New N₄-substituted piperazine naphthamide derivatives as BACE-1 inhibitors

Figures & data

Figure 1.  General structure of new N₄-substituted piperazine naphthamide derivatives as BACE-1 inhibitors.

Scheme 1.  Reagents and conditions: (i) (a) N-Boc-piperazine (b) or N-benzylpiperazine, i-PrOH, reflux, 24 h; (ii) Zn powder, 1 M KH₂PO₄/THF, reflux, 24 h; (iii) 1-naphthoyl chloride, CH₂Cl₂, TEA, rt, 4 h; (iv) HCO₂NH₄, 10 wt% Pd/C, CH₃OH, reflux, 6 h; (v) TFA, CH₂Cl₂, rt, 12 h; (vi) R₂COCl, CH₂Cl₂, Et₃N; (vii) R₂CO₂H, DCC, HOBt, DMAP, rt, 2 h.

Table I.  BACE-1 inhibition activity of N₄-substituted piperazine naphthamide derivatives.

No.	R1	R2	BACE-1^a IC50 (μM)	C log P^b	No.	R1	R2	BACE-1^a IC50 (μM)	ClogP^b
4a	H	H	Inactive	2.72	4b		Br	Inactive	4.17
5a	H		10**	4.41	6a	Br		1*	5.58
6a	H		1*	4.64	6b	Br		1*	5.81
7a	H		10**	3.84	7b	Br		10**	5.01
8a	H		Inactive	5.07	8b	Br		Inactive	6.24
9a	H		Inactive	2.85	9b	Br		Inactive	4.02
10a	H		Inactive	6.11	10b	Br		Inactive	7.28
11a	H		Inactive	2.13	11a	Br		Inactive	3.30

^a The BACE-1 fluorescence resonance energy transfer assay kit was purchased from PanVera (No. P2985). BACE-1 activity assays were carried out according to the manufacturer's instructions. Average value is from three independent experiments. Values show means of at least three independent experiments each performed in triplicates, with standard errors of mean. *P < 0.5 and **P < 2; ^b Calculated log P values from ACD (Advanced Chemistry Development, Inc., Toronto, Ont., Canada) log P 1.0 base calculations.