Synthesis, Structure-Activity Relationships, and Pharmacological Evaluation of a Series of Fluorinated 3-Benzyl-5-Indolecarboxamides: Identification of 4-[[5-[((2R)-2-Methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methylindol-3-yl]methyl]-3methoxy-N-[(2-methylphenyl)sulfonyl]benzamide, a Potent, Orally Active Antagonist of Leukotrienes D4 and E4

Abstract

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-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), which has been chosen for clinical evaluation. This compound exhibited a Ki of 0.42 nM for displacement of [3H]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 mumol/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-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.

Copper-Catalyzed Ring-Opening 1,3-Aminotrifluoromethylation of Arylcyclopropanes

“…In this context, γ-trifluoromethylated amines are a unique class of compounds of important biological activities. For example, γ-CF 3 -substituted amine Zeneca ZD 3523 ( 1 ) is a potent, orally active antagonist of leukotrienes D 4 and E 4 discovered by the Zeneca Pharmaceutical Co . Another example is that 3-(trifluoromethyl)-3-arylpropylamine 2 has been identified as a powerful inhibitor of retinol dehydrogenases for treating ophthalmic diseases and disorders .…”

Lewis Acid Enabled Copper-Catalyzed Asymmetric Synthesis of Chiral β-Substituted Amides

“… 17 Similarly, β-alkyl-substituted chiral amines, and in particular trifluoromethylated ones, are known precursors in the synthesis of leukotriene receptor antagonists used, for instance, to treat asthma. 18 To showcase the utility of our catalytic protocol, we demonstrated that chiral β-substituted amide 2e can easily be transformed into a number of corresponding valuable molecules ( Figure 1 c). Deprotection 19 of 2e afforded chiral β-ethyl amide 4 , which in turn can be used for the synthesis of the chiral γ-ethyl chiral amine 5 via reduction of the carbonyl moiety or to β-ethyl chiral amine 6 through Hoffman rearrangement.…”

“…When subjected to deprotection and Hoffman rearrangement, this product could lead to a direct precursor of the drug candidate ZENECA ZD 3523. 18 Another synthetically important transformation in which this catalytic system can be engaged is the trapping of the product enolate ( Figure 1 e). To demonstrate this, we performed the CA reaction to Br-substituted enamide 1w .…”

“…β-Alkyl-substituted chiral secondary amides as well as β-alkyl substituted chiral amines are interesting synthetic targets as these structures are present in various pharmaceutically active ingredients − including Cyclotheonamide E5 and Orbiculamide A , both known for their cytotoxic activities . Similarly, β-alkyl-substituted chiral amines, and in particular trifluoromethylated ones, are known precursors in the synthesis of leukotriene receptor antagonists used, for instance, to treat asthma . To showcase the utility of our catalytic protocol, we demonstrated that chiral β-substituted amide 2e can easily be transformed into a number of corresponding valuable molecules (Figure c).…”

Copper-Catalyzed Radical Aminotrifluoromethylation of Alkenes

“…Subsequent hydrolysis of 3a delivered β-CF 3 -amine 4a in 73% yield (eq ). The two-step method provides a convenient and efficient entry to 4a , a key structural motif to increase leukotriene antagonist activity, whose synthesis required six steps starting from diethyl malonate according to the literature . Similarly, the aminotrifluoromethylation of methyl but-3-enoate followed by acid hydrolysis led to the efficient and rapid synthesis of β-trifluoromethylated GABA ( 4b ), a potential drug candidate (eq 2 ).…”