- Synthesis and determination of absolute configuration of a non-peptidic αvβ6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis
-
A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).
- Anderson, Niall A.,Campbell, Ian B.,Fallon, Brendan J.,Lynn, Sean M.,Macdonald, Simon J. F.,Pritchard, John M.,Procopiou, Panayiotis A.,Sollis, Steven L.,Thorp, Lee R.
-
-
Read Online
- PYRIMIDONE DERIVATIVES USED AS TAU PROTEIN KINASE 1 INHIBITORS
-
A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: wherein Z represents nitrogen atom or C-X; X represents hydrogen atom or fluorine atom; R1 is hydrogen atom or a C1 -C3 alkyl group; L represents single bond or a C1 -C6 alkylene group which may be substituted; Y represents single bond, sulfur atom, oxygen atom, NH, or the like; R2 represents hydrogen atom or a cyclic group which may be substituted, which is used for preventive and/or therapeutic treatment of a disease caused by abnormal activity of tau protein kinase 1 such as a neurodegenerative diseases (e.g. Alzheimer disease).
- -
-
-
- 4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure-activity relationships
-
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
- Fish, Paul V.,Andrews, Mark D.,Jonathan Fray,Stobie, Alan,Wakenhut, Florian,Whitlock, Gavin A.
-
scheme or table
p. 2829 - 2834
(2010/03/03)
-
- New chiral 3-naphthylaminomethylpyrrolidines: An unexpected epimerisation reaction
-
New enantiomerically pure 3-naphthylaminomethylpyrrolidines (8), (9), (14) and (15) were obtained through simple steps starting from chiral 4- ethenylpyrrolidin-2-ones (2) and (3). On the other hand, starting from pyrrolidine (16), an epimerisation reacti
- Fava, Cristiana,Galeazzi, Roberta,Mobbili, Giovanna,Orena, Mario
-
p. 2463 - 2470
(2007/10/03)
-
- GABA Agonists and Uptake Inhibitors. Synthesis, Absolute Stereochemistry, and Enantioselectivity of (R)-(-)- and (S)-(+)-Homo-β-proline
-
The cyclic analogue of 4-aminobutyric acid (GABA), 3-pyrrolidineacetic acid (homo-β-proline), is a potent agonist at GABAA receptors, it interacts effectively with GABA-uptake mechanisms, and it is a moderately potent inhibitor of GABAB/s
- Nielsen, Lone,Brehm, Lotte,Krogsgaard-Larsen, Povl
-
-