Synthesis of 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides and their evaluation as ligands for NMDA receptor glycine binding site

Figures & data

Figure 1. Structure of DCKA, naphthoic acid II, target compounds III and IV, MRZ-2/596 and quinoxaline VI.

Scheme 1. Synthesis route to compounds 8a, b, c. Reagents and conditions: (a) SOCl₂, ClSO₃H, 0 °C – r.t.; (b) t-BuNH₂, Et₃N, CH₂Cl₂; (c) H₅IO₆, CrO₃, (CH₃CO)₂O, MeCN, 0 °C – r.t.; (d) TFA; (e) PMBCl, NaH, DMF, 80 °C; (f) NaBH₄, THF/H₂O; (g) NaH, ethyl bromoacetate, THF, 50 °C.

Scheme 2. Synthesis route to compounds 13a, b, c. Reagents and conditions: (a) MnO₂, THF; (b) NaH, THF; (c) TFA; (d) DIEA, DMF, 3-ClC₆H₄CH₂Cl or 3-BrC₆H₄CH₂Br; (e) LiOH, THF/H₂O; (f) NaOH, THF/H₂O.

Scheme 3. Synthesis of target compounds 18 and 19. Reagents and conditions: (a) PBr₃, Et₂O; (b) NaH, THF; (c) TFA, CH₂Cl₂; (d) R4CH₂Hal, NaH, DMF; (e) LiOH^.H₂O or NaOH, THF/H₂O.

Table 1. Activity of compounds 18 and 19 in binding experiments.

Nr.	R1	R^2	R^3	R4	I (%)*	IC50 (µM)	K^i (µM)†
18a	H	H	Cl	4-MeOPh	46
18b	Cl	H	Cl	4-MeOPh	48
18c	H	H	Cl	3-MeOPh		3.6	2.5
18d	H	H	Cl	4-ClPh		8.9	6.2
18e	H	H	Cl	3-ClPh		2.5	1.8
18f	H	H	Cl	3-BrPh		2.0	1.4
18g	H	H	Cl	Ph	59
18h	H	Cl	Cl	3-ClPh	55
18i	H	H	Cl	Bn	38
18j	H	H	Cl	3-MeOBn	61
18k	H	H	Cl	2-MeOBn	66
18l	H	H	Cl	2-FBn	40
18m	H	Cl	Cl	Bn	80
18n	H	H	Cl	3-MeOPhCO		1.5	1.1
18o	H	H	Cl	2-MeOPhCO		2.1	1.7
18p	H	H	Cl	3-FPhCO		7.2	5.0
18q	H	H	Cl	4-ClPhCO		4.5	3.2
18r	H	H	Cl	2-Py	80
18s	H	H	Cl	3-Py	68
18t	H	H	Cl	4-(2-MeTh)‡	88
18u	H	H	Cl	CO2t-Bu	82
19	H	H	Cl	–¶		13.2	9.2

*Remaining radioactivity of [³H]MDL-105,519 at 10 µM concentration of substrate.

†Affinity for Gly binding site; displacement of [³H]MDL-105,519 from rat cortical membrane preparations.

‡2-Methyl-1,3-thiazol-4-yl.

¶Unsubstituted at N(2).

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