Quinoxalinediones

Details Quinoxalinediones Quinoxalinediones

1999-08-02

2001-12-25

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S354000

Reexamination Certificate

active

06333326

ABSTRACT:

This invention relates to 2,3(1H,4H)-quinoxalinedione derivatives which are selective antagonists of N-methyl-D-aspartate receptors. More particularly, this invention relates to 5-triazolyl-2,3(1H,4H)-quinoxalinedione derivatives and to the preparation of, compositions containing, and the uses of, such derivatives.
L-Glutamic acid is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named after the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. The fourth receptor is termed the metabotropic receptor. In addition to a binding site for glutamic acid, the NMDA receptor possesses high affinity binding sites for dissociative anaesthetics (e.g. ketamine), polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg
2+
, Zn
2+
). Since the NMDA receptor has an absolute requirement to bind glycine for activation to occur, glycine antagonists can act as functional NMDA antagonists.
In the region of a cerebral infarct, anoxia, for example, causes abnormally high concentrations of glutamic acid to be released. This leads to an over-stimulation of NMDA receptors resulting in the degeneration and death of neurones. Thus, NMDA receptor antagonists, which have been shown to block the neurotoxic effects of glutamic acid in vitro and in vivo, may be useful in the treatment and/or prevention of any pathological condition in which NMDA receptor activation is thought to be important. Examples of such conditions include acute neurodegenerative disorders arising from events such as stroke, transient ischaemic attack, peri-operative ischaemia, global ischaemia (following cardiac arrest) and traumatic head injury to the brain or spinal cord. In addition, NMDA antagonists may be of use in treating certain chronic neurological disorders such as senile dementia, Parkinson's disease and Alzheimer's disease. They may also have utility in conditions in which peripheral nerve function has been impaired such as retinal and macular degeneration.
Furthermore, NMDA antagonists have been shown to possess anti-convulsant and anxiolytic activity and may therefore be used to treat epilepsy and anxiety. NMDA antagonists may also attenuate the effects of alcohol withdrawal from physically dependent animals (K. A. Grant et al., J. Pharm.Exp.Ther., 260, 1017 (1992)) and thus NMDA antagonists may be of use in the treatment of alcohol addiction and pain. NMDA antagonists may also be useful in the treatment of hearing disorders (e.g. tinnitus), migraine and psychiatric disorders.
EP-A-0572852 describes pyrrol-1-yl-substituted 2,3(1H,4H)-quinoxalinedione derivatives useful for the treatment of neurodegenerative illnesses and neurotoxic disorders of the central nervous system.
EP-A-0556393 discloses, inter alia, imidazolyl- or triazolyl-substituted 2,3(1H,4H)-quinoxalinedione derivatives with glutamate receptor antagonising activity, particularly NMDA-glycine receptor and AMPA receptor antagonising activities. However, no 5-triazolyl-substituted compounds are specifically described therein.
International Patent Application Publication No. WO 97132873 discloses 5-heteroaryl-2,3-(1H,4H)-quinoxalinedione derivatives with NMDA receptor antagonist activity. Example 114 of that Application allegedly describes the preparation of (−)-6,7-dichloro-5-[3-methoxymethyl-5-(1-oxidopyridin-3-yl)4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione. However, further analysis of the product of Example 114 shows the stated title compound to be bound to a stoichiometric quantity of silica (see Reference Example 1 herein). This silica complex has been shown to have different properties compared with, and to be distinct, analytically, from, the stated title compound. Example 114 of that Application therefore discloses the preparation of a different compound to the alleged title compound although the skilled person, realising that a silica complex had been obtained, could readily apply common knowledge to prepare the stated title compound therefrom.
The present compounds are potent antagonists of the NMDA (glycine site) receptor. In addition, they are highly selective antagonists for the NMDA (glycine site) receptor in comparison to the AMPA receptor to which they have little, if any, affinity.
The present invention provides a novel, substantially pure compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof.
The expression “substantially pure” means the compound preferably is at least of 90% w/w purity, more preferably is at least of 95% w/w purity and most preferably is at least of 98% w/w purity. For the purpose of pharmaceutical applications, the compound would normally be manufactured to at least 99% w/w purity.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the calcium, lithium, magnesium, potassium, sodium, zinc, ethanolamine, diethanolamine and triethanolamine salts.
For a review on suitable salts see Berge et al, J.Pharm.Sci., 66, 1-19 (1977).
Suitable solvates include hydrates.
The compounds of the formula (I) are single stereoisomers known as atropisomers. Atropisomers are isomers that can be separated only because rotation about single bonds is prevented or greatly slowed (see “Advanced Organic Chemistry”, Third Edition, Jerry March, John Wiley and Sons (1985)). They may be prepared conventionally from a corresponding optically pure intermediate or by resolution of a racemic mixture containing the opposite stereoisomer. This can be achieved by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base.
The compounds of the formula (I) can be prepared by the following methods.
1) The compounds of the formula (I) can be prepared by acidic or basic hydrolysis of a compound of the formula:
 wherein R is group of the formula:
 and R
1
and R
2
, either when taken alone or together, represent a group or groups that can be hydrolytically cleaved under acidic or basic conditions to provide a quinoxalinedione of the formula (I). Such group or groups are conventional and suitable examples will be well-known to the skilled person. Where R is a group of the formula (III), the reaction is followed by separation of the atropisomer of the formula (I) using conventional conditions.
Preferably R
1
and R
2
are either each independently selected from C
1
-C
4
alkyl (preferably methyl or ethyl) and benzyl, optionally ring-substituted by from 1 to 3 substituents each independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo, nitro and trifluoromethyl, or, when taken together, represent C
1
-C
6
alkylene, CH(phenyl), CH(4-methoxyphenyl) or CH(3,4-dimethoxyphenyl).
Preferably, the reaction is carried out by acidic hydrolysis of a compound of the formula (II).
In a typical procedure, a compound of the formula (II) is treated with an aqueous solution of a suitable acid, e.g. a mineral acid such as hydrochloric acid, optionally in the presence of a suitable organic co-solvent, e.g. 1,4-dioxane. The reaction is usually carried out by heating the mixture at up to the reflux temperature of the solvent(s).
The intermediates of the formula (II) can be prepared by conventional methods, for example,
a) by the route shown in Scheme I:
 wherein R, R
1
and R
2
are as previously defined for a compound of the formula (I

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