The synthesis and antiallergic potential of a series of novel indolecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated basophilic leukocytes obtained from allergic donors. Optimal inhibition is exhibited by compounds with 3-alkoxy, 5-methoxy, and 1-phenyl substituents on the indole core structure. Compound 8d (5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide; designated CI-949) is a potent inhibitor of histamine release from human basophils and from guinea pig and human chopped lung.

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The synthesis of novel indole‐2‐carboxylic acids with amino‐ and sulfur‐containing substituents in the indole 3‐position is described. An Ullmann reaction with bromobenzene converted 1H‐indoles with 3‐(acetylamino)‐ and 3‐(diethylamino)‐substituents into 1‐phenyl‐1H‐indoles. Reaction of 3‐unsubstituted indoles with thionyl chloride provided indole 3‐sulfinyl chlorides, which reacted with alkyl and aryl Grignard reagents to form the corresponding sulfoxides. The indole sulfoxides thus obtained were reduced to sulfides or oxidized to sulfones.

(1 994).Reaction of primary amides (e.g., l a or 6-13) or 0-methylhydroxamates ( l b and lc) with a catalytic amount of TiC1, and one equivalent of aqueous HCI converts these compounds in good yields to carboxylic esters (when an alcohol is used as solvent) or to carboxylic acids (when 9 : 1 dioxane : H' O is used as solvent). These conversions are chemoselective for primary amides: mono-and dialkyl amides are not affected by the reaction conditions. The hydrolysis conditions described do not compromise the stereochemical integrity of an adjacect chiral center. This is exemplified by the hydrolysis of naproxen amide (34) La rCaction des a~nides primaires (par exemple l a ou 6-13) ou des 0-mCthylhydroxamates ( l b ou l c ) avec une quantitC catalytique de Tic]? et un Cquivalent de HC1 aqueux permet de transformer ces composCs, avec d'excellents rendements, en esters carboxyliques (lorsqu'on utilise un alcool comme solvant) ou en acides carboxyliques (lorsqu'on utilise un mClange 9 : 1 dioxane : eau comme solvant). Ces transformations sont chCmosClectives pour les amides primaires; les mono-et dialkyl amides ne sont pas affect& par les conditions des rkactions. Les conditions d'hydrolyse dCcrites ne compromettent pas I'intCgritC stCrCochimique d'un centre chiral adjacent. Pour dCmontrer cette assertion, on prCsente comme exemple l'hydrolyse de la naproxenamide (34) en naproxen (33) qui, d'aprks une CLHP chirale, se fait sans racCmisation detectable.[Traduit par la ridaction]

Methods for the synthesis of novel 3‐hydroxy, 3‐alkoxy, and 3‐alkyl indole‐2‐carboxylic acids and esters are described. Dieckmann cyclization of various 2‐[(carboxymethyl)amino]benzoic acid diesters yielded 1‐unsubstituted‐, 1‐methyl‐, and 1‐phenyl‐3‐hydroxy‐1H‐indole‐2‐carboxylic acid esters. An Ullmann reaction with bromobenzene converted 1H‐indoles to 1‐phenylindoles.