Synthesis and biological activity of N-substituted spiro[benzoxazepine-piperidine] Aβ-peptide production inhibitors

Figures & data

Figure 1.  Structure of DAPT and LY-411, 575.

Figure 2.  General structure of spiro[benzoxazepine-piperidine].

Scheme 1 Reagents and conditions: (i) N-benzyl piperidone, pyrrolidine, MeOH, reflux; (ii) HCl.H₂N-OH, pyridine, EtOH, reflux; (iii) DIBAH, CH₂Cl₂, 0°C; (iv) H₂, Pd(OH)₂ (10%), MeOH, rt, 80%.

Scheme 2 Reagents and conditions: (i) ClCH₂CH₂CH(Ph)OH (S) or (R), CH₃CN, K₂CO₃, 35°C, 24 h; (ii) Br(CH₂)₄-phthalimide, CH₃CN, K₂CO₃, reflux, 12 h; (iii) H₂NNH₂, 24 h; (iv) RCO₂H, BOP, DIEA, CH₂Cl₂, rt, 18 h.

Table I.  Inhibitory activities of spiro[benzoxazepine-piperidine] derivatives.

Compounds	Aβ40 IC50 (μM)^a, b
2a	0.2 ± 0.3
2b	0.5 ± 0.1
2c	Inactive (100 μM)
2d	Inactive (100 μM)
3a	Inactive (100 μM)
3b	4.7 ± 0.2
3c	Inactive (100 μM)
3d	6 ± 0.7

^a Potency determination for the ability of compounds to reduce Ab40 production from HEK293 cells

^b using a cell viability standard assay [23], the whole compounds did not elicit any cell cytotoxicity at least below 1 mM concentrations.

LD Plant, JP Boyle, IF Smith, C Peers, HA Pearson. The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci (2003); 23(13):5531–5535.

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