- A study on the synthesis of risedronic acid: The role of an ionic liquid additive
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Background: The synthesis of high value risedronic acid is not fully resolved, as, for the time being, the best method based on the preparation from 3-pyridylcarboxylic acid by reaction with phosphorus trichloride in methanesulfonic acid gives risedronic acid in a good yield, but in an unpure form. Methods: Alternative protocols realizing the synthesis in sulfolane as the solvent and/or in the presence of suitable IL additive were developed to obtain the target dronic acid in a pure form. Results & Conclusion: Using phosphorus trichloride and phosphorous acid in two equivalents quantities together with 0.6 equivalents of [bmim][BF4] without any solvent, the method afforded the target dronic acid in a yield of 66% in a pure form.
- Nagy, Dávid Illés,Grün, Alajos,Sinkovicz, Júlia,Garadnay, Sándor,Greiner, István,Keglevich, Gy?rgy
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- Potentiating the Anticancer Properties of Bisphosphonates by Nanocomplexation with the Cationic Amphipathic Peptide, RALA
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Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.
- Massey, Ashley S.,Pentlavalli, Sreekanth,Cunningham, Richard,McCrudden, Cian M.,McErlean, Emma M.,Redpath, Philip,Ali, Ahlam A.,Annett, Stephanie,McBride, John W.,McCaffrey, Joanne,Robson, Tracy,Migaud, Marie E.,McCarthy, Helen O.
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- An easy and effective method for synthesis and radiolabelling of risedronate as a model for bone imaging
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This study aimed to provide an easy method for synthesis of 1-hydroxy-2-(3-pyridyl) ethylidene bisphosphonic acid monosodium (sod. risedronate) with a high yield of 71%. The synthesized risedronate was labeled with technetium-99 m using two different reducing agents (SnCl2.2H2O and NaBH4) where NaBH4 gave stable complex and higher radiochemical yield more than SnCl2.2H2O. The results showed that, the radiochemical purity of 99mTc(NaBH4)-risedronate was 99.2 ± 0.6% and its stability was up to 6 h. Biodistribution study showed high uptake and long retention of 99mTc(NaBH4)-risedronate in bone starting from 15 min (29 ± 2.5% ID/organ) up to 4 h (35.1 ± 3.2 ID/organ) post injection. This research could introduce an easy and effective method for synthesis and labeling of risedrionate and affording a good tracer for bone imaging.
- Motaleb,Adli,El-Tawoosy,Sanad,Abdallah
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- Microwave-assisted synthesis of nitrogen-containing 1- hydroxymethylenebisphosphonate drugs
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A simple, rapid one-pot synthesis of heterocyclic (risedronate, zoledronate) and aminoalkyl (pamidronate, alendronate, neridronate) bisphosphonate drugs using microwave irradiation is presented. Good yields of product are achieved within 20 min, in contrast to conventional synthesis, which typically requires a day or longer.
- Mustafa, Dana A.,Kashemirov, Boris A.,McKenna, Charles E.
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- Environmentally friendly syntheses and tools
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Recent results obtained by our group on MW-assisted reactions, such as the alkylation of PO-functionalized CH-acidic compounds and the addition of dialkyl phosphites to α-ketophosphonates, are summarized together with the rational synthesis of hydroxy-met
- Keglevich, Gyoergy,Kovacs, Rita,Gruen, Alajos,Greiner, Istvan
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- The synthesis of risedronic acid and alendronate applying phosphorus oxychloride and phosphorous acid in methanesulfonic acid
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The synthesis of risedronic acid and alendronate from 3-pyridylacetic acid and γ-aminobutyric acid, respectively, using phosphorus oxychloride and phosphorous acid as the P-reagents and methanesulfonic acid as the solvent was optimized, and the role of phosphorus oxychloride and phosphorous acid in the reaction was clarified.
- Grün, Alajos,Kovács, Rita,Garadnay, Sándor,Greiner, István,Keglevich, Gy?rgy
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- Rational synthesis of α-hydroxyphosphonic derivatives including dronic acids
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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.
- Grün, Alajos,Rádai, Zita,S?regi-Nagy, Dávid Illés,Greiner, István,Keglevich, Gy?rgy
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p. 386 - 387
(2019/01/18)
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- A method for preparing sodium
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The invention discloses a preparation method of risedronate sodium. The preparation method comprises the following steps of: (1) dissociating 3-pyridinecarboxylicacid chloride in 3-pyridinecarboxylicacid chloride hydrochloride; (2) reacting 3-pyridinecarboxylicacid chloride with diazomethane to generate a diazoketone compound represented by a formula (I); (3) generating 3-pyridylacetic acid under the common action of a catalyst and water; (4) adding hydrochloric acid, separating an organic phase from an inorganic phase, and evaporating and concentrating the inorganic phase to obtain 3-pyridylacetic acid hydrochloride; (5) converting 3-pyridylacetic acid hydrochloride into risedronic acid in the presence of phosphorus trichloride and phosphorous acid; and (6) reacting risedronic acid with sodium hydroxide solution to generate risedronate sodium. The preparation method of risedronate sodium disclosed by the invention has the advantages of being few in reaction step, short in reaction time, simple in post-treatment and higher in product yield.
