Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-07-11
2002-04-09
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S578000, C540S580000, C540S593000
Reexamination Certificate
active
06369222
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with novel mGluR antagonists, methods of their synthesis and the treatment and/or prevention of neurological disorders.
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 a neuroreceptor on another neuron.
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 II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands, particularly antagonists, 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, psychoses, anxiety, vomiting, dyskinesia and depression.
It is an object of the present invention to provide pharmaceutically active substances, medicaments and a method of their manufacture for the control or prevention of illnesses of the aforementioned kind. It is another object to provide radiolabeled mGluR1 receptor antagonists for use in binding assays.
SUMMARY OF THE INVENTION
It has surprisingly been found that the compounds of formula I are antagonists of metabotropic glutamate receptors of the first group:
wherein
R
1
signifies oxygen, hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy;
R
2
signifies nitro or cyano;
R
3
signifies hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
R
4
signifies hydrogen, lower alkyl, lower alkenyl, or is absent, if the adjacent nitrogen atom already is the origin of three bonds as —N═ or ═N—;
R
5
, R
6
, R
9
and R
10
signify, independently from each other, hydrogen or lower alkyl;
R
7
, R
8
, R
11
or R
12
signify, independently from each other, hydrogen, lower alkyl, or hydroxy;
R
13
and R
14
signify, independently from each other, hydrogen or lower alkyl;
R
15
and R
16
signify, independently from each other, hydrogen or lower alkyl;
R
17
signifies hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
R
18
signifies hydrogen or hydroxy;
R
19
signifies hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
V signifies NH, S or O; and
the dotted line may be a bond,
as well as with their pharmaceutically acceptable salts in their racemic and optically active form.
The present invention encompasses 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 illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments. Furthermore, the use of radiolabeled mGluR1 receptor antagonists of formula I in a binding assay is also encompassed by the present invention.
The present invention is further illustrated by the following descriptions of preferred embodiments and examples. These preferred embodiments and examples are not limiting on the invention. One of skill in the arts of organic synthesis and/or pharmaceutical chemistry would well recognize a variety of obvious variations to these preferred embodiments and examples which would still be encompassed by this invention. The invention is limited only by the claims that follow and their equivalents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Compounds of formula I′
wherein
R
1
is oxygen, hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy;
R
2
is nitro or cyano;
R
3
is hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
R
4
is hydrogen, lower alkyl, lower alkenyl or is absent, if the adjacent nitrogen atom is part of a covalent double bond;
R
5
, R
6
, R
9
and R
10
are, independently from each other, hydrogen or lower alkyl;
is selected from the group consisting of
wherein
R
7
, R
8
, R
11
or R
12
are, independently from each other, hydrogen, lower alkyl, or hydroxy;
R
13
and R
14
are, independently from each other, hydrogen or lower alkyl;
R
15
and R
16
are, independently from each other, hydrogen or lower alkyl;
R
17
is hydrogen, lower alkyl, lower alkoxcy, hydroxy or amino;
R
18
is hydrogen or hydroxy;
R
19
is hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
V is NH, S or O; and
a dotted line is an optional bond,
and pharmaceutically acceptable salts of a compound of formula I′ are antagonists of mGluR.
Formula I′ defines the same set of compounds as formula I. The compounds encompassed by Formula I′ may be sub-divided into compounds of formulas I′a, I′b and I′c:
wherein
R
1′
is hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy;
R
3′
is hydrogen, lower alkyl, lower alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
R
4′
is hydrogen, lower alkyl or lower alkenyl; and
R
2
, R
5
, R
6
, R
9
, R
10
and
are as defined for formula I′.
Preferred compounds of formulas I, I′, I′a, I′b and I′c in the scope of the present invention are those in which R
2
is NO
2
.
Further preferred are compounds of formula I in the scope of the present invention,
wherein
R
1
is ═O or lower alkoxy and
HET represents a thiophene group.
The following are examples of such compounds:
[rac]-6-(4-Hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d] azepin-6-yl)-2-methyl-5-nitro-3H-pyrimidin-4-one,
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4-one,
6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine, or
3-Ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno [2,3-d] azepin-6-yl)-3H-pyrimidin-4-one.
Also preferred are compounds of formula I in the scope of the present invention,
wherein
R
1
is ═O or lower alkoxy, and
HET represents a thiazole group.
The following are examples of such compounds:
2-Methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one,
6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine,
3-Ethyl-2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one,
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl) -2-methyl-5-nitro-3H-pyrimidin-4-one,
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo [4,5-d]azepin-6-yl)-3-ethyl-2-methyl-5-nitro-3H-pyrimidin-4-one, or
2-M
Binggeli Alfred
Maerki Hans-Peter
Mutel Vincent
Wostl Wolfgang
Dubberley F. Aaron
Ford John M.
Hoffmann-La Roche Inc.
Johnston George W.
Tramaloni Dennis P.
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