HYDROXY AND/OR CARBOXY SUBSTITUTED PHOSPHONIC AND BISPHOSPHONIC ACIDS USABLE AS CORROSION AND SCALE INHIBITORS

Abstract

2-Dihydroxyphosphonyl-2-hydroxy-propionic acid (DHHPA), 1,4-bis[(dihydroxyphosphonyl)hydroxy-methyl]benzene (BDHB) and 2,3-bis(dihydroxyphosphonyl)-1,4-butanedioic acid (BDBA) were synthesized by acid catalyzed hydrolysis of the corresponding substituted phosphonates or bisphosphonates. The structure of these compounds was confirmed by elemental analysis as well as by infrared (IR) and proton nuclear magnetic resonance (¹H-NMR) spectroscopy. They can be used as corrosion and scale inhibitors.     

Fluorimetric quantification of clodronate and alendronate in aqueous samples and in serum

The bisphosphonates clodronate and alendronate are drugs in the therapy of osteoporosis or Paget's disease. They are highly hydrophilic and therefore of low oral bioavailability. Determination methods for bisphosphonates are often laborious and expensive equipment is needed. The presented quantification method based on kinetic measurement of the fluorescence decrease of an Al³⁺-morin complex can be used to determine the bisphosphonate content in aqueous and plasma samples. The intra- and inter-assay accuracies were found to be within 98.8% and 102.3% of the target samples for clodronate and within 97.2% and 105.0% of the target samples for alendronate. The LOQ was defined as 15.6 ng/ml for clodronate and 62.5 ng/ml for alendronate. In serum samples, intra- and inter-assay accuracy was found to be within 99.0% and 101.6% of the target samples for clodronate and within 97.8% and 102.6% of the target samples for alendronate. In serum samples, the LOQ was defined as 1.55 mg/ml for clodronate and 0.39 mg/ml for alendronate. Though less sensitive in serum, the presented method could support research on the development of drug delivery systems in vitro and in vivo for the investigated and other structurally related bisphosphonates.     

Zoledronic acid: pharmacologic profile of a potent bisphosphonate

Bisphosphonates are an important class of osteotropic compounds that are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclast-mediated bone resorption (i.e., osteoporosis, Paget’s disease, and tumor-induced osteolysis). The evolution of bisphosphonates has led to compounds with ever-increasing potency. First-generation bisphosphonates, including etidronate and clodronate, contained simple side chains and were relatively weak inhibitors of bone resorption. Second-generation compounds, including pamidronate, alendronate, and ibandronate, have an aliphatic R² side chain containing a single nitrogen atom. These nitrogen-containing bisphosphonates (N-BPs) are up to 100-fold more potent than the first-generation compounds. Zoledronic acid, a novel N-BP with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates in both in vitro and in vivo preclinical models. Recent data suggest that N-BPs inhibit farnesyl diphosphate (FPP) synthase, an enzyme in the mevalonate biosynthetic pathway that is critical for protein prenylation and activation of important signaling molecules. Inhibition of FPP synthase also leads to production of triphosphoric acid 1-adenosin-5′yl ester 3-[3-methylbut-3-enyl] ester (ApppI), which induces apoptosis of osteoclasts and tumor cells. Our current knowledge of the pharmacology of N-BPs at the molecular level largely explains their observed effects on bone metabolism and tumor growth in animal models and their clinical activity in the treatment of benign and malignant bone diseases.     

A new 3,4-seco-lupane triterpenene glycosyl ester from the leaves of Eleutherococcus sessiliflorus

Abstract

A new minor 3,4-seco-lupane triterpenene glycosyl ester, named sessiloside-A1 (1), along with three known 3,4-seco-lupane triterpenenes were isolated from the which alcohol extract of the leaves of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y. Hu by silica gel column chromatography, and their structures were determined by spectroscopic methods (UV, IR, NMR and HRMS). Compound 1 was elucidated to be β-D-glucopyranosyl ester of chiisanogenin. At the same time, a new efficient two-step enzymatic hydrolysis method was established to transform chiisanoside (2) → divaroside (3) → 1.     

