New antihistamines: substituted piperazine and piperidine derivatives as novel H1-antagonists.
Structural manipulation of polycyclic piperazinyl imide serotonergic agents led to the synthesis of compound 8, 2-[4-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-4, 4a,5,5a,6,6a-hexahydro-4,6-ethenocycloprop[f]isoindole-1,3(2H,3 aH)-dione, which demonstrated good H1-antagonist activity. Substitution of a xanthinyl moiety for the polycyclic imide group led to the identification of novel xanthinyl-substituted piperazinyl and piperidinyl derivatives with potent antihistamine H1-activity without the undesirable antidopaminergic activity of 8. One compound, 24, 7-[3-[4-(diphenylmethoxy)-1-piperidinyl]propyl]- 3,7-dihydro-1,3-dimethyl-1H-pyrine-2,6-dione (WY-49051), is a potent, orally active H1-antagonist with a long duration of action and a favorable central nervous system profile.
Abou-Gharbia
M
M
Chemical Sciences Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
Moyer
J A
JA
Nielsen
S T
ST
Webb
M
M
Patel
U
U
D000818:Animals; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D006634:Histamine H1 Antagonists; D010879:Piperazines; D010880:Piperidines