A1 adenosine receptor antagonists

Details A1 adenosine receptor antagonists A1 adenosine receptor antagonists

2001-11-30

2003-08-12

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...

C514S267000, C544S244000, C544S251000

Reexamination Certificate

active

06605601

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention relates to medicinal chemistry and pharmacology. More particularly, it relates to antagonists of the adenosine receptors, pharmaceutical compositions comprising these compounds and methods of making and using the same in the treatment of diseases.
BACKGROUND OF THE INVENTION
Adenosine is a ubiquitous biochemical messenger. Adenosine binds to and activates seven-transmembrane spanning G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e., A
1
, A
2a
, A
2b
, and A
3
). These receptor subtypes mediate different, 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 mammalian 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 exerts 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 produces 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 and II are potent and selective inhibitors of particular subtypes of adenosine receptors. Based on this discovery, the invention features adenosine antagonists 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 general, the invention features highly potent and selective antagonists of the adenosine A
1
receptor.
The invention features compounds of formula I or II:
wherein
R
1
and R
2
are independently selected from the group consisting of:
a) hydrogen;
b) alkyl, alkenyl or alkynyl, wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or functionalized with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and
c) aryl or substituted aryl;
R
3
is selected from the group consisting of:
(a) a bicyclic, tricyclic or pentacyclic group selected from the group consisting of:
 wherein the bicyclic, tricyclic or pentacyclic group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of:
(i) 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 (alkoxycarbonyl)aralkylcarbamoyl, (amino)(R
5
)acylhydrazinylcarbonyl, (amino)(R
5
)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acylaminoalkylamino, acyloxy, aldehydo, alkenoxy, alkenylamino, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, alkylaminoalkylamino, alkylcarbamoyl, alkylphosphono, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoacyloxy, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, carbonyl, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkylamino, dialkylaminoalkylcarbamoyl, dialkylphosphono, haloalkylsulfonylamino, halogen, heterocyclyl, heterocyclylalkylamino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphate, phosphono, —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, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted arylsulfonylaminoalkylamino, substituted heteroarylsulfonylamino, substituted heterocyclyl, substituted heterocyclylaminoalkylamino, substituted heterocyclylsulfonylamino, sulfoxyacylamino, thiocarbamoyl, trifluoromethyl; and
(ii) (alkoxycarbonyl)aralkylcarbamoyl, (amino)(R
5
)acylhydrazinylcarbonyl, (amino)(R
5
)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acylaminoalkylamino, acyloxy, aldehydo, alkenoxy, alkenylamino, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, alkylaminoalkylamino, alkylcarbamoyl, alkylphosphono, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoacyloxy, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, carbonyl, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkylamino, dialkylaminoalkylcarbamoyl, dialkylphosphono, haloalkylsulfonylamino, halogen, heterocyclyl, heterocyclylalkylamino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphate, phosphono, —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, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted arylsulfonylaminoalkylamino, substituted heteroarylsulfonylamino, substituted heterocyclyl, substituted heterocyclylaminoalkylamino, substituted heterocyclylsulfonylamino, sulfoxyacylamino, thiocarbamoyl, trifluoromethyl;
R
4
is selected from the group consisting of hydrogen, C
1-4
-alkyl, C
1-4
-alkyl-CO
2
H, and phenyl, wherein the C
1-4
-alkyl, C
1-4
-alkyl-CO
2
H, and phenyl groups are either unsubstituted or functionalized with one to three substituents selected from the group consisting of halogen, —OH, —OMe, —NH
2
, NO
2
, benzyl, and benzyl functionalized with one to three substituents selected from the group consisting of halogen, —OH, —OMe, —NH
2
, and —NO
2
;
R
5
is selected from the group consisting of —(CR
1
R
2
)
n
COOH, —C(CF
3
)
2
OH, —CONHNHSO
2
CF
3
, —CONHOR
4
, —CONHSO
2
R
4
, —CONHS
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
NHCOR4, —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
, and the following:
A is selected from the group consisting of —CH═CH,
13
(CH)
m
—(CH)
m,
, CH═CH—CH
2
, and
—CH
2
—CH═CH;
m=1 or 2;
X is O or S;
Z is selected from the group consisting of a single bond, —O—, —(CH
2
)
n
—, —O(CH
2
)
1-2
—, —CH
2
OCH
2
—, —(CH
2
)
1-2
O—, —CH═CHCH
2
—, —CH═CH—, and —CH
2
CH═CH—; and
R
6
is selected from the group consisting of

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