- Chemoenzymatic Synthesis of Racemic and Enantiomerically Pure Phosphaaspartic Acid and Phosphaarginine
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Diisopropyl allyloxymethylphosphonate prepared by a one-pot procedure was isomerized to give racemic 1-hydroxy-3-butenylphosphonate with LDA by a [2,3]-sigmatropic rearrangement. Chloroacetylation delivered an ester, which was resolved in a two-phase system by using the lipase from Thermomyces lanuginosus. Racemic and (S)-α-hydroxyphosphonate 6 were converted to (±)- and (R)-phosphaaspartic acid by functional-group manipulation. (±)-, (R)- and (S)-6 were first esterified with 4-nitrobenzenesulfonyl chloride before hydroboration to transform the double bond into a hydroxyethyl group. The hydroxyl group was manipulated to give a guanidinyl group and the 4-nitrobenzenesulfonyloxy to give an amino group. Global deprotection of the α-aminophosphonates yielded the desired phosphaamino acids.
- Qian, Renzhe,Kuliszewska, Edyta,Macoratti, Elena,Hammerschmidt, Friedrich
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Read Online
- PHOSPHONATE CONJUGATES AND USES THEREOF
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Phosphonate conjugates, preferably, bisphosphonate conjugates; methods of inhibiting Ron receptor tyrosine kinase and methods of treatment of bone destruction due to cancer or other conditions utilizing the provided phosphonate conjugates.
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Paragraph 0089
(2020/07/31)
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- THYROID HORMONE RECEPTOR AGONIST AND USE THEREOF
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A thyroid hormone receptor agonist and its use in the treatment of a disease associated thyroid hormone receptor beta are described. The compound can be effective in lowering cholesterol with minimum or no adverse effects on the heart or thyroid hormone axis.
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Paragraph 0128; 0129
(2017/11/15)
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- NOVEL ANTIVIRAL COMPOUNDS, A PROCESS FOR THEIR PREPARATION, AND THEIR USE FOR TREATING VIRAL INFECTIONS
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The present invention relates to novel pro-drugs of L-2'-deoxythreose nucleoside phosphonates, such as phosphoramidate, phosphorodiamidate and phospho-diester prodrugs. The invention also relates to a process for preparing these novel prodrugs of nucleoside phosphonates. The invention also relates to the use of these novel phosphonatemodified nucleosides to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses belonging to the HBV family.
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Page/Page column 22
(2017/01/05)
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- Copper-catalyzed synthesis of α-hydroxy phosphonates from H-phosphonates and alcohols or ethers
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Easy PC: α-Hydroxy phosphonates were synthesized by copper/tert-butyl hydroperoxide (TBHP)-catalyzed oxidative addition reactions of H-phosphonates with alcohols or ethers. Diverse α-hydroxy phosphonates were obtained from substituted benzyl alcohols or alkyl alcohols and alkyl ethers in moderate to good yields. Copyright
- Zhao, Zengxiang,Xue, Wanhua,Gao, Yuxing,Tang, Guo,Zhao, Yufen
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supporting information
p. 713 - 716
(2013/05/09)
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- GUANINE ANALOGS AS TELOMERASE SUBSTRATES AND TELOMERE LENGTH AFFECTORS
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This invention relates to compounds useful for inhibiting telomere elongation. More specifically, the invention provides nucleotide analogs that are incorporated into telomeres by telomerase thereby inhibiting elongation of telomeres. The compounds are useful in treating cancer and other cell proliferative diseases.
