- Cellular delivery of nucleoside diphosphates: A prodrug approach
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Purpose. This study is concerned with cellular delivery/generation of 2'-azido-2'-deoxyuridine and -deoxycytidine diphosphate (N3UDP or N3CDP), potent inhibitors of ribonucleotide reductase. It characterizes the phosphorylation steps involved in the conversion of 2'-azido-2'-deoxyuridine (N3Urd) and 2'-azido-2'-deoxycytidine (N3Cyd) to the corresponding diphosphates and explores a prodrug approach in cellular delivery of the inhibitor which circumvents the requirement of deoxynucleoside kinases. Methods. Cell growth of CHO and 3T6 cells of known deoxycytidine kinase level was determined in the presence of N3Urd and N3Cyd. Activity of ribonucleotide reductase was determined in the presence of the azidonucleosides as well as their mono- or di-phosphates in a Tween 80-containing permeabilizing buffer. A prodrug of 5'-monophosphate of N3Urd was prepared and its biological activity was evaluated with CHO cells as well as with cells transfected with deoxycytidine kinase. Results. N3Urd failed to inhibit the growth of both cell lines, while N3Cyd was active against 3T6 cells and moderately active against CHO cells. These results correlate with the deoxycytidine kinase levels found in the cells. Importance of the kinase was further established with the finding that the nucleoside analogs were inactive as reductase inhibitors in a permeabilized cell assay system while their mono- and di-phosphates were equally active. The prodrug was active in cell growth inhibition regardless of the deoxycytidine kinase level. Conclusions. The azidonucleosides become potent inhibitors of the reductase by two sequential phosphorylation steps. The present study indicates that the first step to monophosphate is rate-limiting, justifying a prodrug approach with the monophosphate.
- Kang, Shin Hong,Sinhababu, Achintya K.,Cory, Joseph G.,Mitchell, Beverly S.,Thakker, Dhiren R.,Cho, Moo J.
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Read Online
- Prodrugs of Vitamin C: The reaction of 1-acyloxyalkyl-1-iodides with Vitamin C 5,6-acetonide
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The reaction of 2 equiv of 1-acyloxyalkyl-1-iodides with vitamin C 5,6-acetonide gave mixtures of products that were O-alkylated on the 3-position and either O-alkylated, 7, or O-acylated, 8, on the 2-position. The 8 products comprised the majority of the mixtures: 56:54 to 94:6. The 3-alkylated-2-acylated prodrugs, 8, hydrolyzed to vitamin C 5,6-acetonide chemically at pH 7.4 with half-lives of 6-12 h.
- McGowan, Jennifer,Thiele, Nikki,Sloan, Kenneth B.
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Read Online
- Esterase-Activatable Synthetic M+/Cl? Channel Induces Apoptosis and Disrupts Autophagy in Cancer Cells
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The formation of a supramolecular synthetic M+/Cl? channel in the membrane phospholipid bilayer has been reported upon activation of a methyl pivalate-linked N1,N3-dialkyl-2-hydroxyisophthalamide by esterases. The channel formation induces apoptosis in cancer cells via the intrinsic pathway. Interestingly, the supramolecular channel was also shown to disrupt autophagy in cancer cells by causing alkalization of lysosomes – a feature that has been confirmed at the cellular and protein level.
- Malla, Javid Ahmad,Sharma, Virender Kumar,Lahiri, Mayurika,Talukdar, Pinaki
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supporting information
p. 11946 - 11949
(2020/08/27)
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- Azacyclo diketone compound and preparation method thereof
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The invention provides an azacyclo diketone compound, which is a compound represented by the following structure defined in the specification, or a pharmaceutically acceptable salt thereof. The invention provides a compound having an inhibitory activity on influenza (flu) virus proliferation, particularly on influenza-related cap-dependent endonuclease to inhibit influenza virus proliferation so as to treat or prevent influenza. The present invention relates to a substituted azacyclo diketone compound having inhibitory activity on cap-dependent endonuclease, and a pharmaceutical composition containing the substituted azacyclo diketone compound.
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Paragraph 0989-0995
(2020/06/17)
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- An improved synthesis of adefovir and related analogues
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An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.
- Jones, David J.,O’Leary, Eileen M.,O’Sullivan, Timothy P.
