Adamantane derivatives

Details Adamantane derivatives Adamantane derivatives

2000-06-01

2002-12-10

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S230500, C514S252120, C514S255030, C514S256000, C514S278000, C514S299000, C514S300000, C514S305000, C514S325000, C514S357000, C514S412000, C514S424000, C514S426000, C514S428000, C548S453000, C548S528000, C546S016000, C546S112000, C546S122000, C546S133000, C546S203000, C546S285000, C544S105000, C544S294000, C544S380000, C540S575000

Reexamination Certificate

active

06492355

ABSTRACT:

The present invention relates to adamantane derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
Adamantane derivatives are known in the art, e.g. from WO 95/04720 for use as gastrin and cholecystokinin receptor ligands, from Chem. Abs. (1977), Volume 86, No. 13 (86: 89560d) for use as analgesics, and from U.S. Pat. No. 3,464,998 as antibiotics.
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;l ) 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.
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
m represents 1, 2 or 3, preferably 1 or 2;
each R
1
independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, preferably a hydrogen atom;
A represents C(O)NH or, preferably, NHC(O);
Ar represents a group
X represents a bond, an oxygen atom or a group CO, (CH
2
)
1-6
, CH═, (CH
2
)
1-6
O, O(CH
2
)
1-6
, O(CH
2
)
2-6
O, O(CH
2
)
2-3
O(CH
2
)
1-3
, CR′(OH), (CH
2
)
1-3
O(CH
2
)
1-3
, (CH
2
)
1-3
O(CH
2
)
2-3
O, NR
5
, (CH
2
)
1-6
NR
5
, NR
5
(CH
2
)
1-6
, (CH
2
)
1-3
NR
5
(CH
2
)
1-3
, O(CH
2
)
2-6
NR
5
, O(CH
2
)
2-3
NR
5
(CH
2
)
1-3
, (CH
2
)
1-3
NR
5
(CH
2
)
2-3
O, NR
5
(CH
2
)
2-6
O, NR
5
(CH
2
)
2-3
O(CH
2
)
1-3
, CONR
5
, NR
5
CO, S(O)
n
, S(O)
n
CH
2
, CH
2
S(O)
n
, SO
2
NR
5
or NR
5
SO
2
;
n is 0, 1 or 2;
R′ represents a hydrogen atom or a C
1
-C
6
alkyl, preferably methyl, group;
one of R
2
and R
3
represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from (i) C
1
-C
6
alkyl optionally substituted by at least one C
3
-C
6
cycloalkyl, (ii) C
3
-C
8
cycloalkyl, (iii) C
1
-C
6
alkyloxy optionally substituted by at least one C
3
-C
6
cycloalkyl, and (iv) C
3
-C
8
cycloalkyloxy, 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;
either R
4
represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C
1
-C
6
alkyl, C
1
-C
6
hydroxyalkyl, —NR
6
R
7
, —(CH
2
)
r
NR
6
R
7
and —CONR
6
R
7
, 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
N
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;
R
6
and R
7
each independently represent a hydrogen atom or a C
1
-C
6
alkyl, C
2
-C
6
hydroxyalkyl 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; with the provisos that,
(a) when A represents C(O)NH and R
4
represents an unsubstituted 3- to 8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and
(b) when A represents C(O)NH and X represents a group (CH
2
)
1-6
or O(CH
2
)
1-6
, then R
4
does not represent an unsubstituted imidazolyl, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl group, and
(c) when A represents NHC(O) and R
4
represents an unsubstituted 3- to 8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and
(d) when A represents NHC(O) and X represents O(CH
2
)
1-6
, NH(CH
2
)
1-6
or SCH
2
, then R
4
does not represent an unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl group, and
(e) when A represents NHC(O) and X represents O(CH
2
)
2-3
NH(CH
2
)
2
, then R
4
does not represent an imidazolyl group;
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. Examples of alkyl groups/moieties containing up to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. 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. In relation to R
4
, a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom may be a monocyclic or bicyclic ring system. Further in relation to R
4
, a 3- to 8-membered saturated carbocyclic ring system may be a monocyclic or bicyclic ring system. When R
6
or R
7
represents a C
2
-C
6
hydroxyalkyl in the substituent NR
6
R
7
, —(CH
2
)
r
NR
6
R
7
or —CONR
6
R
7
, it will be appreciated that the hydroxyl group will not be bonded to the same carbon atom as the nitrogen atom. When R
6
and R
7
together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring, the ring obtained is monocyclic.
Preferably X represents a bond, an oxygen atom or a group CO, (CH
2
)
1-6
, CH═, O(CH
2
)
1-6
, O(CH
2
)
2-6
O, O(CH
2
)
2-3
O(CH
2
)
1-3
, CR′(OH), NR
5
, (CH
2
)
1-6
NR
5
, CONR
5
, S(O)
n
or S(O)
n
CH
2
.
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 (i) C
1
-C
6
alkyl, preferably C
1
-C
4
alkyl, optionally substituted by at least one (e.g. 1, 2 or 3) C
3
-C
6
cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (ii) C
3
-C
8
cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (iii) C
1
-C
6
alkyloxy, preferably C
1
-C
4
alkyloxy, optionally substituted by at least one (e.g. 1, 2 or 3) C
3
-C
6
cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and (iv) C
3
-C
8
cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), 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.
Preferably, one of R
2
and R
3
represents a halogen (especially chlorine or bromine) atom or a nitro, amino or C
1
-C
6
alkyl (especially methyl or ethyl) group and the other of R
2
and R
3
represents a hydrogen atom.
R
4
may represent a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, 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, carboxyl, cyano, C
1
-C
6
alkyl, preferably C
1
-C
4
alkyl, C
1
-C
6
hydroxyalkyl, p

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