1,2,4,5-Tetrahydro-benzo[D]azepin derivatives

Details 1,2,4,5-Tetrahydro-benzo[D]azepin derivatives 1,2,4,5-Tetrahydro-benzo[D]azepin derivatives

2000-08-01

2001-04-17

Kifle, Bruck (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S594000

Reexamination Certificate

active

06218385

ABSTRACT:

BACKGROUND OF THE INVENTION
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter sent out by a neuron, with another 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 some of these even have sub-types. On the basis of structural parameters, the different second messenger signaling pathways and their 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 III 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 medicaments 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 OF THE INVENTION
It has surprisingly been found that the compounds of formula I, below, are antagonists at metabotropic glutamate receptors. Therefore, the compounds of formula I are useful for treating conditions related to stimulation of these glutamate receptors, particularly acute or chronic neurological disorders. In addition, the compounds of this invention are useful in assays for glutamate receptor inhibition.
Thus the present invention is concerned with 1,2,4,5-tetrahydro-benzo[d]azepin derivatives of the formula
wherein
R
1
signifies hydrogen, hydroxy, lower alkyl, oxygen, halogen, or
 —OR, —O(C
3
-C
6
)cycloalkyl, —O(CHR)
n
—(C
3
-C
6
)cycloalkyl, —O(CHR)
n
CN, —O(CHR)
n
CF
3
, —O(CHR)(CHR)
n
NR
2
, —O(CHR)(CHR)
n
OR, —O(CHR)
n
-lower alkenyl, —OCF
3
, —OCF
2
—R, —OCF
2
-lower alkenyl, —OCHRF, —OCHF-lower alkenyl, —OCF
2
CRF
2
, —OCF
2
Br, —O(CHR)
n
CF
2
Br, —O(CHR)
n
-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups,
 —O(CHR)(CHR)
n
-morpholino, —O(CHR)(CHR)
n
-pyrrolidino, —O(CHR)(CHR)
n
-piperidino, —O(CHR) (CHR)
n
-imidazolo, —O(CHR)(CHR)
n
-triazolo, —O(CHR)
n
-pyridino, —O(CHR)(CHR)
n
—OSi-lower alkyl, —O(CHR)(CHR)
n
OS(O)
2
-lower alkyl, —(CH
2
)
n
CH═CF
2
, —O(CHR)
n
-2,2-dimethyl-[1.3]dioxolane, —O(CHR)
n
—CHOR—CH
2
OR, —O(CHR)
n
—CHOR—(CHR)
n
—CH
2
OR or
 —SR or —S(CHR)
n
COOR, or
 —NR
2
, —N(R)(CHR)(CHR)
n
OR, —N(R)(CHR)
n
CF
3
, —N(R)(CHR)(CHR)
n
-morpholino, —N(R)(CHR)(CHR)
n
-imidazolo, —N(R)(CHR)(CHR)
n
-pyrrolidino, —N(R)(CHR)(CHR)
n
-pyrrolidin-2-one, —N(R)(CHR)(CHR)
n
-piperidino, —N(R)(CHR)(CHR)
n
-triazolo, —N(R)(CHR)
n
-pyridino, or
 R
1
and R
4
are interconnected to the groups —(CH
2
)
3-5
—, —(CH
2
)
2
—N═, —CH═N—N═—, —CH═CH—N═, —NH—CH═CH— or
 —NR—CH
2
—CH
2
— and form together with any N or C atoms to which they are attached an additional ring;
n is 1-6;
R signifies hydrogen, lower alkyl or lower alkenyl, independently from each other, if more than one R is present;
R
2
signifies nitro or cyano;
R
3
signifies hydrogen, lower alkyl, ═O, —S, —SR, —S(O)
2
-lower alkyl, —(C
3
-C
6
)cycloalky or piperazino, optionally substituted by lower alkyl, or
 —CONR
2
, —(CHR)
n
CONR
2
, —(CHR)
n
OR, —(CH
2
)
n
—CF
3
, —CF
3
, —(CHR)
n
OC(O)CF
3
, —(CHR)
n
COOR, —(CHR)
n
SC
6
H
5
, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups,
