2-(purin-9-yl)-tetrahydrofuran-3, 4-diol derivatives

Details 2-(purin-9-yl)-tetrahydrofuran-3, 4-diol derivatives 2-(purin-9-yl)-tetrahydrofuran-3, 4-diol derivatives

2000-08-29

2003-08-26

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S027230

Reexamination Certificate

active

06610665

ABSTRACT:

This invention relates to new chemical compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.
Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue. Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases). Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.
The primary function of leukocytes is to defend the host from invading organisms such as bacteria and parasites. Once a tissue is injured or infected a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.
There is evidence from both in vitro and in vivo studies to suggest that compounds active at the adenosine A2a receptor will have anti-inflammatory actions. The area has been reviewed by Cronstein (1994). Studies on isolated neutrophils show an A2 receptor-mediated inhibition of superoxide generation, degranulation, aggregation and adherence (Cronstein et al, 1983 and 1985; Burkey and Webster, 1993; Richter, 1992; Skubitz et al, 1988. When agents selective for the A2a receptor over the A2b receptor (eg CGS21680) have been used, the profile of inhibition appears consistent with an action on the A2a receptor subtype (Dianzani et al, 1994). Adenosine agonists may also down-regulate other classes of leukocytes (Elliot and Leonard, 1989; Peachell et al, 1989). Studies on whole animals have shown the anti-inflammatory effects of methotrexate to be mediated through adenosine and A2 receptor activation (Asako et al, 1993; Cronstein et al, 1993 and 1994). Adenosine itself, and compounds that raise circulating levels of adenosine also show anti-inflammatory effects in vivo (Green et al, 1991; Rosengren et al, 1995). In addition raised levels of circulating adenosine in man (as a result of adenosine deaminase deficiency) results in immunosuppression (Hirschorn, 1993).
We have now found a novel group of compounds with broad anti-inflammatory properties which inhibit leukocyte recruitment and activation and which are agonists of the adenosine 2a receptor. The compounds are therefore of potential therapeutic benefit in providing protection from leukocyte-induced tissue damage in diseases where leukocytes are implicated at the site of inflammation. The compounds of the invention may also represent a safer alternative to corticosteroids in the treatment of inflammatory diseases, whose uses are severely limited by their side-effect profiles.
More particularly, the compounds of this invention may show an improved profile over known A2a-selective agonists in that they generally lack agonist activity at the human A3 receptor. They may even possess antagonist activity at the human A3 receptor. This profile can be considered of benefit as A3 receptors are also found on leukocytes (eg eosinophil) and other inflammatory cells (eg mast cell) and activation of these receptors may have pro-inflammatory effects (Kohno et al, 1996; Van Schaick et al 1996). It is even considered that the bronchoconstrictor effects of adenosine in asthmatics may be mediated via the adenosine A3 receptor (Kohno et al, 1996).
Thus, according to the invention we provide compounds of formula (I):
wherein R
1
and R
2
independently represent a group selected from:
(i) C
3-8
cycloalkyl-;
(ii) hydrogen;
(iii) aryl
2
CHCH
2
—;
(iv) C
3-8
cycloalkylC
1-6
alkyl-;
(v) C
1-8
alkyl-;
(vi) arylC
1-6
alkyl-;
(vii) R
4
R
5
N—C
1-6
alkyl-;
(viii) C
1-6
alkyl-CH(CH
2
OH)—;
