Use of compounds in the prevention or treatment of radiation-induced brain injury

Abstract

This invention relates to the use of 5α-androsta-3β,5,6β-triol and its derivatives in the prevention or treatment of radiation-induced brain injury, and to methods for preventing or treating radiation-induced brain injury with 5α-androsta-3β,5,6β-triol and its derivatives.

Description

[Technical Field]

[0001] This disclosure relates to the use of 5α-androsta-3β,5,6β-triol and its derivatives in the prevention or treatment of radiation-induced brain injury. [Background technology]

[0002] Radiotherapy is an important treatment method for primary and metastatic head and neck tumors. Diseases involving central nervous system injury symptoms that occur in head and neck tumor patients after radiotherapy are serious complications following radiotherapy. The incidence of radiation-induced brain injury (RBI) after stereotactic radiotherapy for meningiomas is 28-50%, the 4-year cumulative incidence of radiation-induced brain injury after radiotherapy for nasopharyngeal cancer is 1.9-5%, the 4-year cumulative incidence of radiation-induced brain injury after radiotherapy for poorly differentiated gliomas is 1-24%, and the 1-year cumulative incidence of radiation-induced brain injury after radiotherapy for brain metastases is 8-20%. In cases of radiation-induced brain injury with nasopharyngeal cancer as the initial disease, 33% of patients eventually progress to bilateral temporal lobe radiation-induced brain injury. The acceptable cumulative total radiotherapy dose to brain tissue is 50-60 Gy; outside this range, the incidence of radiation-induced brain injury clearly increases as the cumulative total radiotherapy dose increases. In patients undergoing re-irradiation therapy, the 5-year cumulative incidence of radiation-induced brain injury exceeds 20%. Radiation damage is receiving increasing attention, especially now that patient quality of life is the second most important factor after survival rate in evaluating the effectiveness of radiation therapy.

[0003] Radiation-induced brain injury (RBI) is classified into acute, early-delayed, and late-delayed types based on the time of onset. Acute radiation-induced brain injury is usually part of the multi-organ damage seen in acute radiation syndrome (ARS). Symptoms usually develop during or within a few days to a month after radiation therapy, and in many cases, symptoms such as headache, nausea, vomiting, and memory impairment appear early after irradiation. In severe cases, it can quickly progress to impaired consciousness, disorientation, and ataxia, and may lead to stupor and death within a few days. Early-delayed types usually develop 1 to 6 months after irradiation and may include lethargy, nausea, vomiting, irritability, and memory impairment, as well as transient fatigue or worsening of focal neurological symptoms. Clinical subtypes such as hypersomnia, brainstem encephalitis, and pseudo-tumor exacerbation may be observed. The late-onset delayed reaction occurs six months after the end of irradiation and is the most common clinical type of radiation-induced brain injury. Also known as late-onset radiation-induced brain injury, it is frequently seen when the radiation dose to the brain exceeds 50 Gy.

[0004] The conventional treatment for radiation-induced brain injury is glucocorticoids, but glucocorticoid treatment for radiation-induced brain injury is currently based almost entirely on clinical experience, case reports, and retrospective studies, and lacks large-scale randomized controlled clinical trials. A randomized, double-blind, placebo-controlled trial in 2011 showed that patients using bevacizumab all experienced some degree of reduction in brain injury lesions and a clear improvement in neurological function. Furthermore, in subsequent 10-month follow-up visits, only two patients experienced a recurrence of radiation-induced brain injury. There are research findings that report that injectable mouse nerve growth factor reduces damage to the blood-brain barrier in animals and has the effect of repairing microvessels, suggesting that it may promote recovery from radiation-induced brain injury. Furthermore, the use of dehydrating agents is not a standard symptomatic treatment for radiation-induced brain injury. Instead, it is recommended for short-term use over a 5-7 day period only when the patient's condition is rapidly progressing and there is radiographic evidence of an acute compressive effect on the radiation-induced brain injury lesion.

[0005] Currently, clinical practice still requires medications for radiation-induced brain injury. [Overview of the project]

[0006] One aspect of the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the prevention or treatment of radiation-induced brain injury, [ka] (Equation I) In the formula, R1 is H, -CN, fluorine, chlorine, C 1~10 C substituted with alkyl groups, fluorine, or chlorine 1~10 Alkyl alkyl group, C 1~10 C substituted with alkoxy groups, fluorine, or chlorine 1~10 Alkoxy groups and C 3~10 Selected from cycloalkyl groups.

[0007] Another aspect of the present invention provides a method for preventing or treating radiation-induced brain injury, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a subject undergoing radiotherapy.

[0008] Another aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for preventing or treating radiation-induced brain injury.

[0009] In any of the above embodiments, in some cases, the radiation dose for radiation-induced brain injury is 50 Gy or more.

