Composition and method for reducing brain damage, disability, and / or death by combined therapy with tetrafluorobenzyl derivative and hypothermia

Abstract

The present invention relates to a pharmaceutical use, of a compound of formula I or a salt thereof, for improving mortality, neurological impairment, and / or daily activity in patients with resuscitated cardiac arrest receiving target temperature management (TTM) for maintaining a temperature between about 32°C and about 36°C, patients with ischemic or hemorrhagic stroke receiving TTM, patients with traumatic brain or spinal cord injury receiving TTM, or patients with hypoxic-ischemic encephalopathy receiving TTM.

Description

Compositions and methods for reducing brain damage, disability, and / or death by combined therapy with tetrafluorobenzyl derivatives and hypothermia

[0001] This application claims priority to Korean Patent Application No. 10-2024-0000132, filed January 2, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to methods, medicinal uses, and pharmaceutical compositions for improving the mortality rate or condition of patients with resuscitated cardiac arrest, patients with ischemic or hemorrhagic stroke, patients with traumatic brain or spinal cord injury, and patients with hypoxic-ischemic encephalopathy (infants) receiving TTM.

[0003] Cardiac arrest, which occurs when the heart suddenly stops beating, is a leading cause of death and disability worldwide. Approximately 3.8 million people worldwide suffer out-of-hospital cardiac arrest (OHCA) each year. The number of patients who experience OHCA and in-hospital cardiac arrest (IHCA) is estimated at 600,000 and 300,000, respectively, in the United States and Europe. The mortality rate for cardiac arrest patients is currently very high; in fact, only about 10% of OHCA patients and 25% of IHCA patients survive hospital discharge. Patients who are successfully resuscitated from cardiac arrest often suffer devastating brain damage following global ischemia-reperfusion, leading to disability and death.

[0004] Target temperature management (TTM) is currently being suggested as a treatment guideline for patients with resuscitated cardiac arrest. TTM is known to alleviate primary ischemic brain injury and secondary reperfusion brain injury by reducing mitochondrial damage, reactive oxygen toxicity, excitatory glutamate toxicity, and brain metabolism (Hosseini, Wilson et al. (2020). "Resuscitating the Globally Ischemic Brain: TTM and Beyond." Neurotherapeutics17(2): 539-562.).

[0005] More than 40% of patients with successfully resuscitated cardiac arrest experience hyperthermia within 48 hours. This hyperthermia further increases brain metabolism, makes neurons more sensitive to excitotoxicity, and damages the blood-brain barrier, leading to neuronal damage and neuronal dysfunction in patients with cardiac arrest (Sekhon, Ainslie et al. (2017). "Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model." Crit Care21(1): 90.). Therapeutic hypothermia reduces brain damage after ischemia-reperfusion through various mechanisms, including modulating brain metabolism, modulating inflammation and glutamate toxicity, and protecting the blood-brain barrier (Yenari, MA and HS Han (2012). "Neuroprotective mechanisms of hypothermia in brain ischemia." Nat Rev Neurosci13(4): 267-278.). In patients with cardiac arrest due to ventricular fibrillation, TTM treatment was first demonstrated in a clinical trial to improve long-term disability (Bernard, Gray et al. 2002, Hypothermia after Cardiac Arrest Study 2002). However, in a large European clinical trial of 939 patients with cardiac arrest who entered a coma after spontaneous circulation, the group receiving hypothermia at 33°C did not show any improvement in neurological function compared to the normothermic group (Nielsen, N. et al., (2013). "Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest." N Engl J Med 369(23): 2197-2206.).Meanwhile, in a recent clinical trial of patients with comatose cardiac arrest who were successfully resuscitated with a non-shockable rhythm, patients who received hypothermia treatment at 33°C for 24 hours compared to normothermia had improved neurological function and higher survival rates after 90 days (Lascarrou, JB et al., (2019). "Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm." N Engl J Med 381(24): 2327-2337.).

[0006] Currently, the American Heart Association (AHA), the International Liaison Committee on Resuscitation (ILCOR), the European Resuscitation Council (ERC), and the Korean Society of Cardiopulmonary Resuscitation recommend TTM therapy for the treatment of post-cardiac arrest syndrome (PCAS) in patients with OHCA and IHCA. However, the efficacy of TTM in improving neurological function and survival is limited. Therefore, active development of drugs that protect brain cells in patients resuscitated from cardiac arrest with TTM is underway to more effectively treat PCAS.

[0007] In the brains of cardiac arrest patients who were successfully resuscitated by resumption of spontaneous circulation, overactivation of NMDA receptors due to excessive release and accumulation of glutamate, rapid influx of calcium ions into neurons, and overload lead to neuronal death (Won, SJ et al., (2002). "Cellular and molecular pathways of ischemic neuronal death." J Biochem Mol Biol 35(1): 67-86.). However, administration of memantine, an NMDA receptor antagonist approved for the treatment of Alzheimer's disease, did not demonstrate neuroprotective effects in a hypothermic cardiac arrest pig model (Rimpilainen, J. et al., (2001). "The N-methyl-D-aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: a study in the chronic porcine model." J Thorac Cardiovasc Surg 121(5): 957-968; discussion 968-970; Lipton, SA (2004). "Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders." J Alzheimers Dis 6(6 Suppl): S61-74.).