Effects of Divalent Metal Ions on pH-Dependent Hydrolysis of p-Nitrophenyl (E)-(Hydroxyminio) Phosphonoacetate

Abstract

The (E-oxime of phosphonoglyoxylic acid, or (E-troika acid [(E)-l] undergoe: fragmentation leading to phosphorylation of the aqueous solvent at neutral pH and room temperature.[1] In contrast, the corresponding C-methyl ester (a-2 is stable under these mild conditions. Conversion of the unreactive (E)-2 to (E)-1 requires dewthylation a pH 13–14, generating the polyanion of (E-1, which becomes reactive on protonation.[1]     

Zur Chemie der 4-Amino-thiazolin-2-thione, 2. Mitt.

Summary 6-Amino-thiazolo[4,5-c]isothiazole derivatives4 are obtained by addition of hydrogen sulfide to the 4-Amino-thiazoline-5-carbonitrile2 followed by cyclooxidation of the intermediate thioamides3. In the presence of sodium sulfite the hydrolysis of the4-amino-2-methylthio-thiazolium salts5 derived from the title compounds1 yields the4-amino-thiazolin-2-ones6. By their further hydrolysis the 2,4-dioxo-thiazolidin-5-carboxamides8 are formed. The 2-oxo-and 2-thioxo-thiazolo [4,5-d]pyrimidin-7-ones and -thiones available from1 undergo ring opening by hydrolysis to give the substituted 4-amino-6-oxo- and 4-amino-6-thioxo-pyrimidine-5-thiols15a–h and13i–e. They have been isolated as their disulfides14 or 5-alkyl derivativesi.e. the substituted 4-amino-5-alkylthiopyrimidin-6-ones and -thiones16. In analogy, the intermediate 6-amino-7-oxo-thiazolo[4,5-d] pyrimidin-2-thione18 and the 7-amino-thiazolo[4,5-d]-pyrimidin-2-thione24 derived from1 react by ring cleveage to yield the 1,4-and 4,6-diamino-pyrimidin-5-thiole derivatives22 and27, respectively, isolated as their disulfides or alkylthio-derivatives. From the pyrimidine16b the pyrimido[5,4-b]1,4-thiazine derivative18 can be obtained.

     

Synthesis of Acyclic γ-Amino Mono-or Bisphosphonates Via Pentacovalent Oxaphosphorane Chemistry

Abstract

Geminal bisphosphonic acids and their salu have long been known to he effective inhibitors of bone resorption and mineralization. which arc common symptoms of diseases such as osteoporosis and Paget's disease [I]. Utilizing penlacovalent nxaphosphoranc chemistry, a variety of acyclic γ-amino mono- and bisphosphonates can be efficiently hynthesizcd. Hydrolysis of the P(V) oxaphospholenes, I and 2. followed by reductive amination [2] of the multing ketones, kds directly to the γ-amino mono and bisphosphonateh 5 and 6. The reaction of secondary amincs with ketones 3 and 4 are slow and low yielding. In reactions with ketones containing a bisphosphonatc. The primary product is the cyclic bisphosphonates. 7. Reactions of primary amines with ketones containing a mono-phosphonate M generally hencr, giving higher yields of the desired prcduct in a rhoncr rcaciion time. Syntheses of compounds, 9–11 were also performed (R₁ ? H, R₂ ? pentyl, cyclohexyl, benzyl, phenyl) in good yields.     

Stereoselective Synthesis of C-Glycosides by Suzuki Cross-coupling Reaction

Carbohydrates and their conjugates have been recognized to play a wide variety of metabolic roles in numerous biological processes.[1] Various modified sugars and analogues have been recently synthesized for further investigation of glycosidase reactions and for the development of specific glycosidase inhibitors.[2] As one of the most important carbohydrate mimics, C-glycosides have attracted great attention due to their stability to chemical or enzymatic hydrolysis of the glycosidic linkage. A number of methodologies for the preparation of C-glycosides have been extensively investigated.[3] We have recently reported the syntheses of novel C-glycosyl amino acids and amino-C-disaccharides possessing a ketose form via the stereoselective 1,3-dipolar cycloaddition of exo-methylenesugars (1) and nitrones.[4,5] As a continuation of our research on the synthesis of C-glycosides using exo-methylenesugar as the precursor, we wish to describe here a stereoselective synthesis of C-glycosides by Suzuki cross-coupling reaction.     

