Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 4. Identification of an Inhibitor with an Intermediate Duration of Action

Abstract

3-Acyl-4-(arylamino)quinolines were previously identified as gastric (H+/K+)-ATPase inhibitors, and clinical efficacy has been demonstrated for compound 3 (SK&F 96067). In the present study the further structure-activity relationship of this series is developed. Only a limited range of substituents are tolerated on the N-aryl ring or the 6- and 7-positions of the quinoline, and although hydroxylated derivatives were identified possessing markedly greater affinity for the enzyme, none of these proved to have adequate potency after oral dosing. In contrast, the 8-position of the quinoline ring proved suitable for a wide variety of substituents, allowing modification of physicochemical properties while retaining primary activity. This led to the identification of compound 4 (SK&F 97574), which combines good oral potency with a somewhat longer duration of action than 3 (though much shorter than covalent inhibitors such as omeprazole). This compound was selected for further development and evaluation in man.

Synthetic Routes to Quinoline Derivatives: Novel Syntheses of 3-Butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline and 3-Butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quinoline

“…Much of the earlier work performed on 1a and 1b was based on this disconnection. The compounds were originally prepared within the Medicinal Chemistry research programme using several routes, the most promising one of which is shown in Scheme 1. , Although this classical route was amenable to the large-scale preparation of 1a , the requirement for either aluminium trichloride or boron tribromide for the demethylation of the 8-methoxyquinoline 4a to give the somewhat unstable 8-hydroxy analogue 4b and poor yields for the alkylation of the latter to give the final product 1b necessitated the acquisition of alternative methodology for the preparation of 1b . The aspects concerning the evolution of an efficient conversion of 1a to 1b are dealt with later in the paper.…”

“…The final hydroxyethylation stage to form 1b was previously performed by using 2-bromoethanol in the presence of potassium tert -butoxide, giving yields of ∼30% . Extensive development work facilitated the evolution of a superior process, which involved the use of ethylene carbonate in the presence of either K 2 CO 3 or DABCO in refluxing 2-propanol and afforded 1b in 60−80% yield.…”

“…The 3,4,8-trisubstituted quinoline derivatives 3-butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline ( 1a ) and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quinoline ( 1b ) emerged from SmithKline Beecham's gastrointestinal research programme as reversible (H + /K + ) ATPase inhibitors for the treatment of peptic ulcers, gastro-oesophageal reflux disease, and related disorders and have been described previously. − This paper summarises exploratory work on a number of alternative routes to these compounds and describes how one route was developed into a viable commercial synthesis. Each of the five general strategies explored featured one of the disconnections a−e shown in Figure as a basis for the critical conversions.…”

Medicinal Chemistry and Properties of 1,2,4-Thiadiazoles

“…other cysteine residues of the proton pump through covalent S-S bond formation, or they could behave as reversible potassium channel antagonists [51].…”

New and Practical Synthesis of N‐(3‐Cyano‐7‐ethoxy‐4‐oxo‐1,4‐dihydroquinolin‐6‐yl)acetamide

“…4‐Hydroxyquinolines (equal to 4‐oxo‐1,4‐dihydroquinolines) are the key synthetic precursors for anticancer , antimalarial , antidiabetic , antiviral agents, and reversible (H + /K + ) ATPase inhibitors . N ‐(3‐Cyano‐7‐ethoxy‐4‐oxo‐1,4‐dihydroquinolin‐6‐yl)acetamide ( 1 ) (Fig.…”