Adamantane derivatives

Details Adamantane derivatives Adamantane derivatives

1999-01-26

2001-06-05

Lambkin, Deborah C. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S369000, C514S613000, C514S623000, C548S187000, C548S205000, C564S123000, C564S191000

Reexamination Certificate

active

06242470

ABSTRACT:

This application is a 371 of PCT/SE 98/02189 filed Dec. 1, 1998.
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 U.S. Pat. No. 3,789,072 as serotonin inhibitors, from Chem. Abs. (1974), Vol. 80, No.5 (26871m) as inflammation and edema inhibitors or analgesics, from Chem. Abs. (1975), Vol. 82, No.1 (3853j) and Chem. Abs. (1977), Vol. 86, No.17 (120855e) as antiviral agents, and also from Chem. Abs. (1968), Vol. 69, No.1 (2562h), Chem. Abs. (1975), Vol. 82, No. 3 (16510v) and Tetrahedron (1988), 44, No. 23, 7234-7242.
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 hepatocyte.
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 A represents a group CH
2
or an oxygen atom; B represents a hydrogen or halogen atom (e.g. fluorine, chlorine, iodine and especially bromine);
D represents a group CH
2
, OCH
2
, NHCH
2
or CH
2
CH
2
, in particular a group CH
2
, OCH
2
or NHCH
2
;
R represents a phenyl, benzothiazolyl, indolyl, indazolyl, purinyl, pyridyl, pyrimidinyl or thiophenyl group, each of which may be optionally substituted by one or more substituents independently selected from a halogen atom or a cyano, carboxyl, hydroxyl, nitro, 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, phenoxy, benzyl, C
1
-C
6
-alkylthio, phenylthio, C
1
-C
6
-alkoxycarbonyl, C
1
-C
6
-alkylsulphinyl or C
1
-C
6
-alkylsulphonyl group, or a C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy group optionally substituted by one or more substituents independently selected from a halogen atom or an amino, carboxyl, hydroxyl, C
1
-C
6
-alkoxy, (di)C
1
-C
6
-alkylamino, C
1
-C
6
-alkoxycarbonyl, imidazolyl, morpholinyl, piperidinyl or pyrrolidinyl group;
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; and
R
3
, R
4
, R
5
and R
6
each independently represent a hydrogen atom or a C
1
-C
6
-alkyl or C
3
-C
8
-cycloalkyl group;
with the provisos that when A is CH
2
, B is H and D is CH
2
, then R does not represent a phenyl, ortho-carboxyphenyl, methylphenyl or para-phenoxyphenyl group, and that when A is CH
2
, D is CH
2
or CH
2
CH
2
and R represents a substituted phenyl group, the substituent or substituents present do not comprise, in an ortho position, a C
1
-C
6
-alkoxy group substituted by an amino, (di)C
1
-C
6
-alkylamino, imidazolyl, morpholinyl, piperidinyl or pyrrolidinyl 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. Furthermore, the (cyclo)alkyl moieties in a dialkylamino, dicycloalkylamino, dialkylamido or dicycloalkylamido substituent group may be the same or different. When D represents a group OCH
2
or NHCH
2
, the group is orientated such that the oxygen or nitrogen atom is directly attached to the adamantyl group. 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 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”:
Similarly, meta and para positions in the phenyl group R are defined relative to the point of attachment of the amide linking group to R and are indicated in the above formula by the symbols + and # respectively.
Preferably, R represents a phenyl, benzothiazolyl, indolyl, indazolyl, purinyl, pyridyl, 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 a cyano, carboxyl, hydroxyl, nitro, 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), phenoxy, benzyl, C
1
-C
6
-alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio), phenylthio, C
1
-C
6
-alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C
1
-C
6
-alkylsulphinyl (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
-alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C
1
-C
6
-alkoxy (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxy) 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, carboxyl, hydroxyl, C
1
-C
6
-alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), (di)C
1
-C
6
-alkylamino (e.g.(di)methylamino or (di)ethylamino), C
1
-C
6
-alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, tert-butoxy-, pentoxy- or hexoxycarbonyl), imidazolyl, morpholinyl, piperidinyl or pyrrolidinyl group.
More preferably, R represents a phenyl, benzothiazolyl, indolyl, indazolyl, purinyl, pyridyl or thiophenyl group, each of which may be optionally substituted by one, two or three substituents independently selected from a halogen atom (especially chlorine) or a hydroxyl, nitro or C
1
-C
4
-alkoxycarbonyl (in particular methoxycarbonyl) group, or a C
1
-C
4
-alkyl (most preferably C
1
-C
2
-alkyl) or C
1
-C
4
-alkoxy (most preferably C
1
-C
3
-alkoxy) group optionally substituted by one or two substituents independently selected from a halogen atom or an amino, carboxyl, hydroxyl, C
1
-C
4
-alkoxy (especially methoxy), (di)C
1
-C
4
-alkylamino (in particular methylamino or dimethylamino), C
1
-C
4
-alkoxycarbonyl(especially tert-butoxycarbonyl), imidazolyl, morpholinyl, piperidinyl or pyrrolidinyl group.
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
, R
4
, R
5
and R
6
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.
Preferred compounds of the invention include:
N-(2-Methyl-6-benzothiazolyl)-tricyclo[3.3.1.1
3,7
]decane

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