2-aminocarbonyl-9H-purine derivatives

Details 2-aminocarbonyl-9H-purine derivatives 2-aminocarbonyl-9H-purine derivatives

2001-06-05

2004-06-22

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S045000, C536S027100, C536S027300, C536S027200, C536S027210, C536S027230

Reexamination Certificate

active

06753322

ABSTRACT:

This invention relates to purine derivatives. More particularly, this invention relates to 2-aminocarbonyl-9H-purine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, for example, superoxide anion radicals (O
2
−
), and granule products, for example, human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B
4
(LTB
4
). LTB
4
is a potent chemo-attractant that recruits additional neutrophils to the inflammatory focus, whereas released O
2
−
and HNE adversely affect the pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O
2
−
and LTB
4
/HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.
Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than the use of non-selective adenosine receptor agonists because interaction with other subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. Furthermore, many patients with respiratory disease will be co-prescribed &bgr;
2
-agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase. Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over the A2b receptor is also advantageous.
We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. They may also have antagonist activity at the adenosine A3 receptor. The present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage)-induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also be used in the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease,
Heliobacter pylori
gastritis, non-
Heliobacter pylori
gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder, or for wound healing.
Accordingly, in a first embodiment, the present invention provides a compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein
R
1
is H, C
1
-C
6
alkyl or fluorenyl, said C
1
-C
6
alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo or cyano;
(A) R
2
is H or C
1
-C
6
alkyl, R
15
is H or C
1
-C
6
alkyl, and X is either (i) unbranched C
2
-C
3
alkylene optionally substituted by C
1
-C
6
alkyl or C
3
-C
8
cycloalkyl, or (ii) a group of the formula:
 —(CH
2
)
n
—W—(CH
2
)
p
—
where W is C
5
-C
7
cycloalkylene optionally substituted by C
1
-C
6
alkyl, n is 0 or 1 and p is 0 or 1, or
(B) R
15
is H or C
1
-C
6
alkyl, and R
2
and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C
1
-C
6
alkyl, or
(C) R
2
is H or C
1
-C
6
alkyl, and R
15
and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C
1
-C
6
alkyl;
either, R
3
and R
4
, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C
1
-C
6
alkyl or C
3
-C
8
cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by —NR
6
R
7
,
or, R
3
is H, C
1
-C
6
alkyl, C
3
-C
5
cycloalkyl or benzyl and R
4
is
(a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, phenyl, benzyl or het, or
(b) —(C
2
-C
6
alkylene)-R
8
,
(c) —(C
1
-C
6
alkylene)-R
13
, or
(d) C
1
-C
6
alkyl or C
3
-C
8
cycloalkyl;
R
5
is CH
2
OH or CONR
14
R
14
;
R
6
and R
7
are either each independently H or C
1
-C
6
alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C
1
-C
8
alkyl;
R
8
is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, phenyl, C
1
-C
6
alkoxy-(C
1
-C
6
)-alkyl, R
9
R
9
N—(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, —CONR
9
R
9
, COOR
9
or C
2
-C
5
alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C
1
-C
6
)-alkoxy, halo, —OR
9
, cyano, —S(O)
m
R
10
, —NR
9
R
9
, —SO
2
NR
9
R
9
, —NR
9
COR
10
or —NR
9
SO
2
R
10
, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C
2
-C
6
alkylene group by C
1
-C
6
alkyl, phenyl, C
1
-C
6
alkoxy-(C
2
-C
6
)-alkyl, R
9
R
9
N—(C
2
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, C
2
-C
5
alkanoyl, —COOR
10
, C
3
-C
8
cycloalkyl, —SO
2
R
10
, —SO
2
NR
9
R
9
or —CONR
9
R
9
, or
(ii) NR
11
R
12
;
R
9
is H, C
1
-C
6
alkyl C
3
-C
8
cycloalkyl or phenyl;
R
10
is C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl or phenyl;
R
11
is H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl or benzyl;
R
12
is H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, phenyl, benzyl, fluoro-(C
1
-C
6
)-alkyl, —CONR
9
R
9
, —COOR
10
, C
2
-C
5
alkanoyl or —SO
2
NR
9
R
9
;
R
13
is (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —(C
1
-C
3
alkylene)-(C
1
-C
6
alkoxy), halo

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