Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-26
2002-12-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S251000
Reexamination Certificate
active
06492377
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to new imidazotriazolopyrimidines, processes for preparing them, pharmaceutical compositions comprising such compounds, and their use as medicaments for the treatment of various disease conditions.
BACKGROUND OF THE INVENTION
It is known that adenosine antagonists may have a therapeutically useful effect in the treatment of diseases or pathological conditions that are somehow caused by activation of adenosine receptors.
Adenosine is an endogenous modulator with predominantly inhibitory effects in the CNS, in the heart, in the kidneys and other organs. The effects of adenosine are mediated via at least three receptor sub-types: adenosine A
1
, A
2
and A
3
receptors. Adenosine A
2
receptors are further subdivided into two subtypes, A
2a
and A
2b
. The two A
2
receptor subtypes can be differentiated, e.g. because specific adenosine antagonists such as CGS 21680 stimulate predominantly only the A
2a
subtype. It is presumed that the A
2b
subtype has a relatively low affinity for adenosine. For this reason, relatively high concentrations of adenosine are necessary in order to stimulate this subtype. Such high concentrations would be expected, for example, in the epithelial surface fluid in the lungs of asthmatics or in ischaemic tissue damage.
In the CNS, adenosine develops inhibitory effects mainly by activating A
1
receptors: presynaptically by inhibiting the synaptic transmission (inhibiting the release of neurotransmitters such as acetylcholine, dopamine, noradrenaline, serotonin, glutamate, etc.), and postsynaptically by inhibiting neuronal activity.
A
1
antagonists cancel out the inhibitory effects of adenosine and promote neuronal transmission and neuronal activity.
A
1
antagonists are therefore of great interest for treating degenerative diseases of the central nervous system such as senile dementia of the Alzheimer's type and age-related disorders of memory and learning capacity.
The disease includes, in addition to forgetfulness in its mild form and total helplessness and absolute dependence on care in its severe form, a number of other accompanying symptoms such as sleep disorders, motor co-ordination disorders ranging up to Parkinson's syndrome, in addition to increased emotional instability and depressive symptoms. The disease is progressive and can lead to death. The treatments used hitherto have been unsatisfactory. At present there are no specific therapeutic agents at all. Attempts at treatment with acetylcholinesterase inhibitors show an effect in only a small proportion of the patients, but involve a high level of side effects.
The pathophysiology of Alzheimer's disease and SDAT is characterised by a severe deterioration of the cholinergic system, but other transmitter systems are also affected. As a result of the loss of presynaptic cholinergic and other neurones and the resulting lack of preparation of neurotransmitters the neuronal transmission and neuronal activity in the areas of the brain essential for learning and memory are significantly reduced.
Selective adenosine A
1
receptor antagonists promote neuronal transmission by the increased production of neurotransmitters, increase the excitability of postsynaptic neurones and can therefore counteract the symptoms of the disease.
The high receptor affinity and selectivity of some of the compounds claimed ought to make it possible to treat Alzheimer's disease and SDAT with low doses, so that hardly any side effects need be expected which cannot be put down to the blockade of A
1
receptors.
Another indication for centrally-acting adenosine A
1
antagonists is depression. The therapeutic success of antidepressant substances appears to be linked to the regulation of A
1
receptors. A
1
antagonists may lead to the regulation of adenosine A
1
receptors and thus offer a new therapeutic approach to the treatment of depressive patients.
Other areas of use for A
2
selective adenosine antagonists, in particular, are neurodegenerative diseases such as Parkinson's disease and also migraine. Adenosine inhibits the release of dopamine from central synaptic endings by interacting with dopamine-D
2
receptors. A
2
antagonists increase the release and availability of dopamine and thus offer a new therapeutic approach to the treatment of Parkinson's disease.
In migraine, the vasodilatation of cerebral blood vessels mediated by A
2
receptors appears to be involved. Selective A
2
antagonists inhibit the vasodilatation and can therefore be useful in treating migraine.
Adenosine antagonists may also be used for treating peripheral indications.
For example, the activation of A
1
, A
2
or A
3
receptors in the lung may lead to bronchoconstriction. Selective adenosine A
1
antagonists relax the tracheal smooth muscle, cause bronchodilatation and can thus be useful as antiasthmatic agents.
Adenosine A
2b
or A
3
receptors are located on mast cells. Their activation causes the release of mast cell products such as histamine, tryptase or interleukin 8. Adenosine A
3
receptors are found on eosinophiles and the stimulation of these receptors can influence the activation, chemotaxis and apoptosis of eosinophiles. Therefore, antagonists of A
2b
or A
3
receptors are very promising for the treatment of allergic diseases such as e.g. rhinitis, urticaria, pruritis, allergic dermatitis, allergic eye diseases and nasal polyps. In addition, the effect of adenosine A
2b
or A
3
antagonists on mast cells and eosinophiles may also be helpful in the treatment of asthma.
Furthermore, the anti-mast cell activity may be useful for reducing reperfusion damage after cardiac ischaemia.
By activating A
2
receptors, adenosine may cause, inter alia, respiratory depression and cessation of breathing. A
2
antagonists bring about respiratory stimulation. For example, adenosine antagonists (theophyllin) are used to treat respiratory distress and prevent sudden infant death in premature babies.
Adenosine stimulates the production of mucus by epithelial cells. The activation of adenosine A
2b
receptors on bronchial epithelial cells stimulates the chloride transportation which affects the consistency of mucus. Consequently, adenosine antagonists offer new therapeutic approaches to the treatment of diseases in which the quantity or consistency of the mucus is pathological, as in bronchitis and chronic obstructive pulmonary diseases, for example.
Adenosine A
2b
receptors are also located on the epithelial cells of the intestine. In the intestinal cells, too, the activation of these receptors can lead to increased chloride transportation. It is suspected that during inflammations of the intestines adenosine is released by neutrophiles, for example. The effect of the released adenosine on the chloride transportation influences the motility and absorption capacity of the intestinal epithelium. As a result, adenosine antagonists are possible therapeutic agents for inflammatory intestinal diseases and diarrhoea.
Other important therapeutic fields for adenosine antagonists are cardiovascular diseases and kidney diseases.
In the heart, adenosine inhibits electrical and contractile activity by activating A
1
receptors. Combined with coronary vasodilatation mediated via A
2
receptors, adenosine has a negative chronotropic, inotropic, dromotropic, bathmotropic and bradycardiac effect and reduces the volume of the heart per minute.
Adenosine A
1
receptor antagonists or adenosine A
3
receptor antagonists can prevent the damage caused to the heart and brain or lungs by ischaemia and subsequent reperfusion. As a result, adenosine antagonists can be used for the prevention or early treatment of damage to the heart caused by ischaemia/reperfusion e.g. after coronary bypass surgery, heart transplants, angioplasty or thrombolytic therapy of the heart and similar interventions. Moreover, adenosine antagonists can be used for the early treatment of cerebral ischaemia. The same is true of the lungs.
On the kidneys, the activation of A
1
receptors causes vasoconstriction of afferent ar
Blech Stefan
Carter Adrian
Gaida Wolfram
Hoffmann Matthias
Kuefner-Muehl Ulrike
Boehringer Ingelheim Pharma KG
McKenzie Thomas
Shah Mukund J.
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