Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-13
2002-06-18
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S517000
Reexamination Certificate
active
06407094
ABSTRACT:
BACKGROUND OF THE INVENTION
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) form the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites 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 group II can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula I
These compounds have been discovered to act as metabotropic glutamate receptor antagonists and accordingly are useful for the treatment of a range of neurological disorders, including psychosis, schizophrenia, Alzheimer's and other cognitive and memory disorders.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production, as well as the use of the compounds in accordance with the invention in the control or prevention of neurologial disorders, and, respectively, for the production of corresponding medicaments.
DETAILED DESCRIPTION
The present invention relates to compounds of formula I
wherein
X is a single bond or an ethynediyl group, wherein,
In case X is a single bond, R
1
is halogen or phenyl which is optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or cyano;
In case X is an ethynediyl group, R
1
is phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy;
R
2
is halogen; hydroxy; lower alkyl; lower halo-alkyl; lower alkoxy; hydroxymethyl; hydroxyethoxy; lower alkoxy-(ethoxy)
n
(n=1 to 4); lower alkoxymethyl; cyanomethoxy; morpholine-4-yl; thiomorpholine-4-yl; 1-oxothiomorpholine-4-yl; 1,1-dioxothiomorpholine-4-yl; 4-oxo-piperidine-1-yl; 4-alkoxy-piperidine-1-yl; 4-hydroxy-piperidine-1-yl; 4-hydroxyethoxy-piperidine-1-yl; 4-lower alkyl-piperazine-1-yl; alkoxycarbonyl; 2-dialkylamino-ethylsulfanyl-; N,N-bis lower alkylamino lower alkyl; carbamoylmethyl; alkylsulfonyl; lower alkoxycarbonyl-lower alkyl; alkylcarboxy-lower alkyl; carboxy-lower alkyl; alkoxycarbonylmethylsulfanyl; carboxymethylsulfanyl; 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; carboxy-lower alkoxy; cyano-lower alkyl; 2,3-dihydroxy-lower alkoxy; carbamoylmethoxy; 2-oxo-[1,3]-dioxolan-4-yl-lower alkoxy; (2-hydroxy-lower alkyl)-lower alkyl amino; hydroxycarbamoyl-lower alkoxy; 2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5c]-pyrrol-5-yl; lower alkoxy-carbamoyl-lower alkoxy; 3R-hydroxy-pyrrolidin-1-yl; 3,4-dihydroxy-pyrrolidin-1-yl; 2-oxo-oxazolidin-3-yl; lower alkyl-carbamoylmethoxy; or aminocarbamoyl-lower alkoxy;
R
3
is a 5 or 6 membered aryl or heteroaryl which are optionally substituted by halogen; cyano; nitro; azido; hydroxy; carboxy; morpholine-4-carbonyl; carbamoyl; thiocarbamoyl; N-hydroxycarbamoyl; trimethylsilyl-ethynyl; or lower alkyl; lower alkoxy; halo-lower alkyl; 4-lower alkyl-piperazine-1-carbonyl; lower alkylcarbamoyl which are optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated; or an optionally substituted five-membered aromatic heterocycle, which may be optionally substituted by amino, lower alkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio, or carboxy which is optionally esterified or amidated, or lower alkyl which is optionally substituted by halogen, amino, lower alkylamino, acylamino, hydroxy, lower alkoxy, lower alkylthio, acyloxy, lower alkenoyl, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, alkoxyimino, carboxy which is optionally esterified or amidated, lower alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl which is optionally substituted by lower alkyl, or amidino which is optionally substituted by lower alkyl, —C(NRR′)═NR″ (where R, R′ and R″ are hydrogen or lower alkyl)
and their pharmaceutically acceptable addition salts.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties.
The compounds of the present invention can be used for the treatment or prevention of acute and/or chronic neurological disorders such as 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 chronic and acute pain, Huntington's chorea, amyotrophic lateral scherosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, indiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead tn glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production, as well as the use of the compounds in accordance with the invention in the control or prevention of illness of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
Preferred compounds of formula I in the scope of the present invention are those in which R
3
is phenyl substituted in meta position by cyano; halogen; or imidazolyl which is optionally substituted by lower alky or methylsulfanyl; 1,2,3-triazolyl; 1,2,4-triazolyl; or isoxazolyl which is optionally substituted by lower alkyl.
The following are examples of such compounds:
3-(8-Chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile
3-[8-(4-Methyl-piperazin-1-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile;
3-(8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile;
[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ylsulfanyl]-acetic acid methyl ester;
2-[4-(3-Cyano-phenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yl]-acetamide;
3-(8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2yl)-benzonitrile
3-(8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile;
4-(3-Iodo-phenyl)-7-(2-methoxy-ethoxy)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]dia
Adam Geo
Alanine Alexander
Goetschi Erwin
Mutel Vincent
Woltering Thomas Johannes
Dawson Arthur D.
Hoffmann-la Roche Inc.
Johnston George W.
Kifle Bruck
Roche-Tramaloni Patricia S.
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