- Pharmacological evaluation of imidazole-derived bisphosphonates on receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation and function
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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.
- Lin, Jianguo,Peng, Ying,Liu, Qingzhu,Li, Ke,Lv, Gaochao,Seimbille, Yann,Huang, Gang,Gao, Feng,Qiu, Ling
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Read Online
- Zoledronic acid: Monoclinic and triclinic polymorphs from powder diffraction data
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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
- Chernyshev, Vladimir V.,Shkavrov, Sergey V.,Paseshnichenko, Ksenia A.,Puryaeva, Tamara P.,Velikodny, Yurii A.
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Read Online
- Zoledronic acid intermediate compound
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The invention belongs to the technical field of medicine synthesis, and particularly relates to a zoledronic acid intermediate compound. According to the method, 2,2-bis-substituted acetate and imidazole are taken as initial raw materials, and a 2,2-imidazole acetic acid hydrochloride intermediate is synthesized through substitution reaction and hydrolysis reaction. The raw materials are simple and easy to obtain, the reaction conditions are mild, the operation process is simple and convenient, and the method is economical and environmentally friendly. The yield of zoledronic acid prepared from the intermediate compound can reach 85.27%, diphosphonic acid impurities do not exist, and the purity is as high as 99.8% or above.
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- “Greener” Synthesis of Zoledronic Acid from Imidazol-1-yl-acetic Acid and P-Reagents Using Diethyl Carbonate as the Solvent Component
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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.
- Grün, Alajos,Keglevich, Gy?rgy,Szalai, Zsuzsanna
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- The synthesis of hydroxymethylenebisphosphonic- (dronic-) and acyl-ethoxycarbonyl-methylphosphonate derivatives
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Recent results on the synthesis of substituted hydroxymethylenebisphosphonic acids (A and B), as well as acylated ethoxycarbonyl-methylphosphonate derivatives (C and D) are summarized. In the first part, solvent mixtures were applied in the preparation of known dronic acids, while in the second series of experiments, new acyl species were synthesized.
- Für, Csilla Sepsey,Grün, Alajos,Gulyás, Kinga V.,Keglevich, Gy?rgy,Szalai, Zsuzsanna,Zahár, Róbert
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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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- Imidazole heterocyclic diphosphonic acid compound as well as preparation method and application thereof
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The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an imidazole heterocyclic diphosphonic acid compound as well as a preparation method and application thereof. The imidazole heterocyclic diphosphonic acid compound has a larger non-toxic concentration range for an osteoclast precursor, and can significantly inhibit the formation of osteoclasts at the same time; the imidazole heterocyclic diphosphonic acid compound can damage actin ring to the utmost extent, thus having an obvious inhibiting effect on the osteoclasts and further being used as an osteoclast inhibitor; the imidazole heterocyclic diphosphonic acid compound solves the problems that diphosphonate in the prior art is low in inhibiting effect on the osteoclasts, high in toxicity and large in side effects.
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- Synthesis process of zoledronic acid
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The invention relates to a synthesis process of zoledronic acid. According to the synthesis process, the zoledronic acid is prepared by performing a reaction on imidazole-1-acetic acid, phosphorous acid and phosphorus trichloride or phosphorus oxychloride as three raw materials, and in the reaction process, a reaction solvent is not used. The synthesis process provided by the invention has the advantages of a simple preparation process, no environment pollution, high synthesis efficiency, high product purity, low cost and the like, and is convenient for large-scale production.
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Paragraph 0038-0042
(2017/07/20)
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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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p. 1217 - 1228
(2016/04/26)
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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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- 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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- 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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experimental part
p. 345 - 351
(2012/07/27)
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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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- PROCESS FOR THE PREPARATION OF [1-HYDROXY-2-(1H-IMIDAZOL-1-YL)- ETHYLIDENE] BISPHOSPHONIC ACID
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A process for the preparation of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid consists of the reaction of aqueous solution of 1H-imidazole-1-acetic acid hydrochloride with phosphorus trichloride followed by removal of the excess of phosphorus trichloride, addition of water and hydrolysis of the reaction products. In order to isolate the product the post-reaction mixture is filtered and the anti-solvent is added to the aqueous filtrate in order to crystallize out [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid monohydrate.
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(2012/05/20)
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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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experimental part
p. 2285 - 2287
(2011/05/16)
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- Optimized synthesis of N-heterocyclic dronic acids; Closing a black-box era
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To clarify the inconsistent patent literature, the synthesis of Zoledronic and Risedronic acids involving a heterocyclic acetic acid (HAA), phosphorous acid (PA) and phosphorus trichloride (PC) as the reagents, and methanesulfonic acid as the solvent was studied in detail. It was found that the best synthesis can be accomplished at 80 °C using HAA and PC in a 1:3.1 molar ratio without any PA.
