N-benzoylmethyl-piperidines

Details N-benzoylmethyl-piperidines N-benzoylmethyl-piperidines

1996-02-20

1997-09-09

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546197, A61K 31445, C07D40512

Patent

active

056657366

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/01007 filed Mar. 17, 1995.
The present invention relates to new N-benzoylmethyl-piperidines of the general formula (I) : ##STR2## wherein X is a halogen atom, as well as their pharmaceutically acceptable addition salts.
In the compounds of the general formula (I), the halogen represented by X is preferably chlorine or fluorine, but more preferably fluorine. Among the pharmaceutically acceptable salts, hydrochloride is preferred.
The compounds of the present invention are prepared by alkylation of (-)-trans-4-(p-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]-piper idine, antidepressant known as paroxetine, having the structural formula (II): ##STR3## with p-halo-phenacyl halide of the general formula (III): ##STR4## wherein X is defined as in (I) and Y may be either chlorine or bromine. This alkylation occurs advantageously in an anhydrous alcohol medium and in the presence of a mineral base that facilitates the uptake reaction of the formed hydracid. Among solvents, low molecular weight alkanols, such as methanol or ethanol, are preferred, and among bases, alkali metal carbonates or hydrogen carbonates, such as sodium hydrogen carbonate, are preferred. As the reaction is enhanced by heat release, it is advisable to perform it at the boiling temperature of the mixture.
British Patent No. 1.422.263 describes the preparation of the piperidine of the formula (II) as well as its antidepressant properties on the basis of its ability to inhibit 5-hydroxytryptamine (5HT) reuptake selectively.
Applicants have found out that the compounds of the present invention are also able to inhibit 5-hydroxytryptamine reuptake in the same manner as the compound they derive from. However, these compounds advantageously exhibit lower toxicity signs while the selective inhibition degree of 5-hydroxytryptamine reuptake is at least the one of paroxetine. The results on the reuptake inhibition of 5-hydroxytryptamine (5HT) and dopamine (DA) in rat brain synaptosomes, which are expressed as molar concentrations, are shown in Table 1. This test was performed according to the method described by Ferris RM et al ("Pharmacol.Drug Dev.Res.", 1, 21-35, 1981) and revealed that the compound of Ex. 1 is at least as selective as paroxetine, while the compound of Ex. 2 is seven times more selective.


TABLE 1 ______________________________________ IC.sub.50 (M) 5HT/DA Relative 5HT DA Selecti- Selecti- Compound (cortex) (striatum) vity vity* ______________________________________ Example 1 2.11 .times. 10.sup.-8 >1 .times. 10.sup.-5 >474 >1.06 Example 2 6.85 .times. 10.sup.-9 2.22 .times. 10.sup.-5 3241 7.25 Paroxetine 2.46 .times. 10.sup.-9 1.10 .times. 10.sup.-6 447 1 ______________________________________ *Relative selectivity versus paroxetine.
The lower toxicity of the compounds of this invention with regard to paroxetine has been made evident by Irwin test ("Science", 136, 123, 1962) in mice administered orally with test substances. Under test conditions, paroxetine at the dose of 400 mg/kg caused convulsions, mydriasis and Straub tail. In contrast, the compound of Ex. 1 at the dose of 600 mg/kg did not show any sign of toxicity, while in the compound of Ex. 2 merely the onset of manifestations of hyperactivity was observed at the dose of 800 mg/kg. These findings are most important, since the safety range of the compounds of this invention makes them be highly useful for their clinical application.


EXAMPLE 1



(-)-Trans-N-p-fluorobenzoylmethyl-4-(p-fluorophenyl)-3-[[3,4-(methylenediox
y)phenoxy]methyl]-piperidine hydrochloride
(-)-Trans-4-(p-fluorophenyl)-3-[[3,4-(methylenedioxy) phenoxy]methyl]-piperidine hydrochloride (7.32 g, 0.02 mole) was dissolved in absolute ethyl alcohol (100 ml). Then, NaHCO.sub.3 (6.38 g, 0.076 mole) and 2-chloro-4'-fluoroacetophenone (4.49 g, 0.026 mole) were added and refluxed for 3 hours. The solution was cooled, the inorganic salts were filtered, the solid was washed with small volumes of ethanol, and the liqui

REFERENCES:
patent: 4721723 (1988-01-01), Barnes
patent: 5158961 (1992-10-01), Jakobsen et al.
Matsubayashi et al. "Mass fragmentographic determination of lofepramine . . . " CA 88:31799 1978.
Kimura et al. "Metabolism of an antidepressant, Lofepramine . . . " CA 90:179852 1979.
Jolles et al. "Drug design: fact of fantasy" Academic Press, pp. 47-49, 57-58 1984.
Bundgaard et al. "A novel solution-stable water soluble prodrug . . ." J. Med. Chem. v. 32, pp. 2503-2507 1989.

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