- Synthesis of substituted oxazoles from N-benzyl propargyl amines and acid chlorides
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The reaction between N-benzylpropargylamines and acid chlorides at elevated temperatures provides efficient, direct access to a variety of di- and tri-substituted oxazoles. The versatility of this reaction is explored and 21 examples are demonstrated. The usefulness of the methodology is showcased through the short and efficient formal syntheses of medicinally relevant drugs aleglitazar and romazarit. The reaction between N-benzylpropargylamines and acid chlorides at elevated temperatures gives oxazoles in up to 99 % yield. Twenty-one examples are demonstrated varying the substitution at all positions of the heterocycle. Copyright
- Wachenfeldt, Henrik V.,Paulsen, Filip,Sundin, Anders,Strand, Daniel
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p. 4578 - 4585
(2013/07/26)
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- Synthesis and antimicrobial evaluation of 3-methanone-6-substituted- benzofuran derivatives
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Seventeen benzofuran derivatives were synthesized and screened for their antibacterial activities against Escherichia coli, Staphylococcus aureus, Methicillin-resistant S. aureus, Bacillus subtilis, and Pseudomonas aeruginosa. Seven of them have showed excellent antibacterial activities compared to the positive controls (Cefotaxime and Sodium Penicillin). The substitutions at C-6 and C-3 positions of these derivatives were found to greatly impact on the antibacterial activity and strains specificity, respectively. Specifically, compounds bearing a hydroxyl group at C-6 (5a, 5b, 5c and 12) offered excellent antibacterial activities against all five above-mentioned strains (MIC 80 = 0.78-12.5 ug/mL), and those with imine (15) and (3, 4, 5-trimethoxyphenyl) methanone (7e), respectively, at C-3 position showed selective activity against S. aureus among five tested strains with great MIC80 values (3.12-12.5 ug/mL).
- Liu, Jingbao,Jiang, Faqin,Jiang, Xizhen,Zhang, Wei,Liu, Jingjing,Liu, Wenlu,Fu, Lei
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p. 879 - 886
(2012/09/10)
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- Design and synthesis of Oxime ethers of β-oxo-γ-phenylbutanoic acids as PPAR a and -γ dual agonists
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Oxime ethers of p-oxo-y-phenylbutanoic acids were prepared to develop more effective PPAR a and y dual agonists. Among them, compound 11k exhibited potent in vitro activities with EC50 of 2.5 nM and 3.3 nM in PPAR a and y, respectively. It showed better g
- Han, Hee Oon,Koh, Jong Sung,Kim, Seung Hae,Park, Ok Ku,Kim, Kyoung-Hee,Jeon, Sang Kweon,Hur, Gwong-Cheung,Yim, Hyeon Joo,Kim, Geun Tae
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scheme or table
p. 1979 - 1982
(2012/08/14)
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- Design, synthesis and antimicrobial activity of chiral 2-(substituted- hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acid derivatives
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Chiral 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acid derivatives were synthesized and their antibacterial activities were evaluated against fungus, Gram-negative and Gram-positive bacteria. In general, these compounds showed in vitro acti
- Zhang, Wei,Liu, Wenlu,Jiang, Xizhen,Jiang, Faqin,Zhuang, Hao,Fu, Lei
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p. 3639 - 3650
(2011/11/05)
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- (S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl)propanoic acid compounds: Synthesis and biological evaluation of dual PPARα/γ agonists
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A series of novel, potent PPARα/γ dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC50 value of 0.012 ± 0.002 and 0.032 ± 0.01 μM, respectively, for hPPARα and hPPARγ in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice.
- Zhou, Xinbo,Chen, Wei,Xu, Cheng,Fan, Shiyong,Xie, Yunde,Zhong, Wu,Wang, Lili,Li, Song
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scheme or table
p. 2605 - 2608
(2010/06/17)
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- Aleglitazar, a new, potent, and balanced dual PPARα/γ agonist for the treatment of type II diabetes
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Design, synthesis, and SAR of novel α-alkoxy-β-arylpropionic acids as potent and balanced PPARαγ coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.