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supporting information
p. 801 - 810
(2019/04/17)
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- Synthetic method 2 - hydroxymethyl -5 - trifluoromethyl pyrimidine (by machine translation)
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The invention relates to a synthetic method. 2 -hydroxymethyl -5 -trifluoromethyl pyrimidine. The technical problem. of 2 - hydroxymethyl -5 - trifluoromethyl pyrimidine lacks industrial synthesis method is mainly solved. The method includes the following steps: reacting methyl chloroformate with sodium iodide in acetonitrile to generate compound 1 pivalate; reacting, reacting 2-chloro 2 -trifluoromethylpyrimidine in a tetrahydrofuran solution and a compound -5 - generating compound 2; reacting compound 3 with sodium methoxide in a methanol solution, and generating a compound 3 in the form of a target compound, wherein the compound is reacted with sodium methoxide in the presence of a solvent, and the compound is reacted with 4 sodium methoxide. As a medical intermediate, 2 - hydroxymethyl -5 - trifluoromethyl pyrimidine is used for the research. (by machine translation)
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Paragraph 0007
(2019/08/12)
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- Preparation method of iodomethyl pivalate
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The invention discloses a preparation method of iodomethyl pivalate as an important medicine intermediate. The preparation method is characterized in that iodomethyl pivalate as a raw material and sodium iodide undergo a replacement reaction in ethyl acetate as a solvent under the condition of reaction backflow time of 6h. Compared with other synthesis methods, the preparation method of iodomethyl pivalate has a high mole yield. The iodomethyl pivalate obtained by the preparation method has product purity (GC) of 98% and thus the product has advantages in cost and purity.
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Paragraph 0011; 0012
(2017/02/24)
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- Visible Light-Induced Room-Temperature Heck Reaction of Functionalized Alkyl Halides with Vinyl Arenes/Heteroarenes
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The first visible light-induced Pd-catalyzed Heck reaction of α-heteroatom substituted alkyl iodides and -bromides with vinyl arenes/heteroarenes has been developed. This transformation efficiently proceeds at room temperature and enables synthesis of valuable functionalized allylic systems, such as allylic silanes, boronates, germanes, stannanes, pivalates, phosphonates, phthalimides, and tosylates from the corresponding α-substituted methyl iodides. Notably, synthesis of the latter substrates failed under existing thermally induced Pd-catalyzed conditions, which highlights the importance of visible light for this transformation.
- Kurandina, Daria,Parasram, Marvin,Gevorgyan, Vladimir
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supporting information
p. 14212 - 14216
(2017/10/13)
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- N-HYDROXYFORMAMIDE COMPOUNDS AND COMPOSITIONS COMPRISING THEM FOR USE AS BMP1, TLL1 AND/OR TLL2 INHIBITORS
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Compounds of Formulas (I) and (II) and salts thereof; methods of making and using the same, including use for inhibiting BMP1, TLL1 and/or TLL2 and in treatment of diseases associated with BMP1, TLL1 and/or TLL2 activity.
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Page/Page column 121
(2017/01/26)
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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; 0135
(2017/11/15)
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- Regioselective synthesis of 2-O-acyl-3-O-(1-acyloxyalkyl) prodrugs of 5,6-isopropylidene-L-ascorbic acid
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An efficient regioselective synthesis of 2-O-acyl-3-O-(1-acyloxyalkyl) prodrugs of vitamin C 5,6-acetonide has been developed which does not involve tedious column chromatographic separation of the desired products from contaminants exhibiting very similar Rf values. Vitamin C 5,6-acetonide is first acylated with one equivalent of acyl halide in the presence of two equivalents of pyridine. The crude 2-O-acylated product is then alkylated with one equivalent of 1-acyloxyalkyl-1-iodide in the presence of one equivalent of triethylamine. The 2-O-acyl-3-O-(1-acyloxyalkyl) vitamin C 5,6-acetonides are obtained in moderate yields.
- Prybylski, John,Thiele, Nikki A.,Sloan, Kenneth B.
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supporting information
p. 1619 - 1621
(2018/03/27)
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- FLUORINATED CYCLIC DINUCLEOTIDES FOR CYTOKINE INDUCTION
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The invention concerns a cyclic dinucleotide compound of Formula (I) wherein X1 is H or F; X2 is H or F; at least one among X1 and X2 is a fluorine atom; Z is OH, OR1, SH or SR1, wherein: R1 is Na or NH4, or R1 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl; B1 and B2 are bases chosen from Adenine, Hypoxanthine or Guanine, and B1 is a different base than B2 and a pharmaceutically acceptable salt thereof. The invention also concerns pharmaceutical compositions comprising said cyclic dinucleotide, as well as their use in the treatment of a bacterial infection, a viral infection or a cancer.
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Page/Page column 39
(2016/07/05)
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- Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (pkan) and methods for the synthesis of such compounds
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The invention relates to (S)-acyl-4'-phosphopantetheine derivatives, methods of their synthesis, and related medical uses of such compounds. Preferred medical uses relate to the treatment ofneurodegenerative diseases, such as PKAN.
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Paragraph 0089
(2015/05/19)
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- STABLE PANTETHEINE DERIVATIVES FOR THE TREATMENT OF PANTOTHENATE KINASE ASSOCIATED NEURODEGENERATION (PKAN) AND METHODS FOR THE SYNTHESIS OF SUCH COMPOUNDS
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The invention relates to (S)-acyl-4'-phosphopantetheine derivatives, methods of their synthesis, and related medical uses of such compounds. Preferred medical uses relate to the treatment of neurodegenerative diseases, such as PKAN.