One Pot Synthesis of Bisphosphonate Esters: A Way to Synthesize Tetraphosphonate Esters

Abstract

Several methods for the preparation of symmetrical bisphosphonates of general type (RO)₂P(O)(R′OH)P(O)(OR)₂, have been developed, and investigated for their pharmacological. Pharmacological screening of these bisphosphonates have shown that these compounds have potent cardiovascular activity and are. potentialy useful in the treatment of hypertension. In this work we described of new method “one pot” for the synthesis of hydroxy bis and tetra phosphonates (I, II, III and IV).     

The determination of phenol in urine by enzymatic hydrolysis/headspace gas chromatography

Summary A new method has been developed for the determination of phenol in urine in which the phenol conjugates are hydrolysed enzymatically and the liberated phenol is analysed by headspace chromatography. The results compare favourably with those obtained by the method of van Haaften and Sie in which acid hydrolysis is carried out in a heated GC precolumn. The enzymatic hydrolysis headspace technique appears to be very reliable and does not suffer from the disadvantages of precolumn acid hydrolysis.Since this paper was submitted, we have found a report on the enzymatic hydrolysis of phenyl glucuronide in urine followed by gas chromatographic analysis which seems to have been overlooked by later workers. The paper is by H. Desoille, T. F. Gandenzi-Britto and M. Philbert in Archives des Maladies Professionelles, de Medecine du Travail et de Securite Sociale (Paris),30 (3), 129 (1969).     

Syntheses of enantiopure Si-centrochiral silicon-based muscarinic antagonists using an enantioselective enzymatic esterification as the key step

The muscarinic antagonists (R)-cyclopentyl(hydroxymethyl)phenyl[2-(piperidin-1-yl)ethyl]silane[(R)-1] and(R)-1-{2-[cyclopentyl(hydroxymethyl)phenylsilyl]ethyl}-1-methylpiperidinium iodide [(R)-2] were synthesized using anenantioselective enzymatic transformation as the key step. Apapain-catalyzed (E.C. 3.4.22.2) esterification ofrac-cyclopentyl(hydroxymethyl)phenyl(vinyl)silane(rac-3) with 5-phenylpentanoic acid afforded(R)-cyclopentyl(phenyl)[(5-phenylpentanoyloxy)methyl]vinylsilane[(R)-4] which upon chemical hydrolysis gave enantiomericallyenriched (R)-3 (68% ee). Repetition of thisesterification/hydrolysis sequence, starting from enantiomericallyenriched (R)-3, finally gave the enantiopure silane (R)-3(98% ee) which served as the starting material for thesubsequent chemical synthesis of (R)-1 and (R)-2{(R)-3 (R)-cyclopentyl(phenyl)[(trimethylsilyloxy)methyl]vinylsilane[(R)-5] (R)-1 (R)-2}.     

Structures of bisphosphonate metal complexes: zinc and cadmium complexes of clodronate and its partial ester derivatives

Four new zinc and cadmium bisphosphonates [{NaZn(Cl2CP2O6H)(H2O)5}]n (1), [{Cd2(Cl2CP2O6)(H2O)4}.H2O]n (2), [{Zn(Cl2CP2O6Pri2)(H2O)3}.H2O]n (3), and [{Cd2(Cl2CP2O6Pri2)2(MeOH)2(H2O)2}.H2O]2 (4) have been prepared and their crystal structures determined by single-crystal X-ray diffractometry. Two bisphosphonate ligands were used: clodronate, (dichloromethylene)bis(phosphonate) and its symmetrical P,P'-diisopropyl ester derivative. The structure of the Zn complex 1 is three-dimensional, consisting of one-dimensional Zn-clodronate chains connected to the three-dimensional network by Na+ ions. The structure of Cd complex 2 consists of double layers, and a unique bond was found between the Cd2+ cation and a Cl atom of clodronate. Zn complex 3 consists of one-dimensional chains, but the binding of the bisphosphonate ligands is unique: in 3 the bisphosphonate ligand is only bidentate. Compound 4 is a tetramer, and hydrogen bonds hold the tetramers together, forming a layered structure.     

