Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-22
2003-10-14
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S234800, C514S249000, C544S354000, C544S062000, C544S116000, C544S119000, C544S328000, C544S331000
Reexamination Certificate
active
06632813
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives and their addition salts effective for the therapy of disorder of cerebral nerve cells as antagonists against excitatory amino acid receptors, in particular, as selective antagonists against AMPA receptor in non-NMDA receptor, processes for the preparation of both, and a medicinal composition containing these compounds.
BACKGROUND TECHNOLOGIES
The glutamic acid being excitatory amino acid is a main excitatory transmitter substance in the central nervous system of vertebrates, and is known as an amino acid contained most rich in brain. It is known, however, that, when releasing from nervous axon terminals exceeding the physiological threshold, it excessively excites the glutamic acid receptor of post-synapse to cause the death of nerve cells. This is called excitotoxicity.
In recent years, it has been clarified that the death of nerve cells due to glutamic acid concerns deeply in various diseases of cerebral nerve such as cerebral hemorrhage, head trauma, epilepsy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. It is considered therefore that, if such excitotoxicity could be prevented effectively, a potential to the therapy for these intractable diseases, for which there are virtually no therapeutic means at present, would be opened.
Roughly classifying, the glutamic acid receptor is divided into ion channel type receptor and G protein-binding type receptor, and this ion channel type receptor is further divided into NMDA (N-methyl-D-aspartic acid) receptor and non-NMDA receptor. Moreover, the latter non-NMDA receptor is classified into AMPA (&agr;-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid) receptor and KA (kainic acid) receptor. Studies on these excitatory amino acid receptors are being put forward, and, above all, with the drug with antagonism against AMPA receptor in non-NMDA receptor, it is known that the adverse effects (learning and memory disturbances, schizophrenia-like symptom, etc.), which the drugs (MK-801 etc.) with antagonism against NMDA receptor have, are not expressed (Neurosci. Biobehav. Rev., 1992, 16, 13-24; J. Pharmacol. Exp. Ther., 1958, 245, 969-974), and that the protective effect on cerebral nerve can be expected even by the administration after ischemia (Science, 1990, 247, 571-574).
Moreover, with the compounds with quinoxalinedione structure and with antagonism against AMPA receptor such as NBQX, drawbacks of causing kidney disturbance that is considered based on physicochemical properties, and the like are reported (J. Cereb. Blood Flow Metab., 1994, 14, 251-261), hence they cannot be said to be satisfactory compounds.
Now, as the compounds with similar structure to quinoxalinecarboxylic acid derivatives, compounds represented by a general formula (15)
(wherein X independently denotes chlorine or bromine atom, and R denotes methyl or ethyl group), described in Jpn. Kokai Tokkyo Koho JP 56,005,416 as compounds with antiviral function by Lily Co., and compounds represented by a general formula (16)
(wherein R and R
1
independently denote halogen atoms, R
2
denotes hydrogen, methyl or ethyl group, R
3
denotes hydrogen, methyl, ethyl, hydroxyethyl, benzyl or ethoxycarbonylmethyl group, and R
4
denotes cyclooctyl, norbonyl group, etc.), described in Jpn. Kokai Tokkyo Koho JP 56,081,569 as compounds with antiviral function similarly by Lily Co., are known. However, these compounds have 6- and 7-positions of symmetric type, it is not known that they have the antagonism against AMPA receptor in excitatory amino acid receptors of the inventive compounds, and they have different structure from that of the inventive compounds.
Furthermore, compounds represented by a general formula (17)
(wherein R and R
4
independently denote hydrogens, nitro or methoxy groups, R
1
and R
2
independently denote hydrogens, nitro or methoxy groups or halogen atoms (one of R, R
1
, R
2
and R
4
is a group other than hydrogen, in the case of R
1
and R
2
being not nitro groups or methoxy groups, R
1
and R
2
are independently halogen atoms together and R and R
4
are hydrogens, and, in the case of one of R, R
1
, R
2
and R
4
is nitro group, either one of R
1
and R
2
is methoxy group), R
3
denotes hydrogen, lower alkyl group which may be substituted with halogen, lower cycloalkyl group, lower alkenyl group or 2-chloroethyl group, and n denotes 0 or 2), described in Jpn. Kokai Tokkyo Koho JP 55,069,514 as compounds with antiviral function similarly by Lily Co., are known. However, disclosed compounds have different structure from that of the inventive compounds, and it is not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors which the inventive compounds have.
Moreover, in WO92-11245 described by Warner-Lambert Co., as compounds with antagonism against excitatory amino acid receptor, compounds represented by a general formula (18)
(wherein Y denotes oxygen, sulfur or nitrogen atom, R
1
, R
2
, R
11
and R
12
denote hydrogens, lower alkyl groups which may be substituted with halogen, halogen atoms, trifluoromethyl groups, cyano groups, nitro groups, methylthio groups, lower alkenyl groups, lower alkynyl groups, sulfonamide groups, etc., or arbitrary two of R
1
, R
2
, R
11
and R
12
may form a ring (6-membered ring or heterocycle which may contain heteroatom), and X denotes sulfonylamide group which may have substituents, etc.) are known. However, in these compounds, those with asymmetric substituents at 6- and 7-position of quinoxaline as the inventive compounds are not disclosed, and, with disclosed compounds, the antagonism against AMPA is not shown and the disclosed antagonism against glycine is not considered to be sufficient as well.
The invention is to provide compounds with antagonism against receptors of glutamic acid that is considered to be an etiology bringing about the memory disorder and dementia due to said diseases and selective death of cells, in particular, with high affinity and selectivity against AMPA receptor in non-NMDA receptor and protective effect on cerebral nerve cells.
DISCLOSURE OF THE INVENTION
As a result of diligent studies exploring an antagonist against excitatory amino acid receptors effective for the therapy of disorder of cerebral nerve cells, in particular, a selective antagonist against AMPA receptor in non-NMDA receptor, aiming at the development of novel therapeutic agent for the disorder of cerebral nerve cells, the inventors have found that the inventive 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives and addition salts thereof have excellent antagonism against AMPA receptor.
Namely, according to the invention, it has been found that 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives represented by a general formula (1)
(wherein A denotes a single bond or methylene (CH
2
),
Y denotes a nitrogen atom or ═CH—,
V denotes a single bond or methylene (CH
2
),
T denotes a hydroxyl group, amino group, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (2)
(wherein X denotes an oxygen atom or sulfur atom, R denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom, or cycloalkyl group), or general formula (3)
(wherein X denotes an oxygen atom or sulfur atom, R denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring. (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom, or cycloalkyl group),
Q denotes a halogen atom, lower alkyl group or lower alkoxy group, and
R
1
denotes a hydroxyl group or lower alkoxy group), and addition salts thereof have excellent antagonism against AMPA receptor, leading to the completion of the invention.
In
Anraku Tsuyoshi
Fukuchi Kazunori
Shiga Futoshi
Takano Yasuo
Berch Mark L.
Kyorin Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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