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Page/Page column 18; 19
(2015/05/19)
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- Synthesis and Anti-herpetic Activity of Phosphoramidate ProTides
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Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) that contain L-alanine or pivaloyloxymethyl iminodiacetate (IDA-POM) exhibit anti-HSV-1 and anti-VZV activity in cell cultures, but they largely lost antiviral potency against TK-deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7-deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs. Copyright
- Maiti, Munmun,Persoons, Leentje,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,Herdewijn, Piet
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p. 985 - 993
(2013/07/27)
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- Birch Reductive Alkylation of Methyl m-(Hydroxymethyl)benzoate Derivatives and the Behavior of o- and p-(Hydroxymethyl)benzoates under Reductive Alkylation Conditions
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Birch reductive alkylation of methyl m-(hydroxymethyl)benzoate derivatives, using lithium in ammonia-tetrahydrofuran in the presence of tertbutyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of o- and p-(hydroxymethyl)benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions.
- Fretz, Samuel J.,Hadad, Christopher M.,Hart, David J.,Vyas, Shubham,Yang, Dexi
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supporting information
p. 83 - 92
(2013/03/29)
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- SUBSTITUTED METHYLFORMYL REAGENTS AND METHOD OF USING SAME TO MODIFY PHYSICOCHEMICAL AND/OR PHARMACOKINETIC PROPERTIES OF COMPOUNDS
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The present invention relates to the synthesis and application of novel chiral/ achiral substituted methyl formyl reagents to modify pharmaceutical agents and/or biologically active substances to modify the physicochemical, biological and/or pharmacokinetic properties of the resulting compounds from the unmodified original agent.
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Page/Page column 93-94
(2012/10/18)
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- CYCLIC NUCLEOTIDE ANALOGS
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Disclosed herein are cyclic nucleotide analogs, methods of synthesizing cyclic nucleotide analogs and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with cyclic nucleotide analogs.
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Page/Page column 64
(2012/07/13)
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- Synthesis of 3',5'-cyclic phosphate and thiophosphate esters of 2'-C-methyl ribonucleosides
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2'-C-Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5'-triphosphates, dosing as appropriately protected 5'-phosphates or 5'-phosphorothioates appears attractive. For this purpose, four potential pro-drugs of 2'-C-methylguanosine, i.e., 3',5'-cyclic phosphorothioate of 2'-C-methylguanosine and 2'-C,O6-dimethylguanosine, 1 and 2, respectively, the S-[(pivaloyloxy)methyl] ester of 2'-C,O6- dimethylguanosine 3',5'-cyclic phosphorothioate and the O-methyl ester of 2'-C,O6-dimethylguanosine 3',5'-cyclic phosphate, 3 and 4, respectively, have been prepared.
- Leisvuori, Anna,Ahmed, Zafar,Ora, Mikko,Beigelman, Leonid,Blatt, Lawrence,Loennberg, Harri
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p. 1512 - 1520
(2012/11/07)
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- Synthesis and biological evaluation of orally active prodrugs of indomethacin
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Synthesis and biological evaluation of orally active prodrugs (1a-d) of indomethacin are described. Prodrugs 1a-c showed a similar degree of anti-inflammatory activity, and prodrug 1d was found to be less potent than the parent drug indomethacin (1). Ulcer index (UI) data indicated that 1a (UI = 19), 1c (UI = 0), and 1d (UI = 0) were substantially less ulcerogenic and 1b (UI = 62) was more ulcerogenic than parent drug 1 (UI = 47). These prodrugs demonstrated good stability at acidic and basic pH and found to be more lipophilic than parent drug compound 1, indicated by partition coefficients measured in octanol-buffer system at pH 7.4 and 3.0. On the basis of in vivo studies, 1a and 1c compounds were selected for metabolic stability in rat liver microsome (RLM) and rat plasma (RP), and both were found to be enzymatically labile. Prodrugs 1a and 1c emerged as potent anti-inflammatory agents with a lesser potential for ulcer than the parent drug indomethacin.
- Bandgar, Babasaheb P.,Sarangdhar, Rajendra Janardan,Viswakarma, Santosh,Ahamed, Fakrudeen Ali
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experimental part
p. 1191 - 1201
(2011/04/26)
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- Synthesis, characterization, and biological evaluation of novel diclofenac prodrugs
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Diclofenac ester pro drugs (4, 5, 6) were synthesized and evaluated in vitro and in vivo for their potential use for oral delivery, with the aim of obtaining enzymatically labile and less ulceration drugs than the parent drug diclofenac sodium (1a). Prodrugs 4, 5, 6 were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium. Prodrugs 4, 5, 6 rapidly underwent enzymatic hydrolysis to release the parent drug diclofenac in 30-60 min in rat liver microsomes (RLM) and rat plasma (RP). Prodrugs were found to be more lipophilic when the partition coefficient was measured in 1-octanol and buffer system at pH 7.4 and 3.0. Diclofenac prodrugs 4, 5, 6 were found to be crystalline in nature (analyzed by PXRD). Prodrug 4 was found to be a superior candidate for the treatment of chronic inflammatory diseases.
