Compositions and methods for treating reperfusion injury or bleeding after reperfusion therapy

Abstract

The present invention relates to pharmaceutical compositions and methods for treating ischemic stroke in humans using a tetrafluorobenzyl derivative of formula (I) or a pharmaceutically acceptable salt thereof in combination with a thrombolytic agent, endovascular thrombectomy, or both (e.g., endovascular thrombectomy and a thrombolytic agent). Administration of a tetrafluorobenzyl derivative of formula (I) or a pharmaceutically acceptable salt thereof can reduce reperfusion injury and other adverse events in patients undergoing a thrombolytic agent, endovascular thrombectomy, or endovascular thrombectomy with a thrombolytic agent in combination.

Description

Technical Field

[0001] Related Applications This application claims the priority and / or benefit of the filing date of U.S. Provisional Application No. 62 / 988,187, filed on March 11, 2020, which is hereby incorporated by reference in its entirety.

[0002] The present invention relates to a pharmaceutical composition comprising a tetrafluorobenzyl compound of formula (I) or a pharmaceutically acceptable salt thereof, and a method for treating patients having ischemic stroke, coronary thrombosis, venous thromboembolism, acute myocardial infarction, occluded catheter, pediatric pleural effusion, and prosthetic valve thrombosis, which can be co-treated with thrombolytic therapy, endovascular thrombectomy, or endovascular thrombectomy with a thrombolytic agent.

Background Art

[0003] Stroke is a major cause of death and long-term disability worldwide. Stroke is a disease in which the blood vessels to the brain are blocked either by a blood clot or a rupture. When the blood supply to the brain is obstructed by local thrombosis, embolic particles, or a blood vessel rupture, primary neuronal death in the ischemic core and secondary death in the ischemic penumbra due to the activation of multiple death pathways associated therewith can be caused. Therapeutically, thrombolytic agents and anticoagulants are used to counter these events by increasing reperfusion and modifying coagulation. Over the past few decades, the number of people suffering from or dying from stroke has been increasing worldwide, suggesting that the global burden of stroke is continuously increasing (Feigin et al., 2016).

[0004] Until 2015, intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) was the only approved effective treatment for patients with acute ischemic stroke within 4.5 hours of symptom onset [Benjamin et al., 2018; The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995]. Clinical benefits were observed when intravenous rt-PA was administered to patients with ischemic stroke within 6 hours of symptom onset (Fugate and Rabinstein, 2014). Intravenous rt-PA significantly improved survival rates and reduced disability, while increasing intracranial hemorrhage complications by approximately 6.4% and showing 4–32% recanalization of cerebral arteries depending on the size and type of occluded vessel [Benjamin et al., 2018; The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators, 2004]. Other intravenous thrombolytic agents, including urokinase, are prescribed to treat patients with acute ischemic stroke (Dong et al., 2017).

[0005] Since 2015, the benefits and safety of endovascular therapy (EVT) involving mechanical removal of blood clots in the anterior circulation for patients with acute ischemic stroke have been demonstrated in several clinical trials (SWIFT PRIME, REVASCAT, MR CLEAN, EXTEND-IA, ESCAPE). Mechanical thrombectomy performed within 6 hours of symptom onset significantly improved functional outcomes in patients with acute ischemic stroke who had proximal anterior circulation occlusion. The DAWN trial confirmed beneficial effects in patients with acute ischemic stroke who underwent endovascular thrombectomy within 6 to 24 hours of stroke onset and had major vessel occlusion in the anterior circulation (Nogueira et al., 2018). The 2018 American Heart Association (AHA) / American Stroke Association (ASA) guidelines for the early management of patients with acute ischemic stroke recommended EVT (endovascular therapy) alone or in combination with rt-PA thrombolytic agent within 24 hours of stroke onset as the standard treatment for patients with acute ischemic stroke who have great vessel occlusion in the anterior circulation [Powers et al., 2018].

[0006] EVT, either alone or in combination with rt-PA thrombolytic agents, offers significant benefits to some patients with acute ischemic stroke; however, such recanalization therapy can be associated with several complications, including vascular and nerve damage, access site hematoma, intracerebral and subarachnoid hemorrhage, extracranial hemorrhage, and pseudoaneurysm (Balami et al., 2018). Furthermore, less than 50% of acute ischemic stroke patients subjected to mechanical thrombectomy showed improved clinical outcomes, suggesting a need for further therapeutic interventions to better manage acute ischemic stroke patients (Chamorro, 2018).

[0007] Recanalization therapy offers beneficial effects in patients with acute ischemic stroke, but it is accompanied by catastrophic pathological processes, such as hyperactivation of ion channel glutamate receptors, primarily sensitive to N-methyl-D-aspartate (NMDA), overproduction and accumulation of toxic free radicals, and apoptosis-induced brain cell death (Won et al., 2002). Indeed, timely administration of NMDA antagonists and antioxidants has significantly suppressed brain injury and functional loss in various stroke animal models. However, over the past several decades, nearly 200 clinical trials of neuroprotective agents, including NMDA receptor antagonists and antioxidants, have failed to demonstrate beneficial effects in patients with acute ischemic stroke (Chamorro et al., 2016; Minnerup et al., 2012; Sutherland et al., 2012). This suggests that the efficacy of neuroprotective agents confirmed in preclinical animal models of stroke does not translate to human stroke patients. Failures in the transition from preclinical trials of such neuroprotective agents to clinical trials in stroke patients are attributed to (1) differences between animal models and human stroke patients, (2) poor quality of preclinical trials, and (3) serious adverse events of NMDA antagonists, such as neurotoxicity in rats and psychosis in humans (Farber et al., 2002; Bang, 2017). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Balami JS et al., Complications of endovascular treatment for acute ischemic stroke: Prevention and management. Int J Stroke. 2018;13(4):348-361. [Non-Patent Document 2] Bang OY et al., Dreaming of the future of stroke: translation of bench to bed. Precis Future Med. 2017;1(4):143-151. [Non-Patent Document 3] Benjamin, EJ, et al., Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation, 2018;137(12):e67-e492. [Non-Patent Document 4] Biteker M. et al., Treatment of prosthetic valve thrombosis: Current evidence and future directions. J Clin Med Res. 2015;7(12):932-936. [Non-Patent Document 5] Blaney M. et al., for CAPS Investigators. Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (the Cathflo Activase Pediatric Study). J Vasc Interv Radiol. 2006;17(11, pt 1):1745-1751. [Non-Patent Document 6] Chamorro A., Neuroprotectants in the era of reperfusion therapy. J Stroke. 2018;20(2):197-207. [Non-Patent Document 7] Chamorro A. et al., Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. 2016;15:869-81. [Non-Patent Document 8] Cho SI et al., Neu2000, an NR2B-selective, moderate NMDA receptor antagonist and potent spin trapping molecule for stroke. Drug News Perspect. 2010;23:549-56. [Non-Patent Document 9] Davis SM et al., Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist. Stroke. 2000;31(2):347-54. [Non-Patent Document 10] Dong Q. et al. The Chinese Stroke Association scientific statement: intravenous thrombolysis in acute ischaemic stroke. Stroke and Vascular Neurology 2017;2(3):147-159. [Non-Patent Document 11] Farber N.B. et al., Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7(1):32-43. [Non-Patent Document 12] Feigin V.L. et al., Global burden of stroke and risk factors in 188 countries, during 1990 - 2013: a systematic analysis for the global burden of disease study 2013. Lancet Neurol. 2016;15(9):913 - 924. [Non-Patent Document 13] Fix A.S. et al., Integrated evaluation of central nervous system lesions: Stains for neurons, astrocytes, and microglia reveal the spatial and temporal features of MK-801-induced neuronal necrosis in the rat cerebral cortex. Toxicol Pathol. 1996;24(3):291 - 304. [Non-Patent Document 14] Fugate J. and Rabinstein A.A. Update on intravenous recombinant tissue plasminogen activator for acute ischemic stroke. Mayo Clin Proc. 2014;89(7):960 - 72. [Non-Patent Document 15] Ginsberg M.D., Neuroprotection for ischemic stroke: Past, Present, and Future. Neuropharmacology. 2008;55(3): 363 - 389. [Non-Patent Document 16] Grotta J. et al., Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. Stroke. 1995;26(4):602-5. [Non-Patent Document 17] Gurwitz JH et al., Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Ann Intern Med. 1998;129(8):597-604. [Non-Patent Document 18] Gwag BJ et al., Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine. J Cereb Blood Flow Metab. 2007;27:1142-51. [Non-Patent Document 19] Hishida A., Clinical analysis of 207 patients who developed renal disorders during or after treatment with edaravone reported during post-marketing surveillance. Clin Exp Nephrol. 2007;11(4):292-296. [Non-Patent Document 20] Hong JM et al., Safety and Optimal Neuroprotection of neu2000 in acute Ischemic stroke with reCanalization: study protocol for a randomized, double-blinded, placebo-controlled, phase-II trial. Trials 2018;19:375. [Non-Patent Document 21] Jiang X et al., Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2018;163-164:144-171. [Non-Patent Document 22] Minnerup J. et al. Neuroprotection for stroke: current status and future perspectives. Int J Mol Sci. 2012;13(9):11753-72. [Non-Patent Document 23] Muir KW et al., Clinical Pharmacology of CNS 1102 in Volunteers. Ann NY Acad Sci. 1995;765:279-89; discussion 298. [Non-Patent Document 24] Muir KW et al., Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers. Br J Clin Pharmacol. 1994;38(1):33-8. [Non-Patent Document 25] Muir K.W. and Lees K.R., Excitatory amino acid antagonists for acute stroke. Cochrane Database of Systematic Reviews. 2003; Issue 3. Art. No.: CD001244.