(ix) arylC
1-5
alkyl-CH(CH
2
OH)—;
(x) arylC
1-5
alkyl-C(CH
2
OH)
2
—;
(xi) C
3-8
cycloalkyl independently substituted by one or more (e.g. 1, 2 or 3) —(CH
2
)
p
R
6
groups;
(xii) H
2
NC(═NH)NHC
1-6
alkyl-;
(xiii) a group of formula
 or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl;
(xiv) —C
1-6
alkyl-OH;
(xv) —C
1-8
haloalkyl;
(xvi) a group of formula
(xvii) aryl; and
(xviii) —(CH
2
)
f
SO
2
NH
g
(C
1-4
alkyl-)
2-g
or —(CH
2
)
f
SO
2
NH
g
(arylC
1-4
alkyl-)
2-g
;
R
3
represents methyl, ethyl, —CH═CH
2
, n-propyl, —CH
2
CH═CH
2
, —CH═CHCH
3
, isopropenyl, cyclopropyl, cyclopropenyl, —CH(OH)CH
3
, —(CH
2
)
q
halogen, —(CH
2
)
h
Y(CH
2
)
i
H, —COO(CH
2
)
i
H, —CON(CH
2
)
m
H((CH
2
)
n
H), —CO(CH
2
)
o
H, or —C((CH
2
)
u
H)═NO(CH
2
)
v
H;
Y represents O, S or N(CH
2
)
j
H;
a and b independently represent an integer 0 to 4 provided that a+b is in the range 3 to 5;
c, d and e independently represent an integer 0 to 3 provided that c+d+e is in the range 2 to 3;
f represents 2 or 3 and g represents an integer 0 to 2;
p represents 0 or 1;
q represents 1 or 2;
h represents 1 or 2 and i represents an integer 0 to 1; such that h+i is in the range 1 to 2;
j represents an integer 0 to 1 such that h+i+j is in the range 1 to 2;
l represents 1 or 2;
m and n independently represent an integer 0 to 2 such that m+n is in the range 0 to 2;
o represents an integer 0 to 2;
u and v independently represent 0 or 1 such that u+v is in the range 0 to 1;
R
4
and R
5
independently represent hydrogen, C
1-6
alkyl, aryl, arylC
1-6
alkyl- or NR
4
R
5
together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N—C
1-6
alkylpiperazinyl;
R
6
represents OH, NH
2
, NHCOCH
3
or halogen;
R
7
represents hydrogen, C
1-6
alkyl, —C
1-6
alkylaryl or —COC
1-6
alkyl;
X represents NR
7
, O, S, SO or SO
2
;
and salts and solvates thereof.
References to C
x-y
alkyl include references to an aliphatic hydrocarbon grouping containing x to y carbon atoms which may be straight chain or branched and may be saturated or unsaturated. References to alkoxy may also be interpreted similarly. Preferably these groups will be saturated.
References to aryl include references to mono- and bicyclic carbocyclic aromatic rings (e.g. phenyl, naphthyl) and heterocyclic aromatic rings, for example containing 1-3 hetero atoms selected from N, O and S (e.g. pyridinyl, pyrimidinyl, thiophenyl, imidazolyl, quinolinyl, furanyl, pyrrolyl, oxazolyl) all of which may be optionally substituted, e.g. by C
1-6
alkyl, halogen, hydroxy, nitro, C
1-6
alkoxy, cyano, amino, SO
2
NH
2
or —CH
2
OH.
Examples of C
3-8
cycloalkyl for R
1
and R
2
include monocyclic alkyl groups (e.g. cyclopentyl, cyclohexyl) and bicyclic alkyl groups (e.g. norbornyl such as exo-norborn-2-yl).
Examples of (aryl)
2
CHCH
2
— for R
1
and R
2
include Ph
2
CHCH
2
— or such a group in which one or both phenyl moieties is substituted, e.g. by halogen or C
1-4
alkyl.
Examples of C
3-8
cycloalkylC
1-6
alkyl- for R
1
and R
2
include ethylcyclohexyl.
Examples of C
1-8
alkyl for R
1
and R
2
include —(CH
2
)
2
C(Me)
3
, —CH(Et)
2
and CH
2
═C(Me)CH
2
CH
2
—.
Examples of arylC
1-6
alkyl- for R
1
and R
2
include —(CH
2
)
2
Ph, —CH
2
Ph or either in which Ph is substituted (one or more times) by halogen (e.g. iodine), amino, methoxy, hydroxy, —CH
2
OH or SO
2
NH
2
; —(CH
2
)
2
pyridinyl (e.g. —(CH
2
pyridin-2-yl) optionally substituted by amino; (CH
2
)
2
imidazolyl (e.g. 1H-imidazol-4-yl) or this group in which imidazole is N-substituted by C
1-6
alkyl (especially methyl).
Examples of R
4
R
5
N—C
1-6
alkyl- for R
1
and R
2
include ethyl-piperidin-1-

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