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Paragraph 0464; 0465
(2013/07/05)
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- Synthesis of cyclopropane-containing phosphorus compounds by radical coupling of butenylindium with iodo phosphorus compounds
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The radical coupling of α- or β-iodo phosphorus compounds such as iodo phosphonate, iodo phosphane oxide, and iodo phosphonothioate with butenylindium species, prepared by transmetalation between a (cyclopropylmethyl)stannane and InBr3, afforded the corresponding cyclopropylmethylated products. The radical reaction was initiated by the radical species generated from butenylindium assisted by a small amount of oxygen. Butenylindium works not only as a cyclopropylmethylating reagent, but also as a radical initiator. For successful coupling, a tin/indium transmetalation was used, where it was important for the tin halide by-product to be inert to the reaction system. In addition, the transmetalation of a (cyclopropylmethyl)stannane and InBr3 provided the dibutenylindium bromide as a single product, which smoothly coupled with the unstable phosphonyl radical species from the iodo phosphorus compound. A photochemical method (UV irradiation) was also applied and accelerated the coupling reaction. The cyclopropylmethylated phosphonate produced was a good intermediate in the Horner-Wadsworth-Emmons reaction and gave functionalized olefins bearing the cyclopropane moiety. Copyright
- Kiyokawa, Kensuke,Suzuki, Itaru,Yasuda, Makoto,Baba, Akio
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supporting information; experimental part
p. 2163 - 2171
(2011/05/16)
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- PHOSPHORUS-CONTAINING THYROID HORMONE RECEPTOR AGONISTS AND METHODS OF USE
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The present invention relates to sulfonic acid containing compounds that bind to thyroid receptors in the liver. Activation of these receptors results in modulation of gene expression of genes regulated by thyroid hormones. The compounds can be used to treat diseases and disorders including metabolic diseases such as NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, and metabolic syndrome X.
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Page/Page column 96-97
(2011/04/24)
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- Preparation of chiral α-oxy-[2H1]methyllithiums of 99% ee and determination of their configurational stability
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(Tributylstannyl)methyl 2,2,6,6-tetramethylpiperidine-1-carboxylate was metalated with t-BuLi/TMEDA at -78 °C and borylated with the mixed borate derived from (R,R)-1,2-dicyclohexylethane-1,2-diol and t-butanol to give diastereomeric boronates 31/32 in equal amounts. Boronates 31 and 32 were reduced with LiBEt3D and then oxidized with basic H2O 2 to give (S)- and (R)-tributylstannyl-[1-2H 2]methanol of 99% ee, respectively. Treatment of their respective phosphates with n-BuLi at -78 and 0 °C gave microscopically configurationally stable phosphinyloxy-substituted [2H 1]methyllithiums, which rearranged to hydroxy-[1-2H 1]-methylphosphonates of ee > 98% (phosphate-phosphonate rearrangement). The N,N-iisopropylcarbamates of the enantiomeric tributylstannyl-[1-2H1]methanols were transmetalated to give carbamoyloxy-substituted chiral [2H1]methyllithiums, which were macroscopically configurationally stable for prolonged periods of time (up to 3 h, ee still 99%) at -78 °C, deduced from trapping experiments with benzaldehyde. The chemical stability of these methyllithiums ended at -50 °C. The stereochemistry of the monoprotected and monodeuterated 1-phenylethane-1,2-diols obtained was secured by spectroscopic comparison of their Mosher esters with that of all four stereoisomeric 1-phenyl-[1- 2H1]ethane-1,2-diols synthesized independently. Furthermore, the configurations of the boronates and the chiral methyllithiums derived from them were deduced from a single-crystal X-ray structure analysis of a carbamate in which the tributylstannyl group had been replaced by the [(1R)-menthyl]dimethylstannyl group.
- Kapeller, Dagmar,Barth, Roland,Mereiter, Kurt,Hammerschmidt, Friedrich
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p. 914 - 923
(2007/10/03)
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- NUCLEOBASE PHOSPHONATE ANALOGS FOR ANTIVIRAL TREATMENT
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The present invention provides novel compounds with activity against infectious viruses. The compounds of the invention may inhibit retroviral reverse transcriptases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases. The present invention also relates generally to the accumulation or retention of therapeutic compounds inside cells. The invention is more particularly related to attaining high concentrations of active metabolite molecules in HIV infected cells. Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.