- Bandgar, Babasaheb P.,Sarangdhar, Rajendra Janardan,Ahamed, Fakrudeen Ali,Viswakarma, Santosh
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experimental part
p. 1202 - 1210
(2011/04/26)
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- CARBACEPHEM BETA-LACTAM ANTIBIOTICS
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Carbacephem β-lactam antibiotics having structure (I) are disclosed, including stereoisomers, pharmaceutically acceptable salts, esters and prodrugs thereof, wherein Ar2, X, R1 and R2 are as defined herein. The compounds are useful for the treatment of bacterial infections, in particular those caused by methicillin-resistant Staphylococcus spp.
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Page/Page column 66
(2010/04/06)
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- CARBACEPHEM β-LACTAM ANTIBIOTICS
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Carbacephem -lactam antibiotics having structure (I) are disclosed, including stereoisomers, pharmaceutically acceptable salts, esters and prodrugs thereof, wherein Ar1, Ar2, R1 and R2 are as defined herein. The compounds are useful for the treatment of bacterial infections, in particular those caused by methicillin-resistant Staphylococcus spp.
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Page/Page column 88-89
(2010/04/06)
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- CARBACEPHEM BETA-LACTAM ANTIBIOTICS
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Carbacephem β-lactam antibiotics having chemical structures (I) and (II) are disclosed: including stereoisomers, pharmaceutically acceptable salts, esters and prodrugs thereof, wherein Ar2, R1, R2 and R6 are as defined herein. The compounds are useful for the treatment of bacterial infections, in particular those caused by methicillin-resistant Staphylococcus spp.
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Page/Page column 62
(2010/11/05)
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- Orally bioavailable anti-HBV dinucleotide acyloxyalkyl prodrugs
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The acyloxyalkyl derivatives of a model anti-HBV dinucleotide were synthesized and evaluated as orally bioavailable prodrugs. Our studies have led to the identification of the first orally bioavailable dinucleotide prodrugs for further therapeutic development against the hepatitis B virus (HBV).
- Coughlin, John E.,Padmanabhan, Seetharamaiyer,Zhang, Guangrong,Kirk, Cassandra J.,Govardhan, Chandrika P.,Korba, Brent E.,O'Loughlin, Kathleen,Green, Carol E.,Mirsalis, Jon,Morrey, John D.,Iyer, Radhakrishnan P.
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experimental part
p. 1783 - 1786
(2010/08/06)
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- Design, synthesis, and cholesterol-lowering efficacy for prodrugs of berberrubine
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In order to enhance oral bioavailability of berberine (BBR) for its cholesterol-lowering efficacy in vivo, a series of ester or ether prodrugs of berberrubine (M1), which is an active metabolite of BBR after first-pass metabolism, were designed, semi-synthesized, and evaluated. Among these M1 prodrugs, compound 5g possessing palmitate at the 9-position showed a moderate Log P value and esterase hydrolysis rate for releasing M1 in blood. Its cholesterol-lowering efficacy in vivo was evaluated in hyperlipidemic SD rats. Compound 5g (100 mg/kg/d) reduced blood CHO and LDL-c by 35.8% and 45.5%, respectively, similar to that by BBR. It also exhibited a good safety in rats with no side-effect on liver and kidney function. Therefore, the design of M1 prodrug appears to be an effective strategy to improve pharmacokinetic feature of BBR for its lipid-lowering efficacy in vivo.
- Li, Ying-Hong,Li, Yi,Yang, Peng,Kong, Wei-Jia,You, Xue-Fu,Ren, Gang,Deng, Hong-Bin,Wang, Yue-Ming,Wang, Yan-Xiang,Jiang, Jian-Dong,Song, Dan-Qing
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experimental part
p. 6422 - 6428
(2010/10/04)
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- The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury
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Puerarin is a naturally occurring isoflavone and is frequently used for the treatment of cardiovascular symptoms in China. By the structural modification of the puerarin molecule at different positions, seven new puerarin derivatives were obtained, and their cardioprotective activities (in vitro and in vivo) were respectively evaluated. The finding that the activities of 3 and 8 markedly exceeded puerarin suggested that the acylated modification of phenolic hydroxyl at C-7 in the puerarin molecule may improve the cardioprotective activity, which will be an important reference for further structural optimization.
- Feng, Zhi-Qiang,Wang, Ying-Yu,Guo, Zong-Ru,Chu, Feng-Ming,Sun, Piao-Yang
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experimental part
p. 843 - 850
(2010/12/25)
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- 2-ARYLMETHYLAZETIDINE-CARBAPENEM-3-CARBOXYLIC ACID ESTER DERIVATIVE OR ITS SALT, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention provides a 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative or its pharmaceutically acceptable salt, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives or their pharmaceutically acceptable salts show high oral absorption rate, and thus can be orally administered. The active metabolites thereof have a broad spectrum of antibacterial activities against Gram-positive and Gram-negative bacteria and excellent antibacterial activities against methicillin-resistant Staphylococcus aurus (MRSA) and quinolone-resistant strains (QRS). In particular, the acid addition salts of the 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivatives are obtained in crystalline forms having excellent stability.
