Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives. 1992

E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.

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.

UI MeSH Term Description Entries
D007074 Immunoglobulin G The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B. Gamma Globulin, 7S,IgG,IgG Antibody,Allerglobuline,IgG(T),IgG1,IgG2,IgG2A,IgG2B,IgG3,IgG4,Immunoglobulin GT,Polyglobin,7S Gamma Globulin,Antibody, IgG,GT, Immunoglobulin
D008297 Male Males
D010323 Passive Cutaneous Anaphylaxis An evanescent cutaneous reaction occurring when antibody is injected into a local area on the skin and antigen is subsequently injected intravenously along with a dye. The dye makes the rapidly occurring capillary dilatation and increased vascular permeability readily visible by leakage into the reaction site. PCA is a sensitive reaction for detecting very small quantities of antibodies and is also a method for studying the mechanisms of immediate hypersensitivity. Anaphylaxis, Passive Cutaneous,PCA,Cutaneous Anaphylaxis, Passive
D011738 Pyrilamine A histamine H1 antagonist. It has mild hypnotic properties and some local anesthetic action and is used for allergies (including skin eruptions) both parenterally and locally. It is a common ingredient of cold remedies. Mepyramine,Pyranisamine,Anthisan,Boots Bite & Sting Relief,Kriptin,Mepyramine Maleate,Pyrilamine Maleate,Maleate, Mepyramine,Maleate, Pyrilamine
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D011969 Receptors, Histamine H1 A class of histamine receptors discriminated by their pharmacology and mode of action. Most histamine H1 receptors operate through the inositol phosphate/diacylglycerol second messenger system. Among the many responses mediated by these receptors are smooth muscle contraction, increased vascular permeability, hormone release, and cerebral glyconeogenesis. (From Biochem Soc Trans 1992 Feb;20(1):122-5) H1 Receptor,Histamine H1 Receptors,H1 Receptors,Histamine H1 Receptor,Receptors, H1,H1 Receptor, Histamine,H1 Receptors, Histamine,Receptor, H1,Receptor, Histamine H1
D001982 Bronchial Diseases Diseases involving the BRONCHI. Bronchial Disease,Disease, Bronchial,Diseases, Bronchial
D002531 Cerebellum The part of brain that lies behind the BRAIN STEM in the posterior base of skull (CRANIAL FOSSA, POSTERIOR). It is also known as the "little brain" with convolutions similar to those of CEREBRAL CORTEX, inner white matter, and deep cerebellar nuclei. Its function is to coordinate voluntary movements, maintain balance, and learn motor skills. Cerebella,Corpus Cerebelli,Parencephalon,Cerebellums,Parencephalons
D003251 Constriction, Pathologic The condition of an anatomical structure's being constricted beyond normal dimensions. Stenosis,Stricture,Constriction, Pathological,Pathologic Constriction,Constrictions, Pathologic,Pathologic Constrictions,Pathological Constriction,Stenoses,Strictures
D003990 Dibenzoxepins

Related Publications

E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
October 1991, Chemical & pharmaceutical bulletin,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
October 1991, Chemical & pharmaceutical bulletin,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
October 1991, Chemical & pharmaceutical bulletin,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
December 2009, Acta crystallographica. Section E, Structure reports online,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
September 1992, Chemical & pharmaceutical bulletin,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
September 1962, Journal of medicinal and pharmaceutical chemistry,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
May 1965, Arzneimittel-Forschung,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
December 1963, Arzneimittel-Forschung,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
July 1962, Experientia,
E Ohshima, and S Otaki, and H Sato, and T Kumazawa, and H Obase, and A Ishii, and H Ishii, and K Ohmori, and N Hirayama
September 1995, Arzneimittel-Forschung,
Copied contents to your clipboard!