- 1H-PYRAZOLO[3,4-D]PYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF PLATINUM-RESISTANT CANCER
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The invention relates to compounds of formula (I) and related compounds and their use in the treatment of cancer, especially platinum resistant cancer. The invention also provides a treatment comprising administration of a compound of formula (I) and a pl
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Page/Page column 48
(2021/06/26)
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- Extensive investigation of benzylic N-containing substituents on the pyrrolopyrimidine skeleton as Akt inhibitors with potent anticancer activity
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Continuous optimization of benzylic substituents on 1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-phenylethan-1-one structure as Akt inhibitors was described in this paper. Particularly, compounds 8 and 14g exhibited high enzymatic potency against all Akt isoforms and antiproliferative effects in mantle cell lymphoma cell lines, as well as favorable cytotoxicities in patient primary cancer cells. Low micromolar doses of both 8 and 14g dose-dependently induced cell apoptosis and G2/M cell cycle arrest, also suppressed the phosphorylation level of Akt downstream targets GSK3β and S6.
- Chen, Xin,Guo, Kaiwen,Liu, Yang,Ran, Fansheng,Zhang, Zhen,Zhao, Guisen
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- Discovery of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 protein-protein interaction inhibitors for inflammatory conditions
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Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor which regulates the constitutive and inducible transcription of a wide array of genes and confers protection against a variety of pathologies. Directly disrupting Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 protein-protein interaction (PPI) has been explored as a promising strategy to activate NRF2. We reported here the first identification of a series of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 inhibitors. Our efforts led to the potent small molecule KEAP1-NRF2 inhibitor, 20c, which exhibited a Kd of 24 nM to KEAP1 and an IC50 of 75 nM in disrupting KEAP1-NRF2 interaction. Subsequent biological studies provided consistent evidence across mouse macrophage cell-based and in vivo models that 20c induced NRF2 target gene expression and enhanced downstream antioxidant and anti-inflammatory activities. Our study not only demonstrated that small molecule KEAP1-NRF2 PPI inhibitors can be potential preventive and therapeutic agents for diseases and conditions involving oxidative stress and inflammation but also enriched the chemical diversity of the KEAP1-NRF2 inhibitors.
- Lu, Meng-Chen,Shao, Hong-Li,Liu, Tian,You, Qi-Dong,Jiang, Zheng-Yu
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supporting information
(2020/09/01)
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- Development of indazole mineralocorticoid receptor antagonists and investigation into their selective late-stage functionalization
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The derivatization of pharmaceuticals is a core activity in the discovery and development of new medicines. Late-stage functionalization via modern C–H functionalization chemistry has emerged as a powerful technique with which to diversify advanced pharma
- Liu, Kun,Kurukulasuriya, Ravi,Dykstra, Kevin,DiMichelle, Lisa,Liu, Jinchu,Vachal, Petr,Ogawa, Anthony,DeVita, Robert J.,Shen, Dong-Ming,Tan, Qiang,Chen, Yili,Gauthier, Don,Verras, Andreas,Crespo, Alejandro,Zamlynny, Beata,Madwed, Jeffrey,Hoek, Maarten,Bateman, Thomas,Yang, Yun-Fang,Houk,Krska, Shane,Cernak, Tim
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p. 1854 - 1858
(2019/05/21)
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- Diastereo- And Enantioselective Synthesis of Quaternary α-Amino Acid Precursors by Copper-Catalyzed Propargylation
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A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is described. This method allows the preparation of a series of non-proteinogenic quaternary α-amino acid precursors featuring two contiguous stereogenic centers and a terminal alkyne moiety in high yields with good to excellent diastereo- and enantioselectivities in most cases. The propargylated adducts were elaborated into a diverse set of quaternary α-amino acid derivatives.
- Zhu, Qiongqiong,Meng, Beibei,Gu, Congzheng,Xu, Ye,Chen, Jie,Lei, Chuanhu,Wu, Xiaoyu
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supporting information
p. 9985 - 9989
(2019/12/24)
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- New 4-aryl-1,3,2-oxathiazolylium-5-olates: Chemical synthesis and photochemical stability of a novel series of S-nitrosothiols
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S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide by-product. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2-Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S-nitrosothiols that lock the –SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound's overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if S-nitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts.
- Eilertsen, Monica,Allin, Steve M.,Pearson, Russell J.
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p. 1106 - 1110
(2018/02/28)
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- Substituted p-chlorophenyl acetylpiperazine-containing compound as well as preparation method and application thereof
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The application provides a substituted p-chlorophenyl acetylpiperazine-containing compound as well as a preparation method and application of the substituted p-chlorophenyl acetylpiperazine-containingcompound. The compound has the structure shown in the formula (I), and has better Akt1 inhibitory activity or growth inhibitory activity to MCL cell lines.
