Studies on Antianaphylactic Agents. 7. Synthesis of Antiallergic 5-Oxo-5H-[1]benzopyrano[2,3-b]pyridines

Abstract

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.

Mechanism of Action of an Antiallergic Agent, Amlexanox (AA-673), in Inhibiting Histamine Release from Mast Cells

“…2-Amino-7-isopropyl-5-oxo-5H-[l]benzopyrano [2,3-b]pyridine-3-carboxylic acid (amlexanox, previously known as amoxanox, AA-673) [5] is a novel orally active antiasthmatic drug ( fig. 1) [6].…”

The Antiallergic Agent Amoxanox Suppresses SRS-A Generation by Inhibiting Lipoxygenase

“…Egg albumin (EA) was purchased from Difco or recrystal lized from Na2S 04 of hen ovalbumin [14]. 2-Amino-7-isopropyl-5-oxo-5H-[l]benzopyrano [2, 3-b]pyridine-3-carboxylic acid (amoxanox, AA-673) was synthesized by Nohara et al [15], LTD4, LTC4, LTE4, 5-hydroxy-6,8,l1,14-eicosatetraenoic acid (5-HETE), 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), 6-keto-PGF1(" TXB2, and 5,8,11,14-eicosatetraynoic acid (ETYA) were synthes ized in our division of Takeda Chemical Industries, Ltd. Rabbit anti-TXB2 and anti-6-keto-PGF,a antiserum were a gift from Mr. Z. Terashita in our division [16,17]. A freeze-dried powder of bovine seminal vesicle (BSV, free of soluble cytoplasmic protein, Miles Labs., South Africa) was used as an enzyme source of PGE2 and PGF2a syntheses.…”

Chemistry of 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes

“…So the nitrile is indeed the preferred starting material for the synthesis of 2-amino-3-formylchromone 1. The formation of 1 by treating 3-cyanochromone 7, derived from the aldehyde 5 via the oxime 6, with an aqueous ethanolic solution (2%) of sodium hydroxide at 70 °C, 3 with a small amount of morpholine in DMF-H 2 O at 60°C, 4,5 with ethylenediamine in aqueous ethanol (1:1) under reflux, 6 or by stirring a solution of 3-cyanochromone in CH 2 Cl 2 with alumina at ambient temperature 7 has been reported. The aldehyde 1 can also be prepared by warming an ethanolic solution of the aldoxime 6 with aqueous NaOH.…”

“…Thus, malondialdehyde tetramethyl acetal 151 reacts with 1 in ether containing BF 3 ·Et 2 O, HCO 2 H at 60°C to give the 2-formylazaxanthone 152 together with a small amount of its deformylated product 153. 4,5 N,N-dimethylacetamide dimethyl acetal 155 and 1-methylpyrrolidine-2-one diethyl acetal 156 give with 1 the condensed products 154 and 157, respectively. 65 Maiti et al 66 have extensively studied the condensation of 2-(monosubstituted amino)-3-formylchromone 2 with several active methylene compounds.…”