Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-16
1996-04-16
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 79, C07D47118, C07D22100, A61K 31435
Patent
active
055082874
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE
This application is a 371 of PCT/US93/00880 filed Feb. 3, 1993.
This invention relates to 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid-octahydro-3-hydroxy-2,6-methano-2H-quinolizin-8-yl ester, a novel 5-HT.sub.3 -receptor antagonist, its method of preparation, and to its end-use application in the treatment of conditions responsive to 5-HT.sub.3 receptor antagonism such as radio- and chemo-therapeutically-induced nausea and vomiting, the treatment of pain associated with migraine, in the treatment of cognitive disorders such as Alzheimer's Disease, the treatment of hallucinatory endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, the treatment of irritable or inflammatory bowel syndrome, or to combat drug abuse.
More specifically this invention relates to compounds of the formula ##STR1## its tautomers, stereo- and geometrical isomers, and mixtures thereof, and to the pharmaceutically acceptable salts thereof.
As used herein, the wavy line bonding the oxygen atom of the ester moiety to the 8-position of the octahydro-2,6-methano-2H-quinolizin moiety (hereinafter sometimes referred to as the methano bridged quinolizinyl moiety) indicates that the bonding may be in the endo (trans) or the exo (cis) configuration. The preferred configuration is endo. Preparation of such geometric isomers may be effected by the processes and techniques of U.S. Pat. No. 4,906,755 which is incorporated herein by reference. A chirality exists at the 3-position of the methano-bridged quinolizinyl moiety presenting d- or 1-isomers and racemate mixtures thereof. When desired resolution of said racemates may be effected by standard procedures and techniques well known in the art. The (+) enantiomer is preferred.
The pharmaceutically acceptable acid addition salts referred to above can be non-toxic salts with suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; or with organic acids such as organic carboxylic acids, for example, acetic, propionic, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicylic, 2-acetyloxybenzoic, nicotinic or isonicotinic; or organic sulfonic acids, for example, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalenesulfonic.
The preparation of the compounds of the present invention may be illustrated by the following example.
EXAMPLE
TRANS-OCTAHYDRO-3-HYDROXY-2,6-METHANO-2H-QUINOLIZIN-8-YL ESTER trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester
A solution of triethylamine (1.79 g), 4-dimethylaminopyridine (1.09 g) and 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid (3.8 g) in dichloromethane (75 ml) was slowly added to a stirred solution of triphosgene (5.28 g) in dichloromethane (100 ml) at 0.degree. C., nitrogen being continuously bubbled through the mixture. After the addition, the mixture was stirred at room temperature overnight under nitrogen, filtered and evaporated.
A suspension of the residue in anhydrous toluene was refluxed with a stirred suspension of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one (3.25 g) overnight. The cooled solution was filtered, the toluene washed with aqueous potassium carbonate, dried over magnesium sulphate and evaporated to give a residue (4.8 g ) containing the title compound. It was then purified by partitioning between ethyl acetate (200 ml) and 1N methanesulphonic acid (40 ml). Basification of the separated methanesulphonic acid solution with a saturated aqueous solution of potassium carbonate gave a crystalline solid which was further purified by crystallization, e.g., from aqueous methanol or by silica gel chromatography to give a pure sample of the title compound. trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester
A solution of trichloromethyl chloroformate (1.76 g, 1.08 ml) in dichloromethane (10 ml) was added to a stirred solution of 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid (2 g) and triethylamine (
REFERENCES:
J. of Med. Chem. vol. 35, No. 2, pp. 310-319 (1992)--D. W. Robertson et al. "Zatosetron, a potent, selective, and long-acting 5HT.sub.3 receptor antagonist: synthesis and structure-activity relationships".
Merrell Pharmaceuticals Inc.
Moon Carolyn D.
Rotman Alan L.
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