Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-01
2004-10-05
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...
C544S280000
Reexamination Certificate
active
06800633
ABSTRACT:
BACKGROUND OF THE INVENTION
Adenosine is an ubiquitous modulator of numerous physiological activities, particularly within the cardiovascular and nervous systems. The effects of adenosine appear to be mediated by specific cell surface receptor proteins. Adenosine modulates diverse physiological functions including induction of sedation, vasodilation, suppression of cardiac rate and contractility, inhibition of platelet aggregability, stimulation of gluconeogenesis and inhibition of lipolysis. In addition to its effects on adenylate cyclase, adenosine has been shown to open potassium channels, reduce flux through calcium channels, and inhibit or stimulate phosphoinositide turnover through receptor-mediated mechanisms (See for example, C. E. Muller and B. Stein “Adenosine Receptor Antagonists: Structures and Potential Therapeutic Applications,”
Current Pharmaceutical Design,
2:501 (1996) and C. E. Muller “A
1
-Adenosine Receptor Antagonists,”
Exp. Opin. Ther. Patents
7(5):419 (1997)).
Adenosine receptors belong to the superfamily of purine receptors which are currently subdivided into P
1
(adenosine) and P
2
(ATP, ADP, and other nucleotides) receptors. Four receptor subtypes for the nucleoside adenosine have been cloned so far from various species including humans. Two receptor subtypes (A
1
and A
2a
) exhibit affinity for adenosine in the nanomolar range while two other known subtypes A
2b
and A
3
are low-affinity receptors, with affinity for adenosine in the low-micromolar range. A
1
and A
3
adenosine receptor activation can lead to an inhibition of adenylate cyclase activity, while A
2a
and A
2b
activation causes a stimulation of adenylate cyclase.
A few A
1
antagonists have been developed for the treatment of cognitive disease, renal failure, and cardiac arrhythmias. It has been suggested that A
2a
antagonists may be beneficial for patients suffering from Morbus Parkinson (Parkinson's disease). Particularly in view of the potential for local delivery, adenosine receptor antagonists may be valuable for treatment of allergic inflammation and asthma. Available information (for example, Nyce & Metzger “DNA antisense Therapy for Asthma in an Animal Model”
Nature
(1997) 385: 721-5) indicates that in this pathophysiologic context, A
1
antagonists may block contraction of smooth muscle underlying respiratory epithelia, while A
2b
or A
3
receptor antagonists may block mast cell degranulation, mitigating the release of histamine and other inflammatory mediators. A
2b
receptors have been discovered throughout the gastrointestinal tract, especially in the colon and the intestinal epithelia. It has been suggested that A
2b
receptors mediate cAMP response (Strohmeier et al.,
J. Bio. Chem.
(1995) 270:2387-94).
Adenosine receptors have also been shown to exist on the retinas of various mammalian species including bovine, porcine, monkey, rat, guinea pig, mouse, rabbit and human (See, Blazynski et al.,
Discrete Distributions of Adenosine Receptors in Mammalian Retina, Journal of Neurochemistry
, volume 54, pages 648-655 (1990); Woods et al.,
Characterization of Adenosine A
1
-
Receptor Binding Sites in Bovine Retinal Membranes, Experimental Eye Research
, volume 53, pages 325-331 (1991); and Braas et al.,
Endogenous adenosine and adenosine receptors localized to ganglion cells of the retina, Proceedings of the National Academy of Science
, volume 84, pages 3906-3910 (1987)). Recently, Williams reported the observation of adenosine transport sites in a cultured human retinal cell line (Williams et al.,
Nucleoside Transport Sites in a Cultured Human Retinal Cell Line Established By SV
-40
T Antigen Gene, Current Eye Research
, volume 13, pages 109-118 (1994)).
Compounds which regulate the uptake of adenosine uptake have previously been suggested as potential therapeutic agents for the treatment of retinal and optic nerve head damage. In U.S. Pat. No. 5,780,450 to Shade, Shade discusses the use of adenosine uptake inhibitors for treating eye disorders. Shade does not disclose the use of specific A
3
receptor inhibitors. The entire contents of U.S. Pat. No. 5,780,450 are hereby incorporated herein by reference.
Additional adenosine receptor antagonists are needed as pharmacological tools and are of considerable interest as drugs for the above-referenced disease states and/or conditions.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery that certain N-6 substituted 7-deazapurines, described infra, can be used to treat a N-6 substituted 7-deazapurine responsive state. Examples of such states include those in which the activity of the adenosine receptors is increased, e.g., bronchitis, gastrointestinal disorders, or asthma. These states can be characterized in that adenosine receptor activation can lead to the inhibition or stimulation of adenylate cyclase activity. Compositions and methods of the invention include enantiomerically or diastereomerically pure N-6 substituted 7-deazapurines. Preferred N-6 substituted 7-deazapurines include those which have an acetamide, carboxamide, substituted cyclohexyl, .e.g., cyclohexanol, or a urea moiety attached to the N-6 nitrogen through an alkylene chain.
The present invention pertains to methods for modulating an adenosine receptor(s) in a mammal by administering to the mammal a therapeutically effective amount of a N-6 substituted 7-deazapurine, such that modulation of the adenosine receptor's activity occurs. Suitable adenosine receptors include the families of A
1
, A
2
, or A
3
. In a preferred embodiment, the N-6 substituted 7-deazapurine is a adenosine receptor antagonist.
The invention further pertains to methods for treating N-6 substituted 7-deazapurine disorders, e.g., asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, renal disorders, gastrointestinal disorders, and eye disorders, in a mammal by administering to the mammal a therapeutically effective amount of a N-6 substituted 7-deazapurine, such that treatment of the disorder in the mammal occurs. Suitable N-6 substituted 7 deazapurines include those illustrated by the general formula I:
and pharmaceutically acceptable salts thereof. R
1
and R
2
are each independently a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or together form a substituted or unsubstituted heterocyclic ring. R
3
is a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety. R
4
is a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety. R
5
and R
6
are each independently a halogen atom, e.g., chlorine, fluorine, or bromine, a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or R
4
and R
5
or R
5
and R
6
together form a substituted or unsubstituted heterocyclic or carbocyclic ring.
In certain embodiments, R
1
and R
2
can each independently be a substituted or unsubstituted cycloalkyl or heteroarylalkyl moieties. In other embodiments, R
3
is a hydrogen atom or a substituted or unsubstituted heteroaryl moiety. In still other embodiments, R
4
, R
5
and R
6
can each be independently a heteroaryl moieties. In a preferred embodiment, R
1
is a hydrogen atom, R
2
is a cyclohexanol, e.g., trans-cyclohexanol, R
3
is phenyl, R
4
is a hydrogen atom, R
5
is a methyl group and R
6
is a methyl group. In still another embodiment, R
1
is a hydrogen atom, R
2
is
R
3
is phenyl, R
4
is a hydrogen atom and R
5
and R
6
are methyl groups.
The invention further pertains to pharmaceutical compositions for treating a N-6 substituted 7-deazapurine responsive state in a mammal, e.g., asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, renal disorders, gastrointestinal disorders, and eye disorders. The pharmaceutical composition includes a therapeutically effective amount of a N-6 substituted 7-deazapurine and a pharmaceutically acceptable carrier.
The present invention also pertains to packaged pharmaceutical compositions for treating a N-6 substituted 7-deazapurine responsive state in a ma
Castelhano Arlindo L.
McKibben Bryan
Witter David J.
Cooper & Dunham LLP
McKenzie Thomas C
OSI Pharmaceuticals, Inc.
Shah Mukund J.
White John P.
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