Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-29
2001-05-29
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S291000, C514S411000
Reexamination Certificate
active
06239128
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the use of indole-2,3-dione-3-oxime derivatives in a method of combating diseases and disorders associated with or mediated by the release of excitatory amino acids.
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.
DETAILED DISCLOSURE OF THE INVENTION
It has now been found that certain indole-2,3-dione-3-oxime derivatives and pharmaceutically acceptable salts hereof have valuable therapeutic properties.
Thus, viewed from one aspect, the present invention provides a method of combating diseases and disorders associated with or mediated by the release of excitatory amino acids, said method comprising administering to a subject a compound of 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.
Diseases included in the method of the invention include in particular diseases of the central nervous system (CNS). In particular, the invention relates to combating diseases associated with reduced blood flow to the brain and other CNS tissue and with instances of a temporary break in blood supply to the brain or to other CNS tissue. Examples include ischaemic diseases, anoxic episodes, and injury to the brain and other parts of the CNS caused by trauma or other injury, for example a blow to the head, or spinal injury. In such reduced blood flow episodes, or episodes where there is a temporary break in blood supply, oxygen supply to the brain is reduced or interrupted. It is believed that this results in a release of neurotransmitters such as glutamate into the area of the brain where there is oxygen deprivation; the binding of the released neurotransmitters to the cellular neurotransmitter receptors triggers various cellular and biochemical events which can lead to cell death. These receptors include the glutamate receptor, the aspartate receptor, the N-methyl-D-aspartate (NMDA) receptor, the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor. It is further believed that the 2,3-dione-3-oxime derivative for use in the invention block these cellular receptors, thereby preventing the catastrophic chain of events including neurone death which can follow the release of neurotransmitters such as glutamate.
The method of the invention may be used in the treatment or prevention of cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as tromboembolic 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 disease, and Huntington's disease. The method can be used in the treatment or prevention of traumatic brain injury, in particular ischaemic, hypoxic or anoxic brain damage, spinal cord injury, tissue ischemia and reperfusion injury in a mammal at risk for such damage.
The brain damage may follow cerebral ischemia, either global or focal, or be caused by cardiac arrest, or may follow high risk surgery such as cardiac surgery. It may also follow or be caused by stroke, neonatal hypoxia, hypoxia caused by compromised lung function, neonatal anoxia, anoxia caused by compromised lung function, cerebral trauma, secondary regional ischemia induced by brain oedema, increased intercranial pressure, open brain surgery, endarterectomy, surgical interventions involving temporary, artificially sustained arrest of cardiopulmonary functions resulting in impairment of cerebral blood flow, and emergency treatment involving cardiopulmonary resuscitation (CPR).
As used herein, reperfusion injury refers to the cellular changes and tissue damage seen after a period of total ischemia followed by reperfusion. Extremity replantation, organ transplantation, free flap tissue reconstruction and even myocardial infarction and stroke are all clinical examples of interval tissue ischemia which can lead to tissue loss due to reperfusion injury after blood flow is re-established. Tissue reperfusion injury, seen in its full clinical extent as the no-reflow phenomenon, appears as inflammatory response to reperfusion resulting in the ultimate death of the tissue.
Thus the chemical compounds of the invention are found to be particularly useful in acute treatment of ischaemic stroke, in treatment of brain damage following global cerebral ischemia, or for prevention of brain damage following high risk surgery.
In many instances of brain ischemia, treatment is not available to the patient for several, e.g. up to 6 hours, in stroke patients typically 3 to 6 hours, after the ischaemic injury
Drejer Jorgen
Watjen Frank
Birch & Stewart Kolasch & Birch, LLP
Henley III Raymond
NeuroSearch A/S
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