- Pharmaceutical agents
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A physical form of (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol -3-ylmethyl]-N-(2-methylphenylsulphonyl)benzamide substantially free of other physical forms, which form is crystalline and has an X-ray powder diffraction pattern with specific peaks at 2θ=14.0, 19.4, 22.0, 22.4 and 24.7° , processes for preparing the form and pharmaceutical compositions containing it. The compound is a leukotriene antagonist useful in the treatment of diseases such as asthma.
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- Synthesis, Structure-Activity Relationships, and Pharmacological Evaluation of a Series of Fluorinated 3-Benzyl-5-indolecarboxamides: Identification of 4--1-methylindol-3-yl>methyl>-3-methoxy-N-benzamide, ...
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The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4--1-methylindol-3-yl>methyl>-3-methoxy-N-benzamide (38p, ZENECA ZD 3523), which has been chosen for clinical evaluation.This compound exhibited a Ki of 0.42 nM for displacement of LTD4 on guinea pig lung membranes, a pKB of 10.13 +/- 0.14 versus LTE4 on guinea pig trachea, and an oral ED50 of 1.14 μmol/kg opposite LTD4-induced bronchoconstriction in guinea pigs.The R enantiomer was found to be modestly more potent than the S enantiomer 38o.Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity.Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist.The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazolidinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in >99percent enantiomeric purity.
- Jacobs, Robert T.,Bernstein, Peter R.,Cronk, Laura A.,Vacek, Edward P.,Newcomb, Lisa F.,et al.
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p. 1282 - 1297
(2007/10/02)
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