Adamantane derivatives

Details Adamantane derivatives Adamantane derivatives

2002-06-10

2004-04-13

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S157000, C564S162000, C564S163000, C564S164000, C564S168000, C562S455000, C548S336100, C514S399000, C514S400000, C514S563000, C514S616000, C514S618000, C514S619000, C514S620000

Reexamination Certificate

active

06720452

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.
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), hepatocytes, erythrocytes, erydiroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones and renal 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 D represents CH
2
or CH
2
CH
2,
preferably CH
2
;
E represents C(O)NH or, preferably, NHC(O);
R
1
and R
2
each independently represent a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, or an amino (NH
2
), nitro (NO
2
), C
1
-C
6
alkyl or trifluoromethyl group;
R
3
group of formula
 X represents an oxygen or sulphur atom or a group NH, SO or SO
2
;
Y represents an oxygen or sulphur atom or a group NR
11
, SO or SO
2
;
Z represents a group —OH, —SH, —CO
2
H, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, C
1
-C
6
-alkylsulphinyl, C
1
-C
6
-alkylsulphonyl, —NR
6
R
7
, —C(O)NR
8
R
9
, imidazolyl, 1-methylimidazolyl, —N(R
10
)C(O)—C
1
-C
6
alkyl, C
1
-C
6
alkylcarbonyloxy, C
1
-C
6
alkoxycarbonyloxy, —OC(O)NR
12
R
13
, —OCH
2
OC(O)R
14
, —OCH
2
OC(O)OR
15
or —OC(O)OCH
2
OR
16
;
R
4
represents a linear or branched C
2
-C
6
alkylene group;
R
5
represents a linear or branched C
1
-C
6
alkylene group;
R
6
, R
7
, R
8
, R
9
, R
10
, R
12
and R
13
each independently represent a hydrogen atom, or a C
1
-C
6
alkyl group optionally substituted by at least one hydroxyl group (e.g., one, two or three hydroxyl groups);
R
11
represents a hydrogen atom, or a C
1
-C
6
alkyl group optionally substituted by at least one substituent (e.g. one, two or three substituents) independently selected from hydroxyl and C
1
-C
6
alkoxy; and
R
14
, R
15
and R
16
each independently represent a C
1
-C
6
alkyl group; with the provisos that (i) when E represents NHC(O), X represents O, S or NH and Y represents O, then Z represents —NR
6
R
7
where R
6
represents a hydrogen atom and R
7
represents either a hydrogen atom or a C
1
-C
6
alkyl group substituted by at least one hydroxyl group, and (ii) when E represents NHC(O), X represents O, S or NH, Y represents NH and
R
5
represents CH
2
CH
2
, then Z is not —OH or imidazolyl;
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. In the present invention, an alkyl group or moiety may contain up to 6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl.
Preferably, R
1
and R
2
each independently represent a hydrogen or halogen atom, or an amino, nitro, C
1
-C
4
alkyl or trifluoromethyl group.
More preferably, R
1
and R
2
each independently represent a hydrogen, chlorine or bromine atom, or an amino, nitro, C
1
-C
3
alkyl or trifluoromethyl group.
Most preferably, R
1
and R
2
each independently represent a hydrogen or chlorine atom.
Preferably X represents an oxygen atom or a group NH.
Preferably Z represents a group —OH, —SH, —CO
2
H, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, C
1
-C
4
-alkylsulphinyl, C
1
-C
4
-alkylsulphonyl, —NR
6
R
7
, —C(O)NR
8
R
9
, imidazolyl, 1-methylimidazolyl, —N(R
10
)C(O)—C
1
-C
4
alkyl, C
1-C
4
alkylcarbonyloxy, C
1
-C
4
alkoxycarbonyloxy, —OC(O)NR
12
R
13
, —OCH
2
OC(O)R
14
, —OCH
2
OC(O)OR
15
or —OC(O)OCH
2
OR
16
.
Particularly preferred groups Z include —OH, —CO
2
H, methoxy, methylthio, methylsulphinyl, methylsulphonyl, —NR
6
R
7
, —C(O)NR
8
R
9
, —N(R
10
)C(O)CH
3
, imidazolyl, 1-methylimidazolyl, C
1
-C
4
alkylcarbonyloxy, C
1
-C
4
alkoxycarbonyloxy, —OC(O)NR
12
R
13
, —OCH
2
OC(O)R
14
, —OCH
2
OC(O)OR
15
and —OC(O)OCH
2
OR
16
.
R
4
preferably represents a C
2
-C
4
alkyl group, for example a linear alkyl group such as —(CH
2
)
2
— or —(CH
2
)
3
—.
R
5
preferably represents a C
1
-C
5
alkyl group, for example —CH
2
—, —(CH
2
)
2
—, —(CH
2
)
3
—, —CH
2
CH(CH
3
)—, —CH(CH
3
)CH
2
—, —(CH
2
)
2
C(CH
3
)
2
— or —CH
2
C(CH
3
)
2
—.
Preferably R
6
, R
7
, R
8
, R
9
, R
10
, R
12
and R
13
each independently represent a hydrogen atom, or a C
1
-C
4
alkyl group optionally substituted by at least one hydroxyl group.
Y is conveniently a group NR
11
. It is preferred that R
11
represents a hydrogen atom, or a C
1
-C
4
alkyl group optionally substituted by at least one substituent independently selected from hydroxyl and C
1
-C
6
, preferably C
1
-C
4
, alkoxy.
R
14
, R
15
and R
16
each independently represent a C
1
-C
6
alkyl group, preferably a C
1
-C
4
alkyl group.
Preferred compounds of the invention include:
2-Chloro-5-[2-(2-methoxyethylamino)ethylamino]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
[2-[4-Chloro-3-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)carbamoyl-phenylamino]-ethyamino]-acetic acid, hydrochloride,
2-Chloro-5-[3-(3-hydroxy-propylamino)-propoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[2-(3-hydroxypropylamino)ethylamino]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, acetate,
5-[2-(2-Aminoethylamino)ethylamino]-2-chloro-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, acetate,
5-[2-(2-Acetylaminoethylamino)ethylamino]-2-chloro-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, acetate,
[2-[4-Chloro-3-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)carbamoyl-phenylamino]-ethylamino]-propionic acid,
2-Chloro-5-[2-(2-methylcarbamoylethylamino)ethylamino]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, acetate,
2-Chloro-5-[2-(2-dimethylcarbamoylethylamino)ethylamino]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, acetate,
2-Chloro-5-[3-(3-hydroxypropylthio)propoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide,
5-[2-(2-Aminoethylthio)ethoxy]-2-chloro-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[2-(3-hydroxypropylamino)ethoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
2-Chloro-5-[3-(3-hydroxypropylsulfonyl)propoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide,
(±)-2-Chloro-5-[3-(3-hydroxypropylsulfinyl)propoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[2-(3-hydroxypropylthio)ethoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide,
(S)-2-Chloro-5-[2-(2-hydroxypropylamino)ethoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
(R)-2-Chloro-5-[2-(2-hydroxypropylamino)ethoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
(S)-2-Chloro-5-[2-(2-hydroxy-1-methylethylamino)ethoxy]-N-(tricyclo[3.3.1.1
3,7
]dec-1-ylmethyl)-benzamide, hydrochloride,
(R)-2-Chloro-5-[2-(2-hydroxy-1-methylethylamino)ethoxy]-N-(tricyclo[3.3.1.1

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