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Paragraph 0023; 0034; 0035
(2017/08/24)
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- Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity
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The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg2+-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized.
- Yanvarev,Korovina,Usanov,Khomich,Veps?l?inen,Puljula,Kukhanova,Kochetkov
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p. 153 - 162
(2016/06/13)
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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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- Novel fluorescent risedronates: Synthesis, photodynamic inactivation and imaging of Bacillus subtilis
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Novel fluorescently-labeled conjugates of risedronate were synthesized using an epoxide linker, enabling conjugation of risedronate via its pyridyl nitrogen with the aromatic succinimidyl esters. The compounds were characterized by using 1H NMR, 13C NMR, 31P NMR, UV-vis and fluorescence emission spectroscopies. Biological activity assays showed that the conjugates 14 and 15 exhibited photodynamic inactivation of Bacillus subtilis (ATCC 6633) with 91% and 47% bacterial lethality at 10 μM upon visible light irradiation, respectively. Both 14 and 15 could be also used for fluorescence imaging of Bacillus subtilis.
- Zhou, Li-Sheng,Yang, Ke-Wu,Feng, Lei,Xiao, Jian-Min,Liu, Cheng-Cheng,Zhang, Yi-Lin,Crowder, Michael W.
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supporting information
p. 949 - 954
(2013/03/14)
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- NOVEL PROCESS FOR THE PREPARATION OF DRONIC ACIDS
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The present invention relates to a new process for the preparation of bisphosphonic acids of general formula (I), characterized in that a reagent which is appropriate for acide halide formation is used in phosphorylation.
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(2012/08/28)
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- Heteroarylacetyl chlorides and mixed anhydrides as intermediates in the synthesis of heterocyclic dronic acids
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It has been recognised that there is no need for phosphorous acid during the conversion of 1-heteroarylacetic acids to the corresponding dronic acids, as phosphorus trichloride (PCl3) is the real reagent. We could prove that the first intermediate toward the formation Risedronic acid is 3-pyridylacetyl chloride that was prepared in different ways using inorganic halides in toluene or in methanesulfonic acid (MSA). The intermediate was then reacted with two equivalents of PCl3 to afford risedronic acid after hydrolysis and pH adjustment. The pyridylacetyl chloride intermediate was identified on the basis of its esterification and amidation reaction. In MSA as the solvent, mixed anhydrides may also be formed as the intermediates from which the dronic acids may be formed in reaction with PCl3. A similar situation was anticipated for the reaction sequence of Zoledronic acid.
- Keglevich, Gyoergy,Gruen, Alajos,Kovacs, Rita,Koos, Katalin,Szolnoki, Beata,Garadnay, Sandor,Neu, Jozsef,Drahos, Laszlo,Greiner, Istvan
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p. 345 - 351
(2012/07/27)
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- Novel Process For Preparing Risedronic Acid
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The present invention relates to a process for preparing risedronic acid comprising the step of combining a 3-pyridyl acetic acid or a salt thereof, phosphorous acid, and a halophosporous compound selected from PCl3, PClS, POCl3, PBr3, POBr3, and PBr5 in the presence of a diluent that is either a bicyclic aliphatic hydrocarbon or a substituted cyclic aliphatic hydrocarbon or a mixture thereof, in combination with a codiluent, that is orthophosphoric acid
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(2010/06/11)
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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 the Preparation of Risedronate Sodium
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Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of risedronic acid or a pharmaceutically acceptable salt thereof, in high yield and purity.
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(2010/12/29)
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- NOVEL PROCESS FOR PREPARING RISEDRONIC ACID
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The present invention relates to a process for preparing risedronic acid comprising the step of combining a 3-pyridyl acetic acid or a salt thereof, phosphorous acid, and a halophosporous compound selected from PCl3, PCI5, POCl3, PBr3, POBr3, and PBr5 in the presence of a diluent that is either a bicyclic aliphatic hydrocarbon or a substituted cyclic aliphatic hydrocarbon or a mixture thereof, in combination with a codiluent, that is orthophosphoric acid.
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Page/Page column 16-17
(2009/05/28)
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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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- IMPROVED PROCESS FOR THE PREPARATION OF RISEDRONATE SODIUM HEMIPENTAHYDRATE
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The invention relates to the process of preparation of Risedronic acid and Risedronate sodium hemipentahydrate in the absence of organic solvents. The process comprises, reacting 3-pyridyl acetic acid with phosphorous acid and phosphorus trichloride to give Risedronic acid which is further reacted with sodium hydroxide in water medium to give Risedronate sodium hemipentahydrate.
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(2009/04/25)
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- PREPARATION OF RISEDRONATE SODIUM HEMI-PENTAHYDRATE
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Processes for the preparation of risedronate sodium hemi-pentahydrate.
