Cyanoiminoquinoxaline derivatives

Details Cyanoiminoquinoxaline derivatives Cyanoiminoquinoxaline derivatives

2000-12-01

2003-02-25

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S249000, C544S354000, C544S356000

Reexamination Certificate

active

06525054

ABSTRACT:

The present application is a 371 of PCT/JP99/02822 filed on May 28, 1999, which was not published in English under PCT article 21(2), which in turn claims priority to Japanese Patent Application 10-151017 filed Jun. 1, 1998.
TECHNICAL FIELD
The present invention relates to novel cyanoiminoquinoxaline derivatives possessing antagonistic effects on glutamate receptors of central neurons, in particular, NMDA receptors and AMPA receptors.
BACKGROUND ART
Amino acids such as L-glutamic acid and L-aspartic acid are indispensable as neurotransmitters for activating neurons in the central nervous system. However, excess accumulation of these excitatory amino acids surrounding neurons is considered to induce hyperexcitation of neurons, causing neurological disorders such as Parkinsonism, senile dementia, Huntington's disease, and epilepsy; and hyponoia and hypokinesis found after ischemia, anoxia, hypoglycemia, or head and spinal cord trauma (see, McGeer et al. Nature, 263, 517-519 (1976); Simon et al. Science, 226, 850-852 (1984), Wieloch, Science, 230, 681-683 (1985); Faden et al. Science, 244, 798-800 (1989); Turski et al. Nature, 349, 414-418 (1991)).
It has been known that the above-mentioned excitatory amino acids act on the central nervous system neurons via a glutamate receptor on the neurons. Thus, compounds competitively inhibiting the binding of the excitatory amino acids to such a receptor have been considered to be useful as therapeutic or preventive reagents for the above-mentioned diseases and conditions such as antiepileptic, ischemic encephalopathy, and Parkinsonism.
The above-mentioned glutamate receptors can be classified into two groups: an ion channel type and a metabolism type. The ion channel type is further classified into three groups based on its selectivity with respect to binding to the agonist. These three are called N-methyl-D-aspartate (NMDA) receptors, 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) receptors, and kainate receptors.
The NMDA receptors are selectively activated by agonists such as NMDA and ibotenic acid. Hyperexcitation of the NMDA receptors allows a large amount of calcium ions to flow into neurons, which has been considered one of the causes for the death of neurons. Hithertofore, as antagonists selectively binding to the NMDA receptors, D-2-amino-5-phosphovalerate (D-AP5), 3-[2-carboxypiperazin-4-yl]propyl-1-phosphate (CPP), and the like are known. Further reported is that the NMDA receptors have an allosteric site bound to glycine as well as a site recognizing the above-mentioned agonists, and that the binding of the allosteric site to glycine remarkably enhances the functions of the NMDA receptors. Examples of antagonists to the glycine-binding sites include e.g., 5,7-dichlorokynurenic acid and HA966 (Eur. J. Pharmacol., 151 161-163 (1988)).
The AMPA receptors are selectively activated by agonists such as AMPA, glutamic acid, and quisqualic acid. Examples of the antagonits to the AMPA receptors include compounds having a quinoxaline structure, particularly quinoxaline-2,3-dione derivatives such as 6,7-dinitroquinoxaline-2,3-dione (DNQX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinoxaline (NBQX), and 6-imidazolyl-7-nitroquinoxaline-2,3-(1H, 4H)-dione (YM900), 6,7-dichloro-8-nitro-1,4-dihydroxyquinoxaline-2, 3-dione (ACEA1021) (Science,241, 701-703(1988), Eur.J.Pharmacol.,174, 197-204(1989), WO92/07847, JP-A 63-83074, JP-A 63-258466, JP-A 1-153680, JP-A 2-48578, JP-A 2-221263, JP-A 2-221264, Exp. Opin. Ther. Patents (1997) 7 (10), etc.).
