Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-25
2002-06-25
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S082000, C514S100000, C514S187000, C514S311000, C560S037000, C560S100000, C546S165000
Reexamination Certificate
active
06410592
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to aminomethylcarboxylic acid derivatives, to pharmaceutical compositions containing the same, as well as to the use of these aminomethylcarboxylic acid derivatives in therapy.
BACKGROUND OF THE INVENTION
The simplest &agr;-amino acid glycine, or aminomethylcarboxylic acid, has a number of important roles in the mammalian central nervous system (CNS). Along with &ggr;-aminobutyric acid (GABA), it is a major post-synaptic inhibitory transmitter in the spinal cord and brainstem, acting through ligand gated ion channels. Interaction of glycine with these receptors can be antagonized by the alkaloid strychnine. These receptors are therefore referred to as ‘strychnine sensitive’ glycine receptors. Glycinergic neurotransmission is important in the processing and control of visual, auditory and motor signalling. Glycine is also an obligatory co-agonist along with glutamate at the N-methyl-D-aspartate (NMDA) receptor. Glycine therefore functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the CNS. In addition the amino acid plays a role in the metabolism of peptides and proteins, including the exchange of one-carbon units.
Control of the availability of glycine for any of the above processes will potentially influence their function and provide means of treating a number of diseases and conditions. Apart from metabolism, one of the major processes controlling the concentrations of free glycine in the proximity of strychnine-sensitive and strychnine-insensitive glycine receptors is the functioning of selective high affinity glycine transporters. These proteins can actively limit the spread of glycine beyond the immediate environs of receptors, thus maintaining both spatial and temporal fidelity of receptor activation. Rapid sequestering of transmitter into neuronal or glial cells via the transporter will also conserve glycine for future release.
Glycine transporters have been cloned to reveal two major classes, GlyT-
1
and GlyT-
2
. GlyT-
1
is expressed throughout the brain with higher mRNA levels being detected in caudal areas and cellular localisation being predominantly glial. Three isoforms of GlyT-
1
,
1
a,
1
b
and
1
c,
arising from differential splicing and exon usage have been identified by Kim et al. (Molecular Pharm. 1994, 45, 608-617).
GlyT-
2
distribution, as indicated by immunochemistry studies, corresponds closely to that of inhibitory ‘strychnine sensitive’ glycine receptors, particularly in the spinal cord.
By regulating the synaptic levels of glycine, the glycine transporters GlyT-
1
and GlyT-
2
are expected to selectively influence the activity at NMDA receptors and at strychnine-sensitive glycine receptors, respectively.
Compounds which after the functional activity of glycine transporters may therefore result in changes in tissue glycine levels which can be useful in the treatment of a number of disease states. Such disease states include those associated with decreased or exaggerated function of NMDA receptors, namely psychosis, depression, dementia and other forms of impaired cognition, such as attention deficit disorders. NMDA receptors have further been implicated in conditions arising from neuronal cell death and neurodegeneration such as, for example, stroke (head trauma), Alzheimer's disease, Parkinson's disease and Huntington's disease. Enhanced inhibitory glycinergic transmission resulting from inhibition of GlyT-
2
or GlyT-
1
activity may be useful in the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy. Compounds elevating spinal glycine may also possess analgesic properties.
Aminomethylcarboxylic acid derivatives, wherein the amino group carries an ethyl or a propyl-group which is substituted by two or three aryl and/or aryloxy groups, are disclosed in WO 97/45115 (TROPHIX PHARM. INC.) as compounds useful in the treatment of the neurological and neuropsychiatric disorders discussed above. Structurally related aminomethylcarboxylic acid derivatives, wherein the aminogroup is part of a cyclic amine which is substituted at a single position with (a substituent containing) two aryl or cycloalkyl groups, are disclosed in WO 97/45423 (TROPHIX PHARM. INC.) as having similar activity.
There exists a need for additional compounds suitable for the treatment of psychiatric and neurological disorders, especially for compounds having a selective pharmacological profile.
