Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-05-08
2002-07-02
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S206000
Reexamination Certificate
active
06413986
ABSTRACT:
The present invention relates to [1-indanon-2-yl]methylpiperidines. More particularly, the present invention relates to [[(aminocarbonyloxy)-1-indanon]-2-yl]methylpiperidines of formula 1
wherein R is hydrogen, loweralkyl, or a group of the formula
R
1
is hydrogen or a group of the formula
W, X, and Y are hydrogen, loweralkyl, loweralkoxy, halogen, nitro, or trifluoromethyl; n is 1 or 2; the optical isomers thereof; or the pharmaceutically acceptable acid addition salts thereof, which are useful in relieving memory dysfunction, alone or in combination with inert adjuvants, and are thus indicated in the treatment of Alzheimer's disease.
The present invention also relates to 6-(aminocarbonyloxy)-2-[(pyridin-4-yl)methyleneyl]-1-indanones of formula 2
wherein R is hydrogen, loweralkyl, or a group of the formula
wherein W and X are hydrogen, loweralkyl, loweralkoxy, halogen, nitro, or trifluoromethyl; the optical and geometrical isomers thereof; or pyridine N-oxides thereof, which are useful as intermediates for the synthesis of the present [[(aminocarbonyloxy)-1-indanon]-2-yl]methylpiperidines.
As used throughout the specification and appended claims, the term “alkyl” refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 8 carbon atoms. Examples of alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl and the like. The term “alkoxy” refers to a monovalent substituent which consists of an alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen. Examples of alkoxy groups are methoxy, ethoxy, propoxy, 1-butoxy, 1-pentoxy, 3-hexoxy, 4-heptoxy, 2-octoxy and the like. The term “alkanoic acid” refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid and the like. The term “halogen” refers to a member of the family fluorine, chlorine, bromine, or iodine. The term “lower” as applied to any of the aforementioned groups refers to a group having a carbon skeleton containing up to and including 6 carbon atoms.
The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipodes may be prepared from the corresponding racemic forms by standard optical resolution techniques, involving, for example, the separation of diastereomeric salts of those instant compounds characterized by the presence of a basic group and an optically active acid, or by synthesis from optically active precursors.
The intermediate 2-[(pyridin-4-yl)methylene]-1-indanones of the present invention exist as geometric isomers in which the pyridinyl group is on the same side or the opposite side of the plane of the carbon-to-carbon bond of the methylene function as the carbonyl bearing moiety of the indanone system. In the trans-isomer the pyridinyl group is on the opposite side of the plane containing the carbon-to-carbon double bond, which is perpendicular to the plane of the page, as the carbonyl moiety; in the cis-isomer the pyridinyl group is on the same side.
The 4-[[6-(aminocarbonyloxy)-1-indanon]-2-yl]methylpiperidines of the present invention are prepared by processes illustrated in the Reaction Scheme.
To gain entry into this system, i.e., to prepare an aminocarbonyloxy-indanonylmethylpiperidine 1, a hydroxy-2-[(pyridin-4-yl)methyleneyl]-1-indanone 3, which is described in European Patent Application 0 296 560, published Dec. 28, 1988, is condensed with isocyanic acid or an isocyanate of formula 6
R—N═C═O 6
wherein R is hydrogen, loweralkyl, or a group of the formula
wherein W and n are as hereinbefore described to provide a carbamoyl-2-[(pyridin-4-yl)-methyleneyl]-1-indanone 2, which is reduced to a [[(carbamoyl)-1-indanon]-2-yl]methylpiperidine 4 and, in turn, benzylated to a benzyl[[(carbamoyl)-1-indanon]-2-yl]methylpiperidine 1. The condensation of a carbinol 3 with an isocyanate 6 is performed in a halocarbon solvent with dichloromethane or trichloromethane, trichloromethane being preferred, in the presence of a base, for example, a tertiary amine such as a trialkylamine selected from the group consisting of trimethylamine, triethylamine, and tri-1- or 2-propylamine at an elevated reaction temperature within the range of about 60° to 120° C., in an enclosed system, a reaction bomb, if necessary. A reaction temperature of about 87°-95° C. is preferred.
To prepare a carbamate 2 wherein R is hydrogen, i.e., an N-unsubstituted (aminocarbonyloxy)-2-[(pyridin-4-yl)methyleneyl]-1-indanone 2, a hydroxyindanone 3 may be treated with cyanic acid, generated by and under conditions well-known in the art.
The reduction of a carbamoyl-2[(pyridin-4-yl)methyleneyl]-1-indanone 2 is accomplished by contacting a methyleneylpyridine 2 with hydrogen over a hydrogenation catalyst such as platinum, platinum oxide, palladium, rhodium, or ruthenium, as such, or supported on a material such as carbon, calcium carbonate, or barium carbonate in an alkanoic acid. Included among alkanoic acids are acetic acid and propionic acid. The preferred hydrogenation system consists of platinum oxide and acetic acid. While the pressure and the temperature at which the hydrogenation is conducted are not narrowly critical, it is preferred to conduct the reduction at a hydrogen pressure of from about 1 to about 20 pounds per square inch (psi) and at a temperature from about ambient temperature to about 60° C. A hydrogen pressure of about 20 psi and a reaction temperature of about ambient temperature are preferred.
The benzylation of a (indanon-2-yl)-methylpiperidine 4 is achieved by following conventional methods involving contacting a piperidine 4 with a benzyl halide of formula 7
wherein Hal is chloro or bromo and Y and n are as hereinbeforedescribed in an alkanone such as, e.g., acetone or 3-butanone in the presence of an acid acceptor such as, e.g., lithium carbonate, potassium carbonate, or sodium carbonate at an alkylation temperature of about ambient temperature. Benzyl bromides and potassium carbonate are the preferred halides and acid acceptor.
Alternatively, a carbamoylindanonylmethylpiperidine 1 is prepared by condensing a [[hydroxy-1-indanon]-2-yl]methylpiperidine 5, which is described in European Patent Application 0 256 506, published Dec. 28, 1988, with isocyanic acid or an isocyanate 6 in an ethereal solvent in the presence of an acid acceptor at a reaction temperature between about 0° C. to about ambient temperature. Among ethereal solvents there may be mentioned diethyl ether, 2-methoxyethyl ether, tetrahydrofuran, or dioxane. Among acid acceptors, there may be mentioned lithium carbonate, potassium carbonate, or sodium carbonate. Tetrahydrofuran and potassium carbonate are the preferred solvent and acid acceptor.
The [1-indanon-2-yl]methylpiperidines of the present invention are useful as agents for the relief of memory dysfunction, particularly dysfunctions associated with decreased cholinergic activity such as those found in Alzheimer's disease. Relief of memory dysfunction activity of the instant compounds is indicated by inhibition of acetyl cholinesterase activity in the assay as described below:
Procedure
A. Reagents
1. 0.05 M Phosphate buffer, pH 7.2
a) 6.85 g sodium dihydrogen phosphate water/100 ml distilled water
b) 13.40 g disodium hydrogen phosphate water/100 ml distilled water
c) add a) to b) until pH reaches 7.2
d) Dilute 1:10
2. Substrate in buffer
a) 198 mg acetylthiocholine chloride (10 mM)
b) q.s. to 100 ml with 0.05 M sodium phosphate, pH 7.2 (reagent 1)
3. DTNB in buffer
a) 19.8 mg 5,5-dithiobisnitrobenzoic acid (DTNB) (0.5 mM)
b) q.s. to 100 ml with 0.05 M sodium phosphate, pH 7.2 (reagent 1)
4. A 2 mM
Effland Richard C.
Kosley, Jr. Raymond W.
Spahl Bettina
Aventis Pharmaceuticals Inc.
Chang Ceila
Strupczewski Joseph
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