Indenopyridazinone derivatives as potential antisecretory and antiulcer agents.
A series of substituted indenopyridazinones (4b-h) has been synthesized and tested for their antisecretory and antiulcer activity, in comparison with ranitidine, as reference drug. While the monomethoxy (4b-d), as well as the benzyloxy (4f) and the 6,9-dimethoxy (4g) derivatives were found to be devoid of overt antisecretory properties, the 9-methoxy (4e) was weakly active. The most interesting compound of this class was the 7,8-dimethoxy substituted (4h), which at an oral dose of 30 mg/kg still retains a significant activity. The dihydroderivatives of 4g,h (compounds 1g,h) were more active (1g) or comparable (1h) to the parent compounds, thus proving that the 4, 4a-double bond, which was an essential requirement in the analogues 2 and 3, is not necessary in this new series. The disubstituted derivatives (1g,h; 4g,h) were also tested as antiulcer agents, in two different models. All compounds were able to prevent haemorragic lesions induced in rats by 90% ethanol in a dose dependent manner. In the indomethacin model they still showed a significant activity, though lower than in the previous test. Attempts have been made to elucidate their mechanism of action.
Barlocco
D
D
Ist. Chim. Farm. e Toss, Milano, Italy.
Cignarella
G
G
Vianello
P
P
Dal Piaz
V
V
Giovannoni
M P
MP
Malandrino
S
S
Barocelli
E
E
Chiavarini
M
M
Impicciatore
M
M
D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000627:therapeutic use*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000627:therapeutic use*; D007192:Indenes / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D011724:Pyridazines / Q000138:chemical synthesis / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D007192:Indenes; D011724:Pyridazines