[0008] The efficacy of drugs that modulate glutamate neurotoxicity, oxidative stress, and inflammation is being evaluated to prevent brain damage after ischemia-reperfusion in resuscitated cardiac arrest patients. However, these investigational drugs have not necessarily been found to be effective in the treatment of TTM. In a phase 2 clinical trial of 110 OHCA patients who were successfully resuscitated and received TTM, administration of xenon gas, an NMDA receptor antagonist, significantly reduced white matter (neural network) damage in patients, but no improvement in neurological function was observed after 6 months (Laitio, R. et al., (2016). "Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial." JAMA315(11): 1120-1128.). Clinical trials are underway to determine the efficacy and safety of antioxidants such as high-dose vitamin C and molecular hydrogen (H2) in successfully resuscitated cardiac arrest patients, and a clinical trial is also underway to determine the effects of methylprednisolone, an anti-inflammatory drug, on inflammatory biomarkers and neurological function improvement in 120 successfully resuscitated coma cardiac arrest patients. However, no effective treatment has yet been developed.

[0009] Accordingly, the problem to be solved by the present invention is to provide a method for reducing disability and / or mortality in patients with resuscitated cardiac arrest; patients with ischemic or hemorrhagic stroke; patients with traumatic brain or spinal cord injury; or patients with hypoxic-ischemic encephalopathy (especially infants) who receive targeted temperature management (TTM) treatment.

[0010] Another problem to be solved by the present invention is to provide a pharmaceutical composition for reducing disability and / or mortality in patients with resuscitated cardiac arrest; patients with ischemic or hemorrhagic stroke; patients with traumatic brain or spinal cord injury; or patients with hypoxic-ischemic encephalopathy (particularly infants) receiving TTM treatment.

[0011] In order to solve the above problem, one aspect of the present invention provides a method for reducing mortality in a subject, improving neurological deficits, or improving activities of daily living, characterized in that it administers a therapeutically effective amount of a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from cardiac arrest undergoing targeted temperature management (TTM); a subject suffering from ischemic or hemorrhagic stroke undergoing TTM; a subject suffering from traumatic brain or spinal cord injury undergoing TTM; a subject suffering from hypoxic-ischemic encephalopathy undergoing TTM; or a subject suffering from hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

[0012] [Chemical Formula 1]

[0013]

[0014] In chemical formula 1,

[0015] R1, R2, and R3 are independently hydrogen or halogen,

[0016] R4 is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C 10 alkanoyloxy or nitro,

[0017] R5 is a carboxylic acid, carboxylic acid ester, carboxamide, sulfonic acid, halogen or nitro.

[0018]

[0019] That is, one aspect of the present invention provides a pharmaceutical use of the compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is useful for reducing mortality, improving neurological deficits, or improving activities of daily living in a resuscitated cardiac arrest subject receiving TTM; a subject with ischemic or hemorrhagic stroke receiving TTM; a subject with traumatic brain or spinal cord injury receiving TTM; a subject with hypoxic-ischemic encephalopathy receiving TTM; or a subject with hypoxic-ischemic encephalopathy receiving TTM (particularly, infants) receiving therapeutic hypothermia.

[0020] In one aspect of the present invention, hypothermia treatment refers to a treatment method in which the core body temperature of an individual is maintained between 32°C and 36°C, and particularly in a resuscitated cardiac arrest individual, hypothermia treatment refers to maintaining the core body temperature of the individual between 32°C and 36°C after successful resuscitation and resumption of spontaneous circulation.

[0021] Accordingly, another aspect of the present invention provides a pharmaceutical composition comprising the compound of the above-mentioned chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for reducing mortality, improving neurological deficits, or improving activities of daily living in a resuscitated cardiac arrest subject receiving TTM; a subject with ischemic or hemorrhagic stroke receiving TTM; a subject with traumatic brain or spinal cord injury receiving TTM; a subject with hypoxic-ischemic encephalopathy receiving TTM; or a subject with hypoxic-ischemic encephalopathy receiving TTM (particularly infants) or a subject with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia.

[0022] The description of the embodiments of the present invention described below applies commonly to all of the methods, pharmaceutical uses, and pharmaceutical compositions mentioned above.

[0023] In the present invention, alkyl and alkoxy are C1-C6 alkyl and C1-C6 alkoxy, respectively. For example, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, and alkoxy means -O-(alkyl) including -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)2H, -OC(CH3)3, and the like. Preferably, alkyl and alkoxy of the present invention are C1-C3 alkyl and C1-C3 alkoxy, respectively.

[0024] In the present invention, alkanoyloxy is C1-C 10 alkanoyloxy, preferably C2-C 10 Alkanoyloxy, more preferably C3-C8alkanoyloxy. For example, alkanoyloxy is ethanolyloxy, propanoyloxy or cyclohexanecarbonyloxy.