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Page/Page column 18
(2009/06/27)
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- GABA ANALOGS, COMPOSITIONS, AND METHODS FOR MANUFACTURING THEREOF
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The invention provides novel compounds of Formula (I), pharmaceutical compositions and methods of synthesis thereof.
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Page/Page column 20
(2009/10/22)
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- GABA ANALOGS, COMPOSITIONS AND METHODS FOR MANUFACTURING THEREOF
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The invention provides novel compounds of Formula (I), pharmaceutical compositions and methods of synthesis thereof.
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Page/Page column 7-8
(2008/12/05)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC
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The present invention provides a process for the preparation of the compound of formula (I) and its salt and esters. More particularly, this present invention relates to an improved process for the preparation Cefcapene of formula (I) and its salt and esters.
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Page/Page column 12-13
(2009/01/23)
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- DEPLETION OF ISOMER IN CEPHALOSPORIN ANTIBIOTIC
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The present invention relates to the process for the depletion of E isomer of Cefditoren sodium of formula (I).
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Page/Page column 6
(2008/06/13)
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- Second-generation cycloSal-d4TMP pronucleotides bearing esterase-cleavable sites - The "trapping" concept
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An extension of the cycloSal-pronucleotide approach is presented. Attachment of an enzyme-cleavable ester/acylal group to the cycloSal-d4TMP triesters should allow these compounds to be trapped intracellularly after cleavage. The ester/acylal groups were introduced in the 3- or 5-position of the cycloSal ring system, and surprising differences were observed in hydrolysis studies in CEM cell extracts with respect to the ester/acylal moiety. While acetyl and levulinyl esters were readily cleaved, alkyl esters of cycloSal-d4TMP acids proved to be resistant to enzymatic cleavage. In contrast, AM-, POM- and POC-acylals were rapidly cleaved in the extracts, leading to cycloSal-d4TMP acids. The antiviral activity of the compounds against HIV is also presented. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Meier, Chris,Ducho, Christian,Jessen, Henning,Vukadinovic-Tenter, Dalibor,Balzarini, Jan
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p. 197 - 206
(2007/10/03)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CEFDITOREN
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The present invention relates to an improved process for the preparation of Cefditoren of formula (I), the said process comprising the steps of: i) converting the compound of formula (II) to a compound of the formula (III) using TPP and sodium iodide in the presence of THF, water, and base; ii) reacting the compound of formula (III) with 4-methyl-5-formyl-thiazole to produce a compound of formula (IV); iii) deesterifying the compound of the formula (IV) to yield compound of formula (V); iv) converting the compound of formula (V) to compound of formula (VI) in the presence of a base and solvent; v) converting the compound of formula (VI) into compound of formula (VII) by enzymatic hydrolysis; and vi) reacting compound of formula (VII) with compound of formula (VIII) in the presence of solvent and base to produce compound of formula (I).
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- COMPOSITION FOR LOWERING BLOOD-SUGAR LEVEL
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The present invention provides compositions, which have an action to lower blood sugar levels in subjects in a hyperglycemic state based on a mechanism that is different from conventional drugs to treat diabetes, and which are used for lowering the blood sugar levels of the subjects. The present invention also provides compositions to prevent or treat diseases caused by hyperglycemia, specifically, diabetes and the complications of diabetes, based on the action above. The invention further provides a method to lower blood sugar levels of subjects in a hyperglycemic state, and a method to prevent or threat diseases caused by hyperglycemia, using a hypoglycemic action based on the novel mechanism of action of the composition. The present invention also provides a method to screen the active ingredient of the above compositions. The present invention provides novel imidazole compounds represented by formula (1), which has an action of lowering the blood sugar level of a subject in a hyperglycemic state, and is useful as an active ingredient of a hypoglycemic composition, or an active ingredient of a composition that can be used for preventing or treating disorders caused by hyperglycemia, specifically diabetes and complications of diabetes.
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Page/Page column 54-55
(2010/02/10)
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- Nucleotide mimics and their prodrugs
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The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.
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- Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs
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Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that is used as an adjunct to L-dopa therapy in the treatment of Parkinson's disease. The bioavailability of orally administered entacapone is, however, relatively low (29-46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in-vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 while maintaining an aqueous solubility equal to entacapone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0% and 10.4%, respectively).
- Leppaenen,Savolainen,Nevalainen,Forsberg,Huuskonen,Taipale,Gynther,Maennistoe,Jaervinen
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p. 1489 - 1498
(2007/10/03)
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- Pivalase catalytic antibodies: Towards abzymatic activation of prodrugs
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Screening of monoclonal-an-tibody libraries generated against the tert-butyl phosphonate hapten 2 and the chloromethyl phosphonate hapten 3 with pivaloyloxymethyl-umbelliferone 1 as a fluorogenic substrate led to the isolation of eleven catalytic antibodies with rate accelerations around kcat/kuncat=103. The antibodies are not inhibited by the product and accept different acyloxymethyl derivatives of acidic phenols as substrates. The highest activity was found for the bulky, chemically less-reactive pivaloyloxymethyl group; there is no activity with acetoxymethyl or acetyl esters. This difference might reflect the preference of the immune system for hydrophobic interactions in binding and catalysis. Pivalase catalytic antibodies might be useful for activating orally available pivaloyloxymethyl prodrugs.
