Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives

Abstract

On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.

Biological study of naphthalene derivatives with antiinflammatory activities

“…Batt et al [1989] showed that 2-benzyl-1-acetoxynaphthalene containing the ester group of the molecule increased the antiinflammatory activity of the naphthalene. This compound was suggested to be the ester prodrug for an active phenolic 5-lipoxygenase inhibitor [Jones et al, 1986]. The activity increased slightly when a morpholine group (compound 7, 9) was incorporated in the pyrrolidine (compound 5) or piperidine (compound 6).…”

Effect of Lonapalene on Metabolism of Exogenous Arachidonic Acid in Human Platelets

“…Assuming that lonapalene, a proven 5-lipoxygenase inhibitor [11], also inhibits cy clooxygenase in the cellular components of human skin and psoriatic plaques, the conse quent deviation of arachidonic acid metabo lism through the 12-lipoxygenase pathway might have some implications as regards the effects of topical lonapelene, and especially local inflammation.…”

Determination of Sudan IV in hot chilli powder with luminol/dissolved oxygen chemiluminescence system

“…Provitamin K 3 ( 36 ; menadione) was derived from the reaction of 1‐acetoxy‐buta‐1,3‐diene ( 32 ) and methylbenzoquinone ( 33 ) in xylene at reflux followed by treatment of the crude regioisomeric mixture ( 34 , 35 ; Scheme ) with nitric acid ( 36 ) 55. The synthesis of lonapalene ( 40 ), which was investigated in a phase III clinical trial for the treatment of psoriasis, by using benzoquinone ( 38 ) as the dienophile and chlorobutadiene ( 37 ) was described by Roche (formerly Syntex, Scheme ) 57…”