Phosphorus Containing Tri-and Hexamacrocycles

Abstract

Multisite receptors containing more than two macrocyclic cavities. despite of the fact that their syntheses, most often, require sophisticated pathways, arc of very high interest since they may allow new insights into ion channel transfer, ion conduction.[1] We report here a method which combine simple reactions, high yields (80%), with easily prepared starting reagents[2], of two new polymacrocyclic system, a tri-(r) and an hexamacrocyck(II). They were obtained by a condensation reaction between 4-formylbenzo-15-crown-5 (3 or 6 quiv, respectively) and phosphouihydrazide (1 equiv.) or hexahydrazide (1 equiv.) in tetrahydrofuran.     

Five-coordinate dicarboxylate complexes of copper (+2) and zinc (+2)

A new dicarboxylic acid, LH₂ , derived from 2-[(2-hydroxy-3,5-dimethylphenyl) (phenyl)methyl]-4,6-dimethylphenol (1) was prepared by reacting it with methyl bromoacetate followed by alkaline hydrolysis. Two five-coordinate mononuclear complexes of L with zinc (+2) and copper (+2), [Zn(L)(py)₂(H₂O)]?·?H₂O?·?py (IV), and [Cu(L)(py)₂(H₂O)] (V), were prepared (py?=?pyridine) and characterized. The packing patterns of these two complexes are different and the H-bond interactions in their lattices are controlled by the presence or absence of water molecules. This difference arises from subtle change in the orientation of carbonyl groups of the carboxylates.     

2-[3-(Trifluoromethyl)phenyl]furo[3,2-b]pyrroles: synthesis and reactions

The synthesis and reactions of methyl 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (1a) are described. Upon reaction with methyl iodide, benzyl chloride, or acetic anhydride, this compound gave N-substituted products 1b-d. By hydrolysis of compounds 1a-c, the corresponding acids 2a-c were formed, or by reaction with hydrazine-hydrate, the corresponding carbohydrazides 3a-c were formed. By heating 2-[3-(trifluoromethyl)phenly]-4H-furo[3,2-b]pyrrole-5-carboxylic acid (2a) in acetic anhydride, 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-b]pyrrole (4) was formed. By hydrolysis of 4, 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole (5a) was formed, and reactions with methyl iodide or benzyl chloride gave N-substituted products 5b-c. The reaction of 4 with dimethyl butynedioate gave substituted benzo[b]furan 6. Compound 3a reacted with triethyl orthoesters giving 7a-c, which afforded with phosphorus (V) sulphide the corresponding thiones 8a-c. The thiones 8a-c reacted with hydrazine hydrate to form hydrazine derivatives 9a-c. The reaction of triethyl orthoformiate with compounds 9a-c led to furo[2′,3′: 4,5]pyrrolo[1,2-d][1,2,4]triazolo[3,4-f][1,2,4]triazines 10a-c. Hydrazones 11a-c were formed from 3a-c and 5-[3-(trifluoromethyl)phenyl]furan-2-carboxaldehyde. The effect of microwave irradiation on some condensation reactions was compared with “classical” conditions. The results showed that microwave irradiation shortens the reaction time while affording comparable yields.     

