Adenosine derivatives and methods of administration

Details Adenosine derivatives and methods of administration Adenosine derivatives and methods of administration

2002-08-13

2004-01-13

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S081000, C514S266400, C536S027230, C536S027300, C536S027630, C544S264000

Reexamination Certificate

active

06677316

ABSTRACT:

The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Publications in this area include WO 98/16539 (Novo Nordisk A/S) which describes adenosine derivatives for the treatment of myocardial and cerebral ischaemia and epilepsy; WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which relates to adenosine derivatives possessing antihypertensive, cardioprotective, anti-ischaemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk A/S) which describes N,9-disubstituted adenine derivatives which are substituted in the 4′ position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders involving cytokines in humans.
Thus the invention provides a compound of formula (1) which is an agonist at the adenosine A1 receptor
wherein
X represents O or CH
2;
R
2
represents C
1-3
alkyl, C
1-3
alkoxy, halogen or hydrogen;
R
3
represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C
1-6
alkoxy, C
1-6
alkylO(CH
2
)
n
where n is 0-6, C
3-7
cycloalkyl, C
1-6
hydroxyalkyl, halogen or a C
1-6
straight or branched alkyl, C
1-6
alkenyl or C
1-6
alkynyl group optionally substituted by one or more halogens.
Y and Z represent O, N, CH, N(C
1-6
alkyl)
W represents CH, O, N, S, N(C
1-6
alkyl)
 and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
 with the proviso that when W represents CH, Z represents N and Y represents O, R
3
cannot be H.
R
4
and R
5
independently represent H or a C
1-16
straight chain or branched alkyl group.
R
1
represents hydrogen or a group selected from
(1) -(alk)
n
-(C
3-7
) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, —(C
1-3
) alkoxy, wherein (alk) represents C
1-3
alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of —(C
1-3
)alkyl, —CO
2
—(C
1-4
)alkyl, —CO(C
1-3
alkyl), —S(═O)
n
—(C
1-3
alkyl), —CONR
a
R
b
(wherein R
a
and R
b
independently represent H or C
1-3
alkyl) or ═O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (═O)
n
, where n is 1 or 2.
(3) Straight or branched C
1-12
alkyl, optionally including one or more O, S(═O)
n
(where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C
3-7
cycloalkyl or NR
a
R
b
wherein R
a
and R
b
independently represent hydrogen, C
3-7
cycloalkyl or a C
1-6
straight chain or branched alkyl optionally substituted by C
3-7
cycloalkyl;
(4) a fused bicyclic aromatic ring
 wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by —CO
2
—(C
1-13
alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, —SO
3
H, -(alk)
n
OH, -(alk)
n
-cyano, —(O)
n
—(C
1-6
)alkyl (optionally substituted by one or more halogens), -(alk)
n
-nitro, —(O)
m
-(alk)
n
-CO
2
R
c
, -(alk
n
)-CONR
c
R
d
-(alk)
n
-COR
c
, -(alk)
n
-SOR
e
, -(alk)
n
-SO
2
R
e
, -(alk)
n
-SO
2
NR
c
R
d
, -(alk)
n
OR
c
, -(alk)
n
-(CO)
m
-NHSO
2
R
e
, -(alk)
n
-NHCOR
c
, -(alk)
n
-NR
c
R
d
wherein m and n are 0 or 1 and alk represents a C
1-6
alkylene group or C
2-6
alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C
1-3
alkyl or NR
c
R
d
.
R
c
and R
d
may each independently represent hydrogen, or C
1-3
alkyl or when part of a group NR
c
R
d
, R
c
and R
d
together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C
1-3
alkyl groups.
R
e
represents C
1-3
alkyl
 and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof for use in therapy.
Preferably the compound is of formula (Ia)
wherein
X represents O or CH
2;
R
2
represents C
1-3
alkyl, C
1-3
alkoxy, halogen or hydrogen;
R
3
represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C
1-6
alkoxy, C
1-6
straight or branched alkyl optionally substituted by one or more halogens, C
3-7
cycloalkyl, C
1-6
hydroxyalkyl or halogen.
Y and Z represent O, N, CH
W represents CH, O, N, S
 and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art)
 with the proviso that when W represents CH, Z represents N and Y represents O, R
3
cannot be H.
R
4
and R
5
independently represent H or a C
1-6
straight chain or branched alkyl group.
R
1
represents a group selected from
(1) -(alk)
n
-(C
3-7
) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, —(C
1-3
) alkoxy, wherein (alk) represents C
1-3
alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of —(C
1-3
)alkyl, —CO
2
—(C
1-4
)alkyl, —CO(C
1-3
alkyl), —S(═O)
n
—(C
1-3
alkyl), —CONR
a
R
b
(wherein R
a
and R
b
independently represent H or C
1-3
alkyl) or ═O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (═O)
n
, where n is 1 or 2.
(3) Straight or branched C
1-12
alkyl, optionally including one or more O, S(═O)
n
(where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C
3-7
cycloalkyl or NR
a
R
b
wherein R
a
and R
b
independently represent hydrogen, C
3-7
cycloalkyl or a C
1-6
straight chain or branched alkyl optionally substituted by C
3-7
cycloalkyl;
(4) a fused bicyclic aromatic ring
 wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by —CO
2
—(C
1-3
alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, —SO
3
H, -(alk)
n
OH, -(alk)
n
-cyano, —(O)
n
—(C
1-6
)alkyl (optionally substituted by one or more halogens), -(alk)
n
-nitro, -(O)
m
-(alk)
n
-CO
2
R
c
, -(alk
n
)-CONR
c
R
d
-(alk)
n
-COR
c
, -(alk)
n
-SOR
e
, -(alk)
n
-SO
2
R
e
, -(alk)
n
-SO
2
NR
c
R
d
, -(alk)
n
OR
c
, -(alk)
n
-(CO)
m
—NHSO
2
R
e
, -(alk)
n
-NHCOR
c
, -(alk)
n
-NR
c
R
d
wherein m and n are 0 or 1 and alk represents a C
1-6
alkylene group or C
2-6
alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C
1-3
alkyl or NR
c
R
d
.
R
c
and R
d
may each independently represent hydrogen, or C
1-3
alkyl or when part of a group NR
c
R
d
, R
c
and R
d
together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C
1-3
alkyl groups.
R
e
represents C
1-3
alkyl
 and salts and solvates thereof, in particular, physiologically acceptable

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