Studies on antihypertensive agents with antithrombotic activity. 2. Syntheses and pharmacological evaluation of pyrrolo[2,3-c]azepine derivatives.
As an extension of our previous investigation, a series of 7-aminoalkylpyrrolo[2,3-c]azepine derivatives was synthesized and evaluated as alpha1-adrenergic- and serotonin 2 (5-HT2)-receptor antagonists, with the aim of finding a novel potent antihypertensive agent with both activities. Among the compounds obtained in this study, (E)-1-ethyl-7-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hy droxyimino-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-on e (16d) displayed potent alpha1-adrenoceptor blocking activity (pA2=7.83+/-0.20) and 5-HT2-receptor blocking activity (pA2=9.47+/-0.17) in isolated guinea pig arteries. At 3 mg/kg oral administration, compound 16d exhibited antihypertensive activity more potent than that of doxazosin in deoxycorticosterone acetate (DOCA)-salt hypertensive dogs. Furthermore, this compound reduced the rate of mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or more, and its effect lasted for at least 6 h at 3 mg/kg.
Mizuno
A
A
Suntory Institute for Biomedical Research, Mishima-gun, Osaka, Japan. Akira_Mizuno@suntory.co.jp
Miya
M
M
Kamei
T
T
Shibata
M
M
Tatsuoka
T
T
Nakanishi
K
K
Takiguchi
C
C
Hidaka
T
T
Yamaki
A
A
Inomata
N
N
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D004341:Drug Evaluation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D000991:Antithrombins; D001381:Azepines; D012702:Serotonin Antagonists