporosis, metastatic cancer in bone and soft tissue and periodontal disease have markedly enhanced intestinal absorption and enhanced bioavailability.
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- Formulation for treatment of osteoporosis
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The present invention provides pharmaceutical formulations comprising at least one bisphosphonate and an absorption enhancing agent essentially consisting of a medium chain glyceride or a mixture of medium chain glycerides. The said pharmaceutical formulations are useful for the inhibition of bone resorption and for the treatment and prevention of osteoporosis.
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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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- 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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- 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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- Process for the production of ω-amino-1-hydroxyalkylidene-1,1-bisphosphonic acid
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A process for the preparation of a ω-amino-1-hydroxyalkylidine-1,1-biphosphonic acid of the formula STR1 wherein n is an integer from 3 to 5, consisting essentially of the steps of reacting an aminocarboxylic acid of the formula wherein m is an integer from 2 to 4, with a phosphonating reactant selected from the group consisting of (a) a mixture of phosphorous acid and PCl3, (b) a mixture of phosphorous acid and PCl5, and (c) a mixture of phosphorous acid and POCl3, hydrolyzing the reaction mixture with a strong acid which does not oxidize aminophosphonic acids, and recovering said ω-amino-1-hydroxyalkylidene-1,1-bisphosphonic acid.
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