Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-01
2002-02-19
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S354000, C544S333000, C544S119000, C514S249000, C514S235200
Reexamination Certificate
active
06348461
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives and their addition salts effective for the therapy of disorder of cerebral nerve cells, as antagonists against excitatory amino acid receptor, in particular, selective antagonists against AMPA receptor in non-NMDA receptor, processes for preparing them, and medicinal compositions containing these compounds.
BACKGROUND TECHNOLOGIES
The glutamic acid being excitatory amino acid is a principal excitatory transmitter substance in the central nervous system of vertebrates, and is known as an amino acid that is contained most rich in brain. It is known, however, that, when released from the axon terminals of nerves exceeding physiological threshold, the overstimutation to the postsynaptic glutamic acid receptors causes the death of nerve cells. This is called excitotoxicity.
In recent years, it is being clarified that the excitotoxicity due to glutamic acid is concerned deeply in the various diseases of cerebral nerves such as cerebral hemorrhage, cephalic injury, epileptic intussusception, Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. If such excitotoxicity can be prevented effectively, it is considered that a potential for the therapy of these intractable diseases, for which currently there is no therapeutic means whatsoever would be opened.
Classifying roughly, 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 (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor and KA (kainic acid) receptor.
Studies on these excitatory amino acid receptors are being put forward and, above all, it is known that a drug with antagonism against AMPA receptor in non-NMDA receptor expresses no side effects (learning and memory disturbances, schizophrenia-like symptom, etc.) that are brought with a drug (MK-801 or the like) with antagonism against NMDA receptor. (Neurosci. Biobehav. Rev., 1992, 16, 13-24; J. Pharmacol. Exp. Ther., 1958, 245, 969-974), and that the protective effect on cerebral nerves can be expected even by administration after ischemia (Science, 1990, 247, 571-574).
Moreover, compounds with antagonism against AMPA receptor like NBQX having a quinoxalinedione structure have reportedly drawbacks of causing kidney disturbance, etc. that are considered to be based on the physicochemical properties (J. Cereb. Blood Flow Metab., 1994, 14, 251-261), therefore they cannot be said to be satisfactory compounds.
Now, as compounds with a structure similar to quinoxalinecarboxylic acid derivatives, compounds represented by a general formula (A)
(wherein X independently denotes a chlorine or bromine atom, and R denotes a methyl or ethyl group), described in Japanese Unexamined Patent Publication No. Sho 56-5416 by Lilly Co. as compounds with antiviral function, compounds represented by a general formula (B)
(wherein R and R
1
independently denote halogen atoms, R
2
denotes a hydrogen, methyl or ethyl group, R
3
denotes a hydrogen, methyl, ethyl, hydroxyethyl, benzyl or ethoxycarbonylmethyl group, and R
4
denotes a cyclooctyl, norbornyl group or the like), described in Japanese Unexamined Patent Publication No. Sho 56-81569 by Lilly Co. similarly as compounds with antiviral function, and the like are known. However, the 6 and 7 positions are symmetric in these compounds, it is not known that they have antagonism against AMPA receptor in excitatory amino acid receptor of the inventive compounds, and they have a structure different from, that of the inventive compounds.
In addition, compounds represented by a general formula
(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
being a nitro group, either one of R
1
and R
2
is a methoxy group), R
3
denotes a 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 Japanese Unexamined Patent Publication No. Sho 55-69514 by Lilly Co. similarly as compounds with antiviral function, are known, but the disclosed compounds have a structure different from that of the inventive compounds and it is not described that they have antagonism against AMPA receptor in excitatory amino acid receptor that the inventive compounds have.
Moreover, in W092-11245 described by Warner-Lambert Co., compounds represented by a general formula (D)
(wherein Y denotes an 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 or the like, 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 a sulfonylamide group which may have substituent, or the like) are known as compounds with antagonism against excitatory amino acid receptors.
However, for these compounds, those having asymmetric substituents of 6 and 7 positions of quinoxaline as the inventive compounds are not disclosed, and, with disclosed compounds, no AMPA antagonism is shown and the disclosed glycine antagonism cannot be considered to be satisfactory as well.
The invention is to provide compounds with antagonism against receptor of glutamic acid that is considered to be an etiology bringing about memory disturbance or 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 with protective effect on the cerebral nerve cells.
DISCLOSURE OF THE INVENTION
As a result of diligent studies exploring an antagonistic drug against excitatory amino acid receptor effective for the therapy of disorder of cerebral nerve cells, in particular, selective antagonistic drug against AMPA receptor in non-NMDA receptor, aiming at the development of novel therapeutic drug for the disorder of cerebral nerve cells, the inventors have found that the inventive 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives and their addition salts have excellent antagonism against AMPA receptor.
Namely, according to the invention, it has been found that 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives represented by a general formula (1)
[wherein, Q denotes a halogen atom, lower alkyl group which may be substituted with halogen atom, general formula (2)
Ar—P— (2)
(wherein Ar denotes a phenyl group which may have one or more substituents or naphthyl group, and P denotes a lower alkylene, lower alkenylene, lower alkynylene, oxygen or sulfur atom), general formula (3)
L—A— (3)
(wherein L denotes a general formula (4)
(wherein V denotes a single bond, lower alkylene or lower alkenylene, T denotes a 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), hydrogen atom, hydroxyl group, thiol group, amino group which may be substituted, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (4-a)
or general formula (4-b)
(wherein U denotes an oxygen atom or sulfur atom, X denotes an oxygen atom or sulfur atom, W denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may
Ando Naoki
Anraku Tsuyoshi
Asano Jun
Fukuchi Kazunori
Shiga Futoshi
Kyorin Pharmaceutical Co. Ltd.
Liu Henry
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Shah Mukund J.
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