Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-22
2003-05-13
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S156000, C546S157000, C546S158000
Reexamination Certificate
active
06562839
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 6-substituted heteroquinolinecarboxylic 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-isooxazol-propionic 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 quinolinecarboxylic acid derivatives, compounds represented by a general formula (13)
(wherein R
1
denotes aldehyde group, amide group, carboxyl group, etc. and R
2
denotes hydrogen atom), described in Korean J. Med. Chem., 5 (1), 28-37 (1995) by Dong-A Pharmaceutical Research Laboratories as compounds with antagonism against angiotensin II, compounds represented by a general formula (14)
(wherein R denotes hydrogen atom or alkyl group, R
1
and R
2
denote hydrogen atoms, halogens, alkyl groups, alkoxycarbonyl groups, nitro groups, cyano groups, etc., R
3
denotes hydrogen atom, alkyl group, aryl group or aralkyl group, or R
3
is absent, A denotes CO, CS, etc., Z denotes nitrogen atom when R
3
is absent and D—Z is single bond, or Z is carbon atom, D denotes C—R when D—Z is double bond, X denotes oxygen atom, N—R, etc., and Y denotes substituted aminoalkyl group, quinuclidyl group, etc.), described in EP 382687 by Instituto De Angeli S.p.A, as compounds with antimuscarine function, and compounds represented by a general formula (15)
(wherein R
1
denotes cyano group, carboxyl group, alkoxycarbonyl group, amide group, nitro group, acetylamino group, etc., X denotes oxygen atom etc., Y denotes oxygen atom, sulfur atom or NH, R
2
and R
4
denote hydrogen atoms, hydroxyl groups, amino groups, trifluoromethyl groups, alkyl groups, etc., R
3
denotes hydroxyl group, amino group, alkylamino group, nitroso group, trifluoromethyl group, etc., and R
5
denotes hydroxyl group, alkyl group, halogen atom, etc.), described in WO93/16064 by Biosignal Co. as compounds with anticancer function (tyrosinekinase inhibitory function), are known. However, none of these compounds as described above have asymmetric substituents at 6- and 7-positions, and it is also not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors.
Moreover, compounds represented by a general formula (16)
(wherein X denotes oxygen atom or NH, m denotes 0 to 6, and A denotes haloalkyl group, hydroxyl group, alkoxy group, carboxyl group, cyano group, amide group, etc.), described in WO95/31455 by Taisho Pharmaceutical Co. as compounds with antagonism against serotonin 4 receptor, and compounds represented by a general formula (17)
(wherein X denotes O or NH, and Y denotes 2-(diethylamino)ethyl, 8-methyl-8-azabicyclo-[3,2,1]octa-3-yl, quinuclidine-3-yl, 1-ethylpiperidine-4-yl, etc.), described in Jpn. Kokai Tokkyo Koho JP 08,311,033 by the same company as compounds with antagonism against serotonin 4 receptor, are known. In these compounds, however, no substituents exist on benzene ring, the structure is different from that of the inventive compounds, and it is not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors.
Moreover, compounds represented by a general formula (18)
(wherein R
1
, R
2
and R
3
denote hydrogen atoms, halogen atoms, alkyl groups, nitro groups, cyano groups, aminosulfonyl groups, etc., and R
4
and R
5
denote hydrogen atoms, alkyl groups, etc.), are opened to public in EP 640612 by Adeal et compagnie as compounds with inhibitory action on the pathologic symptoms relevant to hyperactivity through the route of excitatory amino acid, and, as synthetic intermediates of this general formula (18), compounds represented by a general formula (19)
(wherein R
1
, R
2
and R
3
are as described above), and compounds represented by a general formula (20)
(wherein R
1
, R
2
and R
3
are as described above), are transcribed. However, the fact that these synthetic intermediates have the antagonism against AMPA receptor in excitatory amino acid receptors is not described, and, in these compounds, those with substituents at 6- and 7-positions as the inventive compounds are of symmetric type, hence the structure is different from that of the inventive compounds.
Moreover, compounds represented by a general formula (21)
(wherein R
1
and R
8
denote hydrogen atoms or alkyl groups, R
3
denotes hydrogen atom, alkyl group, carboxyl group, cyano group, etc., R
4
denotes hydrogen atom, alkyl group, alkoxy group, etc., R
5
denotes hydrogen atom, amino group, etc., R
6
denotes hydrogen atom, and R
7
denotes hydroxyl group, amino group, alkylamino group, etc.), described in Jpn. Kokai Tokkyo Koho JP 03,162,483 by Pioneer Electronics Co. as compounds for fluorescent material in organic luminescence device, are known. These compounds however are irrelevant to medicinal drugs, and it is not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors as well.
Moreover, recently, compounds represented by a general formula (22)
(wherein R, R
1
and R
2
denote hydrogen atoms, chlorine atoms, fluorine atoms or nitro groups, and X denotes carboxylic acid, phosphoric acid, boric acid, amide, etc.), are reported in J. Med. Chem., 39, 197-206 (1996) by Alex A. Cordi et al, with respect to the conversion of functional group at 3-position of 2-oxoquinoline skeleton as antagonists against excitatory amino acid. Among these compounds, however, they aimed to compounds, X being phosphoric acid in the general formula (22), and, in addition, those with asymmetric substituents at 6- and 7-position of quinoline ring as the inventive
Anraku Tsuyoshi
Asano Jun
Fukuchi Kazunori
Takano Yasuo
Kyorin Pharmaceutical Co. Ltd.
Seaman D. Margaret
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