Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-11-08
2003-03-11
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06531600
ABSTRACT:
The present invention relates to a novel method of treatment and to certain novel compounds having pharmacological activity, to a process for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
Molecular Pharmacology, Volume 6, No. 6, 1970, p. 597-603 discloses 1,3-dimethyl-8-nitro-xanthine. This compound is disclosed as having lipolytic activity.
Annalen der Chemie, 47, 362-365 (1957) discloses 1, 3-dimethyl-8-amino-xanthine and a process by which it may be prepared. No pharmacological utility is disclosed for this compound.
Drug Res. 27 (1) Nr. 19, 1977, pages 4-14, Van K. H. Klingler discloses certain 1, 3-dimethyl-8-substituted xanthines as intermediates solely in the synthesis of phenylethyl aminoalkyl xanthines.
Drug Res. 31 (11), Nr. 12, 1981, R. G. Werner et al, pages 2044-2048 discloses certain 1, 3-dimethyl-8-substituted xanthines. No pharmacological activity is disclosed for these compounds.
It has now been discovered that certain 8-substituted xanthines have a protective effect against the consequences of cerebral metabolic inhibition. The said compounds improve data acquisition or retrieval following transient forebrain ischaemia and are therefore useful in the treatment of cerebral vascular and neuronal degenerative disorders associated with learning, memory and cognitive dysfunctions including cerebral senility, multi-infarct dementia, senile dementia of the Alzheimer type, age associated memory impairment and certain disorders associated with Parkinson's disease.
These compounds are also indicated to have neuroprotectant activity. They are therefore useful in the prophylaxis of disorders associated with neuronal degeneration resulting form ischaemic events, including cerebral ischaemia due to cardiac arrest, stroke and also after cerebral ischaemic events such as those resulting from surgery and or during childbirth. In addition treatment with the compound is indicated to be of benefit for the treatment of functional disorders resulting from disturbed brain function following ischaemia.
These compounds are also active in increasing the oxygen tension in ischaemic skeletal muscle. This property results in an increase in the nutritional blood flow through ischaemic skeletal muscle which in turn indicates that the compounds of the invention are of potential use as agents for the treatment of peripheral vascular disease such as intermittent claudication.
These compounds also act as phosphodiesterase inhibitors and elevate cyclic AMP levels and are therefore of potential use in the treatment of proliferative skin disease in human or non-human mammals.
These compounds are also indicated to have bronchodilator activity and thus to be of potential use in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma.
It has now also surprisingly been discovered that these compounds are good inhibitors of induced blood eosinophilia and that they are therefore potentially useful in the treatment and/or prophylaxis of disorders associated with increased numbers of eosinophils, such as asthma, and allergic disorders associated with atopy, such as urticaria, eczema and rhinitis.
Certain of the novel compounds are also indicated to possess useful adenosine Al antagonist activity.
Finally the present compounds also show good metabolic stability.
Accordingly, the invention provides a method for the treatment of cerebrovascular disorders and/or disorders associated with cerebral senility and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events and/or peripheral vascular disease and/or proliferative skin disease and/or for disorders of the respiratory tract and/or the treatment or prophylaxis of disorders associated with increased numbers of eosinophils and allergic disorders associated with atopy, which method comprises the administration of an effective, non-toxic amount of a compound of formula (I):
or if appropriate a pharmaceutically acceptable salt thereof, wherein R
1
and R
2
each independently represent alkyl or a moiety of formula (a):
−(CH
2
)
m
−A (a)
wherein
m represents zero or an integer 1, 2 or 3;
A represents a substituted or unsubstituted cyclic hydrocarbon radical; and
R
3
represents a halogen atom, a nitro group, or a group −NR
4
R
5
wherein R
4
and R
5
each independently represents hydrogen, alkyl or alkylcarbonyl or R
4
and R
5
together with the nitrogen to which they are attached form an optionally substituted, heterocyclic group; to a human or non-human mammal in need thereof.
In another aspect, the invention provides the use of a compound of formula (I), or if appropriate a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cerebrovascular disorders and/or disorders associated with cerebral senility and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events and/or peripheral vascular disease and/or proliferative skin diseases and/or disorders of the respiratory tract and/or the treatment or prophylaxis of disorders associated with increased numbers of eosinophils and allergic disorders associated with atopy.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or if appropriate a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or if appropriate a pharmaceutically acceptable salt thereof, providing that in the compound of formula (I) when R
1
and R
2
both represent methyl then R
3
is not a nitro group, and a pharmaceutically acceptable carrier therefor.
In a further aspect the invention provides a compound of formula (I), or if appropriate a pharmaceutically acceptable salt thereof, providing that in the compound of formula (I) when R
1
and R
2
both represent methyl then R
3
is not a nitro group, for use as an active therapeutic substance.
The invention also provides a compound of formula (I), or if appropriate a pharmaceutically acceptable salt thereof, providing that in the compound of formula (I) when R
1
and R
2
both represent methyl then R
3
is not a nitro group, for use in the treatment of cerebrovascular disorders and/or disorders associated with cerebral senility and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events and/or peripheral vascular disease and/or proliferative skin diseases and/or disorders of the respiratory tract and/or the treatment or prophylaxis of disorders associated with increased numbers of eosinophils and allergic disorders associated with atopy.
As indicated above, certain of the compounds of formula (I) are novel and form a further aspect of the present invention.
Accordingly, the invention also provides a compound of formula (IA):
or if appropriate a pharmaceutically acceptable salt thereof, wherein R
1
and R
2
each independently represent alkyl or a moiety of formula (a):
−(CH
2
)
m
−A (a)
wherein
m represents zero or an integer 1, 2 or 3, A represents a substituted or unsubstituted cyclic hydrocarbon radical, providing that when R
1
represents methyl then R
2
is not methyl; and
R
3a
represents a halogen atom, a nitro group, or a group −NR
4
R
5
wherein R
4
and R
5
each independently represent hydrogen, alkyl or alkylcarbonyl or R
4
and R
5
together with the nitrogen to which they are attached form an optionally substituted heterocyclic group.
Suitably, R
1
represents a moiety of formula (a).
Suitably, R
2
represents a moiety of formula (a).
Preferably, R
1
and R
2
each independently represent a moiety of formula (a).
Suitably, A is unsubstituted. Favourably, A represents a substituted or unsubstituted C
3-8
cycloalkyl group, especially a C
3-6
cycloalkyl group.
In particular, A represents a substituted or, pre
Maschler Harald
Smith Harry
Spicer Barbara Ann
Beecham Group p.l.c.
Berch Mark L.
Dinner Dara L.
Kinzig Charles M.
Venetianer Stephen
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