Substituted 8-phenylxanthines useful as antagonists of A2B...

Details Substituted 8-phenylxanthines useful as antagonists of A2B... Substituted 8-phenylxanthines useful as antagonists of A2B...

2000-02-17

2003-04-08

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S263200, C514S263340, C544S269000, C544S270000, C544S271000

Reexamination Certificate

active

06545002

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds and pharmaceutical compositions that are selective antagonists of A
2B
adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.
BACKGROUND OF THE INVENTION
The alkylxanthine theophylline (compound 1, FIG.
1
), a weak non-selective adenosine antagonist (See Linden, J., et al., in
Cardiovascular Biology of Purines
, eds. G. Burnstock, et al., 1998, pp 1-20.) is useful therapeutically for the treatment of asthma. However, its use is associated with unpleasant side effects, such as insomnia and diuresis. (See Vassallo, R. et al.,
Mayo. Clin. Proc
. 1998, 73, 346-354.) In recent years, the use of theophylline as a bronchodilator, for relief of asthma, has been supplanted by drugs of other classes, i.e., selective &bgr;
2
-adrenergic agonists, corticosteroids, and recently leukotriene antagonists. (See Drazen, J. M., et al.,
New Eng. J. Med
. 1999, 340, 197-206.) These compounds also have limitations, thus, the development of a theophylline-like drug with reduced side effects is still desirable.
It has been recognized that theophylline and its closely related analogue caffeine block endogenous adenosine acting as a local modulator of adenosine receptors in the brain and other organs at therapeutically useful doses. Adenosine activates four subtypes of G protein-coupled adenosine receptors (ARs), A
1
/A
2A
/A
2B
/A
3
. (See Fredholm, B. B., et al.,
Pharmacol. Rev
. 1999, 51, 83-133.) In comparison to the other known actions of theophylline, e.g., inhibition of phosphodiesterases, theophylline is more potent in antagonism of adenosine receptors. Enprofylline, (compound 3,
FIG. 1
) a compound that is used to treat asthma, is another example of a xanthine that has been reported to block A
2B
adenosine receptors. However, this compound only weakly blocks A
1
, A
2A
and A
3
adenosine receptors.
It has been reported that therapeutic concentrations of theophylline or enprofylline block human A
2B
receptors, and it has been proposed that antagonists selective for this subtype may have potential use as antiasthmatic agents. (See Feoktistov, I., et al.,
Pharmacol. Rev
. 1997, 49, 381-402; and Robeva, A. S., et al.,
Drug Dev. Res
. 1996, 39, 243-252. Enprofylline has a reported K
i
value of 7 &mgr;M and is somewhat selective in binding to human A
2B
ARs. (See Robeva, A. S., et al.,
Drug Dev. Res
. 1996, 39, 243-252 and Linden, J., et al.,
Mol. Pharmacol
. 1999, 56, 705-713.) A
2B
ARs are expressed in some mast cells, such as the BR line of canine mastocytoma cells, which appear to be responsible for triggering acute Ca
2+
mobilization and degranulation. (See Auchampach, J. A., et al.,
Mol. Pharmacol
. 1997. 52, 846-860 and Forsyth, P., et al.,
Inflamm. Res
. 1999, 48, 301-307.) A
2B
ARs also trigger Ca
2+
mobilization, and participate in a delayed IL8 release from human HMC-1 mast cells. Other functions associated with the A
2B
AR are the control of cell growth and gene expression, (See Neary, J., et al.,
Trends Neurosci
. 1996, 19, 13-18.) endothelial-dependent vasodilation (See Martin, P. L., et al.,
J. Pharmacol. Exp. Ther
. 1993, 265, 248-253.), and fluid secretion from intestinal epithelia. (See Strohmeier, G. R., et al.,
J. Biol. Chem
. 1995, 270, 2387-2394.) Adenosine acting through A
2B
ARs has also been reported to stimulate chloride permeability in cells expressing the cystic fibrosis transport regulator. (See Clancy, J. P., et al.,
Am. J. Physiol
. 1999, 276, C361-C369.)
Although adenosine receptor subtype-selective probes are available for the A
1
, A
2A
, and A
3
ARs, only few weakly selective antagonists and no selective agonists are known for the A
2B
receptor. Therefore, a continuing need exists for compounds that are selective A
2B
receptor antagonists.
SUMMARY OF THE INVENTION
The present invention provides compounds that act as antagonists of A
2B
adenosine receptors. Accordingly, the present invention provides a compound of formula I:
wherein R, and R
1