 —(CHR)
n
-1,3-dioxo-1,3-dihydro-isoindol, —(CHR)
n
-tetrahydro-pyran-2-yloxy or —(CHR)
n
—S-lower alkyl, or
 —NR
2
, —NRCO-lower alkyl, —NRCHO, —N(R) (CHR)
n
CN, —N(R)(CHR)
n
CF
3
, —N(R)(CHR)(CHR)
n
—OR, —N(R)C(O)(CHR)
n
O-lower alkyl, —NR(CHR)
n
-lower alkyl, —NR(CHR)(CHR)
n
—OR, —N(R)(CHR)(CHR)
n
—O-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups,
 —N(R)(CHR)
n
-lower alkenyl, —N(R)(CHR)(CHR)
n
—O—(CHR)
n
OR, —N(R)(CHR)
n
C(O)O-lower alkyl, —N(R)(CHR)
n
C(O)NR-lower alkyl, —N(R)(CH
2
)
n
-2,2-dimethyl-[1.3]dioxolane, —N(R)(CHR)(CHR)
n
morpholino, —N(R)(CHR)
n
-pyridino, —N(R)(CHR)(CHR)
n
-piperidino, —N(R)(CHR)(CHR)
n
-pyrrolidino, —N(R)(CHR)(CHR)
n
—O-pyridino, —N(R)(CHR)(CHR)
n
imidazolo, —N(R)(CHR)
n
—CR
2
—(CHR)
n
—OR, —N(R)(CHR)
n
—CR
2
—OR, —N(R)(CHR)
n
—CHOR—CH
2
OR, —N(R)(CHR)
n
—CHOR—(CHR)
n
—CH
2
OR, or
 —OR, —O(CHR)
n
CF
3
, —OCF
3
, —O(CHR)(CHR)
n
—O-phenyl, wherein the phenyl group maybe optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups,
 —O(CHR)(CHR)
n
—O-lower alkyl, —O(CHR)
n
-pyridino or
 —O(CHR)(CHR)
n
-morpholino;
 or R
3
and R
4
are interconnected to the groups —(CH
2
)
3-5
—, —(CH
2
)
2
—N═, —CH═N—N═—, —CH═CH—N═, —NH—CH═CH— or
 NR—CH
2
—CH
2
— and form together with any N or C atoms to which they are attached an additional ring; and
R
4
signifies hydrogen, lower alkyl, lower alkenyl or nitro, or
 —OR, —OCF
3
, —OCF
2
—R, —OCF
2
-lower alkenyl, —OCHRF, —OCHF-lower alkenyl, —O(CHR)
n
CF
3
, or
 —(CHR)
n
CHRF, —(CHR)
n
CF
2
R, —(CHR)
n
CF
3
, —(C
3
-C
6
)cycloalkyl, —(CHR)
n
(C
3
-C
6
)cycloalkyl, —(CHR)
n
CN, —(CHR)
n
-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one, to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups,
 —(CHR)(CHR)
n
OR, —(CHR)
n
CHORCH
2
OR; —(CHR)(CHR)
n
NR
2
, —(CHR)
n
COOR, —(CHR)(CHR)
n
OSi-lower alkyl, —(CHR)(CHR)
n
—OS(O)
2
-lower alkyl, —(CH
2
)
n
—CH═CF
2
, —CF
3
, —CF
2
—R, —CF
2
-lower alkenyl, —CHRF, —CHF-lower alkenyl, —(CHR)
n
-2,2-dimethyl-[1.3]dioxolane, —(CH
2
)
n
-2-oxo-azepan-1-yl, —(CHR)(CHR)
n
-morpholino, —(CHR)
n
-pyridino, —(CHR)(CHR)
n
-imidazolo, —(CHR)(CHR)
n
-triazolo, —(CHR)(CHR)
n
-pyrrolidino, optionally substituted by —(CH
2
)
n
OH, —(CHR)(CHR)
n
-3-hydroxy-pyrrolidino or —(CHR)(CHR)
n
-piperidino, or
 —NR
2
, —N(R)(CHR)
n
-pyridino, —N(R)C(O)O-lower alkyl, —N(CH
2
CF
3
)C(O)O-lower alkyl, —N[C(O)O-lower alkyl]
2
, —NR—NR—C(O)O-lower alkyl or —N(R)(CHR)
n
CF
3
, —NRCF
3
, —NRCF
2
—R, —NRCF
2
-lower alkenyl, —NRCHRF, —NRCHP-lower alkenyl;
 or is absent if X is —N═ or ═N—;
R
5
, R
6
signify hydrogen, lower alkyl, lower alkoxy, amino, nitro, —SO
2
NH
2
or halogen; or
R
5
and R
6
are interconnected to the group —O—CH
2
—O— and form together with the C atoms to which they are attached an additional 5-membered ring;
R
7
, R
8
signify hydrogen, lower alkyl, lower alkoxy, amino, nitro or halogen;
R
9
, R
10
signify hydrogen or lower alkyl;
R
11
, R
12
signifies hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyloxy or lower alkanoyloxy;
R
13
, R
14
signify hydrogen, tritium or lo

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