Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-17
2002-07-02
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S209000
Reexamination Certificate
active
06413989
ABSTRACT:
The invention relates to the compound 5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-3-(4-hydroxy-phenyl) oxazolidin-2-one of the formula I
and to physiologically acceptable salts thereof.
The invention relates to the compound of the formula I according to claim
1
and also to its enantiomers and to its salts.
Piperidinylmethyloxazolidone derivatives are known as psychopharmacologically effective substances from EP 0 763 535.
With regard to this protective right, the compound according to the invention should be regarded as a selection invention.
The invention had the object of providing novel compounds which can be employed for the production of medicaments, but which have a more pronounced activity spectrum than the active compounds of the prior art and which act selectively on the central nervous system, have few side effects, can, at the same time, owing to a modified structure, be administered in a dose which is as low as possible and have a very low, if any, addictive potential.
It has now been found that, while being well tolerated, the compound of the formula I and its physiologically acceptable salts have useful pharmacological properties. It displays effects in particular on the central nervous system, and has neuroleptic, tranquillizing, anxiolytic, antidepressive and memory-enhancing actions.
The invention therefore relates to the compound of the given formula I and to salts thereof, and to their use as pharmacologically active compound.
However, the invention also relates to suitable processes for preparing these compounds and/or salts thereof.
Specifically, the compound of the given formula I and salts thereof have neuroleptic action; it inhibits the apomorphine-induced climbing behaviour in mice, the apomorphine-induced stereotypical behaviour in rats (for method see Costall et al., European J. Pharmacol. 50 (1978), 39-50, and Puech et al., European J. Pharmacol. 50 (1978) 291-300, respectively) and the conditioned avoiding reaction in rats (for method see Niemegeers et al., Psychopharmacology 16 (1969), 161-174), without the occurrence of catalepsy (for method see Stanley and Glick, Neuropharmacology 15 (1976), 393-394), which is seen as an indication of the lack of a side-effect potential with respect to extrapyrimidal motor side effects (Hoffmann and Donovan, Psychopharmacology 120 (1995), 128-133). It inhibits ultrasound vocalization after electric stimulation in rats (proof of the anxiolytic action; for method see De Vry et al., European J. Pharmacol. 249 (1993), 331-339) and has a depressive effect on the spontaneous behaviour of mice and rats (for method see Irwin, Psychopharmacology 13 (1968), 222-257). Additionally, in the binding experiment this active compound displaces tritiated ifenprodil in the forebrain of rats from its binding site (for method see Schoemaker et al., European J. Pharmacol. 176 (1990), 249-250), which represents a receptor at the N-methyl-D-aspartate (NMDA) receptor/ion channel complex as a subtype of the glutamate receptors.
Based on the glutamate deficiency hypothesis of schizophrenia (Ishimaru and Toru, CNS Drugs 7 (1997), 47-67; Carlsson et al., Int. Acad. Biomed. Drug Res., 4 (1993), 118), substances which display agonistic action at glutamate receptors represent an entirely novel principle of action for the treatment of schizophrenia, whereas customary neuroleptics, in contrast, act directly as antagonists at the dopamine receptor (in accordance with the classic dopamine overactivity hypothesis of schizophrenia, Carlsson et al., Life Sciences 61 (1997), 75′94) , with the disadvantage that they cause the typical extrapyrimidal motor side effects which, in some cases, are irreversible after long-term treatment, and which induce mental impairments such as anxiety (Casey, Int. Clinical Psychopharmacology 10 Suppl. 3 (1995), 105-114).
Surprisingly, it has now been found that the 5S-enantiomer of the compound according to the invention is a potent ligand in vitro in the nanomolar concentration range for the polyamine binding site and has, in comparison to the compounds of the formula A, B and C (C see EP 0 763 535; page 9, line 18), neuroleptic actions.
The pharmacological test data are summarized in Table I.
Based on these results of the investigations, it has been found that the compound of the formula I and physiologically acceptable acid addition salts thereof can be used as active compound for medicaments, and also as intermediate for the preparation of other active compounds for medicaments.
The invention furthermore relates to a process for preparing the compound of the formula I according to claim
1
, characterized in that
a) a compound of the formula II
in which
L is Cl, Br, I or a free or reactively functionally modified OH group
is reacted with a compound of the formula III
or
b) a compound of the formula IV
is the reacted with a compound of the formula V
in which L and L′ independently of one another are in each case Cl, Br, I or a free or reactively functionally modified OH group or
c) a compound of the formula VI
is hydrogenated or
d) the compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent and/or in that a basic compound of the formula I is converted into one of its salts by treatment with an acid.
Otherwise, the preparation of the compounds of the formula I is carried out by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag; J. March, Advanced Organic Chemistry 3rd. Ed. (1984) or Organic Reactions, both John Wiley & Sons, Inc. New York), specifically under reaction conditions known and suitable for the said reactions. It is moreover possible to make use of variants which are known per se but not mentioned here in detail.
The compound of the formula I can preferably be obtained by reacting a compound of the formula II with the compound of the formula III.
Some of the starting materials of the formulae II and III are known. Those which are not known can be prepared by methods known per se.
Primary alcohols of the formulae II are obtainable, for example, by reduction of the corresponding carboxylic acids or esters thereof. Treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds generates the corresponding halides of the formula II.
The compound of the formula III can be prepared, for example, analogously to scheme 1.
The reaction of the compounds of the formula II with the compound of the formula III is generally carried out in an inert solvent, in the presence of an acid binder, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, or another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline, may also be favourable. Depending on the conditions employed, the reaction time is between some minutes and 14 days, the reaction temperature is between about 0° and 150°, normally between 20° and 130°.
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme) ; ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile, sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid
Bartoszyk Gerd
Gottschlich Rudolf
Leibrock Joachim
Prucher Helmut
Seyfried Christoph
Merck Patent Gesellschaft mit beschrankter Haftung
Millen White Zelano & Branigan P.C.
Morris Patricia L.
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