SUMMARY OF THE INVENTION
To that aim the present invention provides in a first aspect aminomethylcarboxylic acid derivatives having the general formula I
wherein
Z is (CH
2
)
n
, O, S, SO, SO
2
or N—R
5
;
n is 0, 1 or 2;
X represents 1-3 substituents independently selected from hydrogen, halogen, (C
1-6
)alkyloxy, (C
3-6
)cycloalkyloxy, (C
6-12
)aryloxy, (C
6-12
)aryl, thienyl, SR
6
, SOR
6
, SO
2
R
6
, NR
6
R
6
, NHR
6
, NH
2
, NHCOR
6
, NHSO
2
R
6
, CN, COOR
6
and (C
1-4
)alkyl, optionally substituted with halogen, (C
6-12
)aryl, (C
1-6
)alkyloxy or (C
6-12
)aryloxy; or 2 substituents at adjacent positions together represent a fused (C
5-6
)aryl group, a fused (C
5-6
)cycloalkyl ring or O—(CH
2
)
m
—O; m is 1 or 2;
Y represents 1-3 substituents independently selected from hydrogen, halogen, (C
1-4
)alkyloxy, SR
6
, NR
6
R
6
and (C
1-4
)alkyl, optionally substituted with halogen;
R
1
is COOR
7
or CONR
8
R
9
;
R
2
and R
6
are (C
1-4
)alkyl;
R
3
, R
4
and R
5
are independently hydrogen or (C
1-4
)alkyl;
R
7
, R
8
and R
9
are independently hydrogen, (C
1-4
)alkyl, (C
6-12
)aryl or arylalkyl;
or a pharmaceutically acceptable salt thereof.
The term (C
1-4
)alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-4 carbon atoms, for example, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
In the term (C
1-6
)alkyloxy, (C
1-6
)alkyl means a branched or an unbranched alkyl group having 1-6carbon atoms, for example hexyl, pentyl, neopentyl (2,2-dimethylpropyl) and the meanings given above for (C
1-4
)alkyl. The (C
1-6
)alkyloxy group may be substituted with halogen, (C
3-6
)cycloalkyl or (C
1-4
)alkyloxy. Examples of such substituted (C
1-6
)alkyloxy groups are trifluoromethyloxy and cyclopropylmethyloxy.
The term (C
3-6
)cycloalkyl means a cyclic alkyl group having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term halogen means F, Cl, Br, or I. When halogen is a substituent at an alkyl group, F is preferred. A preferred halogen substituted alkyl group is trifluoromethyl.
In the term (C
6-12
)aryloxy, as used in the definition of formula I, (C
6-12
)aryl means an aromatic group having 6-12 carbon atoms for example phenyl, naphthyl or biphenyl. These aromatic groups may be substituted with halogen, or with (C
1-4
)alkyl or (C
1-4
)alkyloxy, wherein (C
1-4
)alkyl has the previously given meaning and may be substituted with halogen or (C
1-4
)alkyloxy.
The term arylalkyl, as used in the definition of Formula I, means a (C
1-4
)alkyl group which is substituted with a (C
6-12
)aryl group, for example, benzyl.
In the definition of formula I, X can represent a fused (C
5-6
)aryl group, which means that X is a 5 or 6-membered aromatic ring fused to the benzene ring to which X is attached to form a (C
11-12
)aromatic ring system, for example a naphthalene or an indene ring. X can also represent a fused (C
5-6
)cycloalkyl ring, which means that X is a 5- or 6-membered saturated ring fused to the benzene ring to which X is attached to form a tetrahydronaphthalene or an indan ring system. X may further represent O—(CH
2
)
m
—O, wherein m is 1 or 2, which is fused to the benzene ring to which X is attached to form a 1,3-benzodioxole (m=1) or a 1,4-benzodioxan (m=2) ring system.
The meaning of R
1
in formula I is exemplified by the groups COOR
7
and CONR
8
R
9
. In addition R
1
may be any other group from which the free acid (R
1
=COOH) can be generated (in vivo). Such alternative acid precursors or prodrugs, such a
Gibson S. G.
Gilfillan R. R.
Jaap D. R.
Thorn S. N.
Akzo Nobel N.V.
Blackstone William M.
Tucker Zachary
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