123319-30-2

Usage

InChI:InChI=1/C12H19NO4/c1-3-16-11(15)13-6-4-12(5-7-13)8-10(14)9(2)17-12/h9H,3-8H2,1-2H3

Upstream product

• 123335-55-7 ethyl (1-ethoxycarbonyl-4-piperidinylidene)acetate 
• 133382-37-3 4-(3-hydroxy-1-butynyl)-1-(ethoxycarbonyl)-4-piperidinol 

Relevant academic research and scientific papers

Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists

2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (17), designed by incorporating the tetrahydrofuran ring moiety of muscarone into an 8-azaspiro[4.5]decane skeleton, and related 1-oxa-8-azaspiro[4.5]decanes were synthesized and assessed as M1 muscarinic agonists for the symptomatic treatment of dementia of Alzheimer's type. The compounds were tested for central muscarinic M1 and M2 receptor affinity and in vivo muscarinic activities: namely, amelioration of scopolamine-induced impairment in rat passive avoidance tasks, and induction of hypothermia, tremor, and salivary secretion. Compound 17 exhibited potent muscarinic activities in vitro and in vivo with no selectivity. Systematic modifications of 17 were conducted, and a number of compounds, including the 2-ethyl analogue (18), 3-methylene analogue (29), 3-dithioketal analogues (26, 28), and 3-oxime analogue (37) were found to display preferential affinity for M1 receptors over M2 receptors and, in addition, to exhibit potent antiamnesic activity sufficiently separated from hypothermia-inducing activity, taken as an index of cholinergic side effects, compared with the reference compound RS86 (1). Structure-activity relationships are discussed in comparison with those for muscarone analogues. Of these compounds only two, 2-ethyl-8-methyl-1-oxa-8-azaspiro[4.5]decan-3-one (18) and 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (29), stimulated phosphoinositide hydrolysis in rat hippocampal slices, indicating partial agonistic activity for M1 muscarinic receptors. The optical resolution of 18 and 29 was performed. Eudismic ratios of both compounds in binding affinity were low, but M1 agonist activity resided preferentially in the (-)-isomers. The absolute configuration of (-)-29 was determined by X-ray crystal structure analysis to be S, being the same as that of muscarone. Based on the in vivo selectivity, (-)-29 was selected for clinical studies.

In vitro muscarinic activity of spiromuscarones and related analogs

The cholinergic hypothesis of Alzheimer's disease suggests that cholinergic agonists may have therapeutic potential for treating the attendant memory deficits of the disease. As part of a program aimed at preparing metabolically stable, nonquaternary analogs of muscarone, 1-oxa- 2,8-dimethyl-8-azaspiro[4.5]decan-3-one, 2a, and related analogs have been synthesized and their in vitro muscarinic activity evaluated. The synthetic strategy in the formation of the 1-spiro[4.5]decan-3-one ring system of 2a involved cyclization of the diol 4 in the presence of Nafion-Hg. The spiromuscarone 2a was found to displace [3H]Oxo-M binding with a K(i) value of 7 nM. Affinities of the oxime and hydrazone analogs of 2a were lower than 2a. The compounds in these series were partial muscarinic agonists as demonstrated by stimulation of phosphatidyl inositol hydrolysis assay, with 2a showing the highest intrinsic activity (60% as compared with carbachol). The results from this study indicate that an exo double bond at the C-3 position is essential for the receptor binding.

Heterocyclic spiro compounds and methods for preparing the same

Heterocyclic spiro compounds represented by the following general formula and salts thereof: STR1 The above compounds act upon muscarinic acetylcholine receptors, thereby activating the acetylcholine nervous functions in the central nervous system.