Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-12-06
2004-08-03
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C560S119000, C560S122000, C560S124000, C560S125000, C560S116000, C562S501000, C514S510000
Reexamination Certificate
active
06770676
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives that are useful as a medicament. In particular, it relates to novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives which exhibit treatment effects and/or prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or on neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
BACKGROUND ART
In recent years, with the repeated cloning of glutamate receptor genes, it has become clear that there are surprisingly many subtypes of glutamate receptors. At present, glutamate receptors are roughly classified into two types: the “ionotropic type”, in which the receptor has an ion channel type structure, and the “metabotropic type”, in which the receptor is coupled to G-proteins (
Science
, 258, 597-603, 1992). In addition, ionotropic receptors are classified pharmacologically into three types: NMDA, &agr;-amino-3-hydroxy-5-methyl isoxazole-4-propionate (AMPA), and kainate (
Science
, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (
J. Neurosci
., 13, 1372-1378, 1993; and
Neuropharmacol
., 34, 1-26, 1995).
The metabotropic glutamate receptors are classified pharmacologically into three groups. Of these, group 2 (mGluR2/mGluR3) bind with adenylcyclase, and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine monophosphate (cAMP) (
Trends Pharmacol. Sci
., 14, 13 (1993)), and for this reason, it is suggested that the compounds acting on group 2 metabotropic glutamate receptors should be useful for the treatment or prevention of acute and chronic psychiatric disorders and neurological diseases.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a medicament acting on group 2 metabotropic glutamate receptors, which has the treatment effects and/or prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or on neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
As a result of a diligent research with regard to 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and ester derivatives thereof, the present inventors discovered novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and ester derivatives thereof, which act on group 2 metabotropic glutamate receptors, and have consequently, completed the present invention.
One mode of the present invention relates to a 2-amino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented by the formula [I]:
(wherein, R
1
and R
2
are the same or different, and each represents a hydrogen atom, a C
1-10
alkyl group, a C
3-8
cycloalkyl group, a C
3-8
cycloalkyl C
1-6
alkyl group, an aryl group, an aryl C
1-6
alkyl group, a C
1-6
alkoxy C
1-6
alkyl group, an C
1-6
hydroxyalkyl group, a C
1-6
alkylthio C
1-6
alkyl group, a C
1-6
mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group;
in R
3
and R
4
, when R
3
is a hydroxyl group, R
4
is a hydrogen atom; alternatively, R
3
and R
4
together form a C—C single bond),
a pharmaceutically acceptable salt thereof.
Another mode of the present invention relates to a medicament comprising the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient, and in particular, relates to an agent for treating or preventing psychiatric disorders or neurological diseases, as well as relates to a group 2 metabotropic glutamate receptor modulator.
Another mode of the present invention relates to use of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, for the manufacture of a group 2 metabotropic glutamate receptor modulator, and for the manufacture of an agent for treating and/or preventing psychiatric disorders and/or neurological diseases.
The terms used in the present invention are defined below. In the present invention, “C
n-m
” means that the group following the “C
n-m
” has a number of carbon atoms n to m.
The C
1-10
alkyl group means a straight-chain or branched-chain alkyl group, examples of which include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 2-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group, a decyl group, and the like.
The C
3-8
cycloalkyl group means, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
The C
3-8
cycloalkyl C
1-6
alkyl group means, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the like.
The aryl group means a phenyl group, a naphthyl group, or the like, and preferably means a phenyl group. The aryl C
1-6
alkyl group means a straight-chain or branched-chain C
1-6
alkyl group substituted with at least one aryl group, and preferably at least one phenyl group. Examples thereof include, for example, a benzyl group, a diphenylmethyl group, a 1-phenylethyl group, a 2-phenylethyl group, and the like.
The C
1-6
alkoxy C
1-6
alkyl group means a group having a combined structure of a C
1-6
alkoxy group and a C
1-6
alkyl group. The C
1-6
alkoxy group means a straight-chain or branched-chain alkoxy group, examples of which include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, a pentyloxy group, an isopentyloxy group, or the like. Therefore, examples of the C
1-6
alkoxy C
1-6
alkyl group include a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, an isopropoxyethyl group, a butoxyethyl group, an isobutoxyethyl group, a pentyloxyethyl group, an isopentyloxyethyl group, and the like.
The C
1-6
hydroxyalkyl group means a C
1-6
alkyl group substituted with at least one hydroxyl group. Therefore, examples of the C
1-6
hydroxyalkyl group include a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and the like.
The C
1-6
alkylthio C
1-6
alkyl group means a group having a combined structure of a C
1-6
alkylthio group and a C
1-6
alkyl group. The C
1-6
alkylthio group means a straight-chain or branched-chain alkylthio group, examples of which include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a t-butylthio group, a pentylthio group, an isopentylthio group, and the like. Therefore, examples of the C
1-6
alkylthio C
1-6
alkyl group include a methylthiomethyl group, a 2-methylthioethyl group, and the like.
The C
1-6
mercaptoalkyl group means a C
1-6
alkyl group substituted with at least one mercapto group. Therefore, examples of the C
1-6
mercaptoalkyl include a 2-mercaptoethyl group, a 3-mercaptopropyl group, a 2,3-dimercaptopropyl group, and the like.
In addition, a pharmaceutically acceptable salt in the present invention refers to, for example, a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, or phosphoric acid; a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, or benzenesulfonic acid; a salt with an amine such as
Kanuma Kosuke
Kumagai Toshihito
Nakazato Atsuro
Sakagami Kazunari
Lorusso, Loud & Kelly
Oh Taylor Victor
Seaman D. Margaret
Taisho Pharmaceutical Co. Ltd.
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