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

2003-08-12

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...

C514S263200, C514S263220, C514S263230, C514S263340, C514S263350, C514S263360, C544S268000, C544S270000, C544S271000, C544S272000, C544S273000, C544S267000

Reexamination Certificate

active

06605600

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to antagonists of 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):
where
R
1
and R
2
are independently chosen from: (a) hydrogen; (b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein the alkyl, alkenyl, or alkynyl is either unsubstituted or functionalized with one or two substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and (c) aryl and substituted aryl.
R
3
is a bicyclic or tricyclic group chosen from:
where the bicyclic or tricyclic group can be unsubstituted or can be functionalized with one or more (e.g., one, two, three, or more) substituents chosen from: (a) alkyl, alkenyl, and alkynyl; wherein the alkyl, alkenyl, and alkynyl are either unsubstituted or functionalized with one or more substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylaminoalkylamino, aralkoxycarbonyl, —R5, dialkylamino, heterocyclylalkylamino, hydroxy, substituted arylsulfonylaminoalkylamino, and substituted heterocyclylaminoalkylamino; (b) acylaminoalkylamino, alkenylamino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, amino, aminoacyloxy, carbonyl, —R
5
, R
5
-alkoxy, R
5
-alkylamino, dialkylaminoalkylamino, heterocyclyl, heterocyclylalkylamino, hydroxy, phosphate, substituted arylsulfonylaminoalkylamino, substituted heterocyclyl, and substituted heterocyclylaminoalkylamino.
R
4
is chosen from —H, —C
1-4
-alkyl, —C
1-4
-alkyl-CO
2
H, and phenyl; and can be unsubstituted or can be functionalized with one or more substituents chosen from halogen, —OH, —OMe, —NH
2
, —NO
2
and benzyl, optionally substituted with one, two, or three groups selected from halogen, —OH, —OMe, —NH
2
, and —NO
2
.
R
5
is chosen from —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
, and the following:
X
1
and X
2
are chosen, independently, from oxygen (O) and sulfur (S).
Z is chosen from a single bond, —O—, —(CH
2
)
1-3
—, —O(CH
2
)
1-2
—, CH
2
OCH
2
—, —(CH
2
)
1-2
O—, and —CH
2
CH═CH—.
R
6
is chosen from hydrogen, alkyl, acyl, alkylsufonyl, aralkyl, substituted aralkyl, substituted alkyl, and heterocyclyl.
R
6
is preferably hydrogen. However, when R
6
is methyl or another non-hydrogen substituent, the compounds can be highly selective for inhibition of adenosine A
2a
receptors.
In certain embodiments, R
1
and R
2
can be the same or different alkyl groups. For example, one or both can be n-propyl.
In some embodiments, Z is a single bond.
In one embodiment, R
3
is chosen from the following bicyclic and tricyclic structures:
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, alkenyl, alkenyloxy, hydroxyalkyl, carboxy, carboxyalkenyl, carboxyalkyl, aminoacyloxy, carboxyalkoxy, dialkylaminoalkenyl, and dialkylaminoalkyl.
In another embodiment, R
3
is:
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, alkenyl, carboxyalkenyl, hydroxyalkyl, dialkylaminoalkenyl, and dialkylaminoalkyl. Thus, for example, the compound can be 8-(5-Hydroxy-tricyclo[2.2.1.0
2,6
]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; 8-(5-Hydroxymethyl-tricyclo[2.2.1.0
2,6
]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; 8-[5-(3-Dimethylaminopropylidene)-tricyclo[2.2.1.0
2,6
]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; or 8-[5-(3-Dimethylaminopropyl)-tricyclo[2.2.1.0
2,6
]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In still another embodiment, R
3
is:
and is functionalized with one or more substituents chosen from hydroxy, carbonyl, alkyl, —R
5
, R
5
-alkyl, dialkylaminoalkylamino, alkoxycarbonylalkylamino, R
5
-alkylamino, heterocyclyl, alkenylamino, amino, alkylamino, heterocyclylalkylamino, acylaminoalkylamino, phosphate, heterocyclylaminoalkylamino, and heterocyclylaminoalkylaminoalkyl.
In yet another embodiment, R
3
is:
and is functionalized with one or more substituents chosen from hydroxy, —R
5
, R
5
-alkyl, and hydroxyalkyl. Thus, for example, the compound can be 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-1-carboxylic acid.
In another embodiment, R
3
is:
and is functionalized with one or more substituents chosen from alkyl, hydroxy, carbonyl, —R
5
, and R
5
-alkyl. Thus, for example, the compound can be 8-(4-Hydroxy-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; or 8-(4-Oxo-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.
In still another embodiment, R
3
is:
and is functionalized with one or more substituents chosen from carbonyl, hydroxy, dialkylaminoalkylamino, —R5, and substituted heterocyclylaminoalkylaminoalkyl. Thus, for example, the compound can be 8-[8-(2-Dimethylaminoethylamino)-bicyclo[3.2.1]oct-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; or 8-(8-Hydroxy-bicyclo&lsqb

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