Adamantane derivatives

Details Adamantane derivatives Adamantane derivatives

1999-01-26

2001-03-13

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S183000, C546S285000, C546S276400, C548S469000, C548S361100, C544S335000, C514S345000, C514S347000, C514S349000, C514S403000, C514S415000, C514S256000

Reexamination Certificate

active

06201024

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;) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X
7
receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes.
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 x represents 1 or 2; A represents a group CH
2
or an oxygen atom;
B represents a hydrogen or halogen atom (e.g. fluorine, bromine, iodine or especially chlorine);
R represents a phenyl, pyridyl, indolyl, indazolyl, pyrimidinyl or thiophenyl group, each of which may be optionally substituted by one or more substituents independently selected from a halogen atom or an amino, cyano, carboxyl, hydroxyl, nitro, C
1
-C
6
-alkyl, halo-C
1
-C
6
-alkyl, —N(R
1
)—C(═O)—R
2
, —C(O)NR
3
R
4
, —NR
5
R
6
, C
3
-C
8
-cycloalkyl, 3- to 8-membered heterocyclyl, C
3
-C
8
-cycloalkyloxy, C
1
-C
6
-alkylcarbonyl, C
1
-C
6
-alkoxycarbonyl, C
1
-C6-alkylsulphinyl or C
1
-C
6
-alkylsulphonyl group, or a C
1
-C
6
-alkoxy, C
1
-C
6
-alkylamino, phenoxy, benzyl, C
1
-C
6
-alkylthio or phenylthio group optionally substituted by one or more substituents independently selected from a halogen atom or an amino, cyano, carboxyl, hydroxyl,nitro, 1-pyrrolidinyl, 1-piperidinyl, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, (di)C
1
-C
6
-alkylamino, halo-C
1
-C
6
-alkyl, C
1
-C
6
-alkoxycarbonyl or one of the following groups:
R
1
represents a hydrogen atom or a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
R
2
represents a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
R
3
and R
4
each independently represent a hydrogen atom or a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
R
5
represents a hydrogen atom or a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
R
6
represents a C
3
-C
8
-cycloalkyl group and, additionally, a C
1
-C
6
-alkyl group when R is not a hydrogen atom;
R
7
represents a hydrogen atom or a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
R
8
represents a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
R
9
represents a hydrogen atom or a hydroxyl group; and
R
10
represents a hydrogen atom or a phenyl or imidazolyl group;
with the provisos that R does not represent an unsubstituted pyridyl group when A represents a group CH
2
and B represents a hydrogen atom, and that when R represents a substituted phenyl, indolyl or indazolyl group, the substituent or substituents present do not comprise an amido, carboxyl, (di) C
1
-C
6
-alkylamido or C
1
-C
6
-alkoxycarbonyl group in an ortho position; 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. Furthermore, the (cyclo)alkyl moieties in a dialkylamino, dicycloalkylamino, dialkylamido or dicycloalkylamido substituent group may be the same or different. A 3- to 8-membered heterocyclyl group should be understood to mean an aliphatic heterocyclic ring system containing a single heteroatom selected from nitrogen, oxygen or sulphur. The term “in an ortho position” defines the ring position on the phenyl, indolyl or indazolyl ring of R which is adjacent to the point of attachment of the amide linking group to R, e.g., as illustrated in the formula below where the asterisks define the “ortho position”:
Preferably, R represents a phenyl, pyridyl, indolyl, indazolyl, pyrimidinyl or thiophenyl group, each of which may be optionally substituted by one, two, three or four substituents independently selected from a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or an amino, cyano, carboxyl, hydroxyl, nitro, C
1
-C
6
-alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), halo-C
1
-C
6
-alkyl (e.g. trifluoromethyl), —N(R
1
)—C(═O)—R
2
, —C(O)NR
3
R
4
, —NR
5
R
6
, C
3
-C
8
-cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), 3- to 8-membered heterocyclyl (e.g. aziridinyl, pyrrolidinyl, piperidinyl), C
3
-C
8
-cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), C
1
-C
6
-alkylcarbonyl (e.g. methyl-, ethyl-, propyl-, butyl-,pentyl- or hexylcarbonyl), C
1
-C
6
-alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C
1
-C
6
-aLlcylsulphinyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphinyl), or C
1
-C
6
-alkylsulphonyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphonyl) group, or a C
1
-C
6
-alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C
1
-C
6
-alkylamino (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylamnino), phenoxy, benzyl, C
1
-C
6
-alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio) or phenylthio group optionally substituted by one, two, three or four substituents independently selected from a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or an amino, cyano, carboxyl, hydroxyl, nitro, 1 -pyrrolidinyl, 1-piperidinyl, C
1
-C
6
-alkyl (e.g. methyl, ethyl, propyl, butyl,pentyl or hexyl), C
1
-C
6
-alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), (di)C
1
-C
6
-alkylamino (e.g. dimethylamnino or diethylamino), halo-C
1
-C
6
-alkyl (e.g. trifluoromethyl), C
1
-C
6
-alkoxycarbonyl (e.g. methoxy-, ethoxy-,propoxy-, butoxy-, tert-butoxy-, pentoxy- or hexoxycarbonyl) or one of the following groups:
More preferably R represents a phenyl, pyridyl or indolyl group, each of which may be optionally substituted by one or two substituents independently selected from a fluorine, chlorine, bromine or iodine atom or an amino, hydroxyl, nitro, aziridinyl, pyrrolidinyl, C
1
-C
4
-alkyl (particularly methyl), trifluoromethyl, —NR
5
R
6
, C
1
-C
4
-alkylsulphinyl (particularly methylsulphinyl) or C
1
-C
4
-alkylsulphonyl (particularly methylsulphonyl) group, or a C
1
-C
4
-alkoxy (especially C
1
-C
2
-alkoxy), C
1
-C
4
-alkylamino (especially C
1
-C
2
-alkylamino), benzyl, C
1
-C
4
-alkylthio (especially C
1
-C
2
-alkylthio) or phenylthio group optionally substituted by one or two substituents independently selected from a halogen atom (especially chlorine atom) or an amino, cyano, carboxyl, hydroxyl, 1-pyrrolidinyl, 1-piperidinyl, methyl, methoxy, dimethylamino, C
1
-C
4
-alkoxycarbonyl (especially tert-butoxycarbonyl) or one of the following groups:
It is preferred that R
1
represents a hydrogen atom or a C
1
-C
4
-alkyl (e.g. methyl, ethyl, propyl or butyl) or C
3
-C
6
-cycloalkyl (e.g. cyclopentyl or cyclohexyl) group.
Preferably R
2
represents a C
1
-C
4
-alkyl (e.g. methyl, ethyl, propyl or butyl) or C
3
-C
6
-cycloalkyl (e.g. cyclopentyl or cyclohexyl) group.
Preferably, R
3
and R
4
each independently represent a hydrogen atom or a C
1
-C
4
-alkyl (e.g. methyl, ethyl, propyl or butyl) or C
3
-C
6
-cycloalkyl (e.g. cyclopentyl or cyclohexyl) group.
It is preferred that R
5
represents a hydrogen atom or a C
1
-C
4
-alyl (e.g. methyl

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