Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-31
2004-02-17
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S232800, C546S084000, C544S126000, C548S429000, C548S433000
Reexamination Certificate
active
06693111
ABSTRACT:
TECHNICAL FIELD
BACKGROUND ART
Excessive excitation by neurotransmitters can cause the degeneration and death of neurones. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA), glutamate and aspartate, at the N-methyl-D-aspartate (NMDA), the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurones in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from near-drowning, pulmonary surgery and cerebral trauma as well as lathyrism, Alzheimer's, and Huntington's diseases. Compounds capable of blocking excitatory amino acid receptors are therefore considered useful for the treatment of the above disorders and diseases, as well as Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain and drug addiction.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel indole-2,3-dione-3-oxime derivatives which are excitatory amino acid antagonists and useful in the treatment of disorders or diseases of mammals, including humans, which are responsive to excitatory amino acid receptor antagonists.
Accordingly, in its first aspect, the invention provides the novel indole-2,3-dione-3-oxime derivatives described in claim 1.
In another aspect the invention relates to the use of a chemical compound of the invention for the preparation of a pharmaceutical composition.
In a third aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the chemical compound of the invention together and a pharmaceutically acceptable excipient, carrier or diluent.
In a fourth aspect the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists.
In a more specific aspect the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
In a fifth aspect the invention provides a method of treating disorders or diseases of living animals, including humans, which are responsive to excitatory amino acid receptor antagonists, comprising administering to a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.
In a more specific aspect the invention provides a method of treating a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
In a sixth aspect the invention relates to the use of the chemical compound of the invention in a method of treating a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists, said method comprising administering to a living animal body, including a human, in need thereof an effective amount of the chemical compound.
In a more specific aspect the invention relates to the use of the chemical compound of the invention in a method of treating a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
In a seventh aspect the invention provides a method of preparing a chemical compound of the invention.
Other objectives of the present invention will be apparent to the skilled person hereinafter.
DETAILED DISCLOSURE OF THE INVENTION
Indole2,3-dione-3-oxime Derivatives
In its first aspect, the present invention provides novel indole-2,3-dione-3-oxime derivatives. The novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (I):
wherein
R
1
represents hydrogen, alkyl or benzyl;
R
3
represents “Het”, or a group of the following formula
wherein
“Het” represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, alkoxy, and oxo; and
at least one of R
31
, R
32
, and R
33
independently represents hydrogen, alkyl, or hydroxyalkyl, and
at least one of R
31
, R
32
, and R
33
independently represents (CH
2
)
n
R
34
; wherein
R
34
represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, CONR
35
R
36
, or “Het”; wherein
R
35
and R
36
represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, aryl, aralkyl, or (CH
2
)
n
—R
37
; wherein
R
37
represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxy-carbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; or
R
35
and R
36
together with the N-atom to which they are attached form a saturated 5- to 6-membered, heterocyclic ring, optionally containing one additional N or O atom; and
“Het” is as defined above; and
n is 0, 1, 2, or 3; and
R
5
represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, NO
2
, amino, alkyl, alkoxy, phenyl and SO
2
NR
51
R
52
; wherein
R
51
and R
52
each independently represents hydrogen or alkyl; or
R
51
and R
52
together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom; and
“A” represents a ring of five to seven atoms fused with the benzo ring at the positions marked “a” and “b”, and formed by the following bivalent radicals:
a—NR
6
—CH
2
—CH
2
—b;
a—CH
2
—NR
6
—CH
2
—b;
a—CH
2
—CH
2
—NR
6
—b;
a—NR
6
—CH
2
—CH
2
—CH
2
—b;
a—CH
2
—NR
6
—CH
2
—CH
2
—b;
a—CH
2
—CH
2
—NR
6
—CH
2
—b;
a—CH
2
—CH
2
—CH
2
—NR
6
—b;
a—NR
6
—CH
2
—CH
2
—CH
2
—CH
2
—b;
a—CH
2
—NR
6
—CH
2
—CH
2
—CH
2
—b;
a—CH
2
—CH
2
—NR
6
—CH
2
—CH
2
—b;
a—CH
2
—CH
2
—CH
2
—NR
6
—CH
2
—b; or
a—CH
2
—CH
2
—CH
2
—CH
2
—NR
6
—b; wherein
R
6
represents hydrogen, alkyl or CH
2
CH
2
OH;
or a pharmaceutically acceptable salt thereof.
In a more preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula, (I), above, wherein “Het” is a lactone ring of the general formula (VI):
and wherein m is 1, 2, 3 or 4; and
In another preferred embodiment, the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II):
wherein
R
1
represents hydrogen, alkyl or benzyl;
“Het” represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, alkoxy, and oxo;
n is 0, 1, 2, or 3;
R
5
represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, NO
2
, amino, alkyl, alkoxy, phenyl and SO
2
NR
51
R
52
; wherein
R
51
and R
52
each independently represents hydrogen or alkyl; or
R
51
and R
52
together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom; and
“A” represents a ring of five to seven atoms fused with the benzo ring at t
Drejer Jorgen
Watjen Frank
Birch & Stewart Kolasch & Birch, LLP
Morris Patricia L.
NeuroSearch A/S
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