- Bensel, Nicolas,Reymond, Martine T.,Reymond, Jean-Louis
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p. 4604 - 4612
(2007/10/03)
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- Prodrugs of CL316243: A selective β3-adrenergic receptor agonist for treating obesity and diabetes
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CL316243 is a highly selective and potent β3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.
- Sum,Gilbert,Venkatesan,Lim,Wong,O'Dell,Francisco,Chen,Grosu,Baker,Ellingboe,Malamas,Gunawan,Primeau,Largis,Steiner
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p. 1921 - 1926
(2007/10/03)
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- Synthesis and biological activity of bis(pivaloyloxymethyl) ester of 2'- azido-2'-deoxyuridine 5'-monophosphate
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Bis(pivaloyloxymethyl) ester of 2'-azido-2'-deoxyuridine 5'- monophosphate was prepared as a prodrug to generate 2'-azido-2'-deoxyuridine 5'-diphosphate inside the cell. A synthetic route utilizing stannyl phosphate was adopted in the preparation. The prodrug was evaluated for cell growth inhibition against a variety of tumor cell lines along with 2'-azido-2'- deoxyuridine and 2'-azido-2'-deoxycytidine.
- Kang, Shin Hong,Sinhababu,Cho, Moo J.
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p. 1089 - 1098
(2007/10/03)
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- Heteroaryl analogues of AMPA. 2. Synthesis, absolute stereochemistry, photochemistry, and structure-activity relationships
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We have previously shown that (S)-2-amino-3-(3-hydroxy-5-phenyl-4- isoxazolyl)propionic acid [(S)-APPA, 2] is a weak agonist at (RS)-2-amino-3- (3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors, specifically activated by (S)-AMPA (1), whereas (S)-2-amino-3-[3-hydroxy-5- (2-pyridyl)-4-isoxazolyl]propionic acid [(S)-2-Py-AMPA, 5] and (RS)-2-amino- 3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid (4) are potent AMPA agonists. On the other hand, (R)-APPA (3) and (R)-2-Py-AMPA (6) have been shown to be weak AMPA antagonists. We now report the synthesis of 2-Py-AMPA (7a) and the isomeric compounds 3-Py-AMPA (7b) and 4-Py-AMPA (7c) as well as the 7a analogues, (RS)-2-amino-3-[3-hydroxy-5-(6-methyl-2-pyridyl)-4- isoxazolyl]propionic acid (7d) and (RS)-2-amino-3-[3-hydroxy-5-(2- quinolinyl)-4-isoxazolyl]propionic acid (7e). Furthermore, (RS)-2-amino-3- [3-hydroxy-5-(2-furyl)-4-isoxazolyl]-propionic acid (2-Fu-AMPA, 7f) and its 5-bromo-2-furyl derivative (7g) were synthesized, and (S)-2-Fu-AMPA (8) and (R)-2-Fu-AMPA (9) were prepared by semipreparative chiral HPLC resolution of 7f. HPLC analyses and circular dichroism spectroscopy indicated the absolute stereochemistry of 8 and 9 to be S and R, respectively. This was confirmed by an X-ray crystallographic analysis of 9·HCl. In receptor binding (IC50 values) and rat cortical wedge electrophysiological (EC50 values) studies, 7c (IC50 = 5.5 ± 0.6 μM; EC50 = 96 ± 5 μM) was shown to be markedly weaker than 7a (IC50 = 0.57 ± 0.16 μM; EC50 = 7.4 ± 0.2 μM) as an AMPA agonist, whereas 7b,d,e were inactive. The very potent AMPA agonist effect of 7f (IC50 = 0.15 ± 0.03 μM; EC50 = 1.7 ± 0.2 μM) was shown to reside exclusively in 8 (IC50 = 0.11 ± 0.01 μM; EC50 = 0.71 ± 0.11 μM), whereas 9 did not interact significantly with AMPA receptors, either as an agonist or as an antagonist. 8 was shown to be photochemically active and is a potential photoaffinity label for the recognition site of the AMPA receptors. Compound 7g turned out to be a very weak AMPA receptor agonist (IC50 = 12 ± 0.7 μM; EC50 = 160 ± 15 μM). None of these new compounds showed detectable effects at N-methyl-D-aspartic acid (NMDA) or kainic acid receptors in vitro. The present studies have emphasized that the presence of a heteroatom in the 2-position of the heteroaryl 5-substituent greatly facilitates AMPA receptor agonist activity.
