Aminophenoxyacetic acid derivatives as neuroprotectants

Details Aminophenoxyacetic acid derivatives as neuroprotectants Aminophenoxyacetic acid derivatives as neuroprotectants

2000-11-01

2003-05-06

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S307000, C514S314000, C514S318000, C514S323000, C514S331000, C546S141000, C546S144000, C546S192000, C546S193000, C546S201000

Reexamination Certificate

active

06559146

ABSTRACT:

This application is a 371 of PCT/JP99/05658 filed Oct. 14, 1999.
TECHNICAL FIELD
The present invention relates to novel aminophenoxyacetic acid derivatives and pharmaceutically acceptable salt thereof, which have neuroprotective effects by inducing or increasing calbindin D28 Kd, one of Ca
2+
-binding proteins, and which are useful in ameliorating and treating functional and organic disorders in the brain. More specifically, the present invention relates to therapeutic and improving agents for the allevivation or treatment of symptoms due to various ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis and so on, and symptoms of organic brain disorder such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and so on.
BACKGROUND ART
It is generally considered that the pathogenesis of progressive, delayed death of nerve cells, observed in cerebral injury and cerebrovascular disease such as intracerebral hemorrhage, transient ischemia attack, and cerebral infarction, is mainly caused by a rise in intracellular Ca
2+
concentration due to various factors related to signal transductions. Such factors related to signal transduction include, for example, abnormal activation of glutamate receptors due to excessive release glutamate, that is, an excitatory neurotransmitter, abnormal activation of ion channels, and excessive production of reactive oxygen species/free radicals. [F. B. Meyer,
Brain Res. Rev.,
14, 227 (1989); E. Boddeke et al.,
Trends Phamiacol. Sci.,
10, 397 (1989); J. M. McCall et al.,
Ann. Rep. Med. Chem.,
21, 31 (1992)].
From these points of view, medicaments for preventing or suppressing the neuronal cell death, such as glutamate receptor antagonists, calcium channel blockers, antioxidants and so on have been developed. However, these clinically used medicaments suppress only a few pathways related to increase of the cellular Ca
2+
concentration, and are not sufficient for preventing or suppressing the neuronal cell death.
On the contrary, calbindin D28 Kd, one of Ca
2+
-binding proteins and mainly distributed in friable site of the brain against ischemic disease, is reported to possess buffering effects for a rise in cytotoxic intracellular Ca
2+
concentration. [A. M. Lacopino et al.,
Neurodegeneration,
3, 1 (1994); M. P. Mattson et al.,
Neuron,
6, 41 (1991)].
Accordingly, it is expected to achieve sufficient neuroprotective effects against the increase of intracellular Ca
2+
concentration caused by any kinds of pathways if calbindin D28 Kd, one of the Ca
2+
-binding proteins per se, can be supplied in a living body. That is, it is expected that medicaments containing calbindin D28 Kd would be effective therapeutic and improving agents for the allevivation or treatment of symptoms due to various ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis and so on, and symptoms of organic brain disorder such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and so on.
However, because calbindin D28 Kd is unstable macromolecular protein having 28 Kd (kilo dalton) of molecular weight, it is difficult to be administered directly into a site in the central nervous system of a living body in view of pharmacological and pharmaceutical standpoints.
On the other hand, the lower molecular compounds having effect on induction of the calbindin D28 Kd can be easily prepared into the various kinds of pharmaceutical compositions by the conventional techniques. Thus, these lower molecular compounds are expected to induce the calbindin D28 Kd after administration in to a body, and to possess buffering action against the increase of the cellular Ca
2+
concentration. That is, these lower compounds can be effective compounds for improving and treating cerebral functional and organic disorders.
Under these circumstances, the objective of the present invention is to provide the lower molecular weight compounds having neuroprotective effect by inducing the calbindin D28 Kd, one of Ca
2+
-binding proteins, of low toxicity in suitable preparations of pharmaceutical compositions such as intravenous injectable solution.
The further purpose of the present invention is to provide the therapeutic and improving agents for the allevivation or treatment of symptoms due to various ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis and so on, and symptoms of organic brain disorder such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and so on.
DISCLOSURE OF THE INVENTION
As one aspect of the present invention, it is provided aminophenoxyacetic acid derivatives represented by the following formula (I):
wherein:
R
1
, R
2
, R
3
and R
4
are, independent from each other, hydrogen atom; halogen atom; hydroxy group; alkoxy group which may be substituted; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted;
R
5
, R
6
, R
7
and R
8
are, independent from each other, hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted;
E
1
is oxygen atom; sulfur atom; or group —NR
9
— (in which, R
9
is hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted);
E
2
is oxygen atom; sulfur atom; or group —NR
10
— (in which, R
10
is hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted);
n is 0 to 5;
X and Y are, independent from each other, connecting bond; alkylene group which may be substituted by hydroxyl group, carboxyl group, oxo group or morpholinyl group; cycloalkylene group; alkenylene group which may be substituted by lower alkyl group; —NHCO—; —CONH—; or —SO
2
—; or —X—Y— represents —CON(CH
3
)—;
Q is hydrogen atom; naphthyl group; phenyl group which may be substituted; phenoxy group which may be substituted; benzoyl group which may be substituted; pyridyl group which may be substituted; quinolyl group which may be substituted; isoquinolyl group which may be substituted; or benzimidazolyl group which may be substituted; (provided that one of E
1
and E
2
represent either oxygen atom or sulphur atom then the other one of E
1
and E
2
represent neither oxygen atom nor sulfur atom at the same time, and in the case of E
1
is nitrogen atom and E
2
is oxygen atom, or in the case of E
1
is oxygen atom and E
2
is nitrogen atom, all of the groups of R
1
, R
2
, R
3
and R
4
do not represent methyl group at the same time), or pharmaceutically acceptable salts thereof.
More specifically, the present invention provides the aminophenoxyacetic acid derivatives of the formula (I), in which;
1. R
1
, R
2
, R
3
and R
4
are, independent from each other, hydrogen atom; halogen atom; alkoxy group; or alxyl group which may be substituted; R
5
is hydrogen atom or alkyl group which may be substituted; E
1
is —NH—; and E
2
is oxygen atom,
2. E
1
is —NH—; E
2
is oxygen atom; either the case in which X is connecting bond and Y is group —CONH—, or the other in which X is the group —CONH— and Y is connecting bond; Q is phenyl group which may be substituted, and
3. E
1
and E
2
are —NH—; X and Y are connecting bond; Q is phenyl group which may be substituted,
or pharmaceutically acceptable salts thereof.
According to the present inventor's investigations, it is confirmed that the aminophenoxyacetic acid in low concentration represent

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