Substituted phenyl compounds with immunosuppressing activity...

Details Substituted phenyl compounds with immunosuppressing activity... Substituted phenyl compounds with immunosuppressing activity...

2000-07-10

2003-04-29

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S255030, C514S422000, C514S327000, C514S426000, C514S252140, C544S400000, C544S393000, C544S295000, C548S518000, C548S557000, C546S217000

Reexamination Certificate

active

06555541

ABSTRACT:

The present invention relates to substituted phenyl compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
The P2X
7
receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X
7
receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1&bgr; (IL-1&bgr;) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). P2X
7
receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
Certain substituted acetamide compounds are known from EP-A-382 216 having anti-allergic activity.
It would be desirable to make compounds effective as P2X
7
receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X
7
receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of general formula
wherein:
each R
1
independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, or a trifluoromethyl, cyano, nitro, C
1
-C
6
alkyl or C
1
-C
6
alkoxy group;
T represents an oxygen atom or, preferably, a group NH;
U represents an oxygen or sulphur atom or a group NH, preferably an oxygen or sulphur atom;
Ar represents a group
X represents a bond, an oxygen atom or a group CO, CH
2
, CH
2
O, O(CH
2
)
m
, CH
2
OCH
2
, NR
5
, CH
2
NR
5
, NR
5
CH
2
, CH
2
NR
5
CH
2
, CONR
5
, S(O)
n
or SO
2
NR
5
;
m is 1, 2or 3;
n is 0, 1 or 2;
one of R
2
and R
3
represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from C
1
-C
6
alkyl optionally substituted by at least one C
3
-C
6
cycloalkyl, C
3
-C
8
cycloalkyl, C
1
-C
6
alkyloxy optionally substituted by at least one C
3
-C
6
cycloalkyl, C
3
-C
8
cycloalkyloxy, S(O)
p
C
1
-C
6
alkyl or S(O)
q
C
3
-C
8
cycloalkyl, each of these groups being optionally substituted by one or more fluorine atoms, and the other of R
2
and R
3
represents a hydrogen or halogen atom or a methyl group;
p is 0, 1 or 2;
q is 0, 1 or 2;
R
4
represents di(C
1-2
alkyl)N(CH
2
)
t
where t is 0, 1 or 2 or imidazolyl, or R
4
represents a 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, C
1
-C
6
alkyl, acetyl, hydroxy C
1
-C
6
alkyl, —NR
6
R
7
, —(CH
2
)
r
NR
6
R
7
, —CONR
6
R
7
and pyrimidinyl, or R
4
represents a 3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from NR
6
R
7
, —(CH
2
)
r
NR
6
R
7
and —CONR
6
R
7
the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C
1
-C
6
alkyl;
r is 1, 2, 3, 4, 5 or 6;
R
5
represents a hydrogen atom or a C
1
-C
6
alkyl or C
3
-C
8
cycloalkyl group; and
R
6
and R
7
each independently represent a hydrogen atom or a C
1
-C
6
alkyl or C
3
-C
8
cycloalkyl group, or R
6
and R
7
together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring, provided that when R
3
represents a cyano group, then X is other than a bond;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched. When one of R
2
and R
3
represents a C
1
-C
6
alkyl/C
1
-C
6
alkyloxy optionally substituted by at least one C
3
-C
6
cycloalkyl, it should be understood that one or both of the alkyl and cycloalkyl moieties may be optionally substituted by fluorine atoms. A 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms may be a monocyclic or bicyclic ring system. Similarly, a 3- to 8-membered saturated carbocyclic ring system may be a monocyclic or bicyclic ring system. The hydroxyl moiety in a hydroxyalkyl substituent group may be located in any suitable position in the alkyl group. Typically, the hydroxyl moiety will be located on a terminal carbon atom in a straight chain alkyl group. The alkyl groups in a dialkylamino moiety may be the same or different.
Preferably, at least one group R
1
is other than a hydrogen atom, especially a halogen atom such as a fluorine or chlorine atom.
Preferably X represents a bond, an oxygen atom or a group CONH, CH
2
or O(CH
2
)
m
.
One of R
2
and R
3
represents a halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl, or a group selected from C
1
-C
6
alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) optionally substituted by at least one (e.g. 1, 2 or 3) C
3
-C
6
cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C
3
-C
8
cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C
1
-C
6
alkyloxy (e.g. methoxy, ethoxy, isopropoxy or tert-butoxy) optionally substituted by at least one(e.g. 1, 2 or 3) C
3
-C
6
cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C
3
-C
8
cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), S(O)
p
C
1
-C
6
alkyl (e.g. S(O)
p
methyl, -ethyl, -propyl, -butyl, -pentyl or -hexyl) or S(O)
q
C
3
-C
8
cycloalkyl (e.g. S(O)
q
cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl), each of these groups being optionally substituted by one or more (e.g. 1, 2, 3 or 4) fluorine atoms, and the other of R
2
and R
3
represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom or a methyl group.
Preferably, one of R
2
or R
3
represents a halogen (especially chlorine) atom or a C
1
-C
6
alkyl (especially methyl) group and the other of R
2
or R
3
represents a hydrogen atom.
In one aspect, R
4
may represent a 3- to 9-membered saturated heterocyclic ring system containing one or two nitrogen atoms, the heterocyclic ring system being optionally substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl, C
1
-C
6
alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), acetyl, hydroxyC
1
-C
6
alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl or hydroxyhexyl), —NR
6
R
7
, —(CH
2
)
r
NR
6
R
7
, —CONR
6
R
7
and pyrimidinyl.
The 3- to 9-membered saturated heterocyclic ring system in the group R
4
may be a monocyclic ring system such as a pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), piperazinyl (e.g. 1-piperazinyl) or homopiperazinyl ring, or a bicyclic ring system such as
In another aspect, R
4
may represent a 3- to 8-membered saturated carbocyclic ring system substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from NR
6
R
7
, —(CH
2
)
r
NR
6
R
7
, and —CONR
6
R
7
, the ring system being optionally further substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl and C
1
-C
6
alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl).
The 3- to 8-membered saturated carbocyclic ring in the group R
4
is preferably a monocyclic ring system such as a cyclopentyl or cyclohexyl ring.
Specific examples of groups R
4
include:
When X represents a bond or a group CO, CH
2
or SO
2
, R
4
preferably represents a group:
When X represents an oxygen or sulphur atom or a group CH
2
O O(CH
2
)
m
, CH
2
OCH
2
, NR
5
, CH
2
NR
5
, NR
5
CH
2
, CH
2
NR
5
CH
2
, CONR
5
, SO or SO
2
NR
5
, R
4
prefera

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