- Falch, Erik,Brehm, Lotte,Mikkelsen, Ivan,Johansen, Tommy N.,Skj?rb?k, Niels,Nielsen, Birgitte,Stensb?l, Tine B.,Ebert, Bjarke,Krogsgaard-Larsen, Povl
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p. 2513 - 2523
(2007/10/03)
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- Inhibitors of farnesyl protein transferase
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Inhibition of farnesyl transferase, which is an enzyme involved in ras oncogene expression, and inhibition of cholesterol biosynthesis, are effected by compounds of the formula STR1 their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs, and solvates, wherein: x is --ONR1 C(O)--, --N(OR1)C(O)--, --NR1 C(O)--, --C(O)NR1 --, --NR1 S(O2)--, --C(O)O--, --OC(O)--, --C(O)--, --O--, --NR1 -- or --(S)q --; Y is --CO2 R2, --SO3 R2 or --P(O) (OR2) (R3); R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenylene or aryl; R3 is --(O)t R4 ; R1, R2 and R4 are each independently hydrogen, alkyl, aryl or aralkyl; m and n are each independently 0 or an integer from 1 to 5; p and t are each independently 0 or 1; and q is an integer from 1 to 2.
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- Methods of using α-phosphonosulfonate squalene synthetase inhibitors including the treatment of atherosclerosis and hypercholesterolemia
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α-Phosphonosulfonate compounds are provided which inhibit the enzyme squalene synthetase and thereby inhibit cholesterol biosynthesis. These compounds have the formula STR1 wherein R2 is OR5 or R5a ; R3 and R5 are independently H, alkyl, arylalkyl, aryl or cycloalkyl; R5a is H, alkyl, arylalkyl or aryl; R4 is H, alkyl, aryl, arylalkyl, or cycloalkyl;, Z is H, halogen, lower alkyl or lower alkenyl; and R1 is a lipophilic group which contains at least 7 carbons and is alkyl, alkenyl, alkynyl, mixed alkenyl-alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl; as further defined above; including pharmaceutically acceptable salts and or prodrug esters of the phosphonic (phosphinic) and/or sulfonic acids.
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- Synthesis of iodoalkylacylates and their use in the preparation of S-alkyl phosphorothiolates
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Synthesis of iodoalkylacylates 3a-f and use of 3c in the preparation of an oligonucleoside phosphorothiate prodrug analog 5 is described.
- Iyer,Yu,Ho,Agrawal
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p. 2739 - 2749
(2007/10/02)
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- Chromium(II)-Mediated Stereodivergent Additions of Allylic Phosphates and Halides to Aldehydes
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The addition of γ-disubstituted allylchromium(III) reagents to aldehydes proceeds in a stereodivergent manner, in contrast to the case of γ-monosubstituted allylchromium(III) species.The method allows the preparation of a variety of homoallylic alcohols bearing a quaternary center of defined relative configuration in the α-position.The preparation of both stereomeric homoallylic alcohols 13 is possible by using either of the two (E)- or (Z)-allylic precursors.The reaction has been extended to a γ-monosubstituted β-(trimethylsilyl)allylic system.The intermediate allylic chromium(III) reagents can be conveniently prepared from the corresponding phosphates (or chlorides) in DMPU or THF in the presence of catalytic amounts of LiI.
- Nowotny, Stefan,Tucker, Charles E.,Jubert, Carole,Knochel, Paul
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p. 2762 - 2772
(2007/10/02)
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- 4-thia-1-aza-bicyclo[4,2,0]oct-2-ene derivatives
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A compound selected from the group consisting of a compound of the formula STR1 wherein R is selected from the group consisting of STR2 and Rb --NH--, Ra is an organic radical, Ri and Rj are individually selected from the group consisting of hydrogen, aliphatic hydrocarbon, aromatic hydrocarbon and heterocycle or taken together with the nitrogen atom to which they are attached form an optionally substituted ring, Rb is selected from the group consisting of carbocyclic aryl and heterocyclic aryl, both optionally substituted, R1A is selected from the group consisting of STR3 RA ' and RB ' are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, ZA is selected from the group consisting of a simple bond, --O-- and optionally oxidize sulfur, R3A is selected from the group consisting of optionally substituted carbocyclic aryl and heterocyclic aryl, optionally substitute quaternary ammonium, acetyl, carbamoyl, alkoxycarbonyl, alkyl and haloalkyl of 1 to 4 carbon atoms, --CN and azido, R4 is selected from the group consisting of hydrogen and methoxy, A is selected from the group consisting of hydrogen, alkali metal, alkaline earth metal, magnesium, --NH4, an organic amine and esterified carboxy or --COOA is --COO?, n2 is an integer from 0 to 2 and their non-toxic, pharmaceutical acceptable acid addition salts having excellent antibiotic activity.
