Pyrazine and triazine derivatives of...

Details Pyrazine and triazine derivatives of... Pyrazine and triazine derivatives of...

2001-12-12

2003-07-01

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S217010, C540S593000, C540S594000

Reexamination Certificate

active

06586422

ABSTRACT:

FIELD OF INVENTION
The present invention relates to compounds with activity as antagonists at metabotropic gluatmate receptors and more particularly to pyrazine and triazine derivatives of 1,2,4,5-tetrahydro-Benzo or Thieno [d]azepine that demonstrate activity as group I mGluR antagonists.
BACKGROUND
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor. L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluRs are known and of these some even have sub-types. On the basis of structural parameters, the different second messenger signaling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits. Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by pharmaceutical compositions as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
SUMMARY
The present invention is a compound of the formula
wherein
R
1
is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, or unsubstituted phenyl or phenyl substituted in meta or para position with at least one substituents selected from the group consisting of lower alkyl, lower alkoxy or halogen, or is absent, in the case when X is —N═ or ═N—;
R
2
is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, ═O, —S-lower alkyl, —SO
2
-lower alkyl or —OR, —O(CHR
a
)
m+1
—OR
b
, NR
c
2
, NHNR
d
2
, —N(R
e
)(CHR
f
)
m+1
—OR
g
, —N(R
h
)(CHR
i
)
m
-pyridino, —N(R
j
)(CHR
k
)
n
—(C
3
-C
6
)cycloalkyl, —N(R
l
)(CHR
m
)
m
(CR
n
2
)—NR
o
2
, or —N(R
p
)(CHR
q
)
m+1
—NH—C(O)—O-lower alkyl;
m is 1, 2, 3, 4, 5 or 6;
n is 0, 1, 2, 3, 4 or 5;
R and R
a-q
are independently selected from the group consisting of hydrogen, lower alkyl or lower alkenyl;
X is selected from the group consisting of —N═, ═N—, >C═ or ═C<; and, in the case where R
2
is ═O or alkenyl, the dotted line is a bond,
Y is selected from the group consisting of —CH═CH—, —CH═CR
3
—, —CR
3
═CH—, —CR
3
—CR
4
— or s; and
R
3
, R
4
are selected, independently from each other, from the group consisting of hydrogen, lower alkyl, lower alkoxy or halogen with the proviso, that when Y represents a vinylene group, only one group R
3
and one group R
4
are present in the resultant benzene ring;
or a pharmaceutically acceptable salt thereof in racemic and optically active form.
It has surprisingly been found that the compounds of formula I are antagonists at metabotropic glutamate receptors.
Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts thereof and their use as pharmaceutically active substances. Methods for the preparation of the above mentioned substances and pharmaceutical compositions based on compounds in accordance with the invention and their production are also objects of the present invention as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses treated by modulation of metabotropic glutamate receptors, and, respectively, for the production of corresponding pharmaceutical compositions.
DETAILED DESCRIPTION
Preferred compounds of formula I within the scope of the present invention are those having the formula
wherein
R
1
is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, or unsubstituted phenyl or phenyl substituted in meta or para positions with at least one substituent selected from the group consisting of lower alkyl, lower alkoxy or halogen, or is absent, when X is —N═ or ═N—;
R
2
is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, ═O, —S-lower alkyl,
 —SO
2
-lower alkyl or
 —OR, —O(CHR
a
)
m+1
—OR
b
, —NR
c
2
, —NH—NR
d
2
, —N(R
e
)(CHR
f
)
m+1
—OR
g
, —N(R
h
)(CHR
i
)
m
-pyridino, N(R
j
)(CHR
k
)
n
—(C
3
-C
6
)cycloalkyl, —N(R
l
)(CHR
m
)
m
(CR
n
2
)NR
o
2
, or —N(R
p
)(CHR
q
)
m+1
—NH—C(O)—O-lower alkyl;
m is 1, 2, 3, 4, 5 or 6;
n is 0, 1, 2, 3, 4 or 5;
R and R
a-q
are independently selected from the group consisting of hydrogen, lower alkyl or lower alkenyl;
X is selected from the group consisiting of —N═, ═N—, >C═ or ═C<; the dotted line is a bond when R is ═O or lower alkenyl; and
a pharmaceutically acceptable salt thereof in racemic and optically active form.
Preferred compounds of formula I-A within the scope of the present invention are those, in which
R
1
is absent and X is —N═ or ═N—; and
R
2
is —NR
c
2
, —NH—NR
d
2
, —N(R
e
)(CHR
f
)
m+1
—OR
g
,
—N(R
h
)(CHR
l
)
m
-pyridino, —N(R
j
)(CHR
k
)
n
—(C
3
-C
6
)cycloalkyl,
—N(R
l
)(CHR
m
)
m
(CR
n
2
)NR
o
2
, or —N(R
p
)(CHR
q
)
m+1
—NH—C(O)—O-lower alkyl.
The following are examples of such compounds:
3-Amino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-(cyclopropylmethyl-amino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-(2-hydroxy-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
(RS)-3-(2-hydroxy-propylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-hydrazino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
{2-[6-cyano-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester, or
3-(2-pyridin-3-yl-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile.
Especially preferred are those compounds of formula I-A, in which
R
1
is absent and X is —N═ or ═N—; and
R
2
signifies —N(R
e
)(CHR
f
)
m+1
—OR
g
,
—N(R
h
)(CHR
i
)
m
-pyridino, or —N(R
j
)(CHR
k
)
n
—(C
3
-C
6
)cycloalkyl.
Examples of such compounds are the following:
3-(cyclopropylmethyl-amino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-(2-hydroxy-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
(RS)-3-(2-hydroxy-propylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile, or
3-(2-pyridin-3-yl-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile.
Compounds of formula I, in which
X signifies >C═ or ═C< and R
1
and R
2
are lower alkyl, are also preferred.
The follo

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