llllllllllllllIllllllllllllllllllllllllllllllllllllllllllllllllIlllllllllll USOO5563140A United States Patent [191 [11] Patent Number: 5,563,140 Ehrenberger et al. [45] Date of Patent: Oct. 8, 1996

[54] USE OF 1-(AMINOALKYL)-3-(BENZYL) Kessler et al, “Quinoxaline derivatives are high-affinity QUINOXALINE-Z-ONE DERIVATIVES FOR antagonists of the NMDA receptor-associated glycine THE PREPARATION OF sites”, Brain Research, vol. 489 (1989), pp. 377-382. NEUROPROTECTIVE COMPOSITIONS A. Mule et al, ‘"Terz-aumrinoalcl?lderivati di chinossalinoni ad attivita analgesica”, Il Farmaco Edizione Scienti?ca, vol. [75] Inventors: Klaus Ehrenberger, Vienna, Austria; 43, No. 7-8 (Aug. 1988), pp. 613—618. Dominik Felix, Zurich, Switzerland Subsidia Medica, 22, 3, pp. 78-85 (1970). Koppi et a1, “Calcium—Chaunel-Blocking Agent in the [73] Assignee: Phafag Aktiengesellschaft, Schaan, Treatment of Acute Alcohol Withdrawal-Caroverine ver Liechtenstein sus Meprobamate in a Randomized Double—Blind Study”, Neuropsychobiology, 17, pp. 49-52 (1987). [21] Appl. No.: 975,328 Presslich et al, “Oesterreichische Apothekerzeitung”, 38/39, Filed: Nov. 16, 1992 p. 757 (1984). [22] Honore et al, “Quinoxalinediones: Potent Competitive [30] Foreign Application Priority Data Non-NMDA Glutamate Receptor Antagonists”, Science, 241, pp. 701-703 (1988). Nov. 15, 1991 [EP] European Pat. 0a...... 91119501 Merck Index, 11th Ed., 1989, #1864. [51] Int. Cl.6 ...... A61K 31/55; A61K 31/495; CA 99:3359, Ishida et al., 1983. A61K 31/50 Kaplan Clinical Hypenension p. 235 1986. [52] US. Cl...... 514/249; 514/212 Merck Manual p. 1308-1309; 1324-1327 1982. [58] Field of Search ...... 514/410, 212, Primary Examiner—Kimberly Jordan 514/249 Attorney, Agent, or Firm-—Millen, White, Zelano, & Brani gan, RC. [56] References Cited U.S. PATENT DOCUMENTS [571 ABSTRACT

5,037,848 8/1991 Olney ...... 514/428 Compounds of the formula FOREIGN PATENT DOCUMENTS R3 N 0032564 7/ 1981 European Pat. O?”. . 228204 7/ 1963 Germany . WO90/ 15606 12/1990 WIPO . (I N O OTHER PUBLICATIONS | R1 “Studies of experimental cerebral artery dilatation (with (CH) N/ caroverin fumarate”, Neurological Surgery, Abstracts of the 7th lntemational Congress of Neurological Surgery, Munich, Germany (Jul. 12-18, 1981), Supplement to Neu wherein rochirugia, Abstract No. 8.3.1, vol. 0, No. SU, p. 332, J. O. R1 and R2 are each independently hydrogen, methyl, Widauer. ethyl, propyl, butyl or R1 and R2 are together . B. Meldrum, “Excitatory amino acid neurotoxicity and cycloalkyl; neurodegenerative disease”, Trends in Pharmacological Sci~ R3 is methoxy, ethoxy, hydroxy, hydrogen, C1_4 alkyl, ences, vol. 11, No. 9 (Sep. 1990), pp. 379-387. halogen; M. Ishida et a1, “Reduction of glutamate responses at the cray?sh neuromuscular junction”, Brain Research, vol. 266, n=l, 2 or 3; No. 1 (Apr. 25, 1983), pp. 174-177. or any pharmaceutically acceptable salts thereof are useful Y. Kudo et a1, “Eifects of caroveiine and diltiazem on for the preparation of neuroprotective pharmaceutical com synaptic responses, L—glutamate—induced depolarization positions, for the prevention or treatment of glutamate and potassium e?lux in the frog spinal cord”, British Journal induced and glutamate receptor mediated neurotoxicity and of Pharmacology, vol. 83, No. 3 (Nov. 1984), pp. 813—-820. functional disturbances of the central nervous system. H. Shinozaki, “Pharmacology of the Glutamate Receptor”, Progress in Technology, vol. 30 (1988), pp. 399—435. 16 Claims, 3 Drawing Sheets US. Patent Oct. 8, 1996 Sheet 1 of 3 5,563,140

IO

m Of .__I'_"_‘1 Glu15 FIG. lu

1mV L20 msec DURING Glu 15 U.S. Patent - 0a. 8, 1996 Sheet 2 of3 5,563,140

1min

1 ....

