Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives.
A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
E
E
Ohshima
S
S
Otaki
H
H
Sato
T
T
Kumazawa
H
H
Obase
A
A
Ishii
H
H
Ishii
K
K
Ohmori
N
N
Hirayama
D000818:Animals; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001982:Bronchial Diseases / Q000188:drug therapy / Q000276:immunology; D002531:Cerebellum / Q000378:metabolism; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000276:immunology; D003990:Dibenzoxepins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D015394:Molecular Structure; D000069605:Olopatadine Hydrochloride; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D011738:Pyrilamine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D001584:Benzoxepins; D003990:Dibenzoxepins; D006634:Histamine H1 Antagonists; D007074:Immunoglobulin G; D011969:Receptors, Histamine H1; D000069605:Olopatadine Hydrochloride; D011738:Pyrilamine