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- Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors
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We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.
- Usui, Yoshihiro,Uehara, Fumiaki,Hiki, Shinsuke,Watanabe, Kazutoshi,Tanaka, Hiroshi,Shouda, Aya,Yokoshima, Satoshi,Aritomo, Keiichi,Adachi, Takashi,Fukunaga, Kenji,Sunada, Shinji,Nabeno, Mika,Saito, Ken-Ichi,Eguchi, Jun-ichi,Yamagami, Keiji,Asano, Shouichi,Tanaka, Shinji,Yuki, Satoshi,Yoshii, Narihiko,Fujimura, Masatake,Horikawa, Takashi
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p. 3726 - 3732
(2017/07/27)
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- SUBSTITUTED INDOLINE DERIVATIVES AS DENGUE VIRAL REPLICATION INHIBITORS
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The present invention concerns substituted indoline compounds, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent
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Page/Page column 20
(2017/11/01)
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- Discovery of novel non-steroidal reverse indole mineralocorticoid receptor antagonists
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Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure-activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound tha
- Ogawa, Anthony K.,Bunte, Ellen Vande,Mal, Rudrajit,Lan, Ping,Sun, Zhongxiang,Crespo, Alejandro,Wiltsie, Judyann,Clemas, Joseph,Gibson, Jack,Contino, Lisa,Lisnock, Jeanmarie,Zhou, Gaochao,Garcia-Calvo, Margarita,Jochnowitz, Nina,Ma, Xiuying,Pan, Yi,Brown, Patricia,Zamlynny, Beata,Bateman, Thomas,Leung, Dennis,Xu, Ling,Tong, Xinchun,Liu, Kun,Crook, Martin,Sinclair, Peter
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p. 2866 - 2869
(2016/06/06)
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- Synthesis of Quinolines by Visible-Light Induced Radical Reaction of Vinyl Azides and α-Carbonyl Benzyl Bromides
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A visible-light induced radical reaction of vinyl azides and α-carbonyl benzyl bromides was developed, which provides an efficient route to polysubstituted quinolines via a C-C and C-N bond formation sequence.
- Wang, Qile,Huang, Jun,Zhou, Lei
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p. 2479 - 2484
(2015/08/18)
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- MINERALOCORTICOID RECEPTOR ANTAGONISTS
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Disclosed are the compounds of the Formula (I) as well as pharmaceutically acceptable salts thereof, which are useful for treating aldosterone-mediated diseases. The processes for preparing compounds of the Formula (I), the use for the therapy and prophyl
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Page/Page column 51; 52
(2012/08/07)
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- PROCESS FOR PRODUCTION OF THIOPHENE COMPOUND AND INTERMEDIATE THEREOF
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To provide a novel process for producing a 2-aryl-3-hydroxy-4-substituted carbonyl thiophene compound or an intermediate thereof useful as an intermediate for production of medicines and agricultural chemicals. A 2-aryl acetate compound represented by the formula (1): wherein R1 is an aryl group or the like, R4 is a C1-3 alkyl group or the like, and X is a leaving group, is reacted with a thioacetic acid compound to form a thioacetyl compound (3), the thioacetyl compound (3) is reacted with a vinyl ketone compound to form a γ-ketosulfide compound (5), which is cyclized under basic conditions to form a dihydrothiophene compound (6), and the dihydrothiophene compound (6) is oxidized by using an oxidizing agent to produce a 2-aryl-3-hydroxy-4-substituted carbonyl thiophene compound (7).
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Page/Page column 12
(2010/11/17)
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- Cold Menthol Receptor Antagonists
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Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: wherein A, L, R1, R2, R4 and R
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Page/Page column 17
(2010/03/31)
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- THE METHOD OF MAKING OPTICALLY ACTIVE 2-HALO-2-(N-SUBSTITUTED PHENYL)ACETIC ACID ESTERS AND 2-HALO-2-(N-SUBSTITUTED PHENYL)ACETIC ACIDS BY ENZYMATIC METHOD
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The present invention relates to the process for the preparation of optically active 2-halo-2-(n-substituted phenyl)acetic acid esters and optically active 2-halo-2-(n-substituted phenyl)acetic acids, which are used intensively as important chiral intermediates, represented by general formula 2 and 3 respectively from racemic 2-halo-2-(n-substituted phenyl)acetic acid ester represented by general formula 1. In more detail, this invention relates to the process for preparing optically active 2-halo-2-(n-substituted phenyl)acetic acid esters and optically active 2-halo-2-(n-substituted phenyl)acetic acids by stereospecific hydrolysis of racemic 2-halo-2-(n-substituted phenyl)acetic acid esters using hydrolases or hydrolase-producing microorganisms in the aqueous phase or organic phase including aqueous solvent. This method is useful in the practical process because the production and separation of compounds with high optical purity is easier.