[0010] In any of the above embodiments, in some cases, the radiation-induced brain injury is gamma-ray radiation-induced brain injury.

[0011] In any of the above embodiments, in some cases, the radiation-induced brain injury is either an early-delayed response type or a late-delayed response type radiation-induced brain injury.

[0012] In any of the above embodiments, in some cases, the radiation-induced brain injury is the edematous or necrotic phase of late-stage radiation-induced brain injury.

[0013] In any of the above embodiments, in some embodiments, R1 is H, -CHCH2CH3, -CH(CH3)2, -CH(CH2)3CH3, or -CH(CH3)(CH2)3CH(CH3)2, preferably R1 is H.

[0014] The compounds provided in this invention reduce brain tissue damage caused by gamma ray irradiation and have a good preventive or therapeutic effect against RBI. [Brief explanation of the drawing]

[0015] [Figure 1] This is a flowchart for a study evaluating the effects of YC-6 on localized radiation-induced brain injury in C57BL / 6 mice induced by gamma knife irradiation. [Figure 2] YC-6 significantly reduces the volume of gamma-ray-induced radiation-induced brain damage. Figure A shows representative MRI images of animals; the five brain images in each column show brain tissue from the same animal, with white signal areas indicating damaged lesions. Figure B shows the reduction of brain tissue damage caused by gamma-ray irradiation. Comparison with the RBI + saline (RBI + Saline) model group, *P<0.05. [Figure 3] YC-6 suppresses astrocyte activation after radiation-induced brain injury. Figure A shows immunofluorescence staining of GFAP in the thalamic region of a brain lesion, with the white scale bar representing 200 μm. Figure B shows the count of GFAP-positive cells in Figure A; that is, three fields of view were randomly selected from the damaged lesion area of ​​a brain section, and GFAP-positive cells were counted in the selected fields of view using ImageJ software, representing the average number of GFAP-positive cells per unit area. ****P<0.0001, n=5. [Figure 4]YC-6 suppresses the reduction of oligodendrocytes and restores the MAG level. Figure A shows the CC1 and MAG immunofluorescence staining of the thalamic region of the brain lesion, and the white scale bar represents 200 μm. Figure B shows the counting of CC1-positive cells in Figure A, that is, three fields of view were randomly selected from the damaged lesion area of the brain section, and using the software Image J, CC1-positive cells were counted for the selected fields of view, which is the average number of CC1-positive cells per unit area. Figure C shows the statistics of the MAG immunofluorescence intensity in Figure A, that is, three fields of view were randomly selected from the damaged lesion area of the brain section, and using the software Image J, the fluorescence signal intensity of MAG was quantified for the selected fields of view, which is the average fluorescence intensity of MAG per unit pixel area. ****P<0.0001, n=5.

Mode for Carrying Out the Invention

[0016] (Definition) As used herein, the term "composition" refers to a formulation suitable for administration to a given animal subject for therapeutic purposes and contains at least one pharmaceutical active ingredient, for example, a compound. Optionally, the composition further contains at least one pharmaceutically acceptable carrier or additive.

[0017] The term "pharmaceutically acceptable" means that the substance in question has no properties that would cause a medical professional to avoid administering the substance to a patient, taking into account the disease or condition being treated and the route of administration. For example, in the case of an injection, it is usually necessary for such a substance to be substantially sterile.

[0018] As used herein, the terms "preventive effective amount" and "therapeutic effective amount" mean that the substance and the amount of the substance are effective in preventing, alleviating or improving one or more symptoms of a disease or medical condition and / or extending the survival period of a subject receiving treatment.

[0019] As used herein, the term "treatment" includes administering a compound of the present application or a pharmaceutically acceptable salt thereof to reduce the symptoms or complications of a disease or medical condition, or to eliminate the disease or medical condition. As used herein, the term "reduction" is used to describe the process in which the phenomenon of a medical condition is alleviated or the severity of the symptoms is reduced. There may be cases where the symptoms are not eliminated but are reduced. In one embodiment, when the pharmaceutical composition of the present application is administered, the phenomenon or symptoms are eliminated.

[0020] As used herein, "prevention" includes administering a compound of the present application or a pharmaceutically acceptable salt thereof to prevent a specific disease, symptom or complication.

[0021] As used herein, "C 1~10 ", "C 3~10 " or similar terms refer to having 1 to 10 or 3 to 10 carbon atoms. For example, a C 1~10 alkyl group refers to an alkyl group having 1 to 10 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a decyl group, etc.