[0025] In this specification, “C 1-6 ”, “C1-6”, or “C1-C6”, this means that it has 1 to 6 carbon atoms. For example, C 1-6 Alkyl refers to alkyl having 1 to 6 carbon atoms.

[0026] In the present invention, "halogen" and "halo" mean fluorine, chlorine, bromine, or iodine. In a preferred embodiment of the present invention, the halogen is fluorine.

[0027] In the carboxylic acid ester of the present invention, carbon may be substituted with methyl, ethyl, isopropyl or butyl.

[0028] Pharmaceutically acceptable salts according to the present invention include ammonium salts; alkali metal salts such as lithium, sodium or potassium; alkaline earth metal salts such as calcium or magnesium; salts of organic bases such as cyclohexylamine, benzylamine, octylamine, ethanolamine, diethylolamine, diethylamine, triethylamine, ethylenediamine, procaine, morpholine, pyrroline, piperidine, N-ethylpiperidine, N-methylmorpholine, piperazine, and the like; or salts of basic amino acids such as lysine, arginine, ornithine, and histidine.

[0029] Preferably, the subject of the methods, pharmaceutical uses, and pharmaceutical compositions of the present invention is a subject who has suffered cardiac arrest and is receiving TTM. Patients who have been resuscitated from cardiac arrest have specific biological responses that differ from normal individuals, and administering the compound according to the present invention together with TTM is very useful in improving the patient's mortality rate, neurological deficits, and decreased daily life. In one aspect of the present invention, the methods, pharmaceutical uses, and pharmaceutical compositions of the present invention can reduce white matter (brain fiber) damage in resuscitated cardiac arrest patients receiving cryotherapy.

[0030] In another aspect of the present invention, the method, pharmaceutical use, and pharmaceutical composition of the present invention are also useful for treating patients with intracerebral hemorrhage, subarachnoid hemorrhage, etc., who are receiving hypothermia treatment at 32-36°C.

[0031] Preferably, the compound of formula 1 according to the present invention

[0032] 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (nelonemdaz),

[0033] 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0034] 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0035] 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0036] 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0037] 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0038] 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid,

[0039] 2-nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol,

[0040] 2-chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)phenol,

[0041] 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide,

[0042] 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzenesulfonic acid,

[0043] Methyl 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoate,

[0044] 2-Ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0045] 2-Propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid,

[0046] 2-Cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, or a pharmaceutically acceptable salt thereof.

[0047] More preferably, the compound of formula 1 according to the present invention is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (nelonemdaz) or a pharmaceutically acceptable salt thereof.

[0048] Even more preferably, the compound of formula 1 according to the present invention is a potassium salt of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid.

[0049] The compound of chemical formula 1 or a salt thereof according to the present invention can be prepared by the reaction scheme shown in U.S. Patent No. 7,511,074, but is not limited thereto.

[0050] One aspect of the present invention also provides a composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or additive. That is, in one aspect of the present invention, the compound of formula 1 or a salt thereof is administered together with a carrier, additive, or the like commonly used in the field to which the present invention pertains. However, the compound of formula 1 or a salt thereof of the present invention may be administered alone.

[0051] In one embodiment of the present invention, the composition according to the present invention comprises from about 50 mg to about 2,000 mg, preferably from about 250 mg to about 2,000 mg, of the compound of formula 1. In another embodiment, the composition of the present invention comprises from about 100 mg to about 1,000 mg of the compound of formula 1. In yet another embodiment, the composition of the present invention comprises from about 50 mg to about 500 mg of the compound of formula 1.

[0052] In one embodiment of the present invention, the formulation (composition) of the present invention for administration may be a single-dose unit or a multi-dose unit. In some embodiments, the formulation (composition) of the present invention is a single-dose unit. In other embodiments, the formulation (composition) of the present invention is a multi-dose unit and is divided into multiple doses for use.

[0053] The pharmaceutical composition of the present invention may be administered in the form of an injectable formulation (e.g., intramuscular, intraperitoneal, intravenous, infusion, subcutaneous, implant), but is not limited thereto. Depending on the route of administration, the pharmaceutical composition of the present invention may be formulated into an appropriate dosage unit containing pharmaceutically acceptable and non-toxic carriers, excipients, and / or vehicles commonly used in the art. Furthermore, sustained-release formulations capable of continuously releasing the drug over a target period of time are also encompassed by the present invention.

[0054] In a preferred embodiment of the present invention, 50 mg to 2000 mg of the compound of formula 1 or a pharmaceutically acceptable salt thereof is contained in a sterile vial(s), the composition is dissolved in nanopure water at a pH ranging from 8 to 11, filtered, and lyophilized under nitrogen-filled conditions. All formulation processes are carried out under nitrogen-filled conditions. The composition contained in the vial is reconstituted with sterile water for injection and further diluted with 0.9% normal saline before injection into a human. Two additional lyophilization procedures are carried out until an almost white fine cake without needle-like crystals is obtained. In one embodiment of the present invention, the compound according to the present invention is administered as an injectable solution containing 50 mg to 2000 mg, preferably the pH of the injectable solution is 8-11.