4

"‘ 0 r0 * LUg (\l E 4 g 5?. 4{I LL. 0

Glu15 US. Patent Oct. 8, 1996 Sheet 3 of 3 5,563,140

1min

CAROVERINE3o FlG.3 ACh6O

Glu60 5,563,140 1 2 USE OF 1-(AMINOALKYL)-3-(BENZYL) the use of Caroverine in treatment of acute alcohol with QUINOXALINE-Z-ONE DERIVATIVES FOR drawal symptoms. Koppi et al were inspired by Presslich THE PREPARATION OF NEUROPROTECTIVE COMPOSITIONS and Brainin (Oesterreichische Apothekerzeitung 38/39, p. 757 (1984)) who has tested Caroverine during alkaloid The present invention relates to the novel use of l-(ami withdrawal. noalkyl)-3-(benzyl)-quinoxaline-2-one derivatives and In contrast to the cited publications the present invention pharmaceutically acceptable salts thereof for the preparation is based on the surprising discovery of 1-(aminoalkyl)-3 of neuroprotective pharmaceutical compositions. (benzyl)-quinoxaline-2-one derivatives as potent, selective Compounds of the formula 10 and reversible glutamate receptor antagonists in the excita tory neurotransmission in the central nervous system. Glutamate is the most abundant and important excitatory neurotransmitter in the central nervous system (Brien Mel drum in Emerging Strategies in Neuroprotection, edited by P. J. Marangos and Harbans Lal, Birkhauser Boston, 1992, chapter 7). In the central nervous system, glutamate func tions to promote rapid neurotransmitter depolarization by opening membrane channels chemically (in contrast to the wherein voltage-gated inhibition of CaH-in?ux in smooth muscle R1 and R2 are each independently hydrogen, methyl, cells) which permit diffusion of sodium and calcium ions. ethyl, propyl, butyl, or R1 and R2 are together cycloalkyl (e.g., of 3-7 C-atoms); These fast effects are mediated by different glutamate sensitive receptor types which act as a speci?c “central R3 is methoxy, ethoxy, hydroxy, hydrogen, C1-C4 alkyl, 25 halogen (e.g., F, Cl, Br or 1); key/lock system” and permit excitation of the subsequent nerve cell. n=1, 2 or 3, hereinafter referred to as l-(aminoalkyl)-3-(benzyl)-qui The glutamate receptors are extremely sensitive to a wide noxaline-Z-one derivatives, have been known for more than range of external damage (noxae), such as injuries, oxygen three decades (OE-A-228 204). l-(Aminoalkyl)-3—substi 30 de?ciency, metabolic disturbances, aging processes, etc., tuted-quinoxaline-2-one derivatives which have in the 3-po and, under these conditions, lead to a speci?c kind of sition a benzyl residue show a papaverine-like activity. overstimulation of the subsequent nerve cell. ( 1 -Diethyl amino ethyl)-3 -(p-methoxybenzyl)- 1 ,2-dihydro Under the conditions of an excessive stimulation of the quinoxaline-Z-one with the International Non-Proprietary receptors, the physiological transmitter glutamate exerts a name (INN) Caroverine, a member of the above class, was 35 discovered to be a powerful spasmolyticum, which is used neurotoxic action (Rothman et al in Trends Neurosci. 10 mainly in the gastrointestinal region. The e?icacy of (1987), pp. 299-302). This excitotoxicity is mediated by the Caroverine is attributed to its calcium-blocking capacities receptors N-methyl-D-aspartate (NMDA) as well as by the whereby it blocks the calcium mediated activation of myo two non-NMDA subtypes, quisqualate and kainate (Frand ?brillar ATPase, predominantly in smooth muscles. sen et al, J. Neurochem. 53 (1990), pp. 297-299), whereby In EP-A 032 564 the use of Caroverine-fumarate for the Ca is involved in the etiology of the glutamate-induced cell inhibition of the aggregation of platelets in blood, increase of the arterial circulation, treating of ischemic heart diseases, damage which can ?nally result in the death of the affected angina pectoris, etc. was described. In addition, speci?c neurons. (Choi, Trends Neurosc, 11 (1988), pp. 465-469). Caroverine salts had i.a. a positive e?ect on the cerebral 45 This glutamate receptor-linked neurotoxicity has been impli blood circulation. It was also found that Caroverine is a cated in pathological conditions like ischemia, hypoglyce speci?c Ca-antagonist (EP-A 032 564; page 18): The cardiac mia, anoxia, trauma and several severe neurodegenerative muscles and the smooth muscles contract under the in?u disorders (Meldrum et al, Trends pharmacol. Sci. 11(1990), ence of calcium ions. The Ca-ions enter the muscle cells through speci?c calcium channels and induce the contract pp. 379-387) as well as