# Patent

## Title
2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists

## Abstract

A suspension of 6.42 g of silver tetrafluoroborate in 300 ml of anhydrous toluene was evaporated to dryness to give a residue of the anhydrous salt. A solution of this anhydrous salt in anhydrous nitroethane (50 ml) was slowly added to a stirred solution of 7.74 g of trans-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one tetrafluoroborate and 6 g of 3-indolylglyoxylyl chloride in 100 ml of anhydrous nitroethane cooled to -10.degree. C. under nitrogen. The mixture was stirred overnight at room temperature, poured into a saturated aqueous solution of potassium carbonate (30 ml) and the resulting mixture was extracted with 200 ml of ethyl acetate. The separated organic phase was dried over magnesium sulfate, the solvent evaporated and the residue redissolved in 200 ml of ethyl acetate. After washing three times with water to remove unchanged starting alcohol, the ethyl acetate solution was dried and evaporated to give a residue (7.4 g) of crude trans-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-o ne base. The residue was treated with a solution of 2.2 g of methanesulphonic acid in 50 ml of ethanol at 60.degree. C. The solid material remaining undissolved was filtered off and the reddish-brown solution was treated with charcoal. On cooling, the filtered solution afforded crystals of trans-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-o ne methanesulphonate monohydrate (66%).y standard procedures.

## Background
## Claims

1. A pharmaceutical composition suitable for use in the treatment of anxiety, psychosis, glaucoma, and for stimulating gastric motility comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula ##STR7## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 ; R.sub.1 is ##STR8## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy, or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxyl, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.

2. A pharmaceutical composition according to claim 1 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-on e.

3. A method for the treatment of anxiety comprising administering to a patient in need thereof of an effective amount of a compound of the formula ##STR9## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR10## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.

4. A method according to claim 3 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-on e.

5. A method for the treatment of psychosis comprising administering to a patient in need thereof an effective amount of a compound of the formula ##STR11## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR12## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.

6. A method according to claim 5 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-on e.

7. A method for stimulating gastric motility comprising administering to a patient in need thereof an effective amount of a compound of the formula: ##STR13## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NH.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR14## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.

8. A method according to claim 7 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-on e.

9. A method for the treatment of glaucoma comprising administering to a patient in need thereof an effective amount of a compound of the formula: ##STR15## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR16## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1.varies.4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.

10. A method according to claim 9 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-on e.

11. A pharmaceutical composition according to claim 1 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.

12. A method according to claim 3 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.

13. A method according to claim 5 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.

14. A method according to claim 7 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.

15. A method according to claim 9 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.