Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-16
2003-07-29
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252110, C514S255050
Reexamination Certificate
active
06599905
ABSTRACT:
The present invention relates to a class of pyrazine compounds which are useful in the treatment of central nervous system (CNS) diseases and disorders and to their pharmaceutically acceptable derivatives, pharmaceutical compositions containing them, to their use in the treatment of such disorders and to methods of preparing them.
Numerous phenyl pyrazine derivatives are known in the prior art. For example, Synthesis (1987), (10), 914-915, describes phenyl pyrazine derivatives including, inter alia, 3-(4-chlorophenyl)-pyrazinamine. No pharmaceutical utility is however described in that prior art document.
The present invention relates to a series of pyrazine derivatives which are sodium channel blockers. These compounds are particularly good anti-convulsants and as such are useful in the treatment of CNS diseases such as epilepsy.
Accordingly, the invention provides a compound of formula (I)
wherein
R
1
is selected from the group consisting of phenyl substituted by one or more halogen atoms, naphthyl and naphthyl substituted by one or more halogen atoms;
R
2
is selected from the group consisting of —NH
2
and —NHC((═O))R
a
;
R
3
is selected from the group consisting of —NR
b
R
c
, —NHC((═O))R
a
and hydrogen;
R
4
is selected from the group consisting of hydrogen, —C
1-4
alkyl (preferably methyl), —C
1-4
alkyl (preferably methyl) substituted by one or more halogen atoms, —CN, —CH
2
OH, —CH
2
OR and —CH
2
S(O)
x
R
d
;
wherein
R
a
represents C
1-4
alkyl or C
3-7
cycloalkyl, and
R
b
and R
c
, which may be the same or different, are selected from hydrogen and C
1-4
alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered nitrogen containing heterocycle, which heterocycle can be further substituted with one or more C
1-4
alkyl;
R
d
is selected from C
1-4
alkyl or C
1-4
alkyl substituted by one or more halogen atoms;
x is an integer zero, one or two;
and pharmaceutically acceptable derivatives thereof;
with the proviso that R
1
does not represent;
when R
2
is —NH
2
, and both R
3
and R
4
are hydrogen.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof (eg. a prodrug). Reference hereinafter to the compounds of formula (I) includes the compound of formula (I) and pharmaceutically acceptable derivatives thereof.
Suitable prodrugs are well-known in the art and include N-acyl derivatives, for example at any of the nitrogens in the compounds of formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as R—O—CH
2
-nitrogen or R—O—C(O)-nitrogen.
As used herein, the term halogen atom includes fluorine, chlorine, bromine or iodine.
The term C
1-4
alkyl as used herein includes straight chained and branched alkyl groups containing 1 to 4 carbon atoms, and in particular includes methyl and isopropyl.
The term C
3-7
cycloalkyl includes groups containing 3 to 7 carbon atoms, and in particular includes cyclopropyl.
The term heterocycle as used herein includes 6 membered heterocycles containing at least one nitrogen heteroatom, and preferably two nitrogen heteroatoms. A particularly suitable heterocycle is piperazinyl.
R
1
is aptly selected from unsubstituted naphthyl and phenyl substituted by one or more halogen atoms. Particularly R
1
represents phenyl substituted by more than one halogen atom, such as di- or tri-halogenated phenyl. Preferably, the halogen substituent in R
1
is chloro. Suitably R
1
is selected from 2,3,5-trichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 1-naphthyl and 2-naphthyl. In particular, R
1
is 2,3,5-trichlorophenyl.
Suitably R
2
is selected from —NH
2
, isopropylcarbonylamino and cyclopropylcarbonylamino. R
2
is preferably —NH
2
.
Suitably R
3
is selected from hydrogen, —NH
2
, dimethylamino, 4-methyl-1-piperazinyl, acetamido, isopropylcarbonylamino, cyclopropylcarbonylamino. R
3
is preferably —NH
2
.
Suitably R
4
is selected from hydrogen, —CN, —CH
2
OH or methyl. R
4
is preferably —CH
2
OH or, more preferably, hydrogen.