in neuronal death in aging. In vitro ing process from the inner'cell. The calcium channels can be and in vivo, glutamate receptor antagonists, as neuroprotec opened either by local voltage changes (voltage gated ionic tive agents, can prevent these pathological conditions. channels), tissue hormones or by the transmitter adrenalin. It Therefore, there is a great interest in the development of has been found that Caroverine is capable of inhibiting 50% new drugs that might selectively block the NMDA and of the flux of Ca-ions into the cell via “voltage gated 55 non-NMDA receptors without in?uencing other receptors channels” opened by electrical stimulation (EP-A 032 564; since such drugs could be used as neuroprotective pharma page 18). The in?uence of calcium on the chemical calcium ceuticals. Applications of these pharmaceuticals could be the channels has not been examined. treatment of glutamate-induced and glutamate-receptor-me Widauer studied the effect of Caroverine fumarate on cerebral artery dilatation (Neurological Surger, suppl. to diated neurotoxic dysfunctions such as functional distur Neurochirurgia, 1981, p. 332, abstract no. 8.3.1). He, too, bances of the inner ear, like tinnitus and impaired hearing, attributed the e?cect of Caroverine to its role as Ca-antago and of the retina, (POSOtraumatic lesions, and degenerative nist. processes of neurons in the central nervous system like In Subsidia med. 22, 3, pp. 78-85 (1970) Moslinger Alzheimer’s, Parkinson’s disease, etc. (Akhlaq et al, Brain reported that Caroverine could suppress epileptic seizures, 65 Research Reviews, 16 (1991), pp. 171-191). Reversibility is even status epilepticus. Recent investigations describe also a highly desired characteristic since a return to normal (Koppi et al in Neuropsychobiology 17, pp. 49-52, 1987) function after preventing a therapeutic function is desired. 5,563,140 3 4 Thus, the invention involves the use of compounds of the system (CNS) since the physiological structures and mecha formula nisms in the cochlea correspond to similar structures and mechanisms in the central nervous system. These ?ndings R3 N are therefore representative for similar synaptic connections \ CH1 LII of the central nervous system. The effectiveness of the l-(aminoalkyl)-3-(benzy1)-qui noxaline-2-one derivatives as potential glutamate receptor If 0 R1 antagonists was studied in the light of the neurotransmission (CH2)n_N between the inner hair cells (IHC) and the peripheral den 10 drites of the afferent neurons in the mammalian cochlea. R2 Experiments were performed on adult pigmented guinea wherein pigs (300-700 g) of both sexes, anaesthetized with a com bination of Rompun (Bayer, Leverkusen, Germany) and R1 and R2 are each independently hydrogen, methyl, Innovar-Vet (Pitman-Moore, Mundelin, Ill., U.S.A.). ethyl, propyl, butyl or R1 and R2 together are Supplementary low doses of pentobarbital (Nembutal, cycloalkyl; Abbott, Chicago, U.S.A.) were given periodically through R3 is methoxy, ethoxy, hydroxy, hydrogen, Cl-C4 alkyl, out the experiments. Rectal temperature was maintained or halogen and within physiological limits. After tracheotomy for arti?cial n=l, 2 or 3; respiration, the auditory bulla was approached ventrolater or a pharmaceutically acceptable salt thereof, ally and the cochlea was exposed. A small opening was for the preparation of neuroprotective compositions for the drilled into the cochlea bone over the pigmented stria prevention or treatment of neurotoxicity and functional vascularis and the ligamentum spiale of the third turn. disturbances of the central nervous system with the excep Multibarrel microelectrodes with overall tip diameter of tion of diseases like epileptic seizures and alcohol with 1.5-2 prn were inserted and microdriven almost parallel to drawal symptoms. 25 the tectorial membrane until the subsynaptic region of the Among the presently known antagonistic substances are H-IC layer was reached at a depth of 200-260 pm. The 6-cyano-7-nitroquinoxaline-2,3-di0ne (CNQX) and 6,7 occurrence of phasic activity was used to identify the dinitroquinoxaline-2,3-dione (DNQX) (Honore et al in Sci location precisely, since such activity occurs in the imme ence 241, pp. 701=703 (1988)). DNQX and CNQX are at diate vicinity of the initial postsynaptic structures. subrrricromolar concentrations competitive non-NMDA Recordings of extracellular action potentials were receptor antagonists binding to quisqualate receptors and at obtained using a 2M NaCl-?lled barrel of the S-barrel glass somewhat higher concentrations block the eifect of NMDA micropipette. Recordings were analyzed on a rate meter (NE receptors (Kessler et al, Brain Research 489, pp. 377-382). 