Purine derivatives

Details Purine derivatives Purine derivatives

2001-02-20

2003-02-25

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S045000, C536S026700, C536S027600, C536S027610, C536S027620

Reexamination Certificate

active

06525032

ABSTRACT:

The present invention relates to certain purine derivatives. More particularly, the present invention relates to purin-2-ylcarboxamide derivatives, to their preparation, and to compositions, uses and intermediates used in the preparation thereof. 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. 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, such as superoxide anion radicals (O
2
−
), and granule products, such as 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 pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O
2
−
and LTB4/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 non-selective adenosine receptor agonists because interaction with other receptor 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 a 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 this 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.
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, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylon gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
Accordingly, in one aspect the present invention provides a compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof,
wherein R
1
is hydrogen, C
1
-C
6
alkyl or C
3
-C
7
cycloalkyl, each optionally substituted by 1 or 2 substituents each independently selected from hydroxyl, fluorenyl, 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 is a bond or C
1
-C
6
alkylene;
R
2
is (i) hydrogen, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl or naphthyl, said C
3
-C
7
cycloalkyl, phenyl and naphthyl being optionally substituted by C
1
-C
6
alkyl, phenyl, C
1
-C
6
alkoxy-(C
1
-C
6
)-alkyl, amino-(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkoxy, C
2
-C
5
alkanoyl, halo, —OR
3
, cyano, —COOR
3
, C
3
-C
7
cycloalkyl, —S(O)
m
R
4
, —NR
3
R
3
, —SO
2
NR
3
R
3
, —CONR
3
R
3
, —NR
3
COR
4
or —NR
3
SO
2
R
4
, with the proviso that R
2
is not hydrogen when A is a bond, or (ii) when A is C
2
-C
6
alkylene, —NR
3
R
3
, —OR
3
, —COOR
3
, —OCOR
4
, —SO
2
R
4
, —CN, —SO
2
NR
3
R
3
, —NR
3
SO
2
R
4
, —NR
3
COR
4
or —CONR
3
R
3
, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C
1
-C
6
alkoxy-(C
1
-C
6
)-alkyl, amino-(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkoxy, fluoro-(C
2
-C
5
)-alkanoyl, halo, cyano, —OR
5
, R
6
, —COR
5
, —NR
5
R
5
, —COOR
5
, —S(O)
m
R
6
, —SO
2
NR
5
R
5
, —CONR
5
R
5
, —NR
5
SO
2
R
6
or —NR
5
COR
6
and optionally N-substituted by C
1
-C
6
alkoxy-(C
1
-C
6
)-alkyl, amino-(C
2
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, fluoro-(C
2
-C
5
)-alkanoyl, R
6
, —COR
5
, —COOR
6
, —SO
2
R
6
, —SO
2
NR
5
R
5
or —CONR
5
R
5
, or (iv) when A is C
2
-C
6
alkylene, N-linked azetidinyl, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl, each being optionally C-substituted by C
1
-C
6
alkyl, phenyl, C
1
-C
6
alkoxy-(C
1
-C
6
)-alkyl, amino-(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkoxy, C
2
-C
5
alkanoyl, halo, —OR
3
, cyano, —COOR
3
, C
3
-C
7
cycloalkyl, —S(O)
m
R
4
, —NR
3
R
3
, —SO
2
NR
3
R
3
, —CONR
3
R
3
, —NR
3
COR
4
or —NR
3
SO
2
R
4
and said piperazinyl being optionally N-substituted by C
1
-C
6
alkyl, phenyl, C
1
-C
6
alkoxy-(C
1
-C
6
)-alkyl, amino-(C
2
-C
6
)-alkyl, fluoro-(C
1
-C
6
)-alkyl, C
2
-C
5
alkanoyl, —COOR
4
, C
3
-C
7
cycloalkyl, —SO
2
R
4
, —SO
2
NR
3
R
3
or —CONR
3
R
3
;
each R
3
is independently selected from H, C
1
-C
6
alkyl, phenyl or pyridinyl;
R
4
is C
1
-C
6
alkyl or phenyl;
R
5
is H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, naphthyl or het;
R
6
is C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, naphthyl or het;
m is 0, 1 or 2;
R
7
is hydrogen, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, naphthyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl or het, said azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted by C
1
-C
6
alkyl;
R
8
is H or C
1
-C
6
alkyl; and
“het”, used in the definitions of R
5
, R
6
and R
7
, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each being optionally substituted by C
1
-C
6
alkyl, C
1
-C
6
alkoxy, cyano or halo.
Preferably, R
1
is cyclohexyl or optionally substituted C
1
-C
6
alkyl. More preferably, R
1
is optionally substituted C
1
-C
5
alkyl, and most preferably R
1
is optionally substituted C
1
-C
2
alkyl. Preferably, the C
1
-C
6
, C
1
-C
5
, or C
1
-C
2
alkyl substitutents are selected from benzyl, fluorenyl, phenyl and hydroxyl. Preferably, when R
1
is substituted by phenyl there are 1 or 2 phenyl group(s). Preferably, R
1
is selected from 2,2-diphenylethyl, cyclohexyl,1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluoren-9-ylmethyl, and 1-benzyl-2-phenylethyl. Preferably, R
1
is 2,2-diphenyleth

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