More preferably, R
2
and R
3
are both —NH
2
.
A preferred class of compounds of formula (I) includes those wherein R
1
, R
2
and R
3
are as defined above and R
4
is selected from the group consisting of hydrogen, —C
1-4
alkyl (preferably methyl) and —C
1-4
alkyl (preferably methyl) substituted by one or more halogen atoms.
A preferred compound of formula (I) is wherein
R
1
is 2,3,5-trichlorophenyl; R
2
is —NH
2
; R
3
is —NH
2
; and R
4
is hydrogen.
According to a particular embodiment of the present invention, there is provided a compound of formula (Ia)
wherein
Hal represents a halogen atom selected from fluorine, chlorine, bromine and iodine;
n is 2 or 3;
R
2
is selected from the group consisting of —NH
2
and —NHC((═O))R
a
;
R
3
is selected from the group consisting of —NR
b
R
c
, —NHC((═O))R
a
and hydrogen;
R
4
is selected from the group consisting of hydrogen, —C
1-4
alkyl (preferably methyl), —C
1-4
alkyl (preferably methyl) substituted by one or more halogen atoms, —CN, —CH
2
OH, CH
2
OR
d
and —CH
2
S(O)
x
R
d
;
wherein
R
a
represents C
1-4
alkyl or C
3-7
cycloalkyl, and
R
b
and R
c
, which may be the same or different, are selected from hydrogen and C
1-4
alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered nitrogen containing heterocycle, which heterocycle can be further substituted with one or more C
1-4
alkyl;
R
d
is selected from C
1-4
alkyl or C
1-4
alkyl substituted by one or more halogen atoms;
x is an integer zero, one or two;
and pharmaceutically acceptable derivatives thereof.
It will be appreciated that R
2
, R
3
and R
4
as defined above for formula (Ia), are substantially as hereinbefore described with reference to formula (I).
Particuarly appropriately in formula (Ia), R
2
and R
3
both represent —NH
2
. Aptly R
4
represents —CN, methyl or, more appropriately, —CH
2
OH or, even more appropriately, hydrogen.
Aptly Hal in formula (Ia) represents chlorine. Suitably n is 3, and appropriately the resulting tri-substitution represents a compound of the following formula (Ib)
wherein R
2
, R
3
and R
4
are substantially as defined above with reference to formula (Ia);
and pharmaceutically acceptable derivatives thereof.
Preferred compounds of the present invention are
2,6-diamino-3-(2,3-dichlorophenyl)pyrazine,
2,6-diamino-3-(2,5-dichlorophenyl)pyrazine,
2,6-diamino-3-(1-naphthyl)pyrazine,
2,6-diamino-3-(2-naphthyl)pyrazine,
2-amino-6-(4-methyl-piperazinyl)-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-dimethylamino-3-(2,3-dichlorophenyl)pyrazine,
2-amino-6-dimethylamino-3-(1-naphthyl)pyrazine,
2,6-dicyclopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-cyclopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2,6-diisopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-isopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2-isopropylcarbonylamino-6-amino-3-(2,3,5-trichlorophenyl)pyrazine,
2-cyclopropylcarbonylamino-6-amino-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-acetamido-3-(2,5-dichlorophenyl)pyrazine,
2-amino-6-acetamido-3-(2-naphthalene)pyrazine,
5-methyl-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine,
5-cyano-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine,
and pharmaceutically acceptable derivatives thereof.
Further preferred is the compound 5-hydroxymethyl-2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine and pharmaceutically acceptable derivatives thereof.
A particularly preferred compound according to the present invention is 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine and pharmaceutically acceptable derivatives thereof.
It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.
The compounds of formula (I) are par
Cox Brian
Edney Dean David
Loft Michael Simon
Nobbs Malcolm Stuart
Shah Gita Punjabhai
Bernhardt Emily
Nixon & Vanderhye P.C.
SmithKline Beecham Corporation
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