4667) and displayed continuously on a UV-oscillograph However, CNQX and DNQX can also act as non-competi (Bell & Howell 5-137). Three other channels of the micropi tive antagonists inhibiting the strychnine-insensitive 35 pette contained the solutions to be ejected rnicroionto NMDA-associated glycine recognition site meaning that phoretically with the appropriate anionic and cationic cur important vital processes are disrupted by these compounds. rents: L-glutarnic acid (0.5M, pH 3.5, adjusted with HCl); Therefore, a pharmaceutical use of CNQX and DNQX is not Caroverine-HCl (l-diethylaminoethyl-3-(p-methoxyben feasible. zyl)-1,2~dihydro-quinoxaline-2-one, 0.05M, natural Ishida et al (Brain Research, 266 (1983) pp. 174-177) pH=6.0). studied the effect of Caroverine at the cray?sh neuromus In order to avoid electrically induced artefacts, compen cular junction. They reasoned that Caroverine might be an sation currents were applied through an NaCl-?lled channel. open channel blocker for glutamate. Their ?ndings, how Correct positioning of the tip of the micropipette in the ever, were rather contradictory as they did not ?nd a synaptic region of the lHC’s resulted in a spontaneous Caroverine effect under more realistic, physiological condi 45 phasic activity characterized by graded potentials. tions. Further investigations by Kudo and Shibata (Br. J. Glutamate, the agonist of NMDA and non-NMDA receptors, Pharrnac. (1984), 83, pp. 813-820) published one year later enhances the ?ring rate in the majority of the ?bers tested led to the opinion that Caroverine was an unspeci?c cal (n=29 out of 31). cium-channel-blocking agent but not a glutamate antagonist. Without further elaboration, it is believed that one skilled They also found that the eifect on glutamate does not take 50 in the art can, using the preceding description, utilize the place at its receptors. present invention to its fullest extent. The following pre The present invention is based upon results received by ferred speci?c embodiments are, therefore, to be construed examining the e?ects of 1-(aminoalkyl)-3-(benzyl)-qui as merely illustrative, and not lirnitative of the remainder of noxaline-2-one derivatives directly in the mammalian the disclosure in any way whatsoever. cochlea and upon subsequent clinical studies. 55 In the foregoing and in the following examples, all In the mammalian cochlea, there is strong evidence that temperatures are set forth uncorrected in degrees Celsius and two classes of glutamate-receptors, the N-methyl-D-aspar unless otherwise indicated, all parts and percentages are by tate (NMDA) subclass and the non-NMDA subclass, com weight. prising the quisqualate and kainate subtypes, mediate The entire disclosure of all applications, patents and ' postsynaptic glutamatergic neurotransmission between the 60 publications, cited above and below, and of corresponding inner hair cells (IHC) and the peripheral dendrites of the application EPA 91 119 501.4 of Nov. 15, 1991 are hereby aiferent neurons (Puel et a1, Hear. Res., 51, (1991), pp. incorporated by reference. 255-264). Using physiological techniques, up to now, no other types of receptor channels could be found at the IHC BRIEF DESCRIPTION OF THE DRAWINGS synapses. Therefore, the IHC synapse is an elegant and 65 easily accessible model for prominent excitatory synapses The experimental results are now explained with refer corresponding to similar structures of the central nervous ence to the drawings: 5,563,140 5 6 FIG. 1 shows the excitatory effect of L-glutamate on a the range of from about 0.1 mg/kg to about 5 mg/kg and spontaneously ?ring ?ber in the subsynaptic region of an preferably from about 0.5 mg/kg to about 2 mg/kg. If IHC, Caroverine salts are used, then the amounts to be adminis a) time frequency histogram of spike-activity during tered should be adjusted according to the increase in L-glutamate (Glu, 15 nA) application. The length of the molecular weight. perisynaptic release of the agent from the rnicropipette Liquid formulations can also be prepared by dissolving or is indicated by the bar