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- Synthesis and antitumor evaluation of bis[(pivaloyloxy)methyl]2'-deoxy-5- fluorouridine 5'-monophosphate (FdUMP): A strategy to introduce nucleotides into cells
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The bis[(pivaloyloxy)methyl] [PIV2] derivative of 2'-deoxy-5- fluorouridine 5'-monophosphate (FdUMP) was synthesized as a potential membrane-permeable prodrug of FdUMP. The compound was designed to enter cells by passive diffusion and to revert to FdUMP after removal of the PIV groups by hydrolytic enzymes. The most convenient preparation of PIV2FdUMP was by condensation of 2'-deoxy-5-fluorouridine (FUdR) with PIV2 phosphate in the presence of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobo reagent). PIV2FdUMP was stable in the pH range 1.0-4.0 (t( 1/2 ) > 100 h). It was also fairly stable at pH 7.4 (t( 1/2 ) = 40.2 h). In 0.05 M NaOH solution, however, it was rapidly degraded (t( 1/2 ) 2FdUMP was converted quantitatively to the mono-[(pivaloyloxy)methyl] [PIV1] analogue PIV1FdUMP. After a 24 h incubation, only trace amounts of FdUMP (1-3%) were observed, indicating that PIV1FdUMP is a poor substrate for carboxylate esterases. In mouse plasma, PIV2FdUMP was rapidly metabolized, first to PIV1FdUMP and then to FdUMP. With continued incubation, FUdR was formed, presumably due to further catabolism of FdUMP by plasma phosphatases or 5'-nucleotidases. Since PIV1FdUMP is a poor substrate for carboxylate esterase, the cleavage of the second PIV group is most likely mediated by plasma phosphodiesterases. The rate of degradation of PIV2FdUMP in the presence of acid and alkaline phosphatase, 5'-nucleotidase, or spleen phosphodiesterase was the same as that in buffer controls, indicating that the compound is not a substrate for these nucleotide catabolizing enzymes. The concentration of PIV2FdUMP and its 3'-O-acetyl ester (PIV2 3'-O-Ac-FdUMP) required to inhibit the growth of Chinese hamster ovary (CHO) cells in vitro to less than 50 cells per colony was 5 x 10-6 M, the same as that required for 5-fluorouracil (FU). Both nucleotide prodrugs showed the same growth-inhibitory potency against a mutant CHO cell line that was 20-fold resistant to FU (CHO/FU). Administered intraperitoneally at optimal dosage for 5 consecutive days, PIV2FdUMP and PIV2 3'-O-Ac-FdUMP were as effective as FU at prolonging the life spans of mice bearing intraperitoneally implanted P388 leukemia. Both prodrugs retained full therapeutic activity against a P388 subline resistant to FU. Collectively, these data indicate that PIV2FdUMP and PIV2 3'-O-Ac-FdUMP are effective membrane-permeable prodrugs of FdUMP.
- Farquhar,Khan,Srivastva,Saunders
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p. 3902 - 3909
(2007/10/02)
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- Synthesis, hydrolytic behavior, and anti-HIV activity of selected acyloxyalkyl esters of trisodium phosphonoformate (foscarnet sodium)
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The synthesis and anti-HIV activity of selected (acyloxy)-alkyl esters of trisodium phosphonoformate (foscarnet sodium) are described. The conversion of bis(trimethylsilyl) (alkoxycarbonyl)phosphonates 11a-d to the corresponding disilver salts 12a-d and their subsequent reaction with iodoalkyl acrylates 4a-c gave the desired bis(acyloxyalkyl) phosphonates 6- 9(a-c). Of the analogs tested, only the dichlorophenyl analog 9a showed a dose-dependent inhibition of HIV activity in H9 cells. Using 31P-NMR, bioreversibility has been investigated in an attempt to rationalize these results.
- Iyer,Boal,Phillips,Thakker,Egan
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p. 1269 - 1273
(2007/10/02)
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- α-phosphonocarboxylate squalene synthetase inhibitors
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α- Phosphonocarboxylate compounds are provided which inhibit the enzyme squalene synthetase and thereby inhibit cholesterol biosynthesis. These compounds have the formula STR1 wherein R1 is a lipophilic group which contains at least 7 carbons and is substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted aryl; Z is H, halogen, hydroxy, hydroxyalkyl or lower alkyl; R2 and R3 are independently H, metal ion or other pharmaceutically acceptable cation, or a prodrug ester; R4 is H, metal ion or other pharmaceutically acceptable cation, lower alkyl, lower alkenyl, arylalkyl, aryl or a prodrug ester.
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- Targeted drug delivery via phosphonate derivatives
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The invention provides compounds of the formula STR1 or a pharmaceutically acceptable salt thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the STR2 moiety; R1 is C1 -C8 alkyl, C6 -C10 aryl or C7 -C12 aralkyl; R2 is hydrogen, C1 -C8 alkyl, C6 -C10 aryl, C4 -C9 heteroaryl, C3 -C7 cycloalkyl, C3 -C7 cycloheteroalkyl or C7 -C12 aralkyl; and R3 is selected from the group consisting of C1 -C8 alkyl; C2 -C8 alkenyl having one or two double bonds; (C3 -C7 cycloalkyl)--Cr H2r --wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C1 -C4 alkyl substituents on the ring portion; (C6 -C10 aryloxy)C1 -C8 alkyl; 2--, 3-- or 4-- pyridyl; and phenyl-Cr H2r -- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms. The compounds are adapted for targeted drug delivery, especially to the brain.
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