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(2009/03/07)
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- PROCESS FOR THE PREPARATION OF BIPHOSPHONIC ACIDS AND SALTS THEREOF
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A process for the preparation of biphosphonic acids and pharmaceutical acceptable salts thereof, comprises reacting a carboxylic acid with phosphorous trichloride and phosphorous acid in the presence of an aprotic polar solvent. Formula (I):
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(2008/12/05)
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- A PROCESS FOR THE PREPARATION OF RISEDRONATE SODIUM HEMIPENTAHYDRATE
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The present invention provides an improved process for the preparation of Risedronate sodium hemipentahydrate by employing novel solvent system.
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(2008/06/13)
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- REAGENT AND USE THEREOF FOR THE PRODUCTION OF BISPHOSPHONATES
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A new liquid reagent is disclosed in form of an ionic liquid containing phosphorous acid and a tertiary amine. The reagent can be used as a replacement of phosphorous acid, where the new reagent as a liquid reagent can be handled using usual equipment for handling liquids and the dosing of the reagent can therefore be controlled more precisely in industrial plants compared to phosphorous acid, which is a solid at ambient temperature. The new liquid reagent is particular suitable for the synthesis of bisphosphonates.
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(2008/12/05)
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- Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof
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This invention relates to the process of making geminal bisphosphonic acids and pharmaceutically acceptable salts and/or hydrates thereof which have the formula (I): wherein X1, X2, X3, X1R1 and R2 are described herein.
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(2008/12/07)
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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 PURE RISEDRONIC ACID OR SALTS
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The present invention relates to an industrially advantageous process of making bisphosphonic acid or its salt in particular risedronic acid, [l-hydroxy-2(3-pyridinyl)ethylidene] bisphosphonic acid, having formula-(I) or its salts in high purity and high yields.
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(2008/06/13)
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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 PREPARING A PURE POLYMORPHIC FORM OF 3-PYRIDYL-1-HYDROXYETHYLIDINE-1,1-BISPHOSPHONIC ACID SODIUM SALT
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This process in general relates to the novel process for preparing polymorphic forms of 3-pyridyl-l-hydroxyethylidine-1,1-bisphosphonic acid sodium salt (Risedronate Sodium) in particular risedronate Form A and B employing a solvent system in an appropriate ratio. An improved process for preparation of risedronic acid is also disclosed in the present invention.
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Page/Page column 8
(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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Page/Page column 3
(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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- PROCESS FOR THE PREPARATION OF [1-HYDROXY-2-(3-PYRIDINYL)ETHYLIDEN] BISPHOSPHONIC ACID AND HEMI-PENTAHYDRATE MONOSODIUM SALT THEREOF
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The invention relates to a novel process for the preparation of [l-hydroxy-2-(3- pyridinyl) ethylidene] bisphosphonic acid and hemi-pentahydrate monosodium salt thereof.
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(2008/06/13)
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- PROCESS AND NOVEL SALT
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The present invention relates to a process of preparing risedronic acid, or a pharmaceutically acceptable salt thereof, novel risedronate ammonium salts and pharmaceutical compositions thereof, and the use of such novels salts and compositions in human therapy.
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(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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Page/Page column 6
(2010/02/11)
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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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(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF ALKYL- AND ARYL-DIPHOSPHONIC ACIDS AND SALTS THEREOF
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The invention relates to a process for the preparation of diphosphonic acids by reaction of a carboxylic acid with a mixture of phosphorous acid and phosphorus oxychloride in defined molar ratios and in the absence of solvents. The invention futher relates to ibandronic acid monosodium salt in the amorphous form.
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(2008/06/13)
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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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- 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 making geminal bisphosphonates
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The present invention relates to a novel process for making geminal bisphosphonates. The process provides for bisphosphorylation using phosphorus trihalide, phosphorous acid as a reactant/solvent, and a base as an acid acceptor/solvent. The present invention is directed to a process for making geminal bisphosphonates of the general formula: 1wherein Q is oxygen, —NR4—, sulfur, selenium, or a single bond; m+n is an integer from 0 to about 5, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine; R1 is hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each R2 is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R3 is one or more substituents selected from the group consisting of hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R4 is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl.
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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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- Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental calculus and plaque
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The present invention relates to quaternary nitrogen-containing phosphonate compounds, and the pharmaceutically-acceptable salts and esters thereof and having the general structure: STR1 wherein R1, R2, R5 and R8 are defined in claim 1, m and n are integers from 0 to 10; m+n is from 0 to 10; Z is a saturated, unsaturated, or aromatic, monocyclic or polycyclic carbocycle or monocyclic or polycyclic heterocycle containing one or more heteroatoms selected from O, S, or N, wherein at least one heteroatom is a quaternary nitrogen atom; R is COOH; PO3 H2 ; SO3 H; or P(O)(OH)R4, wherein R4 is substituted or unsubstituted alkyl of 1-8 carbon atoms; The present invention further relates to pharmaceutical compositions containing a safe and effective amount of a compound of the present invention, and pharmaceutically-acceptable excipients. Finally, the present invention relates to methods for treating or preventing pathological conditions characterized by abnormal calcium and phosphate metabolism such as osteoporosis, rheumatoid arthritis, and osteoarthritis in humans or other mammals and to methods for treating or preventing dental calculus, plaque and gingivitis.
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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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