- Keglevich, Gy?rgy,Grün, Alajos,Aradi, Klára,Garadnay, Sándor,Greiner, István
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experimental part
p. 2744 - 2746
(2011/06/19)
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- Process for Making Zoledronic Acid
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Processes for making zoledronic acid can be advantageously carried out in a solvent/diluent that comprises a mixture of (i) a polyalkylene glycol and (ii) a cyclic carbonate of the formula (3) wherein n is an integer from 2 to 4, and R1 and R2 each independently represent a hydrogen or a C1-C4 alkyl group.
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(2010/06/14)
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- Process for making zoledronic acid
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The invention relates to a process a process, which comprises: reacting in a solvent/diluent a compound of formula (2) or a salt or ester thereof with a phosphonation agent to form phosphonated intermediates; and subsequently hydrolyzing said intermediates to form a compound of formula (1) or a salt or hydrate thereof wherein said solvent/diluent comprises a mixture of (i) a polyalkylene glycol and (ii) a cyclic carbonate of the formula (3) wherein n is an integer from 2 to 4, and R1 and R2 each independently represent a hydrogen or a C1-C4 alkyl group and to the use of intermediates therein.
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(2010/06/17)
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- PROCESS FOR THE PREPARATION OF [1-HYDROXY-2-(1H-IMIDAZOL-1-YL)- ETHYLIDENE]BISPHOSPHONIC ACID
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A process for the preparation of [1-hydroxy-2-(1H-imidazol-1-yl)- ethylidene]bisphosphonic acid consists of the reaction of aqueous solution of 1Η-imidazole-1-acetic acid hydrochloride with phosphorus trichloride followed by removal of the excess of phosphorus trichloride, addition of water and hydrolysis of the reaction products. In order to isolate the product the post-reaction mixture is filtered and the anti-solvent is added to the aqueous filtrate in order to crystallize out [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid monohydrate.
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Page/Page column 5-6
(2010/05/14)
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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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- 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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Page/Page column 11
(2008/12/05)
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- PROCESSES FOR MANUFACTURING BISPHOSPHONIC ACIDS
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Processes are provided for preparing bisphosphonic acids, wherein phosphorous acid and phosphorous halide compound are fed into composition comprising imidazole-1 - ylacetic acid, or the like, and polar solvent; the reaction mixture remains stirrable and is quenched by inputting into water; and after cooling, bisphosphonic acid can be isolated, wherein R1 comprises: i) CH3 , Formulae ii), iii), iv), v), vi), vii), viii) and ix).
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Page/Page column 10-13
(2009/01/23)
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- PROCESS FOR MANUFACTURING BISPHOSPHONIC ACIDS
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A manufacturing process for the preparation of bisphosphonic acids and in particular zoledronic acid is provided wherein diglyme, monoglyme, or a mixture thereof, is utilized to produce a homogenous, water soluble, solid reaction mass that upon cooling, dissolving in water and stripping results in a high purity product and comparatively good yield.
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(2008/06/13)
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- A CRYSTALLINE FORM OF THE ZOLEDRONIC ACID, A PROCESS TO OBTAIN IT AND THE PHARMACEUTICAL COMPOSITION COMPRISING IT
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This invention refers to a new crystalline form of the Zoledronic acid, characterized by its X-rays diffractogram as well as by its spatial atomic distribution in the red crystalline and its curves of thermal analysis. There is also included a method to obtain this crystalline form, which includes the synthesis of the corresponding acid and the pharmaceutical composition this crystalline form comprises.
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Page/Page column 5-6
(2008/06/13)
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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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- PROCESSES FOR THE PREPARATION OF PURE ZOLEDRONIC ACID
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The invention relates to processes for the preparation of pure zoledronic acid or pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions that include the pure zoledronic acid.
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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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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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Page/Page column 9-10
(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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Page/Page column 6
(2008/06/13)
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- METHOD FOR PRODUCING PURE DISODIUM PAMIDRONATE
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Biphosphonates and especially disodium pamidronate are becoming more and more important for the therapy of a wide variety of diseases. Pure and stable disodium pamidronate is a prerequisite for the manufacture of the respective pharmaceutical formulations. In the literature, there is a controversy on the stability of the various hydrates of disodium 10 pamidronate. The present invention presents a facile, easy to scale-up method of producing disodium pamidronate pentahydrate of high purity and high stability, at yield >90 %. This method avoids any steps that may introduce impurities. It is based on the fact that pamidronic acid can be transferred into its diammonium salt at high concentration, at room temperature. This highly concentrated solution is converted into the disodium salt via ion-exchange, at conditions that maintain the high concentration. The ion-exchange step simultaneously eliminates any undesired divalent or trivalent cations. The disodium salt can be directly crystallized in the eluate of the ion-exchange column, without the need of further concentration and/or addition of any alcohol, by only lowering the temperature down to 5°C.
