Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-08
2003-01-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S407000
Reexamination Certificate
active
06503909
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, to pharmaceutical compositions containing them, to their use in the treatment of such disorders and to methods of preparation.
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 pyrazine derivatives which are sodium channel blockers. The compounds are surprisingly potent anti-convulsants having increased potency with respect to lamotrigine and increased selectivity in terms of CNS side-effects and inhibition of the enzyme dihydrofolate reductase. The compounds are therefore useful in the treatment of CNS diseases such as epilepsy.
Accordingly, the present invention provides a compound of formula (I)
wherein
R
1
is phenyl substituted by one or more halogen atoms;
R
2
is —NH
2
;
R
3
is —NH
2
or hydrogen;
R
4
is —CXNR
a
R
b
, —CXNH—(CH
2
)
y
—NR
a
R
b
;
wherein
X is ═O or ═S;
y is an integer zero, 1 or 2;
R
a
and R
b
, 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 saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms, which heterocycle can be further substituted with one or more C,4 alkyl groups;
and pharmaceutically acceptable derivatives thereof.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester 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).
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
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 saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms as used herein includes 5- or 6-membered heterocycles containing at least one nitrogen heteroatom, and preferably two nitrogen heteroatoms, which heterocycle can be further substituted with one or more C
1-4
alkyl groups. A particularly suitable heterocycle is a pyrrolidine or a piperazine ring.
R
1
is aptly selected from phenyl substituted by one or more halogen atoms. Particularly, R
1
represents phenyl substituted by more than 1 halogen atom, such as di- or tri-halogenated phenyl. Preferably, the halogen atoms are all identical. Preferably, the halogen substituents in R
1
are chloro. Suitably R
1
is selected from 2,3,5-trichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl. Preferably, R
1
is 2,3,5-trichlorophenyl.
R
3
is preferably —NH
2
.
When R
4
is the group —CXNR
a
R
b
or —CXNH—(CH
2
)
y
—NR
a
R
b
where R
a
and R
b
, together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms atoms, this saturated 5- or 6-membered heterocycle is suitably a pyrrolidine or piperazine ring.
X is preferably ═O.
The integer y is preferably 2.
When R
4
is the group —CXNH—(CH
2
)
y
—NR
a
R
b
, R
a
and R
b
are preferably C
1-4
alkyl. Preferred values for —CXNH(CH
2
)
y
NR
a
R
b
include for example —CONH—(CH
2
)
2
—N(CH
3
)
2
.
R
4
is preferably the group —CXNR
a
R
b
. Preferably X is ═O and, further preferred, are compounds where R
a
and R
b
are selected from hydrogen and C
1-4
alkyl. Preferably R
4
is —CONH
2
, —CONH(CH
3
), —CONH(CH
2
CH
3
), —CONH[CH(CH
3
)
2
] or —CON(CH
3
)
2
. A particularly preferred R
4
is —CONH
2
.
It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
Preferred compounds of the present invention include:
5-Carboxamido-2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-N-methylcarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-N-ethylcarboxamido-3-(2,3,5-trichlorophenyl )pyrazine
2,6-Diamino-5-N-isopropylcarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-N,N-dimethylcarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-thiocarboxamido-3-(
2,3,5-
trichlorophenyl)pyrazine
and pharmaceutically acceptable derivatives thereof.
A particularly preferred compound according to the invention is:
5-Carboxamido-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 as described herein above.
The compounds of formula (I) are particularly useful as anticonvulsants. They are therefore useful in treating epilepsy. They may be used to improve the condition of a host, typically a human being, suffering from epilepsy. They may be employed to alleviate the symptoms of epilepsy in a host. “Epilepsy” is intended to include the following seizures:- simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
The compounds of formula (I) are additionally useful in the treatment of bipolar disorder, alternatively known as manic depression. Type I or II bipolar disorder may be treated. The compounds of formula (I) may thus be used to improve the condition of a human patient suffering from bipolar disorder. They may be used to alleviate the symptoms of bipolar disorder in a host. The compounds of formula (I) may also be used in the treatment of unipolar depression.
The compounds of formula (I) are also useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compounds of formula (I) may be used as a pre-emptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compounds of formula (I) may also be used in the treatment or prevention of pain associated with migraine.
The compounds of formula (I) are further useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non-cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterised by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compou
Cox Brian
Healy Mark Patrick
Wild Deborah
Bacon & Thomas
Balasubramanian Venkataraman
Raymond Richard L.
SmithKline Beecham Corporation
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