Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-09
2004-02-03
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S578000
Reexamination Certificate
active
06686352
ABSTRACT:
FIELD OF INVENTION
The present invention is related to substituted imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine derivatives of formula
Compounds of formula 1 are ligands for GABA A receptors containing the &agr;5 subunit and are therefore useful in therapy where cognition enhancement is desirable.
BACKGROUND
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion. channel superfamily and (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of &agr;, &bgr; and &ggr; subunits.
Presently a total number of 21 subunits of the GABA A receptor have been cloned and sequenced. Three types of subunits (&agr;, &bgr; and &ggr;) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding. site lies between the cc and y subunits. Among the recombinant GABA A receptors, &agr;1&bgr;2&ggr;2 mimics many effects of the classical type-I BzR subtypes, whereas &agr;2&bgr;2&ggr;2, &agr;3&bgr;2&ggr;2 and &agr;5&bgr;2&ggr;2 ion channels are termed type-II BzR.
It has been shown by McNamara and Skelton in
Psychobiology,
21:101-108 that the benzodiazepine receptor inverse agonist &bgr;-CCM enhance spatial learning in the Morris watermaze. However, &bgr;-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A &agr;5 receptor partial or full inverse agonist which is relatively free of activity at GABA A &agr;1 and/or &agr;2 and/or &agr;3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A &agr;5 inverse agonists which are not free of activity at GABA A &agr;1 and/or &agr;2 and/or &agr;3 receptor binding sites but which are functionally selective for &agr;5 containing subunits. However, inverse agonists which are selective for GABA A &agr;5 subunits and are relatively free of activity at GABA A &agr;1, &agr;2 and &agr;3 receptor binding sites are preferred.
SUMMARY
The present invention is a compound of formula
wherein
R
1
is selected from the group consisting of halogen and lower alkyl;
R
2
is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, —(CH
2
)
m
-phenyl, —(CH
2
)
m
-phenyl substituted by lower alkoxy and —(CH
2
)
m
-indolyl;
R
3
is selected from the group consisting of —C(O)O-lower alkyl, —C(O)OH, a five-membered heteroaromatic group and a five-membered heteroaromatic group substituted by lower alkyl or cycloalkyl;
n is 0, 1 or 2; and
m is 0, 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof
It has now been found that a compound of formula 1 shows high affinity and selectivity for GABA A &agr;5 receptor binding sites and might be useful as a cognitive enhancer or for the treatment of cognitive disorders like Alzheimer's disease.
An object of the present invention is compounds of formula I and pharmaceutically acceptable salts thereof. A further object of the invention is the preparation of the compounds of formula I and pharmaceutically acceptable salts thereof. Pharmaceutical compositions containing a therapeutically effective amount of the compound of formula I and salts thereof and their manufacture are objects of the present invention. Another object of the invention is a method of treatment for modulating GABA A &agr;5 receptor binding sites as a cognitive enhancer or treatment of cognitive disorders like Alzheimer's disease comprising the administration of a therapeutically effective amount of the compounds of formula I or a pharmaceutically acceptable salt. The most preferred indication in accordance with the method of treatment of the present invention is the treatment of cognitive disorders, like Alzheimer's disease.
DETAILED DESCRIPTION
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight-or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term “lower alkoxy” denotes a croup wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “cycloalkyl” denotes a cyclic alkyl ring, having from 3 to 7 carbon ring atoms, for example, cyclopropyl, cyclopentyl or cyclohexyl.
The term “five-membered heteroaromatic group” denotes, for example 1,2,4-oxadiazoles, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl and the like. Preferred are 1,2,4-oxadiazolyl and isoxazolyl groups.
The term “pharmaceutically acceptable acid addition salts” embraces salts with pharmaceutically acceptable inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred are compounds, which have a binding activity (Ki) of lower 15 nM and are selective for GABA A &agr;5 subunits and are relatively free of activity at GABA A &agr;1, &agr;2 and &agr;3 receptor binding sites.
Preferred compounds of formula I are those, in which R
3
is the group —C(O)O-lower alkyl. Exemplary preferred are compounds of this group, wherein R
1
is hydrogen and R
2
is as described above, for example compounds selected from the group consisting of:
9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
6-[(4-methoxyphenyl) methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester and
6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester.
Further preferred compounds of formula I are those, in which R
3
is the group —C(O)O-lower alkyl, R
2
is as described above and R
1
is halogen, for example compounds selected from the group consisting of:
3-fluoro-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
3-fluoro-6-propyl-9H-imidazo [1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
3-fluoro-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester,
6-cyclopropyl-3-fluoro-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester and
3-bromo-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid ethyl ester.
Further preferred compounds of formula I are those, in which R
3
is the group 1,2,4-oxadiazolyl or isoxazolyl, R
2
is lower alkyl, n is 0 or 1 and R
1
is halogen, for example compounds selected from the group consisting of:
10-(3-cyclopropyl-1,2,4-oxadiazol-5-
Masciadri Raffaello
Thomas Andrew William
Wichmann Juergen
Coleman Brenda
Hoffmann-La Roche Inc.
Johnston George W.
Prior Kimberly J.
Rocha-Tramaloni Patricia S.
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