below the histogram; integrating suspending the active substance in a conventional liquid ?ring frequency immediately at right. vehicle acceptable for pharmaceutical administration. b) the same glutamate-induced irregular spike-activity For parenteral administration, the active substance will be characterized by bursts, illustrated on an original oscil 10 employed in an amount within the range of from about 0.1 loscope trace (calibrations: 20 msec, 1 mv); mg/kg to about 5 mg/kg and preferably from about 0.8 FIG. 2 shows the eifect of Caroverine on glutamate mg/kg to about 2 mg/kg. induced spike-activity, demonstrated on time frequency his~ The neuroprotective effect of Caroverine was tested in a tograms. The excitatory action of L-glutamate (Glu, 15 nA) clinical study with patients who suffered from tinnitus. The is blocked by Caroverine (30 nA for about 5 minutes) in a 15 etiology of tinnitus can be very di?erent in different patients. potent but reversible manner; One of the most frequent tinnitus type is, however, the FIG. 3 shows the neural response to a four times higher cochlear tinnitus. If a functional disturbance between the amount of L-glutamate (Glu, 60 nA) and the same amount IHC and the peripheral dendrites of the efferent neurons is of acetylcholine (Ach, 60 nA) before, during and after deemed to be the initiating, etiological factor, then this is ejection of Caroverine, using the same amount as in FIG. 2 20 called a “cochlear synaptic tinnitus”. A neuroprotective (Caroverine, 30 nA). Caroverine selectively blocks the pharmaceutical like Caroverine should therefore have a glutamate action whereas the acetylcholine-induced ?ring positive effect on the cochlear synaptic tinnitus. rate remains unaffected. The ejection periods of substances In a pilot study Caroverine was applied to 72 patients ejected from the same micropipette at the same synapse are suffering from tinnitus. Caroverine was applied intrave indicated by different bars. 25 nously (160 mg/100 ml physiological NaCl-solution). The As shown in the original tracing a) of FIG. 1, the real dosage depended on the tinnitus reduction perceived by glutamate-induced excitatory effect (glutamate: 15 nA for the individual patient and varied between 70 and 160 mg. 100 msec) is characterized by an irregular discharge inter The eifectiveness of Caroverine was measured by a rupted by bursts. The time frequency re?ects the diffusion subjective rating and tinnitus-matching before and after the time of the agent between the rnicropipette and the synaptic infusion of the drug. cleft. 66.7% of the patients noted a tinnitus reduction of at least Caroverine ejected simultaneously with glutamate (FIG. 50% in absolute value immediately after infusion of 2) antagonizes the membrane response to glutamate in an Caroverine. No sincere side‘eifects could be observed. enduring but reversible manner. In a double-blind, placebo-controlled clinical study on a In a second series of experiments, the selectivity of the 35 group of 15 persons, the cerebral effect of Caroverine was described Caroverine effect was tested by comparing suc tested by means of electro-encephalogram (EEG)-mapping. cessively the putative antagonism of Caroverine on the The 15 caucasian probands were 7 females and 8 males glutamate-induced as well as on the acetylcholine-induced between 20 and 35 years old (average 27 years). The weight postsynaptic excitation of identical dendritic ?bers. As ranged between 53 and 84 kg (average weight: 69 kg) and shown in FIG. 3, Caroverine applied iontophoretically in an the height varied between 162 to 186 cm (average height: adjusted dosage, which promises a nanomolar concentration 175 cm). of the agent on the synapse, blocked regularly and exclu Doses of 40 mg or 80 mg of Caroverine or placebo were sively the potent glutamate receptors, but exhibited no effect administered either orally or intravenously for random sam~ on the membrane response to the excitatory elferent trans pling to the persons in weekly intervals. EEG-tracings as mitter substance acetylcholine. well as recordings of pulse, blood pressure and side effects Another effective 1-(arninoalkyl)-3-(benzyl)-quinoxaline were carried out 0, 1, 2, 4, 6 and 8 hours after medication. 