Adenosine receptor antagonists and methods of making and...

Details Adenosine receptor antagonists and methods of making and... Adenosine receptor antagonists and methods of making and...

2000-11-13

2003-11-18

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S263220, C514S263240, C514S263340, C514S263350, C514S263360, C544S244000, C544S267000, C544S268000, C544S270000, C544S271000, C544S272000, C544S273000

Reexamination Certificate

active

06649600

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to antagonists of the adenosine receptors and methods of making and using the same in the treatment of diseases.
Adenosine is an intracellular and extracellular messenger generated by all cells in the body. It is also generated extracellularly by enzymatic conversion. Adenosine binds to and activates seven transmembrane G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine itself, substances that mimic the actions of adenosine (agonists), and substances that antagonize its actions have important clinical applications. Adenosine receptors are divided into four known subtypes (i.e., A
1
, A
2a
, A
2b
, and A
3
). These subtypes elicit unique and sometimes opposing effects. Activation of the adenosine A
1
receptor, for example, elicits an increase in renal vascular resistance while activation of the adenosine A
2a
receptor elicits a decrease in renal vascular resistance.
In most organ systems, periods of metabolic stress result in significant increases in the concentration of adenosine in the tissue. The heart, for instance, produces and releases adenosine to mediate adaptive responses to stress, such as reductions in heart rate and coronary vasodilatation. Likewise, adenosine concentrations in kidneys increase in response to hypoxia, metabolic stress and many nephrotoxic substances. The kidneys also produce adenosine constitutively. The kidneys adjust the amount of constitutively produced adenosine in order to regulate glomerular filtration and electrolyte reabsorption. Regarding control of glomerular filtration, activation of A
1
receptors leads to constriction of afferent arterioles while activation of A
2a
receptors leads to dilatation of efferent arterioles. Activation of A
2a
receptors may also exert vasodilatory effects on the afferent arteriole. Overall, the effect of activation of these glomerular adenosine receptors is to reduce glomerular filtration rate. In addition, A
1
adenosine receptors are located in the proximal tubule and distal tubular sites. Activation of these receptors stimulates sodium reabsorption from the tubular lumen. Accordingly, blocking the effects of adenosine on these receptors will produce a rise in glomerular filtration rate and an increase in sodium excretion.
SUMMARY OF THE INVENTION
The invention is based on the discovery that compounds of Formula I are unexpectedly highly potent and selective inhibitors of particular subtypes of adenosine receptors. Adenosine antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable.
In one embodiment, the invention features a compound of formula I:
In formula I, R
1
and R
2
can, independently, be:
a) hydrogen;
b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons (e.g., where the alkyl, alkenyl, or alkynyl can be unsubstituted or can be functionalized with one or more substituents selected from hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; or
c) aryl or substituted aryl;
R
3
is selected from the group consisting of:
(a) a bicyclic, tricyclic or pentacyclic group selected from:
 where the bicyclic or tricyclic group can be unsubstituted or can be functionalized with one or more substitents selected from:
(a) alkyl, alkenyl, and alkynyl; where each alkyl, alkenyl, or alkynyl group can be unsubstituted or can be functionalized with one or more substituents selected from the group consisting of (amino)(R
5
)acylhydrazinylcarbonyl, (amino)(R
5
)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acyloxy, aldehydo, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylaminoalkylamino, alkylphosphono, alkylsulfonylamino, carbamoyl, R
5
, R
5
-alkoxy, R
5
-alkylamino, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkylamino, dialkylphosphono, haloalkylsulfonylamino, heterocyclylalkylamino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted heteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, and trifluoromethyl; or
(b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydo, alkenoxy, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl, alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, carbonyl, —R
5
, R
5
-alkoxy, R
5
-alkyl(alkyl)amino, R
5
-alkylalkylcarbamoyl, R
5
-alkylamino, R
5
-alkylcarbamoyl, R
5
-alkylsulfonyl, R
5
-alkylsulfonylamino, R
5
-alkylthio, R
5
-heterocyclylcarbonyl, cyano, cycloalkylamino, dialkylaminoalkylcarbamoyl, halogen, heterocyclyl, heterocyclylalkylamino, hydroxy, oximino, phosphate, substituted aralkylamino, substituted heterocyclyl, substituted heterocyclylsulfonylamino, sulfoxyacylamino, or thiocarbamoyl; and
(b) the tricyclic group:
 where the tricyclic group is functionalized with one or more substitents selected from the group consisting of:
(a) alkyl, alkenyl, and alkynyl; wherein each alkyl, alkenyl, or alkynyl group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of (amino)(R
5
)acylhydrazinylcarbonyl, (amino)(R
5
)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acyloxy, aldehydo, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylaminoalkylamino, alkylphosphono, alkylsulfonylamino, carbamoyl, R
5
, R
5
-alkoxy, R
5
-alkylamino, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkyiamino, dialkylphosphono, haloalkylsulfonylamino, heterocyclylalkylamino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted heteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, and trifluoromethyl; and
(b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydo, alkenoxy, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl, alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, carbonyl, —R
5
, R
5
-alkoxy, R
5
-alkyl(alkyl)amino, R
5
-alkylalkylcarbamoyl, R
5
-alkylamino, R
5
-alkylcarbamoyl, R
5
-alkylsulfonyl, R
5
-alkylsulfonylamino, R
5
-alkylthio, R
5
-heterocyclylcarbonyl, cyano, cycloalkylamino, dialkylaminoalkylcarbamoyl, halogen, heterocyclyl, heterocyclylalkylamino, oximino, phosphate, substituted aralkylamino, substituted heterocyclyl, substituted heterocyclylsulfonylamino, sulfoxyacylamino, and thiocarbamoyl;
R
4
can be hydrogen, C
1-4
-alkyl, C
1-4
-alkyl-CO
2
H, or phenyl; where the C
1-4
-alkyl, C
1-4
-alkyl-CO
2
H, and phenyl groups can be unsubstituted or can be functionalized with one, two, three, or more substituents such as halogen, —OH, —OMe, —NH
2
, —NO
2
, and benzyl, or benzyl functionalized with one, two, three, or more substituents such as halogen, —OH, —OMe, —NH
2
, and —NO
2
;
R
5
can be —CH
2
COOH, —C(CF
3
)
2
OH, —CONHNHSO
2
CF
3
, —CONHOR
4
, —CONHSO
2
R
4
, —CONHSO
2
NHR
4
, —C(OH)R
4
PO
3
H
2
, —NHCOCF
3
, —NHCONHSO
2
R
4
, —NHPO
3
H
2
, —NHSO
2
R
4
, —NHSO
2
NHCOR
4
, —OPO
3
H
2
, —OSO
3
H, —PO(OH)R
4
, —PO
3
H
2
, —SO
3
H, —SO
2
NHR
4
, —SO
3
NHCOR
4
, —SO
3
NHCONHCO
2
R
4
, or any of the following:
X
1
and X
2
are chosen from oxygen (O) and sulfur(S).
Z can be a single bond, —O—, —(CH
2
)
1-3
—, —O(CH
2
)
1-2
—, —CH
2
OCH
2
—, —(CH
2
)
1-2
O—, —CH═CHCH
2
—, —CH═CH—, or —CH
2
CH═

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