[0022] (Compound and pharmaceutically acceptable salt thereof) The compounds that can be used in the method or use of the present invention include compounds of formula I or pharmaceutically acceptable salts thereof,

Chemical formula

[0023] In one embodiment, R1 is H, that is, the compound is 5α-androsta-3β,5,6β-triol (sometimes denoted as "YC-6" in this invention), and its structural formula is as shown in formula (II). [ka] (Formula II)

[0024] In one embodiment, R1 is -CHCH2CH3, and the compound is 17-propylene-androsta-3β,5α,6β-triol. In one embodiment, R1 is -CH(CH3)2, and the compound is 17-isopropyl-androsta-3β,5α,6β-triol. In one embodiment, R1 is -CH(CH2)3CH3, and the compound is 17-butyl-androsta-3β,5α,6β-triol. In one embodiment, R1 is -CH(CH3)(CH2)3CH(CH3)2, and the compound is cholestane-3β,5α,6β-triol.

[0025] The compounds of the present invention can be formulated as pharmaceutically acceptable salts. Desired pharmaceutically acceptable salt forms include, but are not limited to, monosal, disal, trisal, and tetrasal forms. Pharmacologically acceptable salts are nontoxic at the amounts and concentrations they are administered. Such salts can be pharmacologically used by altering the physical properties of the compound, provided that their physiological effects are not hindered. Useful alterations to physical properties include lowering the melting point for transmucosal administration and increasing solubility for drug administration at higher concentrations.

[0026] Pharmacologically acceptable salts may be acid addition salts, such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclamate, and quinate. Pharmacologically acceptable salts may also be derived from acids, such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, fumarate, and quinic acid.

[0027] When acidic functional groups, such as carboxylic acids or phenols, are present, pharmaceutically acceptable salts may be base addition salts, such as those containing benzylpenicillin benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. Such salts can be prepared using appropriate corresponding bases.

[0028] Pharmaceutically acceptable salts can be prepared using standard techniques. For example, a compound in the form of a free base is dissolved in a suitable solvent, such as an aqueous solution or water-alcohol solution containing a suitable acid, and then the solution is evaporated to separate the compounds. In another example, the salt is prepared by reacting the free base with an acid in an organic solvent.

[0029] When a particular compound is a base, a pharmaceutically acceptable salt of the desired type can be produced by any suitable method of the art. For example, the free base is treated with an inorganic or organic acid. The inorganic acid is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an analog; the organic acid is, for example, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidylic acid (e.g., glucuronic acid, galacturonic acid), α-hydroxy acids (e.g., citric acid, tartaric acid), amino acids (e.g., aspartic acid, glutamic acid), aromatic acids (e.g., benzoic acid, cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid, ethanesulfonic acid, or analogs).

[0030] Similarly, when a particular compound is an acid, a pharmaceutically acceptable salt of the desired type can be produced by any suitable method. For example, by treating the free acid with an inorganic or organic base. The inorganic or organic base is, for example, an amine (primary, secondary, or tertiary amine), an alkali metal hydroxide, an alkaline earth metal hydroxide, or an analogue. Non-limiting examples of suitable salts include organic salts derived from amino acids (e.g., L-glycine, L-lysine, L-arginine), ammonia, primary, secondary, and tertiary amines, cyclic amines (e.g., hydroxyethylpyrrolidine, piperidine, morpholine, piperazine), and inorganic salts containing sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0031] pharmaceutically acceptable salts of compounds may exist in the form of complexes. Examples of such complexes include 8-chlorotheophylline complexes (e.g., dimenhydrinate, a 1:1 complex of diphenhydramine and 8-chlorotheophylline) and various complexes including cyclodextrins.

[0032] (Pharmaceutical composition) In another aspect of the present invention, a pharmaceutical composition is provided comprising a therapeutic or prophylactic effective amount of a compound of formula I (e.g., YC-6) or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0033] In the present invention, “pharmaceutical composition” refers to a composition comprising a compound of formula I and a pharmaceutically acceptable carrier, wherein the compound and the pharmaceutically acceptable carrier are mixed in the composition. The compositions are generally used for the treatment of human subjects. They are also used for the treatment of the same or similar medical conditions in other animals. In this specification, “subject,” “animal subject,” or similar terms refer to humans and non-human vertebrates, such as mammals (e.g., non-human primates), sports animals and farm animals (e.g., horses, cattle, pigs, sheep, rodents), and companion animals (e.g., dogs, cats).

[0034] The appropriate dosage form is determined in part by the route of use or administration (e.g., oral, dermal, mucosal, inhalation, or injection (parenteral)). The dosage form is determined so that the compound is delivered to the target cells. Other factors are well known in this art and include considerations such as toxicity and dosage forms that may delay the onset of action of the compound or composition.

[0035] A carrier or additive can be used to manufacture the composition. The carrier or additive may be selected to facilitate the administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate, various sugars (e.g., lactose, glucose, sucrose), starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and physiologically suitable solvents. Examples of physiologically suitable solvents include water for injection (WFI), sterile solutions, salt solutions, and glucose.