Further, compounds to be used as therapeutic agents effective against the above-mentioned diseases and disorders, protecting neurons from death or denaturation caused by the excitatory amino acids, are required to effectively work as antagonists to both of the NMDA receptors and the AMPA receptors (Mosinger et al., Exp. Neurol., 113 10-17 (1991)). Examples of such compounds include quinoxaline-2,3-dione derivatives having a 4-oxo-4H-pyridyl group at the 7-position (JP-A 7-324084, U.S. Pat. No. 5,677,305), quinoxaline-2,3-dione derivatives having an alkylsulfonylimino group at the 2-position (WO97/32858).
DISCLOSURE OF INVENTION
In general, most of the known excitatory amino acid antagonists, which have quinoxaline structures therein, precipitate in renal, uriniferou tubule or the like to show side-effects such as nephrotoxicity, as reported on NBQX for example (J. Cerb Blood Flow Metab., Vol. 14, No. 2 (1994)). Thus, the antagonists are difficult to develop and have not practically been utilized as medicines. Further, even if the side-effect could be inhibited to some extent, it was not always easy to maintain the pharmacological effect on the level applicable to clinical use. Accordingly, it has been desired to develop a novel glutamate receptor antagonist which has a quinoxaline structure and can be administered safely to human.
The present inventors have intensively studied to find out that novel quinoxaline derivatives possess potent antagonistic effects on glutamate receptors without side-effects such as nephrotoxicity in the body. The finding is preferably characterized by the conversion of at least one of the oxo (═O) groups at the 2- and 3-positions into a cyanoimino (═NCN) group(s). Further, methods for preparing the present compounds and the intermediates thereof have been found out to accomplish the present invention shown below.
(1) a compound having a quinoxaline structure wherein at least one of the 2- and 3-positions is substituted with a cyanoimino group (hereinafter referred to as a cyanoiminoquinoxaline derivative of the present invention),
(2) a compound described in above (1), which has, in the quinoxaline structure, a partial structure of the formula:
wherein X and Y each is independently O or NCN, provided that at least one of X and Y is NCN (hereinafter referred to as partial structure (I)),
(3) a compound of the formula:
 wherein,
X and Y each is independently O or NCN, provided that at least either X and Y is NCN;
R
1
, R
2
, R
3
, and R
4
each is independently hydrogen, halogen, nitro, cyano, hydroxy, optionally substituted amino, optionally substituted lower alkyl, optionally substituted lower cycloalkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkylcarbonyl, carbamoyl optionally substituted with lower alkyl, carbamoylamino optionally substituted with lower alkyl, sulfamoyl optionally substituted with lower alkyl, sulfamoylamino optionally substituted with lower alkyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio;
R
5
is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted lower cycloalkyl;
R
1
and R
2
, R
2
and R
3
, R
3
and R
4
, and R
4
and R
5
, each together with the atoms adjacent thereto may form a carbocycle which may be substituted or contain a heteroatom(s), the pharmaceutically acceptable salt, or the hydrate thereof (these hereinafter referred to as compound(II)),
(4) a compound (II) described in above (3), wherein X is NCN: Y is O,
(5) a compound (II) described in above (3), wherein X is O; Y is NCN,
(6) a compound (II) described in above (3), wherein both X and Y are NCN,
(7) a compound (II) described in above (3), wherein R
5
is hydrogen,
(8) a compound (II) described in above (3), wherein X is NCN; Y is O; R
5
is hydrogen,
(9) a compound (II) described in above (3), wherein R
1
is hydrogen, halogen, or nitro,
(10) a compound (II) described in above (3), wherein R
2
is hydrogen, halogen, nitro, or halogenated lower alkyl,
(11) a compound (II) described in above (3), wherein R
3
is hydrogen, halogen, nitro, halogenated lower alkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio,
(12) a compound (II) described in above (3), wherein R
4
is hydrogen, halogen, or nitro,
(13) a compound (II) describe

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