1,3,6-Trisubstituted indoles as peptidoleukotriene antagonists: benefits of a second, polar, pyrrole substituent

Abstract

1,6-Substituted and 3,5-substituted indoles and indazoles containing acylamino and N-arylsulfonyl amide appendages are potent antagonists of the peptidoleukotrienes LTD4 and LTE4. A compound from the 3,5-substituted indole series, N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]-1-methylindol- 3-yl]methyl]-3-methoxybenzoyl]-2-methyl-benzenesulfonamide (ICI 204,219), is undergoing clinical evaluation for asthma. Two new elements of structural diversity were introduced to this series of antagonists. An investigation of pyrrole substituents in the 1,6-substituted indoles demonstrated that substitution at C-2 was detrimental to biological activity, but the incorporation of hydrophilic groups at C-3 was beneficial. The introduction of a propionamide moiety at C-3 enhanced activity by 1 order of magnitude; N-[4-[[6-(cyclopentylacetamido)-3-[2-(N- methylcarbamoyl)ethyl]indol-1-yl]methyl]-3-methoxy- benzoyl]benzenesulfonamide (15c) has a pKB of 10.7 at the LTD4 receptor on guinea pig trachea. Modifications of the acylamino portion of the disubstituted antagonists demonstrated that a transposition of the amide CO and NH atoms was viable. N-Cyclopentylmethyl amides in both the 1,6- and 3,5-disubstituted indole series were 1 order of magnitude less potent than the corresponding cyclopentylacetamides. In both series this potency loss could be regained by the incorporation of a propionamide substituent at either C-3 or N-1, respectively. For example, N-[4-[[6-[N-(cyclopentylmethyl)carbamoyl]-3-[2-(pyrrolidin-1 - methylbenzenesulfonamide (39c) has a pKB of 9.5.

Chemoselective reactions of dimethyl carbonate catalysed by alkali metal exchanged faujasites: the case of indolyl carboxylic acids and indolyl-substituted alkyl carboxylic acids

“…Spectroscopic data of 2b-d, 2f, 3b, 4b, 5b, and 6 were already reported in the literature. 9,[20][21][22][23][24] The structures of new compounds 3c and 3d were confirmed also by 13 C NMR. 1 H NMR spectra were recorded at 300 MHz, 13 C NMR at 75 MHz.…”

“…Mp 74-76 uC (pale yellow solid) [lit. 24 mp 71-72 uC] 1 H NMR (300 MHz, CDCl 3 ) d 3.93 (s, 3H), 6.61 (m, 1H), 7.38 (m, 1H), 7.66 (d, 1H, J = 8.3 Hz), 7.82 (dd, 1H, J 1 = 8.5 Hz, J 2 = 1.5 Hz), 8.17 (m, 1H), 8.45 (brs, 1H). MS (EI), m/z (relative int.…”

“…Mp 96-98 uC (white solid) [lit. 25 (12), 189 (M + , 100%), 144 (82), 130 (M + 2 CO 2 Me, 48), 103 (16), 77 (24).…”

Facile Synthesis of 9-Substituted 9-Deazapurines as Potential Purine Nucleoside Phosphorylase Inhibitors.

“…Previously, the Friedel-Crafts alkylation of 1 with benzyl bromide using a Lewis acid catalyst such as stannic chloride, or aluminum chloride in nitromethane, or acetonitrile, produced a mixture of 9-deazaxanthines benzylated at C-8, C-9, N-1, or N-7. Attempts to prepare the desired compound using silver oxide as catalyst, 12) which had been successfully used in an indole system, resulted in benzylation at N-7 and C-8 positions. Treatment of 1 with benzyl alcohol, a good source of benzyl cation, 13,14) in triflic acid at room temperature yielded 8,9-dibenzylated derivatives.…”

New N-(Pyridin-4-yl)-(indol-3-yl)acetamides and Propanamides as Antiallergic Agents

“…20 Although the corresponding indolylalkylamides exhibited only moderate anti-edematous effect, to our surprise, results of pharmacological screening tests revealed that some of these compounds significantly inhibited IL-4, IL-5 biosynthesis and/or histamine release. These data and the fact that indole constitutes the central core of numerous potent LTD 4 antagonists, [21][22][23] PAF antagonists, 24 or inhibitors of FLAP, 12 prompted us to carry out an extensive pharmacomodulation in this series. We report here the results of in vitro and in vivo investigations in the N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 (Table 3).…”