Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1993-08-03
2001-11-20
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06320048
ABSTRACT:
BACKGROUND OF THE INVENTION
In EP-A-0,196,132 there are described a number of 3-piperidinyl-1,2-benz-isoxazoles having antipsychotic activity.
The compounds of the present invention differ therefrom by the specific substitution on the (2-C
1-4
alkyl-6,7,8,9-tetrahydro-4-oxo-4
H
-pyrido[1,2-a]-pyrimidin-3-yl)alkyl substituent at the 1 position of the piperidinyl moiety.
DESCRIPTION OF THE INVENTION
The present invention is concerned with novel 3-piperidinyl-1,2-benzisoxazoles having the formula
the pharmaceutically acceptable acid addition salts thereof, and the stereochemically isomeric forms thereof, wherein
Alk is C
1-4
alkanediyl;
R
1
is hydrogen, C
1-4
alkyl or halo;
R
2
is C
1-4
alkyl;
R
3
is hydroxy or R
4
—C(═O)O—; and
R
4
is C
1-19
alkyl.
In the foregoing definitions C
1-4
alkanediyl defines bivalent straight and branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomers thereof; C
1-4
alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethyl-ethyl; C
1-19
alkyl defines C
1-4
alkyl radicals as defined hereinabove and the higher homologs thereof having from 5 to 19 carbon atoms such as, for example, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and the like; halo is generic to fluoro, chloro, bromo and iodo. R
3
as defined hereinabove may be substituted on any of the 6,7,8 or 9 positions of the 6,7,8,9-tetrahydro-2-C
1-4
alkyl-4
H
-pyrido[1,2-a]pyrimidin-4-one moiety.
Particular compounds are those compounds of formula (I) wherein R
3
is substituted on the 9 position of the 6,7,8,9-tetrahydro-2-C
1-4
alkyl-4
H
-pyrido[1,2-a]pyrimidin-4-one moiety.
More particular compounds within the invention are those particular compounds wherein Alk is ethanediyl; and/or R
1
is halo, in particular fluoro and more in particular 6-fluoro; and/or R
2
is methyl.
Among the above defined groups of compounds of formula (I) those compounds wherein R
4
is C
7-13
alkyl, in particular heptyl, nonyl, undecyl or tridecyl are of particular interest.
The most interesting compounds within the invention are selected from the group consisting of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]lethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4
H
-pyrido[1,2-a]pyrimidin-4-one, the pharmaceutically acceptable acid addition salt forms and the enantiomeric forms thereof.
From formula (I) it is evident that the compounds of this invention have at least one asymmetric carbon atom in their structure, namely the carbon atom bearing the R
3
substituent. The absolute configuration of this centre may be indicated by the stereo-chemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem. 1976, 45, 11-30. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of the invention.
The compounds of formula (I) can generally be prepared by
N
-alkylating a 3-piperidinyl-1,2-benzisoxazole of formula (II) with an alkylating reagent of formula (III) following art-known
N
-alkylation procedures.
In formula (III) W represents an appropriate reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-methylbenzenesulfonyloxy and the like leaving groups. Said
N
-alkylation reaction can conveniently be carried out by mixing the reactants, optionally in a reaction-inert solvent such as, for example, water; an aromatic solvent, e.g. benzene, methylbenzene, dimethylbenzene, chlorobenzene, methoxy-benzene and the like; a C
1-6
alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ester, e.g. ethyl acetate, &ggr;-butyrolactone and the like; an ether, e.g. 1,1′-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; a dipolar aprotic solvent, e.g.
N
,
N
-dimethylformamide,
N
,
N
-dimethylcetamide, dimethylsulfoxide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1
H
)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylurea, 1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile and the like; or a mixture of such solvents. The addition of an appropriate base such as, for example, an alkali metal or an earth alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide and the like, or an organic base such as, for example, a tertiary amine, e.g.
N
,
N
-diethylethanamine,
N
-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]octane, pyridine and the like, may optionally be used to pick up the acid which is formed during the course of the reaction. In some instances the addition of an iodide salt, preferably an alkali metal iodide, or a crown ether, e.g. 1,4,7,10,13,16-hexaoxa-cyclooctadecane and the like, may be appropriate. Stirring and somewhat elevated temperatures may enhance the rate of the reaction; more in particular the reaction may be conducted at the reflux temperature of the reaction mixture. Additionally, it may be advantageous to conduct said
N
-alkylation under an inert atmosphere such as, for example, oxygen-free argon or nitrogen gas.
Alternatively, said
N
-alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions. Said conditions comprise stirring the reactants, with an appropriate base and optionally under an inert atmosphere as defined hereinabove, in the presence of a suitable phase transfer catalyst such as, for example, a trialkylphenylmethylammonium, tetraalkyiammonium, tetraalkylphosphonium, tetraarylphosphonium halide, hydroxide, hydrogen sulfate and the like catalysts. Somewhat elevated temperatures may be appropriate to enhance the rate of the reaction.
In this and the following preparations, the reaction products may be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
The compounds of formula (I) can also be obtained by the cyclization of an oxime of formula (IV), wherein Y is a reactive leaving group such as, for example, halo or nitro. Preferably Y is a halo group and more particularly fluoro.
Said cyclization reaction of the oxime of formula (IV) may conveniently be conducted by treatment with an appropriate base, preferably in a suitable reaction-inert solvent at temperatures in the range of 20° to 200° C., preferably at 50° to 150° C., and in particular at the reflux temperature of the reaction mixture. Or, if desirable, said base may first be added, preferably at room temperature, whereupon the thus formed oxime salt is cyclized, preferably at an increased temperature and more preferably at the reflux temperature of the reaction mixture. Appropriate bases for said cyclization are, for example, alkali and earth alkaiine metal carbonates, hydrogen carbonates, hydroxides, alkoxides or hydrides, e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride or organic bases such as amines, e.g.
N
,
N
-diethylethanamine, 4-ethylmorpholine and the like bases. Suitable solvents are, for example, water; aromatic hydrocarbons, e.g. benzene,
Janssen Cornelus Gerardus Maria
Kennis Ludo Edmond Josephine
Knaeps Alfonsus Guilielmus
Vandenberk Jan
Berch Mark L.
Janssen Pharmaceutica N.V.
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