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Page/Page column 6
(2008/06/13)
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- METHODS FOR AVOIDING EDEMA IN THE TREATMENT OR PREVENTION OF PPARγ-RESPONSIVE DISEASES, INCLUDING CANCER
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Compounds, compositions, and methods of avoiding edema while treating or preventing PPARγ-mediated diseases, including cancer, using derivatives and prodrugs are provided.
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Page/Page column 70
(2008/06/13)
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- Combinational therapy involving a small molecule inhibitor of the MDM2: P53 interaction
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The present invention is directed to a combinational therapy for treating cancer or other cell proliferative diseases. Such a therapy combines the use of radiation therapy or chemotherapy with the use of a small molecule inhibitor of the MDM2: p53 interaction.
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Page/Page column 53
(2008/06/13)
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- [1H-PYRAZOLO[3, 4-D]PYRIMIDIN-4-YL]-PIPERIDINE OR -PIPERAZINE COMPOUNDS AS SERINE-THEORONINE KINASE MODULATORS (P70S6K, ATK1 AND ATK2) FOR THE TREATMENT OF IMMUNOLOGICAL, INFLAMMATORY AND PROLIFERATIVE DISEASES
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The invention provides compounds of formula (I) and methods for inhibition of kinases, more specifically p70S6 kinases, and more preferably p70S6, Akt-1 and Akt-2 kinases. The invention provides compounds for modulating protein kinase enzymatic activity f
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Page/Page column 80
(2008/06/13)
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- MELANIN-CONCENTRATING HORMONE RECEPTOR ANTAGONISTS CONTAINING PIPERIDINE DERIVATIVES AS THE ACTIVE INGREDIENT
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The invention provides melanin-concentrating hormone receptor antagonists containing as the active ingredient piperidine derivatives represented by the general formula [I]: ???[wherein R1 is hydrogen, hydroxyl, lower alkyl, or the like; R2, R3a, R3b, R4a, R4b, R5a, R5b and R6 each stands for hydrogen, halogen, or the like; W1 and W2 each independently stands for -O-, -CH2-, or the like; Y1, Y2, Y3 and Y4 stand for -CH-, -CF-, -N-, or the like; Z stands for lower alkyl, an aliphatic heterocyclic group, or the like; Ar is a mono- or bi-cyclic aliphatic heterocycle or an aromatic heterocycle; and n is an integer of 1 to 8]. The compounds act as antagonist against melanin-concentrating hormone receptor and are useful as drugs for central diseases, circulatory diseases, or metabolic diseases.
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Page/Page column 29
(2010/02/14)
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- Substituted 1,4-diazepines and uses thereof
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The present invention is directed to novel 1,4-diazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R1, R2, R9, R10, Ra, Rd and M are defined herein; X is a bivalent radical of: an alkane, a cycloalkane, an optionally-substituted arene, an optionally-substituted heteroarene, an optionally-substituted arylalkane or an optionally-substituted heteroarylalkane; and R3 is —CO2Rd, —CO2M, —OH, —NHRd, —SO2Rd, —NHCONHRd, optionally-substituted amidino or optionally-substituted guanidino; or R3—X— is hydrogen or an electron pair; R4 is oxygen or —NR9R10; R5 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; and R6, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R6 and R7, together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring optionally substituted 1 to 3 times with Ra.
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- Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
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The present invention provides the use of (?) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia.
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- Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia
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The present invention provides the use of (?) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia.
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- Use of (?) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia
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The present invention provides the use of (?) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. It further provides (?) (3-trihalomet
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- Use of phenethyl acrylamides, novel phenethyl acrylamides, method for the production thereof and agents containing the same
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The invention relates to the use of phenethyl acrylamides of formula I for controlling phytopathogenic fungi, wherein the substituents of said phenethyl acrylamides have the following significations: X signifies halogen, alkyl, halogenalkyl, alkoxy halogenalkoxy and —O—C(Ra, Rb)—C≡C—R6; Ra, Rb and Rc have the signification given in the description; m, n independently signify 1 to 4, the radicals X or Y being potentially different if m or n is higher than 1; Y signifies halogen, nitro, cyano, alkyl, CF3, alkoxy and phenyl; R1, R2 independently signify hydrogen, halogen, alkyl, alkoxy, halogenalkoxy and CF3; R3, R4, R5, and R6 independently signify hydrogen, alkyl and alkoxy, or R3 and R4 together form a cyclopropyl ring, whereby the C—R5 and C—R6 bonds can be in position E or Z in relation to each other. The invention also relates to novel phenethyl acrylamides, a method for the productio thereof, and agents containing the same.