[0036] The composition or its components can be administered via various routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, transrectal, transdermal, and inhalation. In some embodiments, it is preferable to use an injectable or lyophilized injectable preparation. For oral administration, for example, the compound can be formulated as a standard oral dosage form (e.g., capsules, tablets) or a liquid preparation (e.g., syrup, elixir, concentrated drops).

[0037] Oral pharmaceutical formulations can be obtained. For example, tablets or sugar-coated tablets can be obtained by combining a composition or its components with a solid additive, optionally polishing the mixture, or (if necessary) adding appropriate auxiliary agents, and then processing the granular mixture. Suitable additives include, in particular, excipients (e.g., sugars such as lactose, sucrose, mannitol, and sorbitol), cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tarakanto gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP, also known as povidone). If necessary, disintegrants (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid, or salts thereof (e.g., sodium alginate)) can be added.

[0038] Optionally, formulations for injection (parenteral administration), such as intramuscular, intravenous, intraperitoneal, and / or subcutaneous administration, may be used. In the case of injection, the composition or components of the present invention are prepared as a sterile liquid solution. Preferably, they are prepared in a physiologically compatible buffer or solution, such as physiological saline, Hank's solution, or Ringer's solution. Alternatively, the composition or components may be prepared in solid form and redissolved or suspended immediately before use. It can also be manufactured as a lyophilized powder.

[0039] It can also be administered via mucosal, topical, or transdermal means. When administered via mucosal, topical, or transdermal means, a penetrating agent suitable for the barrier to be penetrated should be used in the formulation. Such penetrating agents are generally known in this field. For example, in the case of mucosal administration, bile salts and fusidic acid derivatives can be used. Detergents can also be used to promote penetration. For mucosal administration, for example, nasal sprays and suppositories can be used.

[0040] The effective dose of each component administered can be determined by standard procedures. Factors to consider include, for example, the IC of the compound in question. 50 These factors include the biological half-life of the compound, the age, volume, and weight of the recipient, and other medical conditions in the recipient. The importance of these and other factors is well known to those skilled in the art. Generally, the dose to the target is approximately 0.01 mg / kg to 50 mg / kg, preferably 0.1 mg / kg to 20 mg / kg. Multiple doses may also be used.

[0041] The compositions or components of the present invention may also be used in combination with other therapeutic agents for the same disease. Such combinations include administering the compound and one or more other therapeutic agents at different times, or using the compound and one or more other therapeutic agents simultaneously. In some embodiments, the doses of one or more compounds of the present invention or other therapeutic agents used in combination may be modified. For example, the dose may be reduced compared to the compound or therapeutic agent used alone, in a manner known to those skilled in the art.

[0042] Furthermore, combined use or concurrent use includes use with other therapies, drugs, medical procedures, etc., where such other therapies or procedures may be administered at different times from the administration of the composition or components of the present invention (for example, within a short period (e.g., a few hours (e.g., 1, 2, 3, 4 to 24 hours)) or within a relatively long period (e.g., 1 to 2 days, 2 to 4 days, 4 to 7 days, 1 to 4 weeks)), or at the same time as the administration of the composition or components of the present invention. Combined use also includes use simultaneously with a one-time or infrequent therapy or medical procedure (e.g., surgery), where the composition or components of the present invention are administered before or after such other therapy or procedure within a short or relatively long period. In some embodiments, the present invention is used to deliver the composition or components of the present invention and one or more other therapeutic agents, which are delivered by the same or different routes of administration.

[0043] Combining administration routes includes simultaneously delivering the composition or components of the present invention and one or more other therapeutic agents as any formulation via the same administration route, such formulations include those in which two chemically bonded compounds retain their respective therapeutic activity upon administration. In one embodiment, such other pharmacotherapy can be used simultaneously with the composition or components of the present invention. Combining administration for simultaneous delivery includes the administration of a co-formulation or a formulation of chemically bonded compounds, or the administration of two or more independent formulations of compounds within a short period of time (e.g., within 1 hour, 2 hours, 3 hours, or 24 hours), which may be administered via the same or different routes.

[0044] Co-administration of independent formulations includes delivery and simultaneous administration using the same device, for example, using the same inhaler, the same syringe, etc., or administration using different devices at short intervals. Combinations of the compounds of the present invention and one or more additional pharmacotherapies delivered via the same route of administration include formulations prepared by combining materials for administration using the same device, formulations in which different compounds are combined into the same formulation, or formulations modified so that the biological activity of each compound is retained even when chemically bonded. Such chemically bonded compounds may contain a linker that separates two active components, and the linker may be substantially retained in the body or may be degraded in the body.

[0045] (Medical use and treatment methods) In one