are independently hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, (C
1
-
8
)alkoxy, (C
3
-C
8
)cycloalkyl, (C
4
-C
16
)cycloalkylalkyl, hetero-cycle, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl or heteroaryl;
X is (C
1
-C
8
)alkylene, (C
2
-C
8
)alkenylene, (C
2
-C
8
)alkynylene, wherein one of the carbon atoms in the alkylene, alkenylene or alkynylene groups can be replaced with group having the formula —O—, —N(R
4
)C(O)—, —OC(O)—, —N(R
5
)(R
6
)—, —S—, —S(O)— or —SO
2
—, wherein
R
2
is hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, (C
1
-C
8
)alkoxy, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)heterocycle, (C
6
-C
10
)aryl, (C
6
-C
10
)heteroaryl, (C
4
-C
16
)cycloalkylalkyl or (C
7
-C
18
)aralkyl, optionally substituted with one or more substituents selected from the group consisting of —OH, —SH, —NH
2
, —NHR
7
, —CN, —CO
2
H, and —SO
3
H, wherein
R
4
, R
5
, R
6
and R
7
are independently hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
3
-C
8
)cycloalkyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl or halo(C
1
-C
6
)alkyl,
wherein R
8
is hydrogen, (C
3
-C
8
)cycloalkyl, (C
4
-C
16
)cycloalkylalkyl, (C
7
-C
18
)aralkyl, heterocycle or heteroaryl, each optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C
1
-C
8
)alkyl, halo(C
1
-C
6
)alkyl, (C
2
-C
8
)alkenyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl, heteroaryl, halo, —OR
15
, —CN, —NO
2
, —CO
2
R
15
, —OC(O)R
16
, —C(O)R
16
, —NR
13
R
14
, —N(R
23
)C(O)R
24
, —C(O)NR
17
R
18
, —SR
19
, —SO
2
R
20
or —SO
3
H; or
R
8
is (C
1
-C
8
)alkyl, substituted with one or more substituents independently selected from the group consisting of oxo, (C
2
-C
8
)alkenyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl, heteroaryl, halo —OR
15
, —CN, —NO
2
, —CO
2
R
15
, —OC(O)R
16
, —C(O)R
16
, —NR
13
R
14
, —N(R
23
)C(O)R
24
, —C(O)NR
17
R
18
, —SR
19
, —SO
2
R
20
and —SO
3
H; or
R
8
is (C
6
-C
10
)aryl, substituted with one or more substituents independently selected from the group consisting of (C
1
-C
8
)alkyl, halo(C
1
-C
6
)alkyl, (C
2
-C
8
)alkenyl, (C
7
-C
18
)aralkyl, heteroaryl, —OR
15
, —CN, —NO
2
, —CO
2
R
15
, —OC(O)R
16
, —C(O)R
16
, —NR
13
R
14
, —N(R
23
)C(O)R
24
, —C(O)NR
17
R
18
, —SR
19
, —SO
2
R
20
and —SO
3
H; and
wherein R
9
is —NR
10
R
11
, or R
9
is (C
3
-C
8
)cycloalkyl, (C
4
-C
16
)cycloalkylalkyl, (C
7
-C
18
)aralkyl, heterocycle or heteroaryl, each optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C
1
-C
8
)alkyl, halo(C
1
-C
6
)alkyl, (C
2
-C
8
)alkenyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl, heteroaryl, —OR
15
, halo, —CN, —NO
2
, —CO
2
R
15
, —OC(O)R
16
, —C(O)R
16
, —NR
13
R
14
, —N(R
23
)C(O)R
24
, —C(O)NR
17
R
18
, —SR
19
, —SO
2
R
20
or —SO
3
H; or
R
9
is (C
1
-
8
)alkyl, substituted with one or more substituents independently selected from the group consisting of oxo, (C
2
-C
8
)alkenyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl, heteroaryl, —OR
15
, halo, —CN, —NO
2
, —OC(O)R
16
, —C(O)R
16
, —NR
13
R
14
, —N(R
23
)C(O)R
24
, —C(O)NR
17
R
18
, —SR
19
, —SO
2
R
20
and —SO
3
H;
R
9
is (C
6
-C
10
)aryl, substituted with one or more substituents independently selected from the group consisting of (C
1
-C
8
)alkyl, halo(C
1
-C
6
)alkyl, (C
2
-C
8
)alkenyl, (C
7
-C
18
)aralkyl, heteroaryl, —OR
15
, —CN, —NO
2
, —CO
2
R
15
, —OC(O)R
16
, —C(O)R
16
, —NR
13
R
14
, —N(R
23
)C(O)R
24
, —C(O)NR
17
R
18
, —SR
19
, —SO
2
R
20
and —SO
3
H, and
wherein R
10
and R
11
are independently hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
3
-C
8
)cycloalkyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl, heterocycle, heteroaryl, —C(O)(CH
2
)
n
CO
2
R
12
, —C(O)CR
21
═CR
22
(CH
2
)
m
CO
2
R
12
, —C(O)R
12
, —C(O)(C
3
-C
8
)cycloalkyl or —C(O)(C
3
-C
8
)cycloalkenyl, each optionally substituted with one or more substituents, wherein the substituents independently are oxo, (C
1
-C
8
)alkyl, halo(C
1
-C
6
)alkyl, (C
2
-C
8
)alkenyl, (C
6
-C
10
)aryl, (C
7
-C
18
)aralkyl, heteroaryl, —OR
15
, halo, —CN, —NO

Affiliated with

Also associated with

Rating

Substituted 8-phenylxanthines useful as antagonists of A2B... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted 8-phenylxanthines useful as antagonists of A2B..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 8-phenylxanthines useful as antagonists of A2B... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3107149