Fluorine-containing amino acid derivatives

Details Fluorine-containing amino acid derivatives Fluorine-containing amino acid derivatives

2000-07-27

2001-11-13

Killos, Paul J. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S561000, C562S501000, C560S119000

Reexamination Certificate

active

06316498

ABSTRACT:

FIELD OF TECHNOLOGY
This invention relates to fluorine-containing amino acid derivatives that are useful as drugs; it relates to novel fluorine-containing amino acid derivatives that are useful for the treatment and prevention of psychiatric disorders such as, for example, schizophrenia, anxiety and associated diseases, neurological diseases such as depression, bipolar disorder and epilepsy, as well as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement impairment associated with muscular stiffness, cerebral ischemia, cerebral insufficiency, spinal cord lesions, and head trauma.
This specification is based on Japanese Patent Application, No. Hei 10-15444 [1998], the content of which is herein incorporated by reference, as part of this specification.
BACKGROUND TECHNOLOGY
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 broadly classified into two types: the “ionotropic type”, in which the receptor has an ion channel structure, and the “metabotropic type”, in which the receptor is coupled to G-proteins (Science, 258, 597-603, 1992). 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 monophosphate (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 disorders. As a substance that acts 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, No. Hei 8-188561 [1996].
Fluorine atoms tend to be strongly electron-attractive and to confer high fat solubility, and 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 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.
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, for example, schizophrenia, anxiety and associated diseases, depression, bipolar disorder, epilepsy and other psychiatric disorders, as well as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement impairment associated with muscular stiffness, cerebral ischemia, cerebral insufficiency, spinal cord lesions, head trauma and other neurological diseases; especially oral drugs that can act on group 2 metabotropic glutamate receptors.
The inventors of this invention, having made a diligent study of fluorine-containing amino acid derivatives in which fluorine atoms are introduced into (+)-(1S, 2S, 5R, 6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, have discovered novel fluorine-containing amino acid derivatives that when taken orally can affect group 2 metabotropic glutamate receptors.
That is, this invention consists of a 2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented by formula [I]
[where X
1
represents a hydrogen atom or fluorine atom, R
1
and R
2
are the same or different and each represents a hydrogen atom or an alkyl group of 1-10 carbon atoms], a pharmaceutically permissible salt thereof, or a hydrate thereof.
In this invention, the alkyl group of 1-10 carbon atoms means a straight-chain or branched-chain alkyl group, or a cycloalkyl group, where one can cite as a straight-chain or branched-chain alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl 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, a decyl group, etc., and one can cite as a cycloalkyl group including an alkyl group that is substituted with a cycloalkyl group of 3-10 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a cyclopentyl group, a cyclobutylmethyl group, a cyclohexyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptyl group, etc.
As a pharmaceutically permissible salt in this invention, one can cite, for example, a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, phosphoric acid, etc., a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, etc., a salt with an amine such as trimethyl amine, methyl amine, etc., or a salt with a metal ion such as sodium ion, potassium ion, calcium ion, etc. The compounds of this invention may exist as various solvates, but from the standpoint of applicability as a drug, hydrates are preferable.
In a compound represented by formula [I], if X
1
is a hydrogen atom, five asymmetric carbon atoms are present in positions 1, 2, 3, 5, and 6. Therefore a compound of this invention in which X
1
is a hydrogen atom can exist as a mixture of two kinds of enantiomers such as optically active substances and racemic compounds, and a mixture of diastereomers. And if X
1
is a fluorine atom, four asymmetric carbon atoms are present in positions 1, 2, 5, and 6. Therefore a compound of this invention in which X
1
is a fluorine atom can exist as a mixture of two kinds of enantiomers such as optically active substances and racemic compounds, and a mixture of diastereomers.
An X
1
that is desirable in the compounds represented by formula [I] is a hydrogen atom. And, if X
1
is a hydrogen atom, it is more desirable that the compounds represented in formula [I] have the following stereochemical configuration.
And if X
1
, R
1
and R
2
are hydrogen atoms, then the optically active substance that is most desirable among the optical isomers of this compound has a positive optical rotation, and this absolute stereochemical arrangement has been determined to be 1S, 2S, 3S, 5R, 6S by x-ray single crystal structural analysis of 2-spiro-5′-hydantoin-3-fluorobicyclo[3.1.0]hexane-6-carboxylic acid (R)-(+)-1-phenylethylamine salt, which is a synthesis precursor of this compound.
On the other hand, if in formula [I] one or both of R
1
and R
2
represent something other than hydrogen, that is, the ester form will not have an effect on group 2 metabotropic glutamate receptors. But this ester form is hydrolyzed in vivo and is transformed into carboxylic acid, which does have an effect on group 2 metabotropic glutamate receptors. In this way, the ester forms of the compounds of this invention are very useful because they function as prodrugs.
The compounds of formula [I] can be manufactured according to the following reaction formulas. In the following reaction formulas, R
1
, R
2
and X
1
are the same as above, R
3
and R
4
are the same or different and each represents a l

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