- PHARMACOLOGICALLY ACTIVE ARYL-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
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The present invention relates to new pyrazolo[1,5-a]pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof that serve as GABAB receptor positive allosteric modulators. The invention also relates to the process for producing such compounds. The invention further relates to pharmaceutical compositions comprising such compounds optionally in combination with two or more different therapeutic agents and the use of such compounds in methods for treating diseases and conditions mediated and modulated by the GABAB receptor positive allosteric mechanism. The invention also provides a method for manufacture of medicaments useful in the treatment of such disorders.
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Page/Page column 28
(2018/10/19)
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- Synthesis and Structure-Activity Studies of a Series of Spirooxazolidine-2,4-diones: 4-Oxa Analogues of the Muscarinic Agonist 2-Ethyl-8-methyl-2,8-diazaspirodecane-1,3-dione
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A series of spirooxazolidine-2,4-dione derivatives related to the putative M1 agonist 2-ethyl-8-methyl-2,8-diazaspirodecane-1,3-dione (RS86; 1) were synthesized.The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice.Four compounds (5a,c,f and 17a) exhibited affinity for cortical M1 receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1.Among these compounds only 5a exhibited M1-receptor stimulating activity in pithed rats.Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirocuccinimide derivatives including 1.The antiamnesic dose of 3-ethyl-8-methyl-1-oxo-3,8-diazaspirodecane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter.These results suggest that the 8-azaspirodecane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.
- Tsukamoto, Shin-ichi,Ichihara, Masato,Wanibuchi, Fumikazu,Usuda, Shinji,Hidaka, Kazuyuki,et al.
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p. 2292 - 2299
(2007/10/02)
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