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Page/Page column 10
(2008/06/13)
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- ZOLEDRONIC ACID CRYSTAL FORMS, ZOLEDRONATE SODIUM SALT CRYSTAL FORMS, AMORPHOUS ZOLEDRONATE SODIUM SALT, AND PROCESSES FOR THEIR PREPARATION
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The invention relates to polymorphs of zoledronic acid and zolidronate sodium salts, amorphous zoledronate sodium salts, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt
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Page/Page column 28-30
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ZOLEDRONIC ACID
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The invention disclosed in this application relates to an improved process for the preparation of zoledronic acid of formula (I) given below which comprises heating at a temperature in the range of 50-80 °C a solution of imidazol-1-ylacetic acid hydrochloride with ortho-phosphoric acid in a solvent medium where boiling point of the solvent used in lesser or close to that of phosphorous trichloride, adding phosphorous trichloride to the reaction mass slowly over a period of 2-3hr at a temperature in the range of 50-80 °C, keeping the resulting reaction mass at a temperature in the range of 50-80 °C for a period of 1-6hr, adding hydrochloric acid to the reaction mass and keeping the reaction mass at a temperature in the range of 60-120 °C, separating the organic solvent from the reaction mass while it is still hot, and diluting the aqueous layer containing zoledronic acid with water miscible solvent. Zoledronic acid is widely used as a bone resorption inhibitor.
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Page/Page column 6
(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 13
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF 2-(IMIDAZOL-1-YL)-1-HYDROXYETHANE-1, 1-DIPHOSPHONIC ACID
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The present invention provides a process for preparation of 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid, compound of formula (1), said process comprising (a) reacting imidazole with chloroacetyl chloride and benzyl alcohol in homogenous system in one pot to obtain benzyl 1-imidazolylacetate, compound of formula (3); (b) debenzylating benzyl 1-imidazolylacetate, a compound of formula (3) to imidazole 1-ylacetic acid, compound of formula (2) and (c) converting compound of formula (2) to compound of formula (1).
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Page/Page column 10
(2008/06/13)
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- Use of bisphosphonates for pain treatment
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A method for the treatment of pain, in particular antinociceptive or anti-allodynic treatment of pain, in a patient in need of such treatment, e.g. a patient with osteoporosis or osteopenia, a tumour patient or a patient suffering from an inflammatory disease, which comprises administering an effective amount of a bisphosphonate, e.g. zoledronic acid or salts or hydrates thereof, to the patient.
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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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- Method of administering bisphosphonates
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Bisphosphonates, in particular more potent N-bisphosphonates such as zoledronic acid and derivatives, can be used with satisfactory results for prolonged inhibition of bone resorption in conditions of abnormally increased bone turnover, e.g. osteoporosis, by intermittent administration, wherein the periods between bisphosphonate administrations are longer than was previously considered appropriate, e.g. a dosing interval of at least about 6 months or less frequently.
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- 3-D QSAR Investigations of the Inhibition of Leishmania major Farnesyl Pyrophosphate Synthase by Bisphosphonates
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We report the activities of 62 bisphosphonatesas inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC 50 values) ranging from ～100 nM to ～80 μM (corresponding to Ki values as low as 10 nM). The most active compounds were found to be zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic amino-methylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl chains, were also active, with 1C50 values in the 200-1700 nM range (corresponding to Ki values of ～20-170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or possessing multiple halogen substitutions or a p-amino group. To put these observations on a more quantitative structural basis, we used three-dimensional quantitative structure-activity relationship techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), to investigate which structural features correlated with high activity. Training set results (N = 62 compounds) yielded good correlations with each technique (R2 = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC50 values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side chain and a hydrophobic feature contributed significantly to activity. Overall, these results are of general interest since they represent the first detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.
- Sanders, John M.,Gómez, Aurora Ortiz,Mao, Junhong,Meints, Gary A.,Van Brussel, Erin M.,Burzynska, Agnieszka,Kafarski, Pawel,González-Pacanowska, Dolores,Oldfield, Eric
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p. 5171 - 5183
(2007/10/03)
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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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- Substituted alkanediphosphonic acids and pharmaceutical use
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Alkanediphosphonic acids, in particular heteroarylalkanediphosphonic acids of formula STR1 wherein R1 is a 5-membered heteroaryl radical which may be fused with benzene or cyclohexene nuclei and which contains, as hetero atoms, 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O- or S-atom, and which is unsubstituted or C-substituted by lower alkyl, phenyl or phenyl which is substituted by lower alkyl, lower alkoxy and/or halogen, or by lower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and/or halogen, and/or is N-substituted at a N-atom which is capable of substitution by lower alkyl, lower alkoxy and/or halogen, and R2 is hydrogen, hydroxy, amino, lower alkylthio or halogen, and salts thereof, have regulatory action on calcium metabolism and can be used as medicaments for the treatment of diseases associated with impairment of calcium metabolism. The compounds are obtained for example by converting, in a compound of formula STR2 wherein X1 is a functionally modified phosphono group and X2 is a free or functionally modified phosphono group, X1 and, if appropriate X2, into the free phosphono group.
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