- Structural optimization of 4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines as antagonists for platelet activating factor: Pharmacological contribution of substituents at the 2- and 6-positions of a condensed ring system
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A series of 4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine derivatives bearing substituents at the 2- and 6-positions were synthesized, and evaluated in vitro for their inhibitory activity on rabbit platelet aggregation induced by platelet activating factor (PAF) and in vivo for their preventing effect on PAF-induced mortality in mice. The length of alkyl or arylalkyl side chain at the 2-position was responsible for enhancing the affinity for the PAF receptor. The simultaneous substitution at both the 2- and 6-positions resulted in a successful separation of the affinity for the PAF receptor from that for the benzodiazepine (BZ) receptor. Thus, (±)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]- 6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine (Y-24180) was confirmed to be a specific antagonist for the PAF receptor and is currently under clinical trials.
- Kawakami,Kitani,Yuasa,Abe,Moriwaki,Kagoshima,Terasawa,Tahara
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p. 683 - 692
(2007/10/03)
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- 2-alkyl thieno(triazolo)diazepine compounds and pharmaceutical uses thereof
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A thienotriazolodiazepine compound of the formula: STR1 wherein Ar is phenyl, pyridyl, substituted phenyl or substituted pyridyl; R1 and R3 are the same or different and each is hydrogen, alkyl having 1 to 4 carbon atoms; R2 is hydrogen, alkyl having 1 to 4 carbon atoms or trifluoromethyl; R4 is straight or branched chain alkyl, alkenyl or alkynyl having 6 to 18 carbon atoms, or a thienodiazepine compound of the formula: STR2 wherein Ar, R1, R2 and R4 are as defined above, and pharmaceutically acceptable acid addition salt thereof. These compounds are useful as drugs for the treatment of circulatory diseases and various PAF-induced diseases. The compound (II) is also useful as an intermediate for preparing the compound (I).
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