Aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide as carbonic anhydrase inhibitors

Figures & data

Scheme 1. Reagents and conditions for the preparation of derivatives 8–12: (i) ICl, AcOH, 40 °C, 24 h, 84%; (ii) KOtBu, CH₃P(C₆H₅)₃Br, THF, RT, 18 h, 83%; (iii) NEt₃, CH₂Cl₂, 0 °C to RT, 4 h, 83%; (iv) toluene, 70 °C, 4 h, 89%; (v) Ar-B(OH)₂, Pd(PPh₃)₄, K₃PO₄, toluene/H₂O, 100 °C, 16 h.

Scheme 2. Reagents and conditions: (i) KOtBu, CH₃P(C₆H₅)₃Br, THF, RT, 18 h, 82%; (ii) 4, NEt₃, CH₂Cl₂, 0 °C to RT, 4 h, 66%; (iii) a) 6 (5 mol% and 10 mol%), toluene, 70 °C, 40 h, 0%; b) Schrock catalyst [Mo] (10 mol%), toluene, 70 °C, 16 h, 0%; c) Schrock–Hoveyda [Mo] (10 mol%), toluene, 70 °C, 16 h, 0%;

Scheme 3. Reagents and conditions: (i) KOtBu, CH₃P(C₆H₅)₃Br, THF, RT, 18 h, 76%; (ii) 4, NEt₃, CH₂Cl₂, 0 °C to RT, 4 h, 54%; (iii) 6, toluene, 70 °C, 4 h, 90%; (iv) Ar-B(OH)₂, Pd(PPh₃)₄, K₃PO₄, toluene/H₂O, 100 °C, 16 h.

Scheme 4. Reagents and conditions: (i) KOtBu, CH₃P(C₆H₅)₃Br, THF, RT, 18 h, 80%; (ii) 4, NEt₃, CH₂Cl₂, 0 °C to RT, 4 h, 86%; (iii) 6, toluene, 70 °C, 4 h, 78%; (iv) Ar-B(OH)₂, Pd(PPh₃)₄, K₃PO₄, toluene/H₂O, 100 °C, 16 h.

Table 1. Inhibition data of human CA isoforms CA I, II, IX and XII with 3H-1,2-benzoxathiepines 2,2-dioxide 7–34 using AAZ as a standard drug.

Cmpd	7 / 8 / 9	R	KI (nM)*
			CA I	CA II	CA IX	CA XII
7	7	I	>100 µM	>100 µM	66.2	455.5
8	7	H	>100 µM	>100 µM	654.8	1376
9	7	OCH3	>100 µM	>100 µM	407.6	2934
10	7	F	>100 µM	>100 µM	330.8	890.5
11	7	CF3	>100 µM	>100 µM	221.4	4017
12	7	CO2CH2CH3	>100 µM	>100 µM	620.8	2398
20	8	Br	>100 µM	>100 µM	47.5	132.9
21	8	H	>100 µM	>100 µM	104.8	473.2
22	8	OCH3	>100 µM	>100 µM	63.1	168.6
23	8	F	>100 µM	>100 µM	95.2	77.9
24	8	CF3	>100 µM	>100 µM	44.0	247.8
25	8	CO2CH2CH3	>100 µM	>100 µM	79.8	289.3
29	9	Br	>100 µM	>100 µM	754.8	3824
30	9	H	>100 µM	>100 µM	21.1 µM	>100 µM
31	9	OCH3	>100 µM	>100 µM	60.9 µM	>100 µM
32	9	F	>100 µM	>100 µM	33.7 µM	>100 µM
33	9	CF3	>100 µM	>100 µM	47.1 µM	>100 µM
34	9	CO2CH2CH3	>100 µM	>100 µM	16.4 µM	>100 µM
AAZ	–	–	250	12	25	5.7

^* Mean from three different assays, by a stopped flow technique (errors were in the range of ± 5–10% of the reported values).