Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor

Abstract

The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.

A Convenient Synthetic Route to 7,8-Fused Heterocyclic Ring Derivatives of (S)-2,3-Dihydro-1,4-benzodioxin-2-methanol

“…The stereochemistry at the 2-position in these tricyclic systems was assigned on the basis of the well-precedented S N 2 substitution of glycidyl arenesulfonates with phenoxides 4,9 and inversion of the stereochemistry upon intramolecular epoxide opening. 10 This was supported by a comparison of specific rotation and chiral HPLC data for (S)-2,3-dihydrofuro[3,2-f] [1,4]benzodioxin-2-methanol 7b and its (R)-enantiomer, which was prepared from (S)-glycidyl tosylate in an analogous manner. 11 In summary, we have established a novel, shorter, higheryielding and less hazardous synthesis of the enantiomerically pure dihydrodioxino[2,3-e]indole system 9a which enables the preparation of multigram quantities.…”

“…The combined extracts were washed with brine (800 mL), dried and evaporated in vacuo to give 3a (40.5 g, 99%) as a pink solid; mp 218-219°C (Lit. 1 Ethyl (R)-5-(2,3-Epoxypropoxy)-4-formylindole-2-carboxylate (4a) A stirred solution of 3a (1.5 g, 6.44 mmol) in anhyd DMF (40 mL) under N 2 was treated with K 2 CO 3 (0.89 g, 6.44 mmol). A solution of (R)-glycidyl tosylate (1.47 g, 6.44 mmol) in anhyd DMF (30 mL) was then added and the mixture stirred at r.t. for 10 min and then at 60°C for 3 h. The mixture was poured into H 2 O (400 mL) and extracted with EtOAc (3 × 200 mL).…”

“…The cooled mixture was then purified by filtration through a flash silica gel pad using a 1:4 solution of EtOAc and petroleum ether as eluant to give 2b (R 2 = H) (18.31 g, 29%) as an orange oil. 1…”

“…The mixture was extracted with CH 2 Cl 2 (2 × 150 mL) and the combined extracts washed with satd aq NaHCO 3 solution (3 × 150 mL), dried and evaporated in vacuo to give 6b (3.10 g, 94%) as a red oil. 1…”

“…In the furan series, final cyclisation of the formate ester 6b with aqueous K 2 CO 3 in THF furnished the required dihydrofuro[3,2-f] [1,4]benzodioxinmethanol 7b in 70% yield. Interestingly, small amounts of the formate 10 were also isolated from the reaction (no corresponding formates were observed to form in the other tricyclic systems).…”