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Page/Page column 98-99; 112-113
(2008/06/13)
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- Synthesis of dialkyl-hydroxymethylphosphonates in heterogeneous conditions
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This article describes the synthesis of a series of dialkyl-hydroxymethylphosphonates bearing various alkyl ester groups by the Pudovik reaction. The employed method uses anhydrous potassium carbonate as a catalyst in heterogeneous (solid/liquid) or mixed (solid/liquid and homogenous) conditions. All these syntheses are performed without any phase transfer agent and involve an anionic intermediate in a low polar or apolar solvent. These different products, obtained with high yields, have been characterised by 1H and 31P NMR and also by mass spectrometry. A study of fragmentation in the FAB ionisation process is given.
- Jeanmaire, Thomas,Hervaud, Yves,Boutevin, Bernard
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p. 1137 - 1145
(2007/10/03)
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- The phosphonate-phosphate and phosphate-phosphonate rearrangements and their applications, VI: Metallation of phosphorylated aliphatic alcohols to configurationally stable α-oxyalkyllithium compounds - use of the phosphoryl group as an activating group and electrophile
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Alkyl diisopropyl phosphates were metallated by sBuLi/TMEDA at -78 °C at the alkyl and isopropyl group in a ratio which is strongly influenced by steric effects. The regioselectivity of deprotonation was very high by use of heptadeuterioisopropyl groups, which reflects a high primary kinetic isotope effect (k(H)/k(D) ≥ 100). The dipole stabilized, phosphoryloxy-substituted alkyllithium compounds formed are configurationally stable and rearrange with retention of configuration (phosphate-phosphonate rearrangement).
- Hammerschmidt, Friedrich,Schmidt, Susanne
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p. 2239 - 2245
(2007/10/03)
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- Phosphonic acid-substituted benzazepinone-n-acetic acid derivatives process for their preparation and pharmaceutical compositions comprising them
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Compounds having NEP-inhibitory activity, corresponding to the formula I in whichR 1 is hydrogen or a group forming a biolabile phosphonic acid ester,R 2 is hydrogen or a group forming a biolabile phosphonic acid ester and R. sup.3 is hydrogen or a group forming a biolabile carboxylic acid esterand physiologically acceptable salts of acids of formula I, and pharmaceutical compositions comprising these compounds.
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- Phosphosulfonate herbicides
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This invention pertains to phosphosulfonates, having the general formula STR1 wherein Y is phenyl, naphthyl, benzyl, a (C5 -C8)cycloalkyl, a 5-membered heteroaromatic ring, a 6-membered heteraromatic ring, a fused 5,6-membered heteroaromatic ring, or a fused 6,6-membered heteroaromatic ring; and X is oxygen or sulfur; and R1 and R2 are each independently selected from substituted or unsubstituted alkyl, alkoxy, alkylthio, alkenyloxy, alkynyloxy, haloalkoxy, cyanoalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkoxy, alkylideneiminooxy, chloro, amino, phenyl or phenoxy; or R1 and R2 are both alkoxy, taken together with the phosphorus atom to form a 6-membered oxygen-containing ring; compositions containing these compounds and their use as herbicides.
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- SULFONIC, PHOSPHONIC OR PHOSPHINIIC ACID BETA-3 AGONIST DERIVATIVES
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Compounds of the formula STR1 and pharmaceutically acceptable salts thereof wherein: A is a bond or--OCH 2--, where the oxygen is linked to R 1 ;B is--CH 2--or when R 3 is hydrogen, B may be--CH 2 O--where the oxygen is linked to the phenyl ring;R 1 is an aryl group; R 2 is hydrogen or lower alkyl;R 3 is hydrogen; or R 2 and R 3 together form the group--CH 2 CH 2--; andR 4 is--SO 3 H,--P(O 2 H) R 5,--P(O 2 R 5')R 5,--PO 3 H 2,--PO 3 HR. sup.5' or--PO 3 (R 5') 2 where R 5 and R 5' are independently lower alkyl. These compounds are beta 3 adrenergic receptor agonists and are useful, for example, in the treatment of diabetes, obesity, achalasia, and gastrointestinal diseases.
