Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-19
2004-04-27
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S211090, C514S211100, C514S215000, C514S224200, C514S230500, C514S301000, C514S435000, C540S544000, C540S552000, C540S568000, C544S005000, C544S047000, C544S048000, C544S091000, C544S278000, C546S114000, C549S015000, C549S019000
Reexamination Certificate
active
06727258
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to certain thiophene derivatives and their use in the practice of medicine as allosteric modulators of adenosine receptors.
Adenosine (Ado) is an autocoid (or local hormone) that modulates numerous functions in the cardiovascular and other organ systems. The actions of Ado are mediated by at least four subtypes of cell surface receptors called A
1
, A
2a
, A
2b
, and A
3
. Because the ubiquity of adenosine receptors (AdoRs) throughout the body of a human, their indiscriminate activation may cause undesirable side effects. Therefore, new drug design approaches to achieve receptor and organ selectivity are needed.
The overall function of Ado appears to be the regulation of the balance between oxygen (or energy) supply and consumption (or work). Ado increases oxygen supply by causing vasodilation and decreases oxygen consumption or work by inhibiting cellular functions, e.g., slowing of heart rate. Consistent with this protective function, A
1
AdoR agonists, Ado uptake blockers and Ado deaminase inhibitors have been shown to reduce cellular damage and dysfunction during hypoxia and ischemia. This protective role of Ado and A
1
AdoR agonists has been shown in heart, brain, liver, and intestines. This and other potentially beneficial actions of Ado have led to increased interest in the development of Ado-related drugs targeted to ameliorate conditions such as myocardial ischemia and stroke.
However, the widespread expression of Ado receptors and the lack of sufficiently selective adenosine agonists have been a major impediment to the successful development of direct-acting AdoR agonists to exploit the cytoprotective properties of Ado. Therefore, other pharmacological approaches such as allosteric modulators of Ado may prove to be a valuable alternative to direct-acting Ado agonists and nucleoside uptake blockers. Such agents should selectively modulate the response to Ado in only those organs or localized areas of a given organ in which production of Ado is increased. Thus, allosteric modulators of Ado function should provide a more selective therapeutic effect than direct-acting AdoR agonists. Their action will be limited to times and locations at which significant release of Ado occurs so that systemic side effects would largely be avoided.
Allosteric modulation of the actions of Ado on the A
1
AdoR by several 2-amino-3-benzoylthiophenes on cultured cells, cardiac and brain preparations have been reported. The specificity of these compounds for A
1
AdoRs have also been demonstrated.
A number of compounds known to modulate the action of neurotransmitters, hormones and peptides bind at sites distinct from, but functionally linked to, the primary recognition site of the respective receptors. This form of interaction between two different ligands at the same receptor protein, which may result in modulation in the form of enhancement or inhibition of each others binding and function, is referred to as allosterism. Positive (enhancement) or negative (inhibition) allosterism is an important mechanism of action of drugs. For example, allosteric interactions between the GABA receptor and benzodiazepines, to atrial natriuretic factor (ANF) receptor and amiloride, the dextromethorphan binding site and ropizine, and the muscarinic receptor and gallamine have been described.
The compounds of the present invention have been found to be potent, yet selective allosteric modulators of AdoR agonists, and in some cases, AdoR antagonists.
BRIEF SUMMARY OF THE INVENTION
Compounds useful as potent, yet selective allosteric modulators of adenosine receptors, with activity as AdoR agonists, and, in come cases AdoR antagonists, and methods of preparation and use thereof, are disclosed.
The compounds have the following general formulas IA and IB:
wherein R
2
is H, C(═O)R
8
;
R
8
is H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl;
R
3
and R
4
are independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, alkoxy, alkylthio, or arylthio;
or if R
3
and R
4
are both alkoxy or alkylthio, may form a 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl, or 1,3-dithian-2-yl group;
or together R
3
and R
4
may form a carbonyl oxygen;
R
5
, R
6
, and R
7
are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, hydroxy, nitro, amino, substituted amino, disubstituted amino, alkoxy, aryloxy, alkylthio, arylthio, sulfonamido, or substituted sulfonamido;
or together R
5
and R
6
or R
6
and R
7
may be CH═CH—CH═CH, such that they form a fused aromatic ring;
A and B are independently O, S, or N—R
8
;
or A and B may independently represent a carbon—carbon single bond;
m and n are independently 0, 1, 2, or 3;
except that A and B cannot both represent a carbon—carbon single bond when m and n are both 0; and
X is CH═CH, CH═N, N═CH, O, S, or N—R
8
.
The compounds can be used in a method for cardioprotection, neuroprotection, pain management, reduction of free fatty acids, triglycerides, or glucose levels, adjunct therapy in diabetes, treatment of GI disorders, treatment of glaucoma; treatment of sleep disorders; treatment of cardiac disarrythmias (peroxysmal supraventricular tachycardia, treatment of congestive heart failure or treatment of inflammation.
The compounds can be used in a pharmaceutical formulation that includes a compounds of formulas IA or IB and one or more excipients. Various chemical intermediates can be used to prepare the compounds of formula IA or IB:
BRIEF DESCRIPTION OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
The present application discloses compounds useful as potent, yet selective allosteric modulators of adenosine receptors, with activity as AdoR agonists, and in some cases, AdoR antagonists, and methods of preparation and use thereof.
The compounds can be used in a method for allosterically modulating adenosine receptors in a mammal, including a human. The methods involve administering an effective amount of a compound of formula IA or IB sufficient to moderate adenosine receptors to the mammal.
The compounds can be used in a pharmaceutical formulation that includes a compound of formula IA or IB and one or more excipients. Various chemical intermediates can be used to prepare the compounds of formula IA or IB.
As used herein the term “lower alkyl” means a monovalent radical, straight or branched chain, derived from the corresponding alkane having one to ten carbon atoms, i.e., methyl, ethyl, propyl, Isopropyl, n-butyl, sec-butyl, t-butyl, pentyl (all isomers), etc. Likewise, “lower alkylene” means a divalent radical of the corresponding alkane. Further, as used herein, other moieties having names derived from alkanes, such as alkoxyl, alkanoyl, alkenyl, cycloalkenyl, etc when modified by “lower,” have carbon chains of ten or less carbon atoms. In those cases where the minimum number of carbons are greater than one, e.g., alkenyl (minimum of two carbons) and cycloalkyl, (minimum of three carbons), it is to be understood that “lower” means at least the minimum number of carbons.
As used herein the term “amino acid” means an alpha amino acid selected from those amino acids which naturally occur in proteins but without regard for specific stereochemical properties. The term “protected amino acid” means an amino acid of which the alpha amino group has been converted to a less reactive moiety, but a moiety which can be converted back to the amino group with relative ease. The terms “amino acid residue” and “amino acid moiety” are use synonymously herein.
As used herein, the term “substituted alkyl” refers to an alkyl group, preferably of from 1 to 10 carbon atoms (“substituted lower alkyl”), having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycl
Butler, Esq. Gregory B.
Edwards & Angell LLP
King Pharmaceutical Research & Development, Inc.
Manso, Esq. Peter J.
Raymond Richard L.
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