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[0009] In some embodiments, compositions comprising a compound of formula (I) are disclosed for treating ischemic stroke patients undergoing thrombolytic therapy or endovascular thrombectomy, or for reducing adverse events of thrombolytic therapy, or for reducing reperfusion injury to the myocardium after coronary thrombectomy, or for reducing nerve loss, reducing hemorrhagic changes, and / or for improving the activities of daily living in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, endovascular thrombectomy, or endovascular thrombectomy with thrombolytic agents. Formula (I) is as follows: [ka]

[0010] (In these embodiments, R1, R2, and R3 are independently hydrogen or halogen, R4 is hydroxy, alkyl, alkoxy, halogen, alkanoyloxy, or nitro, and R5 is a carboxylic acid, carboxylic acid ester, carboxamide, sulfonic acid, halogen, or nitro) or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound of formula (I) is: 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as "2-hydroxy-TTBA" or "nelonemdaz"), 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2- Romo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid, 2-nitro-4-(2,3,5,6-tetrafluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid, 2-nitro-4-(2,3,5,6-tetrafluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid Lafluoro-4-trifluoromethylbenzylamino)phenol, 2-chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid, methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro- The compounds are selected from 4-trifluoromethylbenzylamino)benzoate, 2-ethanoloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, and 2-cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, or pharmaceutically acceptable salts thereof. In some embodiments, the composition contains 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, a vial containing any of these disclosed compositions contains 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, dissolved in water for injection at pH 8 to 11. In some embodiments, a vial containing any of these disclosed compositions contains 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is filled to the top with N2 gas, buffered with tris(hydroxymethyl)aminomethane [THAM], and sterile filtered, and the vial is reconstituted with sterile water for injection. In some embodiments, a vial containing any of these disclosed compositions contains 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is filled to the top with N2 gas, and the vial is reconstituted with THAM buffer.

[0013] In some embodiments, a method for treating ischemic stroke patients undergoing thrombolytic therapy includes administering to the patient any of the compounds or compositions of the other disclosed embodiments. In some embodiments, a method for treating ischemic stroke patients undergoing endovascular thrombectomy, possibly in combination with thrombolytic therapy, includes administering to the patient any of the compounds or compositions of the other disclosed embodiments. In some embodiments, a method for reducing adverse events of thrombolytic therapy, e.g., rt-PA, modified rt-PA, or urokinase, in patients with venous thromboembolism, myocardial infarction, catheter occlusion, pediatric pleural effusion, catheter-directed therapy, and / or prosthesis thrombosis includes administering to the patient any of the compounds or compositions of the other disclosed embodiments. In some embodiments, a method for reducing reperfusion injury to the myocardium after coronary thrombectomy in patients includes administering to the patient any of the compounds or compositions of the other disclosed embodiments.

[0014] In some embodiments, a method for reducing neurological deficits and / or improving activities of daily living in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, endovascular thrombectomy, or endovascular thrombectomy with thrombolytic agents includes administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in other embodiments. In some embodiments, a method for reducing hemorrhagic changes in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, endovascular thrombectomy, or endovascular thrombectomy with thrombolytic therapy includes administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in other embodiments. In some embodiments, a method for reducing adverse events of thrombolytic therapy in patients with venous thromboembolism, myocardial infarction, catheter occlusion, pediatric pleural effusion, catheter-directed therapy, and / or prosthesis thrombosis includes administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in other embodiments. In some embodiments, a method for reducing reperfusion injury to the myocardium after coronary thrombectomy in a patient includes administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any of the other embodiments disclosed.

[0015] In some embodiments, the compound of formula (I) is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)benzoic acid ("neronemdaz") or its potassium salt ("neronemdaz K"). In some embodiments, the compound is neronemdaz K and is administered in doses of 250 mg to 1500 mg twice daily for 1 to 5 days. In some embodiments, neronemdaz K is administered to ischemic stroke patients undergoing recanalization therapy in a total dose of 6,000 mg for 5 days (1,500 mg first dose + 500 mg second to tenth doses approximately 12 hours apart, all administered intravenously over 30 minutes) or a total dose of 5,250 mg (750 mg first dose + 500 mg second to tenth doses approximately 12 hours apart over 5 days). In some embodiments, the compound is administered in a composition defined in any of the disclosed embodiments. In some embodiments, the patient is human.

[0016] In some embodiments, a method for improving recanalization therapy in a subject includes administering to the subject a treatment that includes both NR2B antagonism and antioxidant properties. In some embodiments, a method for improving recanalization therapy in a subject includes simultaneously administering to the subject both a treatment that includes NR2B antagonism and a second treatment that includes antioxidant properties.

[0017] In some embodiments, recanalization therapy includes thrombolytic agents, endovascular thrombectomy, or both. In some embodiments, the subjects are patients with ischemic stroke. In some embodiments, improving recanalization therapy includes reducing reperfusion injury or other adverse events in the subjects. In some embodiments, the NR2B antagonistic effect is a safe (fast / weak) antagonistic effect. In some embodiments, the treatment includes an agent having both the NR2B antagonistic effect and antioxidant properties (e.g., neronemdaz or neronemdaz K). In some embodiments, the treatment includes a first agent having NR2B antagonistic properties and a second agent having antioxidant properties. In some embodiments, the first and second agents are administered in combination.

[0018] The above and other objects, features, and other advantages of the present invention will be better understood from the following detailed description, which is to be interpreted in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0019] [Figure 1A] This figure shows the suppression of rt-PA-induced hemorrhagic changes after 3-hour occlusion of the middle cerebral artery in adult rats. The upper and lower panels show that neronemdaz K [2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)potassium benzoate] suppresses hemorrhagic changes in the brains of adult rats treated with rt-PA after 3-hour occlusion of the middle cerebral artery. [Figure 1B] This figure shows the effects of tPA and neronemdaz on acute brain injury 24 hours after embolic stroke in mice. The upper and lower panels show that neronemdaz K suppresses hemorrhagic changes in the brains of adult mice treated with rt-PA after embolic stroke. [Figure 1C] This figure shows the suppression of rt-PA-induced hemorrhagic changes in normal adult rats. The upper and lower panels show the suppression of rt-PA-induced hemorrhagic changes in normal adult rats. [Figure 1D] This figure shows the suppression of rt-PA-induced brain injury in normal adult rats. The upper and lower panels show the suppression of rt-PA-induced brain injury in normal adult rats. [Figure 2A] This graph shows the percentage change in mRS distribution at 14, 30, and 90 days after drug treatment in patients with baseline (day 0) NIHSS scores of 6-24. Figure 2A shows that in patients with acute ischemic stroke, administration of neronemdaz K increases the proportion of mRS scores of 0-2 (functionally independent) and 0 (no symptoms at all). [Figure 2B] Figure 2B is a graph showing the percentage of patients with a baseline (day 0) NIHSS score of 6-24 or 9-24 who showed a reduction of 0-1 or 4 in their NIHSS score at day 14 after drug treatment. Figure 2B shows that neronemdaz K administration resulted in better functional recovery in patients with moderate to severe (NIHSS score ≥ 6) ischemic stroke compared to patients with mild stroke (4 ≤ NIHSS score ≤ 5). Figures 2A and 2B both show the ("ENIS" trial) regarding the beneficial effects of neronemdaz in patients with acute ischemic stroke treated with thrombolytic agents. The bars, from left to right, represent placebo, neronemdaz K, placebo, and neronemdaz K. [Figure 3A] This graph shows the distribution of mRS before drug treatment (baseline) and at weeks 1, 4, and 12 afterward. Figure 3A shows that in patients with acute ischemic stroke treated with endovascular thrombectomy, administration of low or high doses of neronemdaz K increases the proportion of mRS scores of 0-2 (functionally independent) and 0 (no symptoms at all). [Figure 3B]This graph shows the percentage of mRS 0 at weeks 1, 4, and 12 after drug treatment. Figure 3B shows that in patients with acute ischemic stroke treated with endovascular thrombectomy, administration of low or high doses of neronemdaz K significantly increases the percentage of mRS 0 at weeks 1, 4, and 12 after drug treatment. The triple vertical bars at each time point represent placebo, neronemdaz K (low), and neronemdaz K (high) from left to right. [Figure 3C] This graph shows the proportion of patients with a Barthel Index score higher than 90 at 12 weeks post-medication. Figure 3C shows that in patients with acute ischemic stroke treated with endovascular thrombectomy, administration of low or high doses of neronemdaz K increases the proportion of patients with a Barthel Index score higher than 90 (good recovery of daily living activities) at 12 weeks post-medication. Figures 3A, 3B, and 3C show the beneficial effects of neronemdaz in patients with acute stroke treated with endovascular thrombectomy ("SONIC" trial). [Modes for carrying out the invention]

[0020] This disclosure relates to compositions and methods relating to one or more tetrafluorobenzyl compounds of formula (I), pharmaceutically acceptable salts thereof, and drug product formulations thereof for recanalization therapy with thrombolytic agents (e.g., rt-PA, modified rt-PA, urokinase, or other suitable thrombolytic agents), EVT, or treatment of ischemic patients undergoing EVT with thrombolytic agents.

