Carboxylic acid derivatives and process for producing same

Details Carboxylic acid derivatives and process for producing same Carboxylic acid derivatives and process for producing same

2001-09-24

2002-11-12

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S475000, C556S437000

Reexamination Certificate

active

06479674

ABSTRACT:

This application is a 371 of PCT/00/00969 Feb. 21, 2000.
FIELD OF TECHNOLOGY
The present invention relates to 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivatives and to a process for producing the same.
BACKGROUND ART
The metabotropic glutamate receptors, which correspond to one type of glutamate receptors, are classified pharmacologically into three groups. Of these, those in 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 have treatment effects and prevention effects on psychiatric disorders such as, for example, schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and on neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
The present inventors discovered 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (7) as one of the useful compounds acting on group 2 metabotropic glutamate receptors (Japanese Patent Application No. Hei 10-246344). In the specification of Japanese Patent Application No. Hei 10-246344, as apreparation method thereof, a synthesis method as described below is proposed. The synthesis method comprises the steps of adding benzyl alcohol to an enone derivative (8) to yield a benzyloxy compound (9), subsequently subjecting the compound (9) to hydantoination to yield a hydantoin derivative (10), subsequently subjecting the derivative (10) to debenzylation, oxidation, and thioketalation to yield a thioketal-hydantoin derivative (11), followed by hydrolysis (in the reaction schemes described below, R
2
, R
3
, and R
5
are identical or different, each represents a lower alkyl group having 1 to 10 carbon atoms, with the proviso that R
2
and R
3
together may represent —(CH
2
)
n
— (wherein n represents 2 or 3)).
DISCLOSURE OF THE INVENTION
An objective of the present invention is to provide novel intermediates which are useful for efficient synthesis of 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid acting on group 2 metabotropic glutamate receptors, which has treatment effects and prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy, and neurological disorders such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy, and head trauma, and a process for producing the same.
As a result of diligent research, the present inventors discovered that a 2-oxobicyclo [3.1.0]hexane-6-carboxylic acid derivative (1), which may be synthesized using, as a starting material, 4-hydroxy-2-cyclopentenone, or the hydroxy-group-protected compound thereof, which is easily derived from furfuryl alcohol, is useful for an efficient synthesis of 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (7), and completed the present invention.
That is, one mode of the present invention corresponds to a 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative represented by formula (1)
[wherein, R
1
represents a hydrogen atom, a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
6
alkyl group, an aryl group, an aryl C
1
-C
6
alkyl group, a C
1
-C
6
alkoxy C
1
-C
6
alkyl group, a C
1
-C
6
hydroxyalkyl group, a C
1
-C
6
alkylthio C
1
-C
6
alkyl group, a C
1
-C
6
mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group; R
2
and R
3
are identical or different, and each represents a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
6
alkyl group, an aryl group, or an aryl C
1
-C
6
alkyl group, or alternatively, R
2
and R
3
together represent —(CH
2
)
n
— (wherein n represents 2 or 3); and Y
1
and Y
2
are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom].
In addition, another mode of the present invention corresponds to a process for producing a 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative (1), comprising the steps of:
reacting a cyclopentenone derivative represented by formula (2)
 [wherein, R
4
represents a hydrogen atom or a protecting group of the hydroxyl group]
with a sulfonium ylide represented by Me
2
S═CHCO
2
R
5
[wherein, R
5
represents a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
6
alkyl group, an aryl group, an aryl C
1
-C
6
alkyl group, a C
1
-C
6
alkoxy C
1
-C
6
alkyl group, a C
1
-C
6
hydroxyalkyl group, a C
1
-C
6
alkylthio C
1
-C
6
alkyl group, a C
1
-C
6
mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group] or alternatively, with a sulfonium salt represented by Me
2
S
+
CH
2
CO
2
R
5
. X
−
[wherein, R
5
is the same as described above; and X represents a chlorine atom, a bromine atom, or an iodine atom]
to yield a bicyclo compound represented by formula (3)
 [wherein, R
4
and R
5
are the same as described above];
protecting the carbonyl group of said bicyclo compound to yield a derivative represented by formula (4)
 [wherein, R
2
and R
3
are identical or different, and each represents a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
6
alkyl group, an aryl group, or an aryl C
1
-C
6
malkyl group, or alternatively, R
2
and R
3
together represent —(CH
2
)
n
— (wherein n represents 2 or 3); Y
1
and Y
2
are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom; and R
4
and R
5
are the same as described above]; and
oxidizing said derivative wherein R
4
represents a hydrogen atom, with the proviso that in the case of R
4
of said derivative representing a group other than a hydrogen atom, the R
4
is converted into a hydrogen atom beforehand.
Furthermore, another mode of the present invention corresponds to a bicyclo[3.1.0]hexane-6-carboxylic acid derivative, which may be derived from the carboxylic acid derivative (1), represented by formula (5)
[wherein, R
1
represents a hydrogen atom, a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
6
alkyl group, an aryl group, an aryl C
1
-C
6
alkyl group, a C
1
-C
6
alkoxy C
1
-C
6
alkyl group, a C
1
-C
6
hydroxyalkyl group, a C
1
-C
6
alkylthio C
1
-C
6
alkyl group, a C
1
-C
6
mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group; R
2
and R
3
are identical or different, and each represents a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, a C
3
-C
6
cycloalkyl C
1
-C
6
alkyl group, an aryl group, or an aryl C
1
-C
6
alkyl group, or alternatively, R
2
and R
3
together represent —(CH
2
)
n
— (wherein n represents 2 or 3); and Y
1
and Y
2
are identical or different, and each represents. a sulfur atom, an oxygen atom, or a nitrogen atom].
The terms used in the present invention are defined in the following. In the present invention, “C
n
-C
m
” means that the group following the “C
n
-C
m
” has from n to m carbon atoms.
The C
1
-C
6
alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, examples of which include, for example, 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 hexyl group, an isohexyl group, and the like.
The C
3
-C
6
cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms, examples of which include, for example, a cyclopropyl group, a cyclope

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