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