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- 9-[(Phosphonoalkyl)benzyl]guanines. Multisubstrate analogue inhibitors of human erythrocyte purine nucleoside phosphorylase
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A series of 9-[(phosphonoalkyl)benzyl]guanines was synthesized and tested for inhibition of human erythrocyte purine nucleoside phosphorylase (PNPase). Inhibitors of PNPase should be T-cell selective, immunosuppressive agents with potential clinical utili
- Kelley,Linn,McLean,Tuttle
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p. 3455 - 3463
(2007/10/02)
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- SYNTHESES OF ENANTIOMERIC N-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL)DERIVATIVES OF PURINE AND PYRIMIDINE BASES
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Methods of preparation of N-(3-hydroxy-2-phosphonomethoxypropyl) (HPMP) derivatives of (2S)- and (2R)-configuration compounds I and XXVII, respectively are described.The general method starts from the corresponding N-(2,3-dihydroxypropyl) derivatives which were converted either into the (R)-enantiomers XIII by reaction of the base with (R)-glycidol butyrate (XII) in the presence of cesium carbonate and subsequent methanolysis, or into the (S)-enantiomers XI by alkylation of the base with (R)-2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane (V) in the presence of the same reagent.The amino groups on the heterocyclic base in compounds XI and XIII were benzoylated by silylation followed by reaction with benzoyl chloride and the obtained N-benzoates XV and XVII on reaction with trityl chloride afforded the corresponding 3'-O-trityl derivatives XVI and XVIII.These compounds were condensed with bis(2-propyl)-p-toluenesulfonyloxymethanephosphonate (XXIII) in dimethylformamide in the presence of sodium hydride to give the fully protected diesters XXIV and XXVIII.These compounds could be selectively acid-hydrolyzed to remove the trityl group only under formation of compounds XXXV, or methanolyzed and then acid-hydrolyzed to remove the trityl and N-benzoyl groups and lead to compounds XXVI and XXX, or treated with bromotrimethylsilane to remove the trityl and 2-propyl group to give phosphonates of the type XXVI.All the three types of compounds were then converted into free phosphonates of the (S)-series (I) and (R)-series (XXVII).Derivatives of cytosine (Ia, XXVIIa), adenine (Ib, XXVIIb), 2,6-diaminopurine (Ic, XXVIIc) and guanine (Id, XXVIId) were prepared.Condensation of the partially blocked adenine derivative XXXV with the tosyl derivative XXIII and subsequent deprotection afforded 9-(S)-(2,3-diphosphonomethoxypropyl)adenine (XLIII).Reaction of the same compound XXXV or its (R)-enantiomer XXXVIII with diethyl chlorophosphonate, followed by deblocking, afforded 3'-O-phosphoryl derivatives (S)-HPMPA (XXXVII) and (R)-HPMPA (XL).
- Holy, Antonin
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p. 649 - 674
(2007/10/02)
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- Biosynthesis of Naturally Products with a P-C Bond. Part 6. Preparation of Deuterium- and Carbon-13-Labelled L-Alanyl- and L-Alanyl-L-alanyl-(2-aminoethyl)phosphonic Acids and their Use in Biosynthetic Studies of Fosfomycin in Streptomyces fradiae
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(2-Aminoethyl)phosphonic acid (AEP) is not taken up by Streptomyces fradiae in the biosynthesis of fosfomycin.Attachment of L-alanine or L-alanyl-L-alanine to the amino group of deuteriated AEP affords di- and tri-peptides 4 and 5 which are transported into the cell. AEP is synthesized from Na(13)CN and the tosyloxymethylphosphonate 7.It is transformed into dipeptide 4d, which acts as a carrier for AEP which is incorporated into fosfomycin with an enrichment of 2 percent.
- Hammerschmidt, Friedrich,Kaehlig, Hanspeter,Mueller, Norbert
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p. 365 - 369
(2007/10/02)
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