- A formal method for the de-N,N-dialkylation of Sommelet-Hauser rearrangement products
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Selective amine de-alkylation enables the conversion of Sommelet-Hauser rearrangement products into 2-aryl-2-bromoacetic acid derivatives. These compounds are valuable synthetic intermediates in the synthesis of α-aryl-α-amino or α-aryl-β-amino acid deriv
- Tayama, Eiji,Sato, Ryota,Takedachi, Keisuke,Iwamoto, Hajime,Hasegawa, Eietsu
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p. 4710 - 4718
(2012/07/28)
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- Resolution of 2-bromo-o-tolyl-carboxylic acid by transesterification using lipases from Rhizomucor miehei and Pseudomonas cepacia
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Several lipases were screened for their ability to catalyze the enantioselective transesterification of 2-bromo-o-tolyl acetic acid. Amongst the preparations tested, the lipases from Rhizomucor miehei and Pseudomonas cepacia were selected. The best enantioselectivity was obtained with Rhizomucor miehei lipase immobilized on polypropylene (E = 11.3), which was more stereoselective than the free form. Hydrophobic solvents with log P higher than 2.5 were the most suitable giving the highest E-values. In addition, factors such as the water activity and the reaction temperature had little effect on the resolution of the racemic mixture. The selectivity of the enzymes with respect to the substrate was also only weakly affected by the structure of the leaving alcohol except in the case of the iso-propyl group, which causes high steric hindrance. Operating conditions under reduced pressure were defined to resolve the racemic mixture with immobilized Rhizomucor miehei lipase.
- Guieysse, David,Salagnad, Christophe,Monsan, Pierre,Remaud-Simeon, Magali
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p. 2473 - 2480
(2007/10/03)
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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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- SUBSTITUTED PHENYL COMPOUNDS WITH A SUBSTITUENT HAVING A 1,3-BENZODIOXOLE RING
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This invention is directed to compounds of formula I STR1 wherein R 1 is CN, CH 2 CN, CH=CHCN, CHO, or CH=CHCO. sub. 2 H;R 2 is aryl lower alkoxy, heteroaryl lower alkoxy, aryl lower alkylthio or heteroaryl lower alkylthio wherein each of the aryl and heteroaryl moieties is optionally substituted;R 3 is halogen;R 4 is optionally substituted aryl or optionally substituted heteroaryl;R. sup.5 is carboxy or an acid isostere; X is oxygen or sulphur; and n is zero or 1; or an N-oxide thereof, prodrug thereof solvate thereof, or pharmaceutically acceptable salt thereof, which compounds have endothelin antagonist activity. The invention is also directed to methods for preparing the compounds of formula I and their pharmaceutical use.
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- Substituted phenyl compounds with a substituent having a thienyl ring
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This invention is directed to compounds of formula I wherein R1 is CN, CH2CN, CH=CHCN, CHO, or CH=CHCO2H; R2 is aryl lower alkoxy, heteroaryl lower alkoxy, aryl lower alkylthio or heteroaryl lower alkylthio wherein each of the aryl and heteroaryl moieties is optionally substituted; R3 is halogen; R4 is optionally substituted aryl or optionally substituted heteroaryl; R5 is carboxy or an acid isostere; X is oxygen or sulphur; and n is zero or 1; or an N-oxide thereof, prodrug thereof solvate thereof, or pharmaceutically acceptable salt thereof, which compounds have endothelin antagonist activity. The invention is also directed to methods for preparing the compounds of formula I and their pharmaceutical use.
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- 1-Aryl-3-azabicyclohexanes, a New Series of Nonnarcotic Analgesic Agents
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A series of 1-aryl-3-azabicyclohexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides.Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa-DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediates 19 and 21.The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25.The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds.Bicifadine, 1-(4-methylphenyl)-3-azabicyclohexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man.Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis.The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive.Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.
- Epstein, Joseph W.,Brabander, Herbert J.,Fanshawe, William J.,Hofmann, Corris M.,McKenzie, Thomas C.,et al.
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p. 481 - 490
(2007/10/02)
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