2-one derivative is 1-diethylaminoethyl-3-(p-hydroxy)-1,2 A multivariate analysis with reference to the EEG-data dihydroquinoxaline-Z-one. showed that Caroverine in both doses and independent of the Thus, it is experimentally established that l-(aminoalkyl) type of administration (orally or intravenously) had a sig 3-(benzyl)-quinoxaline-2-one derivatives are a potent, 50 ni?cant effect on-the central nervous system in comparison reversible and selective class of new glutamate receptor to placebo. With respect to the time-eifect-curve no signi? antagonists on the excitatory efferent synapses of the cant diiferences as to administration could be recorded at the cochlear inner hair cells. The application of Caroverine and different points in time. The maximum effect was around 1 its salts, respectively, also in high doses, produces no critical hour after medication, but even after 8 hours signi?cant side-effects. As Caroverine does not impair other physi 55 diiferences from placebo were registered. ological processes of the CNS its use as a neuroprotective The preceding examples can be repeated with similar pharmaceutical is straightforward. success by substituting the generically or speci?cally The pharmaceutically effective 1~(aminoalkyl)-3-(ben described reactants and/or operating conditions of this zyl)-quinoxaline-2-one derivatives may be incorporated in a invention for those used in the preceding examples. conventional systemic dosage form (e.g., oral, rectal or From the foregoing description, one skilled in the art can parenteral), such as a tablet, capsule, elixir or injectable. The easily ascertain the essential characteristics of this invention, above dosage forms will also include the necessary carrier and without departing from the spirit and scope thereof, can material, excipient, lubricant, bulking agent or the like. make various changes and modi?cations of the invention to The dose administered can be adjusted according to age, adapt it to various usages and conditions. weight and condition of the patient. Thus, for oral admin 65 We claim: istration, a satisfactory result may be obtained employing 1. A method of preventing or treating neurotoxicity in a the active substance, e.g., Caroverine, in an amount within mammalian patient in need thereof, wherein said neurotox~ 5,563,140 7 8 icity is induced by glutamate or mediated by a glutamate 6. A method according to claim 4, wherein the compound receptor, comprising administering an eifective amount of a is 1~diethylaminoethyl-3-(p-methoxybenzyl)-1,Z-dihydro compound of the formula: quinoxaline-2-one. 7. A method of claim 1, wherein said patient has post N synaptic tinnitus. 8. A method of claim 7, wherein the-compound is admin istered in an amount of about 70 mg to about 160 mg. N 1%O I R‘ 9. A method according to claim 7, wherein the compound / is 1-diethylaminoethyl-3-(p-methoxybenzyl)-1,2-dihydro quinoxaline-Z-one. R2 10. A method of claim 1, wherein said patient has a functional disturbance of the retina and is accompanied by loss of vision. wherein: 11. A method according to claim 10, wherein the com R1 and R2 are each independently hydrogen, methyl, pound is l-diethylaminoethyl-3-(p-methoxybenzyl)-1,2-di ethyl, propyl, or butyl, or R1‘ and R2 together are C3_7-cycloalkyl; hydroquinoxaline-Z-one. R3 is methoxy, ethoxy, hydroxy, hydrogen, C1_4-alkyl, or 12. A method of claim 1 wherein said patient has a halogen; and 20 (post)traumatic cerebral lesion, or cerebral damage follow ing oxygen de?ciency. n is 1, 2, or 3, or a pharrnaceutically acceptable salt thereof. 13. A method of claim 1, wherein said patient has a 2. A method of claim 1, wherein the compound is l-di concussion, asphyxiation or oxygen loss due to drowning. ethylaminoethyl-3 - (p-methoxybenzyl)- 1 ,2-dihydroquinoxa 14. A method of claim 1, wherein said patient has Alzhe line-2-one or a pharmaceutically acceptable salt thereof. 25 imer’s, Huntington’s or Parkinson’s disease, or Wernicke 3. A method of claim 1, wherein the compound is l-di Korsakoff or Jakob-Creutzfeldt syndrome. ethylaminoethyl-3 -(p-hydroxybenzyl)- 1 ,2- dihydroquinoxa 15. A method of claim 1, wherein said compound is line-2-one or a pharrnaceutically acceptable salt thereof. effective in penetrating the blood-brain barrier. 4. A method of claim 1, wherein said patient has a 16. A method of claim 1, where said compound is a functional disturbance of the inner ear. glutamate receptor antagonist. 5. A method of claim 4, wherein the functional distur bance of the inner ear is impaired hearing. * * * * *