6-fluorobicyclo[3.1.0]hexane derivatives

Details 6-fluorobicyclo[3.1.0]hexane derivatives 6-fluorobicyclo[3.1.0]hexane derivatives

2001-02-22

2001-12-25

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S119000, C560S122000, C560S124000, C560S125000

Reexamination Certificate

active

06333428

ABSTRACT:

FIELD OF TECHNOLOGY
This invention relates to 6-fluorobicyclo[3.1.0]hexane derivatives that are useful as drugs. In particular, it relates to novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives that are useful for the treatment and prevention of psychiatric disorders such as, for example, schizophrenia, anxiety and its associated diseases, depression, bipolar disorder and epilepsy; and 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. Ionotropic receptors are classified pharmacologically into three types: N-methyl-D-asparaginic acid (NMDA), &agr;-amino-3-hydroxy-5-methyl isoxazole-4-propionate (AMPA), and kynate (Science, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (J. Neurosci., 13, 1372-1378, 1993; 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 momophosphate (cAMP) (Trends Pharmacol. Sci., 14, 13(1993)), which suggests that compounds that act on group 2 metabotropic glutamate receptors should be useful for the treatment or prevention of acute and chronic psychiatric and neurological diseases. As substances that act on group 2 metabotropic glutamate receptors, (+)-(1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid has been disclosed in Japanese Unexamined Patent Publication, First Publication No. Hei 8-188561 [1996]. And, (1S*,2S*,5R*,6R*)-2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, (1S*,2S*,4S*,5R*,6R*)-2-amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and (1S*,2R*,4S*,5S*,6S*)-2-amino-4-flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid have been disclosed in EP-A-878,463.
Fluorine atoms tend to be strongly electron-attractive and to confer high fat solubility, so that compounds into which fluorine atoms are introduced greatly change their physical properties. Thus introducing fluorine atoms might greatly affect the absorbability, metabolic stability, and pharmacological effects of a compound. But it is by no means easy to introduce fluorine atoms. In fact, Japanese Unexamined Patent Publication, First Publication No. Hei 8-188561 [1996] does not even discuss the introduction of fluorine atoms into (+)-(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Further, (1S*,2R*,4S*,5S*,6S*)-2-amino-4-flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid which has been disclosed in EP-A-878,463 was prepared by merely a substitution of a hydroxyl group in (1S*,2S*,4S*,5R*,6R*)-2-amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, by a fluorine atom by use of normal fluorination agents.
DISCLOSURE OF THE INVENTION
In view of the aforementioned present state of the prior art, the purpose of this invention is to provide drugs that are effective for the treatment and prevention of psychiatric disorders such as, for example, schizophrenia, anxiety and its associated diseases, depression, bipolar disorder and epilepsy; and 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; especially oral drugs that can act on group 2 metabotropic glutamate receptors.
The inventors of the present invention, who made a diligent study of 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives in which a fluorine atom is introduced into the 6position of (+)-(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, (1S*,2S*,5R*,6R*)-2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and (1S*,2S*,4S*,5R*,6R*)-2-amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, have discovered novel 2-amino-4-flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives that when taken orally can affect group 2 metabotropic glutamate receptors, thereby completed this invention.
That is, the present invention relates to 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 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 or a C
3-8
cycloalkyl-C
1-5
alkyl group: Y
1
and Y
2
are the same or different, and each represents a hydrogen atom, a C
1-10
alkylthio group, a C
3-8
cycloalkylthio group, a C
3-8
cycloalkyl-C
1-5
alkyl thio group, a C
1-5
alkoxy group, a C
3-8
cycloalkoxy group or a C
3-8
cycloalkyl-C
1-5
alkoxy group; or one represents a hydrogen atom and the other represents a hydroxyl group, a C
1-5
alkoxy group, a C
3-8
cycloalkoxy group or a C
3-8
cycloalkyl-C
1-5
alkoxy group; or Y
1
and Y
2
together represent an oxygen atom or —X(CH
2
)
n
X— group (X represents an oxygen atom or a sulfur atom: n is 2 or 3)], pharmaceutically acceptable salts thereof, or hydrates thereof.
In the present invention, 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 1-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group, and a decyl group. The C
3-8
cyclopropyl group means, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. The C
3-8
cycloalkyl-C
1-5
alkyl group means, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, etc. The C
1-10
alkylthio group means a straight-chain or branched-chain alkylthio group, examples of which include a methylthio group, a ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a t-bytylthio group, a pentylthio group, an isopentylthio group, a 1-ethylpropylthio group, a hexylthio group, an isohexylthio group, a 1-ethylbutylthio group, a heptylthio group, an isoheptylthio group, an octylthio group, a nonylthio group, and a decylthio group. The C
3-8
cycloalkylthio group means, for example, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, etc. The C
3-8
cycloalkyl-C
1-5
alkylthio group means, for example, a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, etc. The C
1-5
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, t-butoxy group, a pentoxy group, an isopentoxy group, and a 1-ethylpropoxy group. The C
3-8
cycloalkoxy group means, for example, a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, etc. The C
3-8
cycloalkyl-C
1-5
alkoxy group means, for example, a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopropylethoxy group, etc.
As the pharmaceutically acceptable salt in this invention, one can cite, for example, a salt with an inorgan

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