- Synthesis of pharmaceutical drugs from cardanol derived from cashew nut shell liquid
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Cardanol from cashew nut shell liquid extracted from cashew nut shells was successfully converted into various useful pharmaceutical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene. 3-Vinylphenol, the key intermediate for the synthesis of these drugs, was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis. The metathesis reaction worked very well using DCM, but the greener solvent, 2-methyl tetrahydrofuran, also gave very similar results. Hydroxyamination of 3-vinylphenol with an iron porphyrin catalyst afforded norfenefrine in over 70% yield. Methylation and ethylation of norfenefrine afforded rac-phenylephrine and etilefrine respectively. A sequence of C-O coupling, isomerising metathesis and selective methoxycarbonylation afforded fenoprofene in good yield. A comparison of the routes described in this paper with some standard literature syntheses of 3-vinylphenol and of the drug molecules shows significant environmental advantages in terms of precursors, yields, number of steps, conditions and the use of catalysts. The Atom Economy of our processes is generally similar or significantly superior to those of the literature processes mainly because the side products produced during synthesis of 3-vinylphenol (1-octeme, 1,4-cyclohexadiene and propene) are easily separable and of commercial value, especially as they are bio-derived. The E Factor for the production of 2-vinylphenol by our process is also very low compared with those of previously reported syntheses.
- Shi, Yiping,Kamer, Paul C. J.,Cole-Hamilton, David J.
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p. 1043 - 1053
(2019/03/12)
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- 2-ARYL-PROPIONAMIDE DERIVATIVES USEFUL AS BRADYKININ RECEPTOR ANTAGONISTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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(R,S) 2-aryl-propionamide derivatives, or their single enantiomers (R) and (S) are disclosed useful in the treatment or prevention of symptoms and disorders such as pain and inflammation associated with the bradykinin B 1 pathway.
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Page/Page column 16
(2011/05/11)
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- Discovery of BIIB042, a potent, selective, and orally bioavailable γ-secretase modulator
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We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
- Peng, Hairuo,Talreja, Tina,Xin, Zhili,Cuervo, J. Hernan,Kumaravel, Gnanasambandam,Humora, Michael J.,Xu, Lin,Rohde, Ellen,Gan, Lawrence,Jung, Mi-Young,Shackett, Melanie N.,Chollate, Sowmya,Dunah, Anthone W.,Snodgrass-Belt, Pamela A.,Arnold, H. Moore,Taveras, Arthur G.,Rhodes, Kenneth J.,Scannevin, Robert H.
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supporting information; experimental part
p. 786 - 791
(2011/12/02)
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- Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach
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Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.
- Xin, Zhili,Peng, Hairuo,Zhang, Andrew,Talreja, Tina,Kumaravel, Gnanasambandam,Xu, Lin,Rohde, Ellen,Jung, Mi-Yong,Shackett, Melanie N.,Kocisko, David,Chollate, Sowmya,Dunah, Anthone W.,Snodgrass-Belt, Pamela A.,Moore Arnold,Taveras, Arthur G.,Rhodes, Kenneth J.,Scannevin, Robert H.
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supporting information; experimental part
p. 7277 - 7280
(2012/02/04)
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- CARBOXYLIC ACID-CONTAINING COMPOUNDS, DERIVATIVES THEREOF, AND RELATED METHODS OF USE
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Compounds that modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase) are described herein. Also disclosed are pharmaceutical compositions, methods of modulating the activity of gamma secretase, and methods of treating Alzheimer's Disease using the compounds described herein.
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Page/Page column 110-111
(2010/12/26)
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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 59-60
(2010/11/27)
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- IMINO ETHER DERIVATIVE COMPOUNDS AND DRUGS CONTAINING THE COMPOUNDS AS THE ACTIVE INGREDIENT
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The compound represented by formula (I) (wherein R1 and R2 are cyclic group which may have a substituent(s) and so on.; W is a spacer of which main chain has an atom number of 1-6.; X is -O- and so on.; ringA is cyclic group which may have a substituent(s).; Y is a spacer of which main chain has an atom number of 1-6 and so on.; Z is acidic group.) a salt thereof, a solvent thereof or an N-oxide thereof or a prodrug thereof Since the compounds in the present invention have a regulatory activity for peroxisome proliferator activated receptor, the compounds in the present invention are useful as a preventive and/or therapeutic agent for diseases associating metabolic disorders (e.g., hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipidemia, atherosclerosis, hypertension, circulatory diseases, overeating, ischemic heart diseases, etc., an HDL cholesterol-elevating agent, an LDL cholesterol and/or a VLDL cholesterol-lowering agent and a drug for relief from risk factors of diabetes or metabolic syndrom.
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Page/Page column 57
(2010/02/14)
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