Enzymatic Synthesis of Phosphoric Monoesters with Alkaline Phosphatase in Reverse Hydrolysis Conditions

Abstract

Title compounds were synthesized on a preparative scale using alkaline phosphatase, orthophosphoric monoester phosphohydrolase E.C. 3.1.3.1, in reverse hydrolysis conditions. Optimization for one of the 25 Fhosphoryl acceptors hvestfgated (glycerol) shovs that up to 55% synthesis yield can be obtained using a large excess of substrate, conditions in which the enzymatic activity remains high. From the results obtained with different phosphoryl group donors, phosphate, pyrophosphate and polyphosphates and with enzymes of different sources, it comes up that the best results are obtained with pyrophosphate and with the weakly purified calf intestine alkaline phosphatase. The extent of enzymatic hydrolysis of the donor can be reduced owing to the existence of two different pH optima for the two reactions, phosphorylation and hydrolysis. The synthesis can be also performed using inert co-solvents which allow to reduce the amount of acceptor used, as long as Zn⁺⁺ is added to the reaction medium. The results are discussed in terms of the catalytic mechanism of alkaline phosphatase.     

Synthesis of phosphinic acids on the basis of hypophosphites: VI. General methods for synthesis of pseudo-γ-glutamylpeptides

A general method for synthesis of 2-substituted pseudo-γ-glutamylpeptides, namely, [2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)propyl]phosphinic acids I which are phosphinic acid analogs of γ-glutamylpeptides. Bis(trimethylsilyl) hypophosphite (IV) formed from ammonium hypophosphite (II) in situ was added to the respective α-substituted acrylate to form bis(trimethylsilyl) [2-R-2-(alkoxycarbonyl)ethyl]-phosphonites V. Treatment of compounds V in situ with excess dibromoethane followed by alcoholysis gave [2-R-2-(alkoxycarbonyl)ethyl](2-bromoethyl)phosphinic acids VI which without isolation were treated with excess triethyl orthoformate. The simultanious esterification and dehydrobromination led to [2-R-2-(alkoxy-carbonyl)ethyl](vinyl)phosphinates III which were isolated and characterized. The Michael addition of diethyl acetamidomalonate to vinylphosphinates III followed by acid hydrolysis of phosphinates VII without their isolation resulted in formation of target [2-R-2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)]proly]phosphinic acids-pseudo-γ-glutamylpeptides I. Original Russian Text V.V. Ragulin, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 5, pp. 763–768. For communication V, see [1].     

New Bisphosphonates,Synthesis and Reactions

Abstract

The synthesis and reactions of new bisphosphonates with different substituents in α-position as well as a new type of trisphosphonate are described.     

Straightforward Syntheses of the Three Possible Isomers of (±)-2-[3-(Hydroxybenzoyl) phenyl]propanoic Acid,Metabolites of (±)-Ketoprofen

The o-, m- and p- isomers of (±)-2-[3-(hydroxybenzoyl)phenyl] propanoic acid (11, 12 and 4) have been prepared from 3-bromopropiophenone or m-propionylbenzoic acid, via 7, 8 and 2, which were submitted to Tl(III) nitrateinduced rearrangement, followed by hydrolysis of the ester and ether functions.     

含吡啶的抗肿瘤转移NAMI-A衍生物的制备和水解机理动力学

目的研究配体结构对NAMI-A衍生物水解机理、电化学性质的影响。方法制备了trans-[RuCl4(DMSO)(3-MePy)][(3-MePy)H](3-MePy=3-甲基吡啶,化合物1)和trans-[RuCl4(DMSO)(4-MePy)][(4-MePy)H](4-MePy=4-甲基吡啶,化合物2)。用UV、NMR、CV法研究化合物1、化合物2的水解机理-动力学、溶液稳定性及电化学性质。结果化合物1和化合物2与NAMI-A相似,在pH7.40的缓冲液中发生脱氯水解反应(Ⅰ氯水解及Ⅱ氯水解)(分步反应);在pH 5.00缓冲液中DMSO(二甲亚砜)及少量吡啶水解。测定各水解反应表观速率常数及半衰期、溶液稳定性及氧化还原电位。结论化合物1、化合物2的Ⅰ氯、Ⅱ氯及DMSO水解反应机理与NAMI-A相似,而且各水解速率与NAMI-A相差不大,即用甲基吡啶取代咪唑环,对NAMI-A衍生物的Ⅰ氯、Ⅱ氯及DMSO水解反应速率影响较小。化合物在酸性溶液中的稳定性明显高于中性溶液。