Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-07
2001-01-23
Huang, Evelyn Mei (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S114000, C548S453000, C549S057000, C549S051000, C540S478000, C540S593000, C514S412000, C514S443000, C514S215000
Reexamination Certificate
active
06177444
ABSTRACT:
FIELD 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.
BACKGROUND OF THE INVENTION
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 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 the 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 the 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 are important mechanisms of action of drugs. For example, allosteric interactions between the GABA receptor and benzodiazepines, atrial natriuretic factor (ANF) receptor and amiloride, the dextromethorphan binding site and ropizine, and the muscarinic receptor and gallamine have been described.
SUMMARY OF THE INVENTION
One aspect of the present invention is a compound selected from a group consisting of compounds of formulas IA, IB, and IC:
wherein:
R
1
is hydrogen, lower alkyl, or haloacetyl;
R
2
, R
3
and R
4
are independently hydrogen, halogen, lower alkyl, phenyl, lower alkenyl, lower alkanoyl, amino, trifluoromethyl, amino lower alkyl, nitro, or cyano;
t is 0, 1, 2, or3;
Z is NH, N—(Gr)
m
(Am)
n
(Alk)
p
(Ph)
q
, or CH—(Gr)
m
(Am)
n
(Alk)
p
(Ph)
q
, wherein
Gr is —SO
2
—, —C(O)O—, or —C(O)—,
Am is —CH(NH
2
)—, amino acid residue, or an amino protected amino acid residue,
Alk is hydrogen, lower alkylene or lower alkenylene,
Ph is phenyl; phenyl substituted with one or more lower alkyl groups; or phenyl substituted with one or more nitro groups,
m is 0 or 1
n, p, and q are independently 0, 1, or 2,
provided that at least one of m, n, p, and q is other than 0;
R
5
and R
6
are independently hydrogen, lower alkyl, or taken together form a lower alkenyl ring of 5 or 6 members,
provided that if R
2
, R
3
, and R
4
are hydrogen, then, both R
5
and R6 may be neither hydrogen nor methyl;
further provided that if R
2
and R
3
are hydrogen while R
4
is trifluoromethyl or if R
2
and R
4
are hydrogen while R
3
is chloro, then both R
5
and R
6
may not be methyl;
R
7
is hydrogen or lower alkyl;
Y is Nitrogen , CH or C(O)OR
8
; and
Wherein R
8
is hydrogen or lower alkyl.
A second aspect of the present invention is a method of allosterically modulating adenosine receptors in a mammal, including a human, comprising the administration to the mammal of an effective amount of a compound of formula IA, IB, or IC sufficient to moderate adenosine receptors.
A third aspect is a pharmaceutical formulation comprising a compound of formula IA, IB, or IC and one or more excipients. A fourth aspect are the novel chemical intermediates useful in the preparation of the compounds of formula IA, IB, or IC.
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Bruns, Robert
Huang Evelyn Mei
Medco Corp.
Roberts Abokhair & Mardula LLC
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