Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-24
2001-05-08
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06229014
ABSTRACT:
The present invention relates to spiro[cyclopent[b]indole-piperidines]. More particularly, the present invention relates to spiro[cyclopent[b]indole-piperidines] of formula 1
wherein X is hydrogen, halogen, loweralkoxy, loweralkyl, hydroxy, trifluoromethyl and m is 1 or 2 or a group of the formula
wherein R is loweralkyl and R
3
is hydrogen or loweralkyl; R
1
is hydrogen or loweralkyl; R
2
is hydrogen, a group of the formula
wherein n is 1 or 2 and X and m are as above, a group of the formula
wherein X and m are as above, or a group of the formula
wherein X and m are as above, Y is hydrogen, or a group of the formula
wherein R
4
is hydrogen or loweralkyl and p is 2 or 3; the optical isomers thereof; or the pharmaceutically acceptable acid addition salts thereof useful in relieving memory dysfunction and thus indicated in the treatment of Alzheimer's disease, as well as useful in the treatment of depression.
Subgeneric to the compounds of formula 1 are those wherein R
2
is hydrogen or a group of the formula
The present invention relates to (N′-phenyl)hydrazones of formula 2
wherein R
2
is hydrogen or loweralkyl; R
5
is hydrogen or loweralkyl; and X is hydrogen, halogen, loweralkoxy, loweralkyl, hydroxy or trifluoromethyl and m is 1 or 2; the optical isomers thereof; or the pharmaceutically acceptable salts thereof, useful as intermediates for the preparation of the spiro[cyclopent[b]indole-piperidines] of formula 1 and also for the treatment of depression, and 4-cyanopiperidines of formula 3
wherein R
6
is loweralkyl; and R
7
is halogen or cyano, useful as intermediates for the preparation of the spiro[cyclopent[b]indole-piperidines] of formula 1.
As used throughout the specification and appended claims, the term “alky” refers to a straight or branched chain hydrocarbon radical containing no saturation and having 1 to 8 carbon atoms. Examples of alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-hexyl, 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 “alkanol” refers to a compound formed by a combination of an alkyl group and hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and 2-propanol, 2,2-dimethylethanol, hexanol, octanol 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 amino group and an optically active acid, or by synthesis from optically active precursors.
The present invention comprehends all optical isomers and racemic forms thereof of the compounds disclosed and claimed herein and the formulas of the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted.
The novel spiro[cyclopent[b]indole-piperidines] of the present invention are prepared by the processes delineated in Reaction Scheme A.
To prepare a spiro[cyclopent[b]indole-piperidine] of formula 1, an 8-azaspiro[4.5]decane-1-one 4 is condensed with a phenylhydrazine of formula 5
wherein R
1
is hydrogen or loweralkyl and X and m are as above to provide a phenylhydrazone of formula 2 wherein R
1
, X and m are as above, which is cyclized to a spiro[cyclopent[b]indole-piperidine] 1 wherein R
1
, X and m are as above and R
2
is hydrogen. The condensation is carried out by treating the cyclopentanone 4 with a phenylhydrazine 5 in the presence of an organic carboxylic acid such as acetic acid or a mineral acid such as hydrochloric acid in an alkanol such as ethanol at an elevated temperature such as that within the steam bath range to provide 2.
The cyclization is accomplished by treating a phenylhydrazone 2 with an aqueous alkanolic mineral acid such as ethanolic hydrogen chloride at a temperature within the steam bath range to provide 1.
To fabricate a 1′-benzoylspiro[cyclopent[b]indole-piperidine] 1 wherein R
1
is loweralkyl, R
2
is
and X, m and n are as above or a 1′-phenylethylspiro[cyclopent[b]indole-piperidine] 1 wherein R
1
is loweralkyl and R
2
is
wherein X, m and n are as above, a spiro[cyclopent[b]indole-piperidine] 1 wherein R
1
is loweralkyl, R
2
is hydrogen and X and m are as above is treated with a benzoyl halide of formula 6
wherein X and m are as above and Hal is bromo or chloro or a propylalkyl halide of formula 7
wherein X, m, n and Hal are as above in the presence of a triloweralkylamnine such as triethylamine in a halocarbon solvent such as dichloromethane at a temperature within the range from about 0° C. to about ambient temperature, or an alkali metal carbonate such as potassium carbonate in an organic solvent such as acetonitrile at a temperature of about the reflux temperature of the reaction medium.
Similarly, a 1′-phenoxyalkylspiro[cyclopent[b]indole-piperidine] 1 wherein R
1
is loweralkyl and R
2
is a group of the formula
wherein X and m are as above, Y is hydrogen or a group of the formula
wherein R
4
is hydrogen or loweralkyl and p is 2 or 3 is prepared by treating a spiro[cyclopent[b]indole-piperidine] 1 wherein R
1
is hydrogen or loweralkyl, R
2
is hydrogen and X and m are as above with a phenoxyalkylhalide of formula 8
wherein X, Y, m, p and Hal are as above and an inorganic base such as cesium carbonate in an organic solvent such as acetonitrile at a temperature of about 80° C.
The preparation of the starting material, 8-azaspiro[4,5]decane-1-one 4, for the elaboration of the spiro[cyclopent[b]indole-piperidines] of the present invention is outlined in Reaction Scheme B and exemplified in the Examples. In this process, commercially available 4-acetamidopiperidine 9 is acylated to N-ethoxycarbonyl-4-acetamidopiperidine 10, which in turn is converted to 4-cyano-N-ethoxycarbonylpiperdine 11 and then alkylated to 4-(3-chloropropyl)-4-cyano-N-ethoxycarbonylpiperidine 12. 4-(3-Chloropropyl)-4-cyano-N-ethoxycarbonylpiperidine 12 is converted to 4-cyano-4-(3-cyanopropyl)-N-ethoxycarbonyl piperidine 13, which is cyclized to 4-cyano-1-imino-8-azaspiro[4,5]decane 14 and hydrolyzed to 1. While the process for the synthesis of the starting material 4 for the preparation of the ultimate spiro[cyclopent[b]indole-piperidines] 1 is illustrated with N-ethoxycarbonylpiperidines (10 to 14), the scheme is equally applicable for N-loweralkoxycarbonylpiperidines.
The spiro[cyclopent[b]indole-piperidines] and related compounds 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 is demonstrated in the in vitro inhibition of acetylcholinesterase assay, an assay for the determination of the ability of a drug to inhibit the inactivation of acetylcholine, a neurotransmitter implicated in the etiology of memory dysfunction and Alzheimer's dementia. In this assay, a modification of a test described by G. L. Ellman, et al., Biochemical Pharmacology, 7, 88 (1961), the following reagents a
O'Malley Gerard J.
Palermo Mark G.
Frommer & Lawrence & Haug LLP
Hoechst Marion Roussel Inc.
Morris Patricia L.
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