[0021] This disclosure relates, at least in part, to compositions and methods relating to one or more tetrafluorobenzyl compounds of formula (I), as well as pharmaceutically acceptable salts and drug product formulations thereof, for treatments to reduce hemorrhagic changes induced by the administration of thrombolytic agents.

[0022] In some embodiments, the disclosure relates to a method for producing a drug product formulation containing 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate potassium salt.

[0023] Accordingly, this disclosure provides pharmaceutical compositions and methods relating to a tetrafluorobenzyl compound of formula (I), or a pharmaceutically acceptable salt thereof, useful for the treatment of ischemic stroke patients undergoing recanalization therapy with a thrombolytic agent, EVT, or EVT with a thrombolytic agent.

[0024] This disclosure provides pharmaceutical compositions and methods relating to a tetrafluorobenzyl compound of formula (I), or a pharmaceutically acceptable salt thereof, that is useful for reducing hemorrhagic changes induced by the administration of thrombolytic agents.

[0025] This disclosure provides a method for producing a drug product formulation containing 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate potassium salt.

[0026] This disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating ischemic stroke patients undergoing thrombolytic recanalization therapy, EVT, or EVT with a thrombolytic agent: [ka] (In the formula, R1, R2, and R3 are each independently hydrogen or halogen, preferably H or F respectively. R4 is hydroxy, alkyl, alkoxy (e.g., unsubstituted or halogen-substituted), halogen, alkanoyloxy, or nitro. R5 is a carboxylic acid, a carboxylic acid ester (e.g., an alkyl ester), a carboxamide, a sulfonic acid, a halogen, or a nitro. To provide.

[0027] In certain embodiments, the alkyl group is a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0028] In certain embodiments, the alkoxy group is a C1-C6 alkoxy, more preferably a C1-C4 alkoxy, such as methoxy, ethoxy, or propanoxy.

[0029] The halogen may be fluorine, chlorine, bromine, or iodine.

[0030] In a particular embodiment, the alkanoyloxy is C2-C 10 Alkanoyloxy, more preferably C3-C8 alkanoyloxy, such as ethanoloxy (i.e., acetoxy), propanoyloxy, or cyclohexanecarbonyloxy.

[0031] In certain embodiments, the carboxylic acid ester may be methyl, ethyl, isopropyl, or butyl ester.

[0032] This disclosure provides a method relating to a tetrafluorobenzyl compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for treating ischemic stroke patients undergoing thrombolytic recanalization therapy, EVT, or EVT with a thrombolytic agent.

[0033] This disclosure provides a method relating to a tetrafluorobenzyl compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for reducing hemorrhagic changes induced by the administration of a thrombolytic agent.

[0034] Preferred compounds of formula (I) include, but are not limited to, the following: 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as "2-hydroxy-TTBA", "Neu2000", or "Neronemdaz"), 2-Nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid 2-Nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol (hereinafter referred to as "2-chloro-TTP"), 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide (hereinafter referred to as "2-Hydroxy-TTA"), 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid (hereinafter referred to as "2-hydroxy-TTS"), Methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate, 2-Ethanoloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as "2-ethane-TTBA"), 2-Propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as "2-propane-TTBA"), or 2-Cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as "2-cyclohexane-TTBA"), or a pharmaceutically acceptable salt thereof.

[0035] In a particularly preferred embodiment, the compound of formula (I) is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid ("2-hydroxy-TTBA", "Neu2000", or "neronemdaz") or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is structure [ka] It has.

[0036] Examples of pharmaceutically acceptable salts of the compounds of the present invention include alkali metal salts, such as lithium, sodium, or potassium salts, and alkaline earth metal salts, such as calcium or magnesium salts. Acid addition salts can be prepared by reacting a pharmaceutically acceptable non-toxic salt, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid, with a solution of the compounds of the present invention.

[0037] Tetrafluorobenzyl compounds of formula (I) and their pharmaceutically acceptable salts can be prepared, for example, by the reaction scheme shown in U.S. Patent No. 7,511,074.

[0038] For example, pharmaceutically acceptable salts of neronemdaz can be prepared by the following reaction scheme 1. However, the reaction scheme is provided for illustrative purposes only and does not limit the scope of this disclosure. In the scheme, M is a pharmaceutically acceptable metal (e.g., lithium, sodium, or potassium) or a basic organic compound, such as a conjugate acid of diethylamine.

[0039] [ka]

[0040] In some embodiments, tetrafluorobenzyl compounds of formula (I), or pharmaceutically acceptable salts thereof, preferably "neronemdaz" ("2-hydroxy-TTBA"), or pharmaceutically acceptable potassium salts thereof ("neronemdaz K") are useful in reducing neuronal loss and improving activities of daily living in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, such as rt-PA, EVT, or EVT with thrombolytic agents.

[0041] In some embodiments, tetrafluorobenzyl compounds of formula (I), or pharmaceutically acceptable salts thereof, preferably "neronemdaz" ("2-hydroxy-TTBA") or its pharmaceutically acceptable potassium salt ("neronemdaz K"), are useful in reducing hemorrhagic changes induced in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, such as rt-PA, EVT, or EVT with thrombolytic agents.

[0042] The disclosure also provides compositions comprising a tetrafluorobenzyl compound represented by the above chemical formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or additives. The tetrafluorobenzyl compound represented by the above chemical formula (I) or a pharmaceutically acceptable salt thereof may be administered alone. In some embodiments, the composition comprising the compound of formula (I) is administered together with any convenient carrier, diluent, etc.

[0043] In some embodiments, the composition contains about 250 mg to about 2,000 mg of the compound of formula (I) per unit dosage form. In some embodiments, the composition is used to administer about 250 mg to about 2,000 mg of the compound of formula (I) per dose. In certain preferred embodiments, the composition contains about 100 mg to about 1,000 mg of the compound of formula (I) per unit dosage form. In certain preferred embodiments, the composition is used to administer about 100 mg to about 1,000 mg of the compound of formula (I) per dose. In particularly preferred embodiments, the composition contains about 50 mg to about 500 mg of the compound of formula (I) per dose.

[0044] In some embodiments, the formulation for administration may be in single-dose units or multi-dose units. In some embodiments, the composition comprises single-dose units. In some embodiments, the composition comprises multi-dose units.

[0045] The compounds and pharmaceutical compositions of this disclosure, though not limited to these, may be administered in the form of injections (e.g., intramuscular, intraperitoneal, intravenous, infusion, subcutaneous, implantation). The compositions of this disclosure may be formulated in suitable dosage units, each containing pharmaceutically acceptable, non-toxic carriers, excipients, and / or vehicles commonly used in the art, depending on the desired route of administration. Depot formulations capable of continuously releasing the drug over a long period of time are also within the scope of this disclosure.

[0046] In some embodiments, the pharmaceutical compositions of this disclosure may be administered in combination with a thrombolytic agent, intravascular thrombectomy, or both (e.g., intravascular thrombectomy and a thrombolytic agent), or in combination with a thrombolytic agent, intravascular thrombectomy, or intravascular thrombectomy accompanied by a thrombolytic agent. The terms “in combination” and “in combination” are defined below.

[0047] As used herein, “a” or “an” may mean one or more. As used in claims herein, when used with the word “comprising,” the words “a” or “an” may mean one or more. As used herein, “another” may mean at least two or more.

[0048] The terms “administer” and / or “to administer” should be understood to mean providing a compound or a prodrug of a compound to a subject requiring treatment.

[0049] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and does not harm the subject. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, sucrose, and mannitol; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate, and microcrystalline cellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) disintegrants, e.g., crosslinked polymers containing crospovidone and croscarmellose sodium; (9) oils, e.g., peanut oil and cottonseed oil , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, e.g., propylene glycol; (11) polyols, e.g., glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic, suitable substances used in pharmaceutical formulations.

[0050] The term "subject" refers to mammals, including but not limited to humans and non-human mammals, such as cattle, horses, dogs, sheep, or cats.

[0051] The term "substance" includes all components that may be present in a pharmaceutical composition (e.g., water, other solvents, carriers, excipients).

[0052] In the context of administering compounds or compositions, the terms “combined” and “in combination” indicate that two different compounds or compositions can be administered without separating their administration regimens from each other, or without discontinuing the administration of one before initiating the administration of the other (for example, they may be administered by a drug containing both, or they may otherwise be administered simultaneously, or they may be administered separately but without a significant time delay between their administrations (e.g., 1 hour, 6 hours, 12 hours, 1 day, 2 days)).

[0053] As used herein, the terms “to treat” or “treatment” include methods of improving or stabilizing a condition, including reversing, reducing, or cessating the symptoms, clinical signs, and underlying pathology of the condition.

[0054] The term "therapeutic procedure" is technically recognized and includes administering a composition to a subject after the onset of an undesirable condition, such as ischemic stroke.

[0055] The compositions disclosed herein may include pharmaceutically acceptable carriers. The pharmaceutical compositions disclosed herein may be delivered by any preferred route of administration, including orally, orally, sublingually, parenterally, and rectally, such as in the form of powders, ointments, infusions, solutions, gels, tablets, capsules, pills, or creams. In certain embodiments, the pharmaceutical compositions are delivered generally (e.g., by oral administration). In certain other embodiments, the compositions disclosed herein are delivered rectally. In some embodiments, the compositions disclosed herein are delivered intravenously.

[0056] The actual dosage level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for the subject, composition, and mode of administration, and that is not toxic to the subject.

[0057] The selected dosage level depends on a variety of factors, including the activity of the specific drug used, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and prior medical history of the person being treated, and similar factors well known in medical technology.

[0058] A physician or veterinarian with ordinary art in this field can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can prescribe and / or administer a dose of the compound used in the pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0059] In some embodiments, the composition is provided in a sterile vial containing 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, dissolved in water (e.g., nanopure water) in the pH range of 8 to 11. Such a composition may be filtered and freeze-dried, for example, under conditions filled with nitrogen gas. The composition in the vial may then be reconstituted with sterile water for injection, further diluted with 0.9% saline, and then injected into a human. Repeated freeze-drying procedures may be carried out, for example, until a nearly white cake is obtained, preferably free or substantially free of needle-shaped crystals.

[0060] In some embodiments, the composition is provided as a sterile vial containing 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, dissolved in tris(hydroxymethyl)aminomethane [THAM] buffer water (e.g., nanopure water). Such a composition may be filtered and lyophilized, for example, under conditions filled with N2 gas. The composition in the vial may then be reconstituted with sterile water for injection, further diluted in 0.9% saline, and then injected into a human.

[0061] In some embodiments, the composition is provided as a sterile vial containing 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof dissolved in tris(hydroxymethyl)aminomethane [THAM] buffer water. Such a composition may be filtered and lyophilized under conditions of N2 gas filling. The composition in the vial may then be reconstituted with THAM buffer for injection, further diluted in 0.9% saline, and then injected into a human.

[0062] In some embodiments, vials (e.g., sterile vials) containing the lyophilized form of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in amounts of 50 mg to 2000 mg) are included. In some embodiments, reconstituted vials containing the reconstituted form of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in amounts of 50 mg to 2000 mg) are included, for example, reconstituted with sterile water or THAM buffer and optionally diluted with 0.9% physiological saline.

[0063] The disclosure also provides the use of a tetrafluorobenzyl compound represented by the above chemical formula (I) or a pharmaceutically acceptable salt thereof for the treatment of ischemic stroke patients undergoing thrombolytic recanalization therapy, EVT, or EVT with a thrombolytic agent.

[0064] The disclosure also provides the use of a tetrafluorobenzyl compound represented by the above chemical formula (I) or a pharmaceutically acceptable salt thereof to reduce hemorrhagic changes induced by the administration of thrombolytic agents.

[0065] This disclosure also provides the use of a tetrafluorobenzyl compound represented by the above chemical formula (I) or a pharmaceutically acceptable salt thereof to reduce thrombolytic agent-induced adverse events in patients undergoing thrombolytic treatment for thromboembolic disorders, including venous thromboembolism (pulmonary embolism, deep vein thrombosis), ST-elevation myocardial infarction (STEMI), IV catheter occlusion, catheter-directed therapy, prosthetic valve thrombosis, and coronary artery thrombectomy.

[0066] In some embodiments, the above chemical formula (I) or a pharmaceutically acceptable salt thereof is administered to humans at doses of 100 mg to 4000 mg per day for 1 to 7 days, as used in the applications mentioned in

[0026] to

[0028] above. In certain preferred embodiments, neronemdaz K is administered to humans at doses of 250 mg to 3000 mg per day for 1 to 7 days. In some embodiments, neronemdaz K is administered by intravenous (IV) infusion to ischemic stroke patients undergoing recanalization therapy for 5 days according to the following dosing schedule. (1) In the case of a total dose of 6,000 mg of neronemdaz K: 1,500 mg in the first infusion, 500 mg in the second infusion at 12 ± 6 hour intervals, and 500 mg each from the 3rd to the 10th infusion. (2) In the case of a total dose of 5,250 mg of neronemdaz K: 750 mg in the first infusion, 500 mg in the second infusion at 12 ± 6 hour intervals, and 500 mg each in the third to tenth infusions. (3) In the case of a total dose of 3,500 mg of neronemdaz K: 750 mg in the first infusion, 250 mg in the second infusion at 12 ± 6 hour intervals, and 250 mg each in the third to tenth infusions. (4) In the case of a total dose of 3,250 mg of neronemdaz K: 500 mg in the first infusion, 250 mg in the second infusion at 12 ± 6 hour intervals, and 250 mg each from the 3rd to the 10th infusion.

[0067] However, the treatment method (dosage, route of administration, interval, type of infusion, etc.) is not limited to the methods described above.

[0068] In various embodiments, the present invention relates to methods for the treatment of patients with ischemic stroke and disease undergoing recanalization therapy, as well as pharmaceutical compositions of neronemdaz and its derivatives. Moderate-affinity and subtype-selective antagonists of the NMDA receptor have been developed to investigate whether they can reduce the unbearable side effects of the NMDA receptor (Cho et al.). Memantine, a moderate NMDA receptor antagonist, has been approved for the treatment of Alzheimer's disease and has improved cognitive function in patients with mild to moderate vascular dementia without serious side effects (Orgogozo et al., 2002) and has shown beneficial effects in preclinical animal models of stroke (Seyedsaadat & Kallmes, 2019). Because NR2B-containing NMDA receptors are localized not only on the extrasynaptic membrane but also on the synapse, they can be excessively activated by glutamate accumulated in the extracellular space after a stroke, potentially leading to excitotoxic neuronal cell death. Several NR2B subunit-selective antagonists have been developed as neuroprotective NMDA receptor antagonists (Wang & Shuaib, 2005). NR2B antagonists, such as eriprodil and ifenprodil, have shown neuroprotective effects in preclinical models of stroke and have not shown psychotropic effects in humans (Muir & Lees, 2003). However, no beneficial effects of such NR2B antagonists in stroke patients have been reported.

[0069] Major antioxidants, such as chililarzad, ebselen, and NXY-059, did not show beneficial effects in clinical trials for stroke patients. However, edaravone, a radical scavenger, was approved in Japan in 2002 for the treatment of acute ischemic stroke patients within 24 hours of symptom onset. However, serious adverse reactions, including renal and hepatic impairment, limit the therapeutic potential of edaravone (Hishida, 2007).

[0070] Neronemdaz is a single molecule possessing both NR2B selective antagonist and antioxidant properties, and has shown beneficial effects in preclinical animal models of stroke (Cho et al., 2010). The inventors conducted preclinical and clinical trials to investigate the potential of neronemdaz to exhibit a safe profile and beneficial effects in ischemic stroke patients treated with recanalization therapy. Administration of neronemdaz did not cause neurotoxicity in rodents, nor psychosis in stroke patients or healthy human volunteers, reduced rt-PA-induced adverse events in rats, and significantly reduced disability without serious adverse events in two independent clinical trials in acute ischemic stroke patients treated with EV or thrombolytic agents.

[0071] table

[0072] [Table 1] Forty animals treated with the vehicle (20 male rats and 20 female rats) did not show neurotoxicity in the brain.

[0073] [Table 2] The 40 animals treated with the vehicle (20 male rats and 20 female rats) did not exhibit any abnormal behavior.

[0074] [Table 3] Phase 1 trial of Aptiganelle (Muir et al., 1994 & 1995); NA, data unavailable.

[0075] [Table 4] Clinical trials of self-fotel in patients with ischemic stroke (Grotta et al., 1995; Davis et al., 2000)

[0076] [Table 5] [Examples]

[0077] [Example 1] Safety of neronemdaz K in normal rats and healthy humans 1. Purpose NMDA receptor antagonists cause undesirable side effects, including neurotoxicity and psychotic symptoms. The inventors conducted tests to determine whether neronemdaz K, an NR2B-selective NMDA receptor antagonist, is safe in normal rats and healthy humans.

[0078] 2. Toxicity of NMDA receptor antagonists Systemic administration of NMDA antagonists, such as MK-801, phencyclidine, and ketamine, has been reported to cause neurotoxic side effects and neuronal cell death in rodents (Olney et al., 1989). In humans, NMDA receptor antagonists may induce serious side effects such as hallucinations, delusions, agitation, catatonia, and transient psychotic states. MK-801, a non-competitive NMDA receptor antagonist, was withdrawn from further development due to neuropsychological adverse events and neurotoxicity (Ginsberg, 2008). Administration of the non-competitive NMDA antagonist aptiganel to healthy humans resulted in hallucinations, paranoia, catatonia, euphoria, disinhibition, and psychomotor retardation (Muir et al., 1994; Muir et al., 1995). Intravenous injection of 2-3 mg / kg of the competitive NMDA receptor antagonist serfotel (CGS19755) resulted in transient side effects including sedation without abnormal neurological findings, dizziness, motion sickness with disorientation, and nausea (Grotta et al., 1995). However, administration of 1 mg / kg of serfotel resulted in hallucinations, paranoia, agitation, confusion, and delirium in stroke patients (Grotta et al., 1995; Davis et al., 2000).

[0079] 3. Comparison of neurotoxicity and abnormal behavior of MK-801 and neronemdaz K (Tables 1a & 1b): Adult rats (n=96) were euthanized at various time points (0, 1, 3, 5, or 9 days) after a single dose of MK-801 (1 or 10 mg / kg, IP), neronemdaz K (200 mg / kg, IV over 15 minutes), or vehicle. Brain sections were stained using de Olmos' amino-cupric-silver technique to examine neurodegeneration as described (Fix et al., 1996).

[0080] All animals treated with 1 mg / kg or 10 mg / kg of MK-801 showed neuronal death in various brain regions, including the posterior corpus callosum, entorhinal cortex, and hippocampus, as reported by Olney et al. (Table 1a). Such neuronal damage was not observed in male and female rats treated with 200 mg / kg of neronemdaz K. Furthermore, administration of MK-801 caused abnormal behaviors, including ataxia and decreased activity, in male and female rats, but these were not observed in animals treated with neronemdaz K (Table 1b). This suggests that neronemdaz K does not cause the neurotoxic and psychotic symptoms often associated with NMDA antagonists.

[0081] 4. Behavioral safety of neronemdaz K compared to the NMDA antagonist aptiganel in healthy volunteers (Table 2) NMDA receptor antagonists have been reported to cause serious side effects in healthy individuals. In a Phase 1 trial involving 94 healthy volunteers, administration of aptiganel caused psychotic symptoms, such as hallucinations, paranoia, and catatonia (Muir et al., 1994 and 1995; Table 2). In two Phase 1 trials conducted in the United States and China involving 165 healthy volunteers, a single dose of neronemdaz K up to 6,000 mg did not cause serious psychiatric and neurological adverse events, such as hallucinations, paranoia, catatonia, agitation, and confusion (Table 2). Furthermore, multiple doses of neronemdaz K up to 6,000 mg over 5 days (initial 1,500 mg IV infusion, followed by 9 additional 500 mg IV infusions twice daily) did not cause psychotic symptoms.

[0082] [Example 2] Behavioral safety of neronemdaz K compared to the NMDA antagonist selfotel in ischemic stroke patients (Table 3) NMDA receptor antagonists may cause adverse events in patients with ischemic stroke. In a clinical trial of ischemic stroke patients, some of the 281 patients treated with serfotel showed psychotic symptoms, such as hallucinations, paranoia, and delirium (Davis et al., 2000; Grotta et al., 1995: Table 3). However, none of the 179 ischemic stroke patients treated with neronemdaz K up to 6,000 mg for 5 days showed such psychotic symptoms.

[0083] [Example 3] Suppression of hemolytic drug-induced hemorrhagic changes 1. Animal models of tMCAO (transient middle cerebral artery occlusion) Male Sprague-Dawley rats (300-350g; 15-16 rats / group) were anesthetized with chloral hydrate (400mg / kg, IP) and anesthesia was maintained for approximately 1.5 hours during the procedure. Rectal temperature was recorded and maintained at 37.0-37.5°C using a constant temperature blanket controlled by a rectal probe and temperature control unit (Letica Scientific Instruments). MCA occlusion was performed according to a previous report (Gwag et al., 2007). Briefly, the right common carotid artery, external carotid artery (ECA), and internal carotid artery (ICA) were exposed. A fixed length of 4-0 monofilament nylon suture (17mm, pre-coated with silicone), with its tip heated and rounded near a flame, was advanced from the lumen of the ICA until it occluded the origin of the middle cerebral artery (MCA). The suture was left in place for 3 hours and then removed for reperfusion. After 24 hours, the brain was immediately removed and placed in a fixative solution for 15 minutes for further analysis.

[0084] 2. rt-PA-induced hemorrhagic change model Male Sprague-Dawley rats (340-380g) were anesthetized with chloral hydrate (400mg / kg, IP). rt-PA (0.66mg / kg, 30μmol total) was intracortically injected into the animals at a flow rate of 0.5μL / min using an infusion pump and Hamilton syringe, with injection points adjusted 2.6mm posteriorly and 5.4mm and 3.8mm laterally from the bregma. After injection, the syringe was removed from the cortex, and neronemdaz K (30mg / kg) was administered intrafemorally via the femoral vein over 5 minutes (3mg / mL; 10mL / kg). Six hours later, the rats were anesthetized and intravenously administered 4% Evans blue solution. Twenty minutes later, the rats were perfused first with saline and then with 4% paraformaldehyde. The brain was immediately removed, placed in fixative for 15 minutes, and scanned for Evans blue extravasation area to indirectly measure rt-PA-induced hemorrhagic changes resulting from blood-brain barrier disruption (Jiang et al., 2018). To assess brain injury volume, brain tissue was preserved in 4% paraformaldehyde for 3 days, followed by overnight treatment for paraffin embedding and cresyl violet staining. Extravasation area was measured using the TINA imaging system (KAIST, South Korea).

[0085] 3. Suppression of rt-PA-induced hemorrhagic changes after 3-hour occlusion of the middle cerebral artery in adult rats (Figure 1A) As described above, animals were subjected to transient focal cerebral ischemia for 3 hours, and after reperfusion, 10 mg / kg of rt-PA or 10 mg / kg of rt-PA and 30 mg / kg of neronemdaz K were administered intravenously. rt-PA (10 mg / kg) dissolved in sterile water for injection (6 mg / mL; 5 mL / kg) was injected into the femoral vein over 20 minutes, starting 5 minutes after reperfusion. Neronemdaz K (30 mg / kg) dissolved in saline (6 mg / mL; 5 mL / kg) was injected into the femoral vein over 5 minutes immediately after the completion of rt-PA infusion. (Upper panel) Neronemdaz K suppressed intracerebral hemorrhage in animals treated with rt-PA after 3 hours of tMCAO. (Lower panel) Administration of neronemdaz K significantly reduced the rate of hemorrhagic changes occurring in animals treated with rt-PA after 3 hours of tMCAO (p<0.05 by Fisher's exact test).

[0086] 4. Neronemdaz K suppresses adverse events that occur in mice treated with rt-PA after embolic stroke (Figure 1B). Embolistic stroke was induced in mice by injecting a blood clot into the right internal carotid artery. 4.5 hours after embolic stroke, the animals were intravenously administered saline, 10 mg / kg of rt-PA, or 10 mg / kg of rt-PA and neronemdaz potassium via the femoral vein. rt-PA was dissolved in water and injected over 20 minutes. Neronemdaz potassium was dissolved in saline and injected over 5 minutes immediately after rt-PA injection. Hemorrhage and brain injury were analyzed 24 hours after embolic stroke.

[0087] Upper panel: Delayed administration of rt-PA resulted in bleeding in the ischemic area of ​​mice subjected to embolic stroke compared to treatment with a vehicle (saline) that did not cause bleeding after embolic stroke. Lower panel: Administration of neronemdaz K significantly reduced hemoglobin levels and bleeding in the ischemic brain area of ​​mice treated with rt-PA after embolic stroke (mean ± SEM, using unpaired t-test). * p<0.05 vs. saline solution, and p<0.05 vs. rt-PA and neronemdaz K).

[0088] 5. Suppression of rt-PA-induced hemorrhagic changes in normal adult rats (Figure 1C) Animals were intracortically injected with 0.66 mg / kg of rt-PA, followed 5 minutes later by IV administration of either a vehicle or 30 mg / kg of neronemdaz K. Hemorrhagic changes were investigated by analyzing extravasation of Evans blue dye 6 hours after rt-PA administration. (Upper panel) Compared to the sham control group, rt-PA administration resulted in hemorrhagic changes evident by extravasation of Evans blue, but these were suppressed by subsequent treatment with neronemdaz K. (Lower panel) Compared to the vehicle treatment group, neronemdaz K administration significantly reduced the volume of extravasation of Evans blue after rt-PA injection (values ​​= mean ± SEM, n = 3 for the sham group and 6 for the rt-PA treatment group; p < 0.05 using one-way ANOVA and Tukey's test).

[0089] 6. Suppression of rt-PA-induced infarct volume in normal adult rats (Figure 1D) Animals were subjected to either sham surgery or intracortical injection of 0.66 mg / kg of rt-PA alone, or in combination with subsequent intravenous administration of a vehicle or 30 mg / kg of neronemdaz K. After 6 hours, the animals were sacrificed, and brain sections were stained with cresyl violet before infarct volume analysis. (Upper panel) Photographs of brain sections stained with cresyl violet. Note that brain lesions after intracortical injection of rt-PA were suppressed by administration of neronemdaz K. (Lower panel) Quantification of infarct volume by sum of lesion areas in brain sections (mean ± SEM, n=3 for the sham group and 6 for the rt-PA treatment group). Compared to the vehicle treatment group, administration of neronemdaz K significantly reduced the infarct volume occurring 6 hours after rt-PA, as determined by one-way analysis of variance (ANOVA) and Tukey's test.

[0090] The above studies demonstrate that intravenous administration of neronemdaz K reduces rt-PA-induced hemorrhagic changes and brain injury.

[0091] [Example 4] Beneficial effects of neronemdaz K in acute ischemic stroke patients receiving thrombolytic drugs. 1. Design of a Phase II clinical trial of neronemdaz K for patients with acute ischemic stroke in China (ENIS trial) The ENIS trial investigated the efficacy and safety of intravenous infusion of neronemdaz K in patients (35-80 years old) with acute ischemic stroke who had received at least one thrombolytic agent, including rtPA or urokinase, within 8 hours of symptom onset. The ENIS trial enrolled a total of 238 patients, who were randomly assigned in a double-blind manner to one of four groups for intravenous infusion of the following study drugs: (Group A) placebo [0.9% saline], (Group B) 2,750 mg of neronemdaz K for 5 days [500 mg in the first infusion, followed by 250 mg in 2-10 infusions approximately 12 hours apart], (Group C) 5,250 mg of neronemdaz K for 5 days [750 mg in the first infusion, followed by 500 mg in 2-10 infusions approximately 12 hours apart], and (Group D) 6,000 mg of neronemdaz K for 5 days [1,500 mg in the first infusion, followed by 500 mg in 2-10 infusions approximately 12 hours apart]. Patients with acute ischemic stroke due to occlusion of the internal carotid artery system within 8 hours of symptom onset were enrolled. The study included patients with National Institutes of Health (NIHSS) Stroke Scale (NIHSS: range 0-42, with higher scores indicating greater stroke severity) scores of 4-22, and with limb weakness including arm or leg movement, and an NIHSS score of ≥2. All patients had received at least one form of thrombolytic therapy prior to treatment with any of the study drugs.

[0092] 2. Efficacy of neronemdaz K in the "ENIS" trial (Figures 2A and 2B) The efficacy of neronemdaz K was analyzed in acute ischemic stroke patients with baseline NIHSS scores of 6–24 using the modified Rankin Scale (mRS; 0 = asymptomatic, 1 = no significant disability, 2 = mild disability, 3 = moderate disability, 4 = moderate to severe disability, 5 = severe disability, 6 = death). Shift analyses of mRS scores at 14, 30, and 90 days after drug treatment showed that administration of 6,000 mg of neronemdaz K increased the percentage of patients with mRS scores of 0–2 (functional independence) compared to the placebo group (Figure 2A). mRS scores represent nearly complete recovery after stroke. The proportion of patients with no symptoms (0) was 12% at 14 days, 16% at 30 days, and 26% at 90 days after placebo treatment in ischemic stroke patients, but further increased to 25%, 34%, and 45%, respectively, after neronemdaz K treatment.

[0093] Furthermore, the beneficial effects of neronemdaz K were observed by analyzing the proportion of patients with a reduction in NIHSS score of 0-1 or ≥4 on day 14 after drug treatment (= good recovery rate). In acute ischemic stroke patients with baseline NIHSS scores of 6-24, the good recovery rates were 25.53% and 41.67% (between groups p=0.106, chi-square test) in the placebo group (N=34) and the neronemdaz K group (N=36), respectively (Figure 2B). In moderate to severe stroke patients with baseline NIHSS scores of 9-24, the good recovery rate was 20% in the placebo group (N=3), but significantly increased to 50% in the neronemdaz K group (N=9) (between groups p=0.022). This suggests that the beneficial effects of neronemdaz K are better in patients with moderate to severe ischemic stroke (NIHSS score ≥ 6) than in patients with mild stroke (NIHSS score ≤ 5).

[0094] [Example 5] Safety and beneficial effects of neronemdaz K in acute ischemic stroke patients undergoing endovascular thrombectomy (SONIC trial) 1. Phase II clinical trial design and statistical analysis of neronemdaz K in acute ischemic stroke patients undergoing endovascular thrombectomy with or without rt-PA. The SONIC trial, as described above, investigated the efficacy and safety of intravenous infusion of neronemdaz potassium (NER) in patients (adults ≥ 19) with acute ischemic stroke who underwent endovascular thrombectomy with or without rt-PA within 8 hours of stroke onset (Hong et al., 2018). A total of 209 patients were enrolled in the SONIC trial and randomly assigned in a double-blind manner to one of three groups for intravenous infusion of the following study drugs: (Group A) placebo [0.9% saline], (Group B) 2,750 mg of neronemdaz potassium for 5 days [500 mg in the first infusion, followed by 250 mg in the second to tenth infusions at approximately 12-hour intervals], and (Group C) 5,250 mg of neronemdaz potassium for 5 days [750 mg in the first infusion, followed by 500 mg in the second to tenth infusions at approximately 12-hour intervals].

[0095] Patients with acute ischemic stroke due to occlusion of the internal carotid artery system within 8 hours of symptom onset were enrolled. Enrolled patients had a National Institutes of Health Stroke Scale (NIHSS: range 0-42, higher score indicates greater stroke severity) score of ≥8 and an Alberta Stroke Program Early CT Score (ASPECTS: 10-point quantitative tissue distribution CT scan score used in patients with middle cerebral artery (MCA) stroke, lower score indicates larger infarction) of ≥6.

[0096] For statistical analysis, the Cochrane-Mantel-Henzel (CMH) chi-squared test was performed to compare the distribution and proportion of mRS scores in each group at weeks 1, 4, and 12 after drug treatment. Ordinal logistic regression was applied to multivariate analysis to control for confounding variables that may cause differences between groups in participating facilities and baseline scores. Generalized Estimation Equation (GEE) analysis was also performed to compare the changes in mRS scores between groups measured at weeks 1, 4, and 12 after drug treatment. For the analysis of Barthel Index scores and adverse events, the chi-squared test or Fisher's exact test was performed to compare the differences between groups at weeks 1, 4, and 12 after drug treatment.

[0097] 2. Efficacy and safety of neronemdaz K in the "SONIC" trial (Figures 3A-3C) The SONIC trial enrolled patients with acute ischemic stroke who had a baseline NIHSS score of ≥8 and an mRS distribution of 2–5. Of the 209 patients in total, 152 successfully completed the procedure, including a 5-day drug treatment and planned analyses over 12 weeks post-treatment, according to the clinical protocol approved by the Korea Food and Drug Administration. The placebo group (N=49) who underwent endovascular thrombectomy showed an increase in the proportion of patients with mRS scores of 0–2 (functionally independent) or 0 (no symptoms) compared to baseline over the next 12 weeks, suggesting improved functional recovery. Patients treated with low-dose (2,750 mg, N=55) or high-dose (5,250 mg, N=48) neronemdaz K showed a further increase in the proportion of patients with mRS scores of 0–2 or 0 compared to placebo (Figure 3A). Shift analysis suggests that administration of neronemdaz K reduces disability in acute stroke patients treated with endovascular thrombectomy.

[0098] The proportion of patients with an mRS of 0 (no symptoms) gradually increased over time from baseline to 12 weeks in all treatment groups. The proportion of asymptomatic mRS 0 patients in those treated with placebo for 1 week was 2.04%, which increased significantly to 2.96% (p=0.04) and 16.67% (p=0.01) in the groups treated with low or high-dose neronemdaz K for 1 week, respectively (Figure 3B). The proportion of patients with an mRS of 0 at 4 weeks post-treatment further increased to 20% (p=0.04) in the low-dose neronemdaz K group and 26.67% (p=0.007) in the high-dose neronemdaz K group compared to 6.12% in the placebo group. At 12 weeks after drug treatment, the proportion of mRS 0 was significantly higher in the low-dose group (23.64%, p=0.03) and the high-dose group (31.25%, p=0.004) compared to the placebo group (8.16%).

[0099] The beneficial effects of neronemdaz K were confirmed by analysis using the Barthel Index (BI), which measures activities of daily living and motor skills on a total score of 0 (total assistance) and 100 (complete independence). All stroke patients before drug treatment were total assistance (BI=0). At 12 weeks after drug treatment, the proportion of patients with a BI score higher than 90 was 41.86% in the placebo group, increased to 54.72% in the low-dose neronemdaz K group, and further increased significantly to 64.44% (p<0.05) in the high-dose neronemdaz K group (Figure 3C).

[0100] In the safety analysis, 208 out of 209 patients (99.52%) enrolled in the SONIC trial were analyzed over 12 weeks after drug treatment. The mortality rates for the placebo group (N=70), the low-dose neronemdaz K group (N=71), and the high-dose neronemdaz K group (N=67) were 8.57% (6 / 70), 4.23% (3 / 71), and 4.48% (3 / 67), respectively. There was no difference in the incidence of adverse events and serious adverse events between the placebo and neronemdaz K groups. No drug-related adverse events were reported. Therefore, intravenous administration of up to 5,250 mf of neronemdaz K over 5 days was safe in patients with acute ischemic stroke treated with or without rt-PA endovascular thrombectomy.

[0101] [Example 6] Superiority of a single molecule possessing dual properties of NMDA antagonist and antioxidant over simultaneous administration of NMDA antagonist and antioxidant. Administration of a single molecule possessing dual properties as an NMDA antagonist and antioxidant ensures co-delivery of these activities at the single-cell and even molecular level. The synergistic effect between NMDA antagonism at the single-cell level and reduction of harmful free radicals may increase neuroprotective efficacy or reduce Olney cytotoxicity that occurs after NMDA antagonist administration. Modulation of NMDA receptors at redox sites may further contribute to the favorable efficacy / safety profile of nelomemdaz in ischemic stroke patients undergoing recanalization therapy and in related neurological disorders.

[0102] [Example 7] Optimization of drug formulations for neronemdaz K (Table 4) The neronemdaz K drug product (neronemdaz KL) used in Phase I clinical trials sometimes showed precipitation after reconstitution before administration to human subjects. Therefore, the inventors developed a novel drug product through an optimized process for neronemdaz K. The novel drug product, named neronemdaz KWL, was produced by a formulation and freeze-drying cycle of neronemdaz K. Briefly, neronemdaz K was dissolved in nanopure water, KOH was added to adjust the pH to 9.2-9.7, and then filtered through a sterile filter (Table 4). The resulting neronemdaz K solution was freeze-dried using a three-step process consisting of pre-freezing, first drying, and second drying, all under N2 gas, to minimize exposure time to air. The novel drug product, named "neronemdaz KWL," is characterized by being a nearly white, good, denser cake without needle-shaped crystals. Neronemdaz KWL can be reconstituted with sterile water for injection without forming a precipitate.

[0103] The precipitation problem of neronemdaz KL can be solved by other means: (1) Reformulating with a novel buffer instead of sterile water for injection (SWFI), such as (tris)hydroxymethyl]aminomethane [THAM, (HOCH2)3CNH2], borate, carbonate, etc.; (2) Replacing the reconstitution vehicle with THAM or bicarbonate and replacing the vial stopper with a coated stopper to reduce DEA loss; (3) Reconstituting the sterile API (active pharmaceutical ingredient) using THAM buffer; (4) Reconstituting the sterile API using DEA-mannitol buffer.

[0104] [Example 8] Ischemic stroke treated with thrombolytic agents Stroke is a disease in which blood vessels to the brain are blocked by a blood clot or rupture. Until 2015, rt-PA was the standard thrombolytic therapy for acute ischemic stroke patients within 4.5 hours of symptom onset, according to the 2018 American Heart Association (AHA) / American Stroke Association (ASA) guidelines for early management of patients with acute ischemia [Benjamin et al., 2018; The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995]. Clinical benefits have been observed when intravenous rt-PA is administered to ischemic stroke patients within 6 hours of symptom onset (Fugate and Rabinstein, 2014). As indicated above, the present invention provides evidence that neronemdaz K has beneficial effects on acute ischemic stroke patients receiving recanalization therapy with one type of thrombolytic agent. The thrombolytic agent may include rt-PA, modified rt-PA, urokinase, and other suitable thrombolytic agents.

[0105] In some embodiments, neronemdaz K is administered to ischemic stroke patients undergoing recanalization therapy at a total dose of 6,000 mg over 5 days. For example, 1,500 mg is administered as the first dose, followed by 500 mg doses at approximately 12-hour intervals, each administered intravenously over 30 minutes. Alternatively, neronemdaz K is administered to ischemic stroke patients undergoing recanalization therapy at a total dose of 5,250 mg. For example, 750 mg is administered as the first dose, followed by 500 mg doses at 12-hour intervals over 5 days, each administered as the second to tenth doses.

[0106] [Example 9] Patients undergoing endovascular thrombectomy for acute ischemic stroke Endovascular thrombectomy with or without thrombolytic agents has been used as a standard treatment for patients with acute ischemic stroke. This invention provides evidence that neronemdaz improves neurological function in patients with acute ischemic stroke who undergo endovascular thrombectomy with or without rt-PA within 8 hours of symptom onset. Furthermore, neronemdaz reduced adverse events observed in patients with ischemic stroke undergoing endovascular thrombectomy with or without rt-PA. Thrombolytic agents used in conjunction with endovascular thrombectomy may include rt-PA, modified rt-PA, urokinase, and other suitable thrombolytic agents. Endovascular thrombectomy devices may include Trevo, Solitaire FR, Penumbra, and other suitable devices.

[0107] [Example 10] Combination therapy with thrombolytic agents Thrombolytic agents, including rt-PA and modified rt-PA, have been used to treat venous thromboembolism, acute myocardial infarction, occluded catheters, pediatric pleural effusion, and prosthetic valve thrombosis (Wandell et al., 2019; Gurwitz et al., 1998; Blany et al., 2006; Biteker et al., 2015). However, such thrombolytic agents can cause serious adverse events, such as intracranial hemorrhage. Neronemdaz can be used to suppress adverse events that occur after administration of thrombolytic agents.

[0108] [Example 11] Combination therapy with coronary artery thrombectomy Coronary thrombosis can lead to myocardial infarction. Thrombolytic therapy has been used to treat coronary thrombosis. Although blood flow to ischemic myocardium is restored after coronary thrombectomy, such restoration of blood flow can lead to reperfusion injury to the myocardium, and neronemdaz can be used to treat reperfusion injury resulting from coronary thrombectomy.

[0109] As described herein, tetrafluorobenzyl compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them as active ingredients can be used to treat patients with acute ischemic stroke receiving thrombolytic agents, patients with acute ischemic stroke undergoing endovascular thrombectomy with or without thrombolytic therapy, patients undergoing thrombolytic therapy, and patients with acute myocardial infarction undergoing coronary thrombectomy. The present invention encompasses the following embodiments. (Embodiment 1) Compound of formula (I): [ka] (In the formula, R 1 、R 2 and R 3 These are independently hydrogen or halogen, R 4 These are hydroxy, alkyl, alkoxy, halogen, alkanoyloxy or nitro, R 5 (which are carboxylic acids, carboxylic acid esters, carboxyamides, sulfonic acids, halogens, or nitros), or pharmaceutically acceptable salts thereof. A composition comprising the above, for the treatment of ischemic stroke patients undergoing thrombolytic therapy or endovascular thrombectomy, or for reducing adverse events of thrombolytic therapy, or for reducing reperfusion injury to the myocardium after coronary artery thrombectomy, or for reducing nerve loss, or for reducing hemorrhagic changes, and / or for improving the daily living activities of ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, endovascular thrombectomy, or endovascular thrombectomy with thrombolytic agents. (Embodiment 2) The compound of formula (I) 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as "2-hydroxy-TTBA" or "neronemdaz"), 2-Nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid, 2-Nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid, Methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate, 2-Ethanoloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, and 2-Cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, or its pharmaceutically acceptable salt A composition for use according to Embodiment 1, selected from the above. (Embodiment 3) The composition for use according to Embodiment 2, wherein the compound of formula (I) is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid ("neronemdaz") or a pharmaceutically acceptable salt thereof. (Embodiment 4) A composition for use according to any one of Embodiments 1 to 3, comprising 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. (Embodiment 5) A vial containing the composition according to any one of Embodiments 1 to 4, comprising 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, dissolved in water for injection with a pH of 8 to 11. (Embodiment 6) N at the top 2 A vial containing 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is filled with gas, buffered with tris(hydroxymethyl)aminomethane [THAM], and sterile filtered, and which is reconstituted with sterile water for injection, comprising the composition according to any one of Embodiments 1 to 4. (Embodiment 7) N at the top 2 - A gas-filled vial containing 50 mg to 2000 mg of a sterile compound of formula (I) or a pharmaceutically acceptable salt thereof, which is reconstituted with THAM buffer, comprising the composition according to any one of Embodiments 1 to 4. (Embodiment 8) A method for treating an ischemic stroke patient undergoing thrombolytic therapy, comprising administering to the patient a compound or composition defined in any one of Embodiments 1 to 7. (Embodiment 9) A method for treating an ischemic stroke patient undergoing endovascular thrombectomy, sometimes in combination with thrombolytic therapy, comprising administering to the patient a compound or composition defined in any one of Embodiments 1 to 7. (Embodiment 10) A method for reducing adverse events of thrombolytic therapy, such as rt-PA, modified rt-PA, or urokinase, in patients with venous thromboembolism, myocardial infarction, catheter occlusion, pediatric pleural effusion, catheter-directed therapy, and / or prosthesis thrombosis, comprising administering to the patient a compound or composition as defined in any one of Embodiments 1 to 7. (Embodiment 11) A method for reducing reperfusion injury to the myocardium after coronary thrombectomy in a patient, comprising administering to the patient a compound or composition defined in any one of Embodiments 1 to 7. (Embodiment 12) A method for reducing neuronal deficits and / or improving activities of daily living in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, endovascular thrombectomy, or endovascular thrombectomy with thrombolytic agents, comprising administering to the patient a compound of formula (I) as defined in Embodiment 1 or a pharmaceutically acceptable salt thereof. (Embodiment 13) A method for reducing hemorrhagic changes in ischemic stroke patients undergoing recanalization therapy with thrombolytic agents, endovascular thrombectomy, or endovascular thrombectomy combined with thrombolytic therapy, comprising administering to the patient a compound of formula (I) as defined in Embodiment 1 or a pharmaceutically acceptable salt thereof. (Embodiment 14) A method for reducing adverse events of thrombolytic therapy in patients with venous thromboembolism, myocardial infarction, catheter occlusion, pediatric pleural effusion, catheter-directed therapy, and / or prosthetic valve thrombosis, comprising administering to the patient a compound of formula (I) as defined in Embodiment 1 or a pharmaceutically acceptable salt thereof. (Embodiment 15) A method for reducing reperfusion injury to the myocardium after coronary artery thrombectomy in a patient, comprising administering to the patient a compound of formula (I) as defined in Embodiment 1 or a pharmaceutically acceptable salt thereof. (Embodiment 16) The compound of formula (I) 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)benzoic acid (hereinafter referred to as "2-hydroxy-TTBA" or "nelonemdaz"), 2-Nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid, 2-Nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid, Methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate, 2-Ethanoloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, and 2-Cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, or its pharmaceutically acceptable salt The method according to any one of embodiments 12 to 15, selected from the above. (Embodiment 17) The method according to any one of Embodiments 12 to 15, wherein the compound of formula (I) is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)benzoic acid ("neronemdaz") or its potassium salt ("neronemdaz K"). (Embodiment 18) The method according to any one of Embodiments 12 to 15, wherein the compound is neronemdaz K, and the drug is administered at a dose of 250 mg to 1500 mg twice daily for 1 to 5 days. (Embodiment 19) The method according to Embodiment 18, wherein neronemdaz K is administered to ischemic stroke patients undergoing recanalization therapy in a total dose of 6,000 mg over 5 days (1,500 mg as the first dose + 500 mg each for the second to tenth doses at approximately 12-hour intervals, all administered intravenously over 30 minutes) or a total dose of 5,250 mg (750 mg as the first dose + 500 mg each for the second to tenth doses over 5 days at approximately 12-hour intervals). (Embodiment 20) The method according to any one of Embodiments 12 to 15, wherein the compound is administered in a composition defined in any one of Embodiments 5 to 7. (Embodiment 21) A compound or method for use according to any one of Embodiments 1 to 20, wherein the patient is human. (Embodiment 22) A method for improving recanalization therapy in a subject, comprising administering a treatment to the subject that includes both NR2B antagonistic activity and antioxidant properties. (Embodiment 23) A method for improving recanalization therapy in a subject, comprising simultaneously administering to the subject both a treatment containing NR2B antagonistic activity and a second treatment containing antioxidant properties. (Embodiment 24) The method according to Embodiment 22 or 23, wherein the recanalization therapy includes a thrombolytic agent, intravascular thrombectomy, or both. (Embodiment 25) The method according to Embodiments 22 to 24, wherein the subject is a patient with ischemic stroke. (Embodiment 26) The method according to any one of Embodiments 22 to 25, wherein the improvement includes reducing reperfusion injury or other adverse events in the subject. (Embodiment 27) The method according to any one of embodiments 22 to 26, wherein the NR2B antagonistic effect is a safe (fast / weak) antagonistic effect. (Embodiment 28) The method according to any one of embodiments 22 to 27, wherein the treatment comprises a drug having both NR2B antagonistic activity and antioxidant properties. (Embodiment 29) The method according to Embodiment 28, wherein the aforementioned drug comprises neronemdaz or neronemdaz K. (Embodiment 30) The method according to any one of Embodiments 22 to 27, wherein the treatment comprises a first agent having the NR2B antagonistic properties and a second agent having the antioxidant properties. (Embodiment 31) The method according to Embodiment 30, wherein the first drug and the second drug are administered in combination.

Claims

1. Compound of formula (I): 【Chemistry 1】 (In the formula, R 1 , R 2 and R 3 These are independently hydrogen or halogen, R 4 These are hydroxy, alkyl, alkoxy, halogen, alkanoyloxy or nitro, R 5 (which are carboxylic acids, carboxylic acid esters, carboxyamides, sulfonic acids, halogens, or nitros), or pharmaceutically acceptable salts thereof. A composition comprising, A composition for use in treating ischemic stroke patients undergoing thrombolytic therapy.

2. The compound of formula (I) 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as 2-hydroxy-TTBA or neronemdaz), 2-Nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid, 2-Nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid, Methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate, 2-Ethanoloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, and 2-Cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, or its pharmaceutically acceptable salt A composition for use according to claim 1, selected from the following.

3. The composition for use according to claim 2, wherein the compound of formula (I) is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (neronemdaz) or a pharmaceutically acceptable salt thereof.

4. The composition for use according to claim 1, wherein the compound of formula (I) is the potassium salt (neronemdaz K) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid.

5. The composition for use according to claim 1, wherein the composition comprises 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

6. The composition for use according to claim 1, wherein the composition is a liquid composition.

7. A composition for use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is freeze-dried.

8. The composition for use according to claim 1, wherein the composition is for intravenous administration.

9. The composition for use according to claim 1, wherein the composition comprises tris(hydroxymethyl)aminomethane [THAM].

10. The composition for use according to claim 1, wherein the composition is further for treating ischemic stroke patients undergoing endovascular thrombectomy.

11. The composition for use according to claim 1, wherein the composition is for administration to patients with ischemic stroke in combination with thrombolytic therapy.

12. (a) The thrombolytic therapy is recombinant tissue plasminogen activator (rt-PA), modified rt-PA, or urokinase, and / or (b) The patient has venous thromboembolism, myocardial infarction, catheter occlusion, pediatric pleural effusion, catheter-directed therapy, and / or prosthetic valve thrombosis, A composition for use as described in claim 1.

13. The composition for use according to claim 1, wherein the composition is for administration in combination with endovascular thrombectomy accompanied by thrombolytic therapy.

14. The composition for use according to claim 1, wherein the composition comprises neronemdaz K, and the composition is for administration at a dose of 250 mg to 1500 mg twice daily for 1 to 5 days.

15. The composition contains neronemdaz K, and the composition is (a) Total dose of 6,000 mg for 5 days, (b) Total dose of 5,250 mg for 5 days (c) A total dose of 3,500 mg for 5 days, or (d) Total dose of 3,250 mg for 5 days A composition for use according to claim 1, for the administration of neronemdaz K to patients over a period of time.

16. The composition for use according to claim 1, wherein the composition comprises neronemdaz K, and the composition is for a total of 10 doses over 5 days.

17. (a) The first dose contains 1500 mg, and the remaining doses each contain 500 mg. (b) The first dose contains 750 mg, and the remaining doses each contain 500 mg. (c) The first dose contains 750 mg, and the remaining doses each contain 250 mg, or (d) The first dose contains 500 mg, and the remaining doses each contain 250 mg. A composition for use according to claim 16.

18. The composition for use according to claim 17, wherein each dose is intended for administration at approximately 12-hour intervals.

19. A composition for use according to any one of claims 1 to 18, wherein the patient is a human being.

20. For the manufacture of pharmaceuticals for treating ischemic stroke patients undergoing thrombolytic therapy, Compound of formula (I): 【Chemistry 2】 (In the formula, R 1 , R 2 and R 3 These are independently hydrogen or halogen, R 4 is hydroxy, alkyl, alkoxy, halogen, alkanoyloxy or nitro, R 5 (which are carboxylic acids, carboxylic acid esters, carboxyamides, sulfonic acids, halogens, or nitros), or pharmaceutically acceptable salts thereof. Use of compositions containing the above.

21. The compound of formula (I) 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (hereinafter referred to as 2-hydroxy-TTBA or neronemdaz), 2-Nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid, 2-Nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide, 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid, Methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate, 2-Ethanoloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, 2-Propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, and 2-Cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, or its pharmaceutically acceptable salt The use according to claim 20, selected from the above.

22. The use according to claim 21, wherein the compound of formula (I) is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (neronemdaz) or a pharmaceutically acceptable salt thereof.

23. The use according to claim 20, wherein the compound of formula (I) is the potassium salt (neronemdaz K) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid.

24. The use according to claim 20, wherein the pharmaceutical product comprises 50 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

25. The use according to claim 20, wherein the pharmaceutical is a liquid composition.

26. The use according to claim 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is freeze-dried.

27. The use according to claim 20, wherein the pharmaceutical product is for intravenous administration.

28. The use according to claim 20, wherein the pharmaceutical product comprises tris(hydroxymethyl)aminomethane [THAM].

29. The use according to claim 20, wherein the pharmaceutical agent is for treating ischemic stroke patients who have further undergone endovascular thrombectomy.

30. The use according to claim 20, wherein the pharmaceutical product is for administration to a patient with ischemic stroke in combination with thrombolytic therapy.

31. (a) The thrombolytic therapy is recombinant tissue plasminogen activator (rt-PA), modified rt-PA, or urokinase, and / or (b) The patient has venous thromboembolism, myocardial infarction, catheter occlusion, pediatric pleural effusion, catheter-directed therapy, and / or prosthetic valve thrombosis, The use described in claim 20.

32. The use according to claim 20, wherein the pharmaceutical product is for administration to a patient in combination with endovascular thrombectomy accompanied by thrombolytic therapy.

33. The use according to claim 20, wherein the pharmaceutical product contains neronemdaz K, and the pharmaceutical product is intended for administration at a dose of 250 mg to 1500 mg twice daily for 1 to 5 days.

34. The aforementioned pharmaceutical contains neronemdaz K, and the aforementioned pharmaceutical contains, (a) Total dose of 6,000 mg for 5 days, (b) Total dose of 5,250 mg for 5 days (c) A total dose of 3,500 mg for 5 days, or (d) Total dose of 3,250 mg for 5 days The use according to claim 20, for the administration of neronemdaz K to patients over a period of time.

35. The use according to claim 20, wherein the pharmaceutical product comprises neronemdaz K, and the pharmaceutical product is intended for administration a total of 10 times over 5 days.

36. (a) The first dose contains 1500 mg, and the remaining doses each contain 500 mg. (b) The first dose contains 750 mg, and the remaining doses each contain 500 mg. (c) The first dose contains 750 mg, and the remaining doses each contain 250 mg. (d) The first dose contains 500 mg, and the remaining doses each contain 250 mg. The use described in claim 35.

37. The use according to claim 36, wherein each dose is intended for administration at approximately 12-hour intervals.

38. The use according to any one of claims 20 to 37, wherein the patient is a human being.

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