- Benardeau, Agnes,Benz, Joerg,Binggeli, Alfred,Blum, Denise,Boehringer, Markus,Grether, Uwe,Hilpert, Hans,Kuhn, Bernd,Maerki, Hans Peter,Meyer, Markus,Puentener, Kurt,Raab, Susanne,Ruf, Armin,Schlatter, Daniel,Mohr, Peter
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scheme or table
p. 2468 - 2473
(2010/03/24)
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- Process development and scale-up of AG035029
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A practical process for the synthesis of PPARγ agonist AG035029 was developed which involved six steps along the longest linear path. The process development utilized automated technology and computational chemistry extensively to accelerate the speed of
- Saenz, James,Mitchell, Mark,Bahmanyar, Sami,Stankovic, Nebojsa,Perry, Michael,Craig-Woods, Bridgette,Kline, Billie,Yu, Shu,Albizati, Kim
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- Design and synthesis of oxime ethers of α-acyl-β-phenylpropanoic acids as PPAR dual agonists
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Oxime ethers of α-acyl-β-phenylpropanoic acids were prepared to apply as PPARα and γ dual agonists. Among them, compound 11l proved to exhibit potent in vitro activities with EC50 of 19 and 13 nM in PPARα and γ, respectively. It showed better g
- Oon Han, Hee,Hae Kim, Seung,Kim, Kyoung-Hee,Hur, Gwong-Cheung,Joo Yim, Hyeon,Chung, Hee-Kyung,Ho Woo, Sung,Dong Koo, Ki,Lee, Chang-Seok,Sung Koh, Jong,Tae Kim, Geun
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p. 937 - 941
(2007/10/03)
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- TYROSINE DERIVATIVES SUBSTITUTED BY N-PHENYLACRYLOYL AS AGONISTS OF HPPAR ALPHA AND HPPAR GAMA
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The present invention relates to a compound of formula I, racemates, optically active isomers, or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutical composition comprising the compound, the various radicals in the formula I are the same as defined in the claims. The present invention also relates to a process for preparing the compound of formula I and use of said compound in the preparation of a medicament for the treatment of hyperglycemia, dyslipidemia, type II diabetes mellitus including associated diabetic dyslipidemia
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Page/Page column 10
(2008/06/13)
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- Substitued A-Piperazingly Phenylpropionic Acid Derivatives As Hppar Alpha And/Or Hppar Gamma Agonists
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The present invention relates to a compound of formula I, racemates, optically active isomers, or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutical composition comprising the compound, the various radicals in the formula I are the same as defined in the claims. The present invention also relates to a process for preparing the compound of formula I and use of said compound in the preparation of a medicament for the treatment of hyperglycemia, dyslipidemia, type II diabetes mellitus including associated diabetic dyslipidemia
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Page/Page column 8
(2008/06/13)
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- Synthesis of 2,4,5-Trisubstituted Oxazoles
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2,4,5-Trisubstituted oxazoles were synthesized in good yields starting from α-methylene ketones by nitrosation, condensation with aldehydes and reduction with zinc in acetic acid at 40 deg C. (5-Methyl-2-phenyloxazol-4-yl)ethanol was prepared by reduction of ethyl (5-methyl-2-phenyloxazol-4-yl)acetate with LiAlH4.
- Cai, Xiao-hua,Yang, Hai-jun,Zhang, Guo-lin
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p. 1569 - 1571
(2007/10/03)
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- NOVEL COMPOUNDS AS AGONIST FOR PPAR GAMMA AND PPAR ALPHA, METHOD FOR PREPARATION OF THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
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The present invention relates to novel compounds accelerating the activity of Peroxisome proliferator-activated receptor gamma (PPARγ) and alpha (PPARα), processes of preparing the same, and pharmaceutical compositions containing the same as an active agent.
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Page/Page column 98
(2010/02/11)
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- Conversion of human-selective PPARα agonists to human/mouse dual agonists: A molecular modeling analysis
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To understand the species selectivity in a series of α-methyl- α-phenoxy carboxylic acid PPARα/γ dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARα. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARα leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARα agonist to a human and mouse dual agonist within the same platform.
- Wang, Minmin,Winneroski, Leonard L.,Ardecky, Robert J.,Babine, Robert E.,Brooks, Dawn A.,Etgen, Garret J.,Hutchison, Darrell R.,Kauffman, Raymond F.,Kunkel, Aaron,Mais, Dale E.,Montrose-Rafizadeh, Chahrzad,Ogilvie, Kathleen M.,Oldham, Brian A.,Peters, Mary K.,Rito, Christopher J.,Rungta, Deepa K.,Tripp, Allie E.,Wilson, Sarah B.,Xu, Yanping,Zink, Richard W.,McCarthy, James R.
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p. 6113 - 6116
(2007/10/03)
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- Process for producing isoxazolidinedione compound
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The present invention relates to a novel method for producing a compound of the formula [11]wherein R is an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group, which is useful as a therapeutic agent for diabetes. The method of the present invention is an industrially utilizable method that enables efficient production of the objective compound [11] from β-methyl L-aspartate via an important intermediate compound [6]wherein R is as defined above, at high yield.
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- Process for the preparation of thiazolidinedione derivatives
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The present invention is concerned with a novel process for the preparation of compounds of formula I comprising bromomethylation or chloromethylation of a compound of formula II and subsequent reaction with a compound of formula IV The compounds of formu
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- New azolidinediones as inhibitors of protein tyrosine phosphatase lb with antihyperglycemic properties
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Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPases may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were Potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12-0.3 μM. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.
- Malamas, Michael S.,Sredy, Janet,Gunawan, Iwan,Mihan, Brenda,Sawicki, Diane R.,Seestaller, Laura,Sullivan, Donald,Flam, Brenda R.
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p. 995 - 1010
(2007/10/03)
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- Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents
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Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKA(y) mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin- sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione 1.
- Shinkai, Hisashi,Onogi, Syoji,Tanaka, Masahiro,Shibata, Tsutomu,Iwao, Megumi,Wakitani, Korekiyo,Uchida, Itsuo
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p. 1927 - 1933
(2007/10/03)
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- Azole phenoxy hydroxyureas as selective and orally active inhibitors of 5- lipoxygenase
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Azole phenoxy hydroxyureas are a new class of 5-lipoxygenase (5-LO) inhibitors. Structure-activity relationship studies have demonstrated that electronegative substituents on the 2-phenyl portion of the oxazole tail increased the ex vivo potency of these
- Malamas,Carlson,Grimes,Howell,Glaser,Gunawan,Nelson,Kanzelberger,Shah,Hartman
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p. 237 - 245
(2007/10/03)
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- Studies on antidiabetic agents. 11. Novel thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents
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In the course of further chemical modification of the novel antidiabetic pioglitazone (AD-4833, U-72, 107), a series of 5-[4-(2- or 4- azolylalkoxy)benzyl- or -benzylidene]-2,4-thiazolidinediones was prepared and evaluated for hypoglycemic and hypolipidemic activities in insulin-resistant, genetically obese, and diabetic KKA(y) mice. Replacement of the 2-pyridyl moiety of pioglitazone by a 2- or 4-oxazolyl or a 2- or 4-thiazolyl moiety greatly enhanced in vivo potency. The corresponding 5-benzylidene-type compounds, in which a methine was used as a linker between the benzene ring and the thiazolidinedione ring, also had potent biological activity. Among the compounds synthesized, 5-[4-[2-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione (18) exhibited the most potent activity, more than 100 times that of pioglitazone. The synthesis and structure-activity relationships for this novel series of derivatives are detailed.
- Sohda,Mizuno,Momose,Ikeda,Fujita,Meguro
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p. 2617 - 2626
(2007/10/02)
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- Novel Thiazolidine-2,4-diones as Potent Euglycemic Agents
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A new series of thiazolidine-2,4-diones was obtained by replacing the ether function of englitazone with various functional groups, i.e., a ketone, alcohol, or olefin moiety.These compounds lower blood glucose levels in the genetically obese and insulin-r
- Hulin, Bernard,Clark, David A.,Goldstein, Steven W.,McDermott, Ruth E.,Dambek, Paul J.,et al.
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p. 1853 - 1864
(2007/10/02)
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- Thiazolidinedione derivatives, their production and use
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Thiazolidinedione derivatives of the general formula: STR1 [wherein R1 is hydrogen or a hydrocarbon residue or heterocyclic residue which may each be substituted; R2 is hydrogen or lower alkyl which may be substituted by hydroxyl group; X is an oxygen or sulfur atom; Z is a hydroxylated methylene or carbonyl; m is 0 or 1; n is an integer of 1 to 3; L and M represent independently a hydrogen atom or L and M combine with each other to cooperate jointly to form a linkage] and their salts, which are novel compounds, possess blood-glucose and blood-lipid lowering actions in mammals, and are of value as a therapeutic agent for diabetes and therapeutic agent for hyperlipemia.
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