Pyrimidine, pyrazine and triazane derivatives

Details Pyrimidine, pyrazine and triazane derivatives Pyrimidine, pyrazine and triazane derivatives

2002-05-29

2004-01-06

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252110, C514S255050, C514S256000, C514S272000, C514S274000, C544S182000, C544S295000, C544S319000, C544S326000, C544S408000

Reexamination Certificate

active

06673795

ABSTRACT:

FIELD OF INVENTION
The present invention relates to pyrimidine, triazine and pyrazine derivatives of the formula
Compounds of formula I are metabotropic glutamate (mGluR 1) receptor antagonists and are useful in the treatment of disorders responsive to mediation of the mGluR 1 receptors, such as acute and/or chronic neurological disorders
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) 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 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
The present invention is a compound of formula
or a pharmaceutically acceptable salt thereof wherein
R
1
is selected from the group consisting of nitro and cyano;
R
2
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl and —NHR
10
, and wherein
R
10
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl, —(CH
2
)
m
—OR
11
, —(CH
2
)
p
—(C
3
-C
6
)-cycloalkyl, —(CH
2
)
m
—NH—C(O)O—(C
1
-C
7
)-alkyl, and —(CH
2
)
p
-pyridyl and R
11
is selected from the group consisting of hydrogen and (C
1
-C
7
)-alkyl;
R
3
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl, fluoro, hydroxy, (C
1
-C
7
)-alkoxy, (C
1
-C
7
)-alkylthio, cyano and nitro;
R
4
is selected from the group consisting of hydrogen and fluoro;
 is selected from the group consisting of
R
5
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl, (C
1
-C
7
)-alkenyl, —(CH
2
)
m
—OR
11
, fluoro-(C
1
-C
7
)-alkyl and —(CH
2
)
n
CN;
R
6
is selected from the group consisting of (C
1
-C
7
)-alkyl, halogen, hydroxy, (C
1
-C
7
)-alkoxy, (C
1
-C
7
)-alkylthio, —O—(CH
2
)
m
—OR
11
, —O-fluoro-(C
1
-C
7
)-alkyl and —NHR
12
, and
R
12
is selected from the group consisting of (C
1
-C
7
)-alkyl, —(CH
2
)
m
—OR
11
, —(CH
2
)
p
—(C
3
-C
6
)-cycloalkyl and —(CH
2
)
p
-pyridyl;
R
7
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl and phenyl;
R
8
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl and phenyl;
Z is selected from the group consisting of
R
9
is selected from the group consisting of hydrogen, hydroxy and cyano;
m is independently from each other in each occurrence 2, 3, 4, 5 or 6;
n is independently from each other in each occurrence 1, 2, 3, 4, 5 or 6; and
p is independently from each other in each occurrence 0, 1, 2, 3, 4, 5 or 6.
It has now been found that the compounds of formula I are antagonists of the metabotropic glutamate receptor.
Objects of the present invention are compounds of formula I or 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 of formula I and their production are also objects of the present invention. The invention also is a method of treatment of conditions responsive to mediation of group I mGluR receptors comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a person in need of such treatment.
DETAILED DESCRIPTION
A preferred compound of formula I within the scope of the present invention has the formula
or a pharmaceutically acceptable salt thereof, wherein
R
1
is selected from the group nitro and cyano;
R
2
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl and —NHR
10
, and wherein R
10
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl, —(CH
2
)
m
—OR
11
, —(CH
2
)
p
—(C
3
-C
6
)-cycloalkyl, —(CH
2
)
m
—NH—C(O)O—(C
1
-C
7
)-alkyl and —(CH
2
)
p
-pyridyl; wherein R
11
is hydrogen or (C
1
-C
7
)-alkyl;
R
3
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl, fluoro, hydroxy, (C
1
-C
7
)-alkoxy, (C
1
-C
7
)-alkylthio, cyano and nitro;
R
4
is hydrogen or fluoro;
R
5
is selected from the group consisting of hydrogen, (C
1
-C
7
)-alkyl, (C
1
-C
7
)-alkenyl, —(CH
2
)
m
—OR
11
, fluoro-(C
1
-C
7
)-alkyl and —(CH
2
)
n
—CN;
Z is selected from the group consisting of
R
9
is selected from the group consisting of hydrogen, hydroxy and cyano;
m is independently from each other in each occurrence 2, 3, 4, 5 or 6;
n is independently from each other in each occurrence 1, 2, 3, 4, 5 or 6; and
p is independently from each other in each occurrence 0, 1, 2, 3, 4, 5 or 6.
A further preferred compound of formula Ia has the formula
wherein R
2
is lower alkyl and R
5
is selected from the group consisting of (C
1
-C
7
)-alkyl, (C
1
-C
7
)-alkyl subsituted by halo and (C
1
-C
7
)-alkyl substituted by hydroxyl.
A preferred compound of formula Ia1 is selected from the group consisting of 6-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one;
3-ethyl-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one; and
6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-(2-hydroxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one.
Another preferred compound of formula Ia has the formula
wherein R
2
is selected from the group consisting of (C
1
-C
7
)-alkyl and —NHR
10
, wherein R
10
is selected from the group consisting of (C
1
-C
7
)-alkyl, —(CH
2
)
m
—OR
11
, —(CH
2
)
p
—(C
3
-C
6
)-cycloalkyl, and R
11
is selected from the group consisting of hydrogen and (C
1
-C
7
)-alkyl, —(CH
2
)
m
—NH—C(O)O—(C
1
-C
7
)-alkyl and —(CH
2
)
p
-pyridyl;
R
3
is selected from the group consisting of hydrogen and fluoro; and
wherein R
9
is hydrogen.
A more preferred compound of formula Ia2 is wherein R
3
is hydrogen and R
5
is selected from the group consisting of (C
1
-C
7
)-alkyl, —(CH
2
)
m
—OR
11
and fluoro-(C
1
-C
7
)-alkyl.
An exemplary more preferred compound of formula Ia2 is selected from the group consisting of 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one, 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one, and 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-3-(2-methoxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one.
An additional preferred compound of formula I has the formula
or a pharmaceutically acceptable salt thereof.
A further pref

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