Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-27
2004-08-03
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S263380, C514S263400, C544S276000, C544S277000
Reexamination Certificate
active
06770651
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds that are 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
1
adenosine receptor agonists modulate the cardiostimulatory effects of catecholamine, thus slowing the heart rate, and also prolong impulse propagation through the AV node. Thus, stimulation of A
1
receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. 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. Binding of A
2B
receptors in the brain leads to the release of IL-6, which provides a protective effect to the cerebrum from ischemia
While many of these biological effects of adenosine are necessary to maintain normal tissue homeostasis, under certain physiological changes it is desirable to curtail 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 adensoine to A
2B
receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibibiting tumor formation. Adensosine also plays a role in vascular disease by causing the apoptosis of smooth muscle cells, leading to atherosclerosis and restenosis.
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
to receptors would therefore mitigate those neurological disorders that are produced by IL-6.
Type I hypersensitivtiy 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, 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;-hexosaminidase 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, useful in the treatment of various disease states related to modulation of the A
2B
receptor, in particular cancer, asthma and diarrhea. Preferably, the compounds would be selective for the A
2B
receptor, thus avoiding side effects caused by interaction with other adenosine receptors.
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:
wherein:
R
1
is optionally substituted alkyl or a group —Y—Z, in which Y is a covalent bond or optionally substituted alkylene, and Z is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl;
R
2
is hydrogen, acyl, optionally substituted alkyl, or a group —Y—Z, in which Y is a covalent bond or optionally substituted alkylene, and Z is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl;
R
3
is hydrogen, optionally substituted alkyl or a group —Y—Z
1
, in which Y is a covalent bond or optionally substituted alkylene, and Z
1
is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino, optionally substituted alkenyl or optionally substituted alkynyl, with the proviso that when Y is a covalent bond Z cannot be optionally substituted amino;
R
4
and R
6
are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
R
5
is hydrogen, optionally substituted alkyl, halo, CF
3
, nitro, cyano, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted amino, optionally substituted sulfoxide, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted acylamino, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
X is oxygen, sulfur, or —NH—;
with the proviso that when Y is a covalent bond and Z or Z
1
is alkenyl or alkynyl, the double bond of the alkenyl or the triple bond of the alkynyl is located at least two carbon atoms away from the attachment to the nitrogen.
A second aspect of this invention relates to pharmaceutica
Palle Venkata
Varkhedkar Vaibhav
Xiao Dengming
Zablocki Jeff
Berch Mark L.
Clarke Pauline Ann
Hartrum J. Elin
Lewis Brian
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