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- [2,3]-Sigmatropic rearrangements of didehydropiperidinium ylids
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The [2,3]-sigmatropic rearrangements of ammonium ylids derived from 1,2,5,6-tetrahydropyridine have been studied: both rearrangement and elimination processes are observed, with rearrangement favoured when aprotic solvents are used in the reaction. The presence of anion-stabilizing substituents on the nucleophilic carbon atom of the intermediate ylid species involved in the tranformation also engenders rearrangement; when certain aryl substituents or two anion-stabilizing groups are present, elimination is not observed, and electron-donating ylid substituents retard rearrangement whilst enhancing elimination.
- Sweeney,Tavassoli, Ali,Carter, Neil B.,Hayes, Jerome F.
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p. 10113 - 10126
(2007/10/03)
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- Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes and hyperlipidemia
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The present invention provides the use of (?) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes and hyperlipidemia.
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- Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
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The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ETA receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ETA antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC50 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC50 of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 μmol/kg) and was duly proposed and accepted as a development candidate.
- Astles, Peter C.,Brown, Thomas J.,Halley, Frank,Handscombe, Caroline M.,Harris, Neil V.,Majid, Tahir N.,McCarthy, Clive,McLay, Lain M.,Morley, Andrew,Porter, Barry,Roach, Alan G.,Sargent, Carol,Smith, Christopher,Walsh, Roger J. A.
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p. 900 - 910
(2007/10/03)
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- Glucose transport-enhancing and hypoglycemic activity of 2-methyl-2- phenoxy-3-phenylpropanoic acids
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A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ob mice. Some compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food consumption observed with some of these compounds was shown by a pair-feeding experiment not to be the primary cause of the hypoglycemia observed.
- Sarges,Hank,Blake,Bordner,Bussolotti,Hargrove,Treadway,Gibbs
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p. 4783 - 4803
(2007/10/03)
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- ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED PYRIDOIMIDAZOLYL RING
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Substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives of the Formula I are useful as angiotensin II antagonists. STR1
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- Certain pyridyl-thiazolidin-4-one having anti-ulcer activity
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A 2-pyridyl-thiazolidin-4-one derivative represented by the formula: STR1 wherein R1 and R2 are each a hydrogen atom, an C1 -C20 alkyl group, an C2 -C20 alkenyl group, an C2 -C20 alkynyl group, an aryl group, a C3 -C8 cycloalkyl group or an aralkyl group which may have a substituent, R3 is a hydrogen atom, an C1 -C20 alkyl group, an C2 -C20 alkenyl group, an C2 -C20 alkynyl group, a C3 -C8 cycloalkyl group or an aralkyl group which may have a substituent, P is a pyridyl group or its N-substituted pyridinium salt which may have a substituent, said substituent being selected from the group consisting of halogen atom, cyano group, hydroxy group, amino group, lower alkyl group, lower alkoxy group, lower alkylamino group, halogenated lower alkyl group, acyl group, acyloxy group, acylthio group, acylamino group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkyl substituted carbamoyl group, heterocyclic group, and lower cycloalkyl group, and n represents an integer of 0, 1 or 2, or a pharmaceutically acceptable salts thereof and an anti-ulcer agent which contains, as an effective ingredient, said 2-pyridyl-thiazolidine-4-one derivative or a pharmaceutically acceptable salt thereof.
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- Novel thiazolidin-4-one derivatives and acid addition salts therof
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A novel 2-pyridylthiazolidin-4-one derivative represented by the general formula STR1 wherein Ar denotes an aryl group unsubstituted or substituted with a halogen atom or with a lower alkoxy group; X denotes a straight-chain or branched-chain lower alkylene group or a single bond; R denotes a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, acyloxy, di(lower alkyl) amino, hydroxyl or aryl group, or denotes an aryl group substituted with a lower alkoxy group; and Py denotes a pyridyl group, and the acid addition salt thereof, which have an excellent platelet activating factor antagonsm.
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- SYNTHESES D'ESTERS OU D'ACIDES α-HALOGENES A PARTIR DES GEM DICYANO EPOXIDES.
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α-halogeno esters or α-halogenoacids were easily prepared by selective one pot reaction of gem-dicyano epoxides with halohydric acids in an alcoholic or aqueous media.
- Robert, A.,Jaguelin, S.,Guinamant, J. L.
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p. 2275 - 2282
(2007/10/02)
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