[0055] In one embodiment of the present invention, 50 mg to 2000 mg of the compound of formula 1 or a pharmaceutically acceptable salt thereof is contained in a sterile vial(s), the composition is dissolved in tris(hydroxymethyl)aminomethane [THAM]-buffered water for injection, filtered, and lyophilized under nitrogen gas-filled conditions. The composition contained in the vial is redissolved in water for injection for injection and further diluted with 0.9% saline prior to injection into a human.

[0056] In another embodiment of the present invention, 50 mg to 2000 mg of the compound of formula 1 or a pharmaceutically acceptable salt thereof is contained in a sterile vial(s), the composition being dissolved in tris(hydroxymethyl)aminomethane [THAM]-buffered water for injection, filtered, and lyophilized under nitrogen gas-filled conditions. The composition contained in the vial is redissolved in THAM buffer for injection and further diluted with 0.9% saline prior to injection into a human.

[0057] In one embodiment of the present invention, the compound of formula 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 100 mg to 4000 mg for the aforementioned purposes. In another embodiment, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid potassium salt ('nelonemdaz K') is administered to a human at a daily dose of 250 mg to 3000 mg for 1 to 3 days. In yet another embodiment, nelonemdaz K is administered intravenously (IV) to the aforementioned patients receiving TTM, particularly to patients with resuscitated cardiac arrest, according to the following dosing schedule:

[0058] (1) For a total dose of 6,000 mg of nelonemdaz K: 1,500 mg for the first dose, 1,500 mg at 12 ± 6 hour intervals for the second dose, and 750 mg at 12 ± 1 hour intervals for the third to sixth infusions;

[0059] (2) For a total dose of 5,250 mg of nelonemdaz K: 1,500 mg for the first dose, 750 mg at 12 ± 6 hour intervals for the second dose, and 750 mg at 12 ± 1 hour intervals for the third to sixth infusions;

[0060] (3) For a total dose of 4,250 mg of nelonemdaz K: 1,500 mg for the first dose, 750 mg at 12 ± 6 hour intervals for the second dose, and 500 mg at 12 ± 1 hour intervals for the third to sixth infusions; or

[0061] (4) For a total dose of 3,250 mg of nelonemdaz K: 750 mg for the first dose, 500 mg at 12 ± 6 hour intervals for the second dose, and 500 mg at 12 ± 1 hour intervals for the third to sixth infusions.

[0062] In another aspect of the present invention, nelonemdaz K is administered intravenously (IV) to the aforementioned patients receiving TTM, particularly to patients with resuscitated cardiac arrest, according to the following dosing schedule:

[0063] (a) Administered at a dose of 250 mg to 1500 mg twice daily for 1 to 3 days;

[0064] (b) administered at a total dose of 5,250 mg for 3 days;

[0065] (c) administered 6 times in total over 3 days, the first dose being 1500 mg and the remaining doses being 750 mg each, with each dose administered approximately 12 hours apart;

[0066] (d) administered in a total dose of 3,250 mg over 3 days; or

[0067] (e) Administer a total of 6 times over 3 days, with the first dose being 750 mg and the remaining doses each being 500 mg, with each dose administered approximately 12 hours apart.

[0068] However, the treatment method (dosage, treatment route, interval, injection type, etc.) of the compound of the present invention or its salt is not limited to the method described above.

[0069] In one aspect of the present invention, the compound and composition of the present invention are administered intravenously, and may be administered by direct intravenous injection or, in the case of a patient undergoing intravenous infusion, may be administered by mixing with the composition during intravenous infusion.

[0070] In one embodiment of the present invention, the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered together with an antioxidant to enhance the effect of hypothermia therapy. In another embodiment, the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be administered first, and an antioxidant may be administered secondarily to enhance the effect of hypothermia therapy.

[0071] The compound of chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be used as follows.

[0072] Application Example 1. Cardiac arrest patient receiving hypothermia treatment

[0073] Sudden cardiac arrest is a leading cause of death and morbidity worldwide, accounting for half of all deaths from cardiovascular disease. Brain damage following complete cerebral ischemia-reperfusion contributes to disability and death following cardiac arrest. Current guidelines recommend hypothermia therapy to reduce ischemia-reperfusion injury in patients with successfully resuscitated cardiac arrest. As described above, the present invention provides evidence that nelonemdaz provides additional therapeutic benefits in patients with successfully resuscitated cardiac arrest receiving hypothermia therapy.

[0074] Application Example 2: Stroke Patient Receiving Hypothermia Therapy

[0075] The Neuroprotective Therapeutics Consensus Review (NTRC) group recommended therapeutic hypothermia for patients with intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and acute ischemic stroke. Stroke, caused by interruption of cerebral blood flow due to a blood clot, embolic material, or the rupture of a blood vessel within the vessel, is a major cause of long-term disability in adults and the second leading cause of death in the United States and Europe. Neuronal cell death following stroke can lead to permanent disability and death. Therapeutic hypothermia provides neuroprotection through various physiological mechanisms in animal models of ischemic and hemorrhagic stroke and in stroke patients. Nelonemdaz may be used adjunctively to reduce brain damage in patients with intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and acute ischemic stroke receiving therapeutic hypothermia.

[0076] Application Example 3: Patients with Traumatic Brain Injury and Spinal Cord Injury Receiving Hypothermia Therapy

[0077] Traumatic brain injury (TBI) is a serious problem, causing disability and death in 69 million people worldwide each year. In animal models, hypothermia has been shown to reduce brain edema and neuronal cell death caused by TBI, and improve disability. The beneficial effects of hypothermia have also been reported in TBI patients. Furthermore, hypothermia's neuroprotective and disability-improving effects have been demonstrated in animal models of traumatic spinal cord injury (TSCI) and in clinical trials. Therefore, nelonemdaz can be used as an adjunct to hypothermia to reduce brain damage and disability in TBI and TSCI patients.

[0078] Application Case 4: Neonatal Hypoxic-Ischemic Encephalopathy Receiving Hypothermia

[0079] Hypoxic-ischemic encephalopathy (HIE) is a serious birth complication in which brain tissue is damaged by a lack of oxygen and blood supply. It affects approximately 400,000 newborns worldwide each year. Therapeutic hypothermia is the only approved standard treatment to reduce brain damage in newborns suffering from HIE. However, HIE still accounts for approximately one-fifth of neonatal deaths worldwide. Therapeutic hypothermia can prevent moderate to severe hypoxic-ischemic encephalopathy in newborns, reducing neuronal cell death. Nelonemdaz can be used as an adjunct to hypothermia in HIE patients to protect brain cells and further reduce disability and death.

[0080] The compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof can be additionally administered to patients with cardiac arrest receiving hypothermia treatment, patients with ischemic or hemorrhagic stroke, patients with traumatic brain and spinal cord injury, and patients with hypoxic and ischemic encephalopathy (especially newborns or infants) to reduce mortality, improve neurological deficits, or improve activities of daily living.

[0081] Figure 1 is a graph showing the proportion of patients with mRS scores of 0-2, 3-4, and 5-6 90 days after the first dose of medication in cardiac arrest patients who were successfully resuscitated and received hypothermia therapy.

[0082] mRS 0-2, patients capable of independent activities (Good neurological outcome)

[0083] mRS 3-4, patients with moderate disability

[0084] mRS 5-6, patients with severe disability (coma) or death (poor neurological outcome)

[0085] HIGH, high-dose nelonemdaz group; LOW, low-dose nelonemdaz group; PLACEBO, placebo group

[0086] Figure 2 is a graph showing the ratio of CPC 1-2, 3, and 4-5 scores 90 days after the first dose of medication in cardiac arrest patients who were successfully resuscitated and received hypothermia therapy.

[0087] CPC 1-2, patients capable of independent activities (Good neurological outcome)

[0088] CPC 3, patients with moderate disability

[0089] CPC 4-5, coma or brain death (poor neurological outcome)

[0090] HIGH, high-dose nelonemdaz group; LOW, low-dose nelonemdaz group; PLACEBO, placebo group

[0091] Hereinafter, the present invention will be described in detail, using examples and the like, to aid understanding. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0092]

[0093] 1. Design of the Phase 2 Cardiac Arrest (AWAKE) Trial

[0094] The Phase 2 clinical trial (AWAKE) was conducted in patients with severe or comatose cardiac arrest who arrived at the emergency department within 4 hours of ROSC and received therapeutic hypothermia (TTM). The study aimed to investigate the efficacy and safety of nelonemdaz administered intravenously for 3 days. A total of 105 patients, aged 19 to 80 years, were enrolled in the AWAKE trial and randomly assigned in a double-blind manner to one of three groups receiving intravenous treatment with the study drug. The placebo group received 250 ml of 0.9% saline intravenously for six doses every 12 hours for 3 days. The low-dose group received a total of 3,250 mg of nelonemdaz (750 mg initially, followed by 500 mg every 12 hours for the second to sixth doses). The high-dose group received a total of 5,250 mg of nelonemdaz (1,500 mg for the first dose, followed by 750 mg every 12 hours for the second to sixth doses). Patients with out-of-hospital cardiac arrest, who regained spontaneous circulation (ROSC) lasting more than 20 minutes, and who received hypothermia at 32-34°C for 24 hours upon arrival at the hospital were enrolled. The patients received the study drug within 4 hours of ROSC. Neurological outcomes were analyzed using the modified Rankin Scale (mRS) and Cerebral Performance Category (CPC) analysis 90 days after the first dose in patients who were severely ill or comatose before administration of the study drug. White matter damage was assessed by diffusion tensor MRI (DTI) imaging on days 4 or 5 after the first dose.

[0095] Modified Rankin Scale (mRS)

[0096] The Modified Rankin Scale (MRS) is a widely used analytical method in clinical trials to assess the degree of disability in patients with stroke and cardiac arrest. The criteria listed in the table below are used for evaluation.

[0097] mRS Score Evaluation Criteria 0 No disability 1 Symptoms but no disability 2 Mild disability that allows independent activities 3 Mild disability that requires assistance but can walk independently 4 Moderate disability that cannot walk but can eat and wash independently 5 Severe disability that requires constant assistance 6 Death

[0098]

[0099] Cerebral Performance Category (CPC)

[0100] The Cerebral Performance Category (CPC) is a scale used to analyze neurological outcomes after cardiac arrest, with scores ranging from 0 (normal) to 5 (death). Evaluations were made using criteria as shown in the table below.

[0101] CPC Score Evaluation Criteria 1. Normal, symptoms may be present but no disability 2. Moderate disability, disability but able to function independently 3. Severe disability, consciousness but needs assistance with daily life 4. Coma, unconscious 5. Brain dead

[0102]

[0103] Diffusion tensor MRI (DTI, diffusion tensor MR imaging)

[0104] In the white matter of the brain, water molecules move in a direction parallel to the direction of nerve fiber bundles. Fractional anisotropy (FA) indicates the direction of water molecule diffusion, and low FA indicates that the directionality of water molecule diffusion is reduced due to damage to the white matter. The white matter protective effect of nelonemdaz was analyzed by comparing whole-brain and regional anisotropy values ​​obtained from DTI images of resuscitated cardiac arrest patients who received nelonemdaz and the placebo group. Resuscitated cardiac arrest patients received TTM treatment upon arrival at the hospital and received the drug for three days within four hours of resuscitation. Diffusion tensor MRI images were acquired within 48 hours after the last drug administration.

[0105] To analyze FA values ​​in the entire brain tissue, preprocessing such as image and motion noise removal and skull removal was performed to extract diffusion parameters, and FA corresponding to the entire brain tissue was calculated.

[0106] To calculate the FA average by region, individual FA maps were moved / aligned to a standardized space using nonlinear alignment techniques, and since FA can mainly identify the white matter part, it was calculated by overlaying only the JHU DTI-based white-matter atlas.

[0107] The Wilcoxon rank sum test was used to analyze the statistical differences between the high-dose group and the placebo control group, and between the low-dose group and the placebo control group.

[0108]

[0109] Experimental Example 1: Safety of nelonemdaz in patients with cardiac arrest who were successfully resuscitated and received hypothermia therapy.

[0110] Unexpected side effects, such as schizophrenic symptoms, have been observed in healthy individuals and patients with ischemic stroke treated with NMDA receptor antagonists, limiting their clinical research and application (Hoyte, L. et al., (2004). "The rise and fall of NMDA antagonists for ischemic stroke." Curr Mol Med4(2): 131-136.). The safety of nelonemdaz, a selective NR2B NMDA receptor antagonist, was investigated in patients with cardiac arrest who were successfully resuscitated and receiving therapeutic hypothermia. The results are presented in the table below.

[0111] Summary of serious adverse events (AEs) occurring after administration of placebo and nelonemdaz K in patients with cardiac arrest who were successfully resuscitated and treated with hypothermia.

[0112] SafetyNelonemdaz K 5.25g (N=37)Nelonemdaz K 3.25g (N=34)Placebo (N=33)Incidence of serious adverse reactionsN0 (0.00%)0 (0.00%)0 (0.00%)Incidence of serious adverse reactions related to medicationN0 (0.00%)0 (0.00%)0 (0.00%)Note: Number of patients with adverse reactions (% of patients with adverse reactions)

[0113] Compared to the placebo group, no specific side effects, including schizophrenic symptoms, were observed in the low-dose (3,250 mg) or high-dose nelonemdaz (5,250 mg) groups.

[0114]

[0115] Experimental Example 2: The effect of nelonemdaz on improving disability in patients with cardiac arrest who were successfully resuscitated and receiving hypothermia treatment (mRS evaluation)

[0116] The efficacy of nelonemdaz in improving disability outcomes in patients with cardiac arrest who were successfully resuscitated and receiving TTM treatment was analyzed using the modified Rankin Scale (mRS). At 90 days after the first dose, the proportion of patients with an mRS of 0 (normal) was 37.04% in the placebo group, while the proportions of patients with an mRS of 0 increased to 48.15% and 55.56% in the low-dose and high-dose nelonemdaz groups, respectively. Detailed results are presented in the table below.

[0117] Modified Rankin Scale (mRS) scores before and 90 days after the first dose of medication in cardiac arrest patients who were resuscitated and treated with hypothermia

[0118] Nelonemdaz K 5.25g (N=27) Nelonemdaz K 3.25g (N=27) Placebo (N=27) Before administration N=27 N=27 N=27 mRS0001002003004003 (10.34%)527 (100%)27 (100%)24 (82.76%)600090 days after the first administration N=27 N=27 N=27 mRS015 (55.56%)13 (48.15%)10 (37.04%)11 (3.70%)2 (7.41%)1 (3.70%)21 (3.70%)0 (0.00%)0 (0.00%)30 (0.00%)1 (3.70%)0 (0.00%)40 (0.00%)0 (0.00%)0 (0.00%)51 (3.70%)3 (11.11%)2 (7.41%)69 (33.33%)8 (29.63%)14 (51.85%)Common Odds Ratio* (95% CI)2.243 (0.806, 6.242)1.975 (0.714, 5.461)1 (Ref)

[0119] * Odds ratio (95% CI) for a shift in the mRS score distribution indicating improvement in disability in the nelonemdaz group compared to the placebo group

[0120] At 90 days after drug administration, there was a clear tendency for disability and death to be reduced in patients administered nelonemdaz K compared to the placebo group. In particular, the proportion of subjects corresponding to mRS 0-2 (good neurological outcome: patients capable of independent activities) increased 1.375-fold from 40.74% (11 / 27) in the placebo group to 55.56% (15 / 27) in the low-dose group, and the proportion of subjects corresponding to mRS 5-6 (poor neurological outcome: severe coma or death) at 90 days after drug administration decreased 1.31-fold from 59.26% (16 / 27) in the placebo group to 40.74% (11 / 27) in the low-dose group, and the proportion of subjects corresponding to mRS 5-6 (poor neurological outcome: severe coma or death) improved 1.38-fold to 37% (10 / 27) in the high-dose group.

[0121] These results suggest that patients with cardiac arrest who are successfully resuscitated and in a coma can improve their disability and reduce coma and death if they receive combination therapy with nelonemdaz and TTM within 4 hours.

[0122]

[0123] Experimental Example 3: The effect of nelonemdaz on improving disability in patients with cardiac arrest who were successfully resuscitated and receiving hypothermia treatment (CPC evaluation).

[0124] Meanwhile, the efficacy of nelonemdaz was analyzed in patients with severe disability or coma who were successfully resuscitated and received cryotherapy from cardiac arrest using the Cerebral Peripheral Component (CPC; 1 = normal, 2 = moderate disability, 3 = severe disability, 4 = coma, 5 = death). The results are shown in the table below.

[0125] Cerebral Performance Category (CPC) scores before and 90 days after the first dose of medication in cardiac arrest patients who were resuscitated and treated with hypothermia therapy

[0126] Nelonemdaz K 5.25g (N=27) Nelonemdaz K 3.25g (N=27) Placebo (N=27) Before administration N272727CPC 10 (0.00%)0 (0.00%)0 (0.00%)CPC 20 (0.00%)0 (0.00%)0 (0.00%)CPC 31 (3.70%)1 (3.70%)1 (3.70%)CPC 426 (96.30%)26 (96.30%)26 (96.30%)CPC 50 (0.00%)0 (0.00%)0 (0.00%)Common Odds Ratio* (95% CI)1.00 (0.06-16.86)1.00 (0.06-16.86)1(Ref)1st administration After 90 daysN272727CPC 116 (59.26%)15 (55.56%)11 (40.74%)CPC 21 (3.70%)0 (0.00%)0 (0.00%)CPC 30 (0.00%)2 (7.41%)0 (0.00%)CPC 41 (3.70%)2 (7.41%)2 (7.41%)CPC 59 (33.33%)8 (29.63%)14 (51.85%)Common OddsRatio* (95% CI)2.22 (0.78-6.30)2.13 (0.75-6.03)1 (Ref)

[0127] *: Odds ratio (95% CI) for a shift in the CPC score distribution indicating improvement in disability in the nelonemdaz group compared to the placebo group

[0128] As shown in the table above, on the 90th day after the first administration of the drug, the proportion of CPC 1 patients who recovered qualitatively in the placebo group was 40.74%, while in the low-dose nelonemdaz group and the high-dose nelonemdaz group, these proportions increased to 55.56% and 59.26%, respectively. In addition, the proportion of patients with CPC 5 who died was found to be reduced in the low-dose (29.63%) and high-dose (33.33%) nelonemdaz groups compared to the placebo group (51.85%).

[0129] The proportion of CPC 1-2 (Good Outcome) patients who recovered to the point of independent living 90 days after drug administration was 40.74% in the placebo group, increased 1.36-fold to 55.55% in the low-dose nelonemdaz group, and improved 1.55-fold to 62.96% in the high-dose nelonemdaz group (Fig. 2). The proportion of CPC 4-5 (Poor Outcome) patients who deteriorated to a coma or brain death state was 59.26% in the placebo group, and decreased to 37.04% in the low-dose and high-dose nelonemdaz groups. The CPC analysis results suggest that administration of nelonemdaz improves disability and reduces coma and brain death in patients with cardiac arrest who are successfully resuscitated and receive cryotherapy.

[0130]

[0131] Experimental Example 4: Brain Tissue Protective Effect of Nelonemdaz in a Cardiac Arrest Patient Who Was Successfully Resuscitated and Received Cryotherapy

[0132] In this study, we investigated the effect of nelonemdaz on white matter (nerve fibers containing axons) damage by comparing fractional anisotropy (FA) values ​​obtained from diffusion tensor MRI (DTI) in cardiac arrest patients who were successfully resuscitated and received TTM treatment. DTI is a method that can determine the level of brain damage by utilizing information on the diffusion of water molecules between nerve fiber bundles that make up the white matter in the brain tissue. Normal cerebral white matter shows high diffusion anisotropy, whereas if there is brain damage, diffusion anisotropy is reduced. By comparing fractional anisotropy (FA), which can quantitatively determine this diffusion anisotropy, we analyzed damage to the entire brain and each region.

[0133] Among 105 patients randomly assigned according to the clinical protocol, 54 patients (14 in the placebo group, 22 in the low-dose nelonemdaz group, and 18 in the high-dose nelonemdaz group) underwent diffusion tensor imaging (DTI), and white matter damage was analyzed in patients for whom imaging was available. The results are presented in the table below.

[0134] Whole brain white matter and regional white matter anisotropy (FA) 5 days after the first dose of medication in a cardiac arrest patient who was successfully resuscitated and treated with hypothermia.

[0135]

[0136] The median total brain white matter FA was 0.441 (0.431-0.464) in the placebo group, 0.462 (0.439-0.480) in the low-dose nelonemdaz group, and 0.465 (0.449-0.485) in the high-dose nelonemdaz group. In particular, the total brain white matter FA value was significantly (P = 0.028) increased in the high-dose nelonemdaz group compared to the placebo group.

[0137] The median FA values ​​by region tended to increase overall in the high-dose nelonemdaz group compared to the placebo group. In particular, damage to the corpus callosum (connecting the left and right hemispheres), superior fronto-occipital fasciculus (connecting the frontal lobe and the occipital lobe), fornix (connecting the limbic system responsible for cognitive function and memory), anterior limb of internal capsule (connecting the cerebral cortex and the thalamus), middle cerebellar peduncle (connecting the pons and microglial gyrus), and superior cerebellar peduncle (connecting the midbrain and cerebellum) was significantly reduced by high-dose nelonemdaz.

[0138] White matter accounts for 50% of the brain and is known to be damaged even by brief transient cerebral ischemia. White matter damage was observed throughout the brains of patients with cardiac arrest who successfully recovered, and DTI images taken within three weeks of cardiac arrest reported greater white matter damage (lower FA values) in patients with a poor prognosis compared to those with a good prognosis. These research results suggest that the early white matter protective effect of nelonemdaz, demonstrated in patients with cardiac arrest who recovered successfully, is associated with long-term improvements in neurological dysfunction.

Claims

1. A method for reducing mortality in a subject, improving neurological deficits, or improving activities of daily living, characterized by administering a therapeutically effective amount of a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from cardiac arrest undergoing targeted temperature management (TTM); a subject suffering from ischemic or hemorrhagic stroke undergoing TTM; a subject suffering from traumatic brain or spinal cord injury undergoing TTM; a subject suffering from hypoxic-ischemic encephalopathy undergoing TTM; or a subject suffering from hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia: [Chemical Formula 1] In chemical formula 1, R1, R2, and R3 are independently hydrogen or halogen, R4 is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C 10 alkanoyloxy or nitro, R5 is a carboxylic acid, a carboxylic acid ester, a carboxamide, a sulfonic acid, a halogen, or a nitro.

2. A method according to claim 1, wherein the subject is a subject who has suffered cardiac arrest and is receiving TTM.

3. In the first or second paragraph, the compound 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid (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 A method wherein at least one of the following is selected from the group consisting of:

4. A method in claim 3, wherein the compound is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid or a pharmaceutically acceptable salt thereof.

5. A method in claim 4, wherein the compound is administered as a potassium salt of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid.

6. A method according to claim 1 or 2, wherein the compound is administered in the form of an injectable solution containing 50 mg to 2,000 mg of the compound.

7. A method in claim 6, wherein the pH of the injectable solution is 8-11.

8. In the first or second paragraph, the compound (a) Administered at a dose of 250 mg to 1500 mg twice daily for 1 to 3 days; (b) administered at a total dose of 5,250 mg for 3 days; (c) administered 6 times in total over 3 days, the first dose being 1500 mg and the remaining doses being 750 mg each, with each dose administered approximately 12 hours apart; (d) administered in a total dose of 3,250 mg over 3 days; or (e) Administered a total of 6 times over 3 days, the first dose being 750 mg and the remaining doses being 500 mg each, with each dose administered at approximately 12 hour intervals. A method characterized by that.

9. A method according to paragraph 8, wherein the administration is performed intravenously.

10. A method according to claim 1 or 2, wherein the hypothermia treatment is performed such that the core body temperature of the subject is maintained between 32°C and 36°C.

Images