The syntheses of 2-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having potent gastric antisecretory properties in the pyloric-ligated (Shay) rat model are described. Two of the more potent compounds tested that were selected for more detailed dose-response evaluation were 4-amino-1-ethyl-1,2-dihydro-2-oxonaphthyridine-3-carboxylic acid ethyl ester (35) and 1-ethyl-1,2-dihydro-7-methyl-4-(4-methyl-1-piperazinyl)-2- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (77). These compounds lowered total acid output in the rat in a dose-related fashion. Both compounds were more potent than cimetidine when tested in the rat. Both 35 and 77 showed inhibitory activity in food-stimulated acid secretion in the Pavlov-pouch, conscious dog. The mechanism of action for this series is not known. Details of structure-activity relationships are described.

Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.

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A novel method for the preparation of esters and amides of thieno[2,3‐d]pyrimidine‐6‐carb‐oxylic acids was described. A typical example was the direct formation of ethyl 5‐amino‐2‐methylthiothieno[2,3‐d]pyrimidine‐6‐earboxylate(IIIa) from 4‐chloro‐2‐methylthio‐5‐pyrimidine‐carbonitrile (Ia) and ethyl mercaptoacetate in refluxing ethanol containing sodium carbonate. Displacement of the methylthio group in IIIa by various amines gave the corresponding amino derivatives. The reactions of IIIa and related compounds with acetylating agents such as acetic anhydride or chloroacetyl chloride gave various products. Treatment of 5‐carbethoxy‐4‐chloro‐2‐phenylpyrimidine(IV) with methyl mercaptoacetate afforded the dechloro intermediate diester Va, which cyclized on reaction with sodium ethoxide to form methyl 5‐hydroxy‐2‐phenylthieno‐[2,3‐d]pyrimidine‐6‐carboxylate (Vla). The synthesis was expanded to include the preparation of various new 2,4,5‐trisubstituted thieno[2,3‐d]pyrimidine‐6‐carboxylic acid esters and amides (Charts I‐V).

Several new 3‐arylsulfonylmethyl‐1,2,4‐oxadiazole‐5‐carboxylic acid derivatives have been synthesized. A typical example, 3‐[(4‐chlorophenylsulfonyl)methyl]‐1,2,4‐oxadiazole‐5‐carboxylic acid ethyl ester (2c), was prepared from the reaction of 2‐(4‐chlorophenylsulfonyl)acetamide oxime (1c) with ethyl oxalyl chloride. The hydrazide derivative (3f) showed antihypertensive activity in rats. Various structural modifications to improve activity are discussed.