Adenosine A2A receptor agonists as antiinflammatory agents

Details Adenosine A2A receptor agonists as antiinflammatory agents Adenosine A2A receptor agonists as antiinflammatory agents

1999-10-15

2001-12-04

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S045000, C514S047000, C536S027600, C536S027610, C536S027620, C536S027630, C536S027700

Reexamination Certificate

active

06326359

ABSTRACT:

The present invention relates to certain adenine derivatives that are selective, functional agonists of the human adenosine A2a receptor, to their preparation, and to compositions and uses thereof. The compounds and compositions 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 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 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 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 adenine 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 ischemia, peripheral vascular disease, post-ischaemic reperfrision injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, 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 gastro-intestinal tract or a psychotic disorder, or for wound healing.
Accordingly, in one aspect the present invention provides a compound of formula (I):
wherein
R
1
is alkyl or cyclopropylmethyl;
R
2
is phenyl-alkylene or naphthyl-alkylene, said alkylene chain being optionally further substituted by phenyl or naphthyl, each phenyl or naphthyl being optionally substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and cyano;
n is 1 or 2;
A is NR
a
, NR
a
C(O), NR
a
C(O)NR
a
, NR
a
C(O)O, OC(O)NR
a
, C(O)NR
a
, NR
a
SO
2
, SO
2
NR
a
, O, S or SO
2
;
R
a
is H, alkyl or benzyl optionally ring-substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and cyano;
R
3
is a group of the formula —(CH
2
)
p
—R
p
—B;
p is 0, 1 or 2;
R
p
is a bond, alkylene, cycloalkylene, phenylene or naphthylene, said cycloalkylene, phenylene and naphthylene each being optionally substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and alkoxyalkylene;
B is
(i) H —NR
b
R
b
, R
b
R
b
N-alkylene, —OR
b
, —COOR
b
, —OCOR
b
, —SO
2
R
b
, —CN, —SO
2
NR
b
R
b
, —NR
b
COR
b
, —NR
b
SO
2
R
b
or —CONR
b
R
b
, in which each R
b
is the same or different and is selected from H, alkyl, phenyl and benzyl, provided that,
(a) when B is —OCOR
b
, —SO
2
R
b
, —NR
b
COR
b
or —NR
b
SO
2
R
b
, then the terminal R
b
is not H, and,
(b) R
p
is a bond, p is 0 and B is H only when A is NR
a
, NR
a
C(O)NR
a
, OC(O)NR
a
, C(O)NR
a
, SO
2
NR
a
, O or S,
(ii) an optionally-substituted, fully- or partially-saturated or -unsaturated, mono- or bicyclic, heterocyclic group, which is linked to R
p
by a ring carbon atom, or
(iii) N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each optionally substituted by one or more alkyl substituents, with the proviso that —(CH
2
)
p
—R
p
— is not —CH
2
—; and
where A is NR
a
, C(O)NR
a
, OC(O)NR
a
or SO
2
NR
a
, R
a
and R
3
taken together with the nitrogen atom to which they are attached can form an azetidine, pyrrolidine, piperidine or piperazine ring, optionally substituted by one or more alkyl substituents:
and pharmaceutically acceptable salts and solvates thereof.
In a second aspect the present invention provides a compound of the formula (I) wherein
R
1
is C
1
-C
6
alkyl or cyclopropylmethyl;
R
2
is phenyl-(C
1
-C
6
)-alkylene or naphthyl-(C
1
-C
6
)-alkylene, said C
1
-C
6
alkylene chain being optionally further substituted by phenyl or naphthyl, each phenyl or naphthyl being optionally substituted by one or more substituents each independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo and cyano;
n is 1 or 2;
A is NR
a
, NR
a
C(O), NR
a
C(O)NR
a
, NR
a
C(O)O, OC(O)NR
a
, C(O)NR
a
, NR
a
SO
2
, SO
2
NR
a
, O, S or SO
2
;
R
a
is H, C
1
-C
6
alkyl or benzyl optionally ring-substituted by one or more substituents each independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo and cyano;
R
3
is a group of the formula —(CH
2
)
p
—R
p
—B;
p is 0, 1 or 2;
R
p
is a bond, C
1
-C
6
alkylene, C
3
-C
7
cycloalkylene, phenylene or naphthylene, said C
3
-C
7
cycloalkylene, phenylene and naphthylene each being optionally substituted by one or more substituents each independently selected from C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo and C
1
-C
6
alkoxy-C
1
-C
6
-alkylene;
B is
(i) H, —NR
b
R
b
, R
b
R
b
N—(C
1
-C
6
)-alkylene, —OR
b
, —COOR
b
, —OCOR
b
, —SO
2
R
b
, —CN, —SO
2
NR
b
R
b
, —NR
b
COR
b
, —NR
b
SO
2
R
b
or —CONR
b
R
b
, in which each R
b
is the same or different and is selected from H, C
1
-C
6
alkyl, phenyl and benzyl, provided that,
(a) when B is —OCOR
b
, —SO
2
R
b
, —NR
b
COR
b
or —NR
b
SO
2
R
b
, then the terminal R
b
is not H, and,
(b) R
p
is a bond, p is 0 and B is H only when A is NR
a
, NR
a
C(O)NR
a
, OC(O)NR
a
, C(O)NR
a
, SO
2
NR
a
, O or S,
(ii) an optionally-substituted, fully- or partially-saturated or -unsaturated, mono- or bicyclic, heterocyclic group, which is linked to R
p
by a ring carbon atom, or
(iii) N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each optionally substituted by one or more C
1
-C
6
alkyl substituents, with the proviso that —(CH
2
)
p
—R
p
— is not —CH
2
—; and
where A is NR
a
, C(O)NR
a
, OC(O)NR
a
or SO
2
NR
a
, R
a
and R
3
taken together with the

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