A2B adenosine receptor antagonists

Details A2B adenosine receptor antagonists A2B adenosine receptor antagonists

2002-11-08

2004-11-30

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

C544S269000, C544S270000, C544S271000, C544S272000

Reexamination Certificate

active

06825349

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to A
2B
adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
BACKGROUND
Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A
1
, A
2A
, A
2B
, and A
3
, all of which modulate important physiological processes. For example, A
2A
adenosine receptors modulate coronary vasodilation, A
2B
receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A
2B
Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153), and A
3
adenosine receptors modulate cell proliferation processes.
Adenosine A
2B
receptors are ubiquitous, and regulate multiple biological activities. For example, adenosine binds to A
2B
receptors on endothelial cells, thereby stimulating angiogenesis. Adenosine also regulates the growth of smooth muscle cell populations in blood vessels. Adenosine stimulates A
2B
receptors on mast cells, thus modulating Type I hypersensitivity reactions. Adenosine also stimulates gastrosecretory activity by ligation with A
2B
in the intestine.
While many of these biological effects of adenosine are necessary to maintain normal tissue homeostasis, under certain physiological changes it is desirable to modulate its effects. For example, the binding of A
2B
receptors stimulates angiogenesis by promoting the growth of endothelial cells. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels occurs in neoplasia. Accordingly, inhibition of the binding of adenosine to A
2B
receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibibiting tumor formation.
A
2B
receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and when acted upon by the appropriate ligand act to increase chloride secretion, thus causing diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and typhus. A
2B
antagonists can therefore be used to block intestinal chloride secretion, and are thus useful in the treatment of inflammatory gastrointestinal tract disorders, including diarrhea.
Insensitivity to insulin exacerbates diabetes and obesity. Insulin sensivity is decreased by the interaction of adenosine with A
2B
receptors. Thus, blocking the adenosine A
2B
receptors of individuals with diabetes or obesity would benefit patients with these disorders.
Another adverse biological effect of adenosine acting at the A
2B
receptor is the over-stimulation of cerebral IL-6, a cytokine associated with dementias and Altheimer's disease. Inhibiting the binding of adenosine to A
2B
receptors would therefore mitigate those neurological disorders that are produced by IL-6.
Type I hypersensitivity disorders, such as asthma, hay fever, and atopic ezcema, are stimulated by binding to A
2B
-receptors of mast cells. Therefore, blocking these adenosine receptors would provide a therapeutic benefit against such disorders.
There are several compounds presently used in the treatment of asthma. For example, theophylline is an effective antiasthmatic agent, even though it is a poor adenosine receptor antagonist. However, considerable plasma levels are needed for it to be effective. Additionally, theophylline has substantial side effects, most of which are due to its CNS action, which provide no beneficial effects in asthma, and to the fact that it non-specifically blocks all adenosine receptor subtypes.
Additionally adenosine treatment, such as inhaled adenosine (or adenosine monophosphate), provokes bronchoconstriction in asthmatics, but not in the normal population. This process is known to involve mast cell activation, in that it releases mast cell mediators, including histamine, PGD2-&bgr;-hexosamimidase and tryptase, and because it can be blocked by specific histamine H
1
blockers and chromolyn sodium. Accordingly, there is an intrinsic difference in the way adenosine interacts with mast cells from asthmatics, and thus A
2B
antagonists are particularly useful in modulating mast cell function or in the activation of human lung cells.
Accordingly, it is desired to provide compounds that are potent A
2B
antagonists, fully or partially selective for the A
2B
receptor, useful in the treatment of various disease states related to modulation of the A
2B
receptor, for example cancer, asthma and diarrhea.
SUMMARY OF THE INVENTION
It is an object of this invention to provide A
2B
receptor antagonists. Accordingly, in a first aspect, the invention relates to compounds of Formula I and Formula II:
wherein:
R
1
and R
2
are independently chosen from hydrogen, optionally substituted alkyl, or a group —D—E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;
R
3
is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
X is optionally substituted arylene or optionally substituted heteroarylene;
Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino;
with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and
Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or
Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond;
with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
A second aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I or Formula II, or a mixture thereof, and at least one pharmaceutically acceptable excipient.
A third aspect of this invention relates to a method of using the compounds of Formula I and Formula II in the treatment of a disease or condition in a mammal that can be usefully treated with an A
2B
receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I or Formula II, or a mixture thereof. Such diseases include, but are not limited to, at least one of asthma, inflammatory gastrointestinal tract disorders, including diarrhea, cardiovascular diseases such as atherosclerosis, neurological disorders such as senile dementia, Alzheimer's disease, and Parkinson's disease, and diseases related to angiogenesis, for example diabetic retinopathy and cancer.
A fourth aspect of this invention relates to methods for preparing the compounds of Formula I and Formula II.
One preferred group of compounds of Formula I and II are those in which R
1
and R
2
are independently hydrogen, optionally substituted lower alkyl, or a group —D—E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, particularly those in which R
3
is hydrogen.
Within this group, a first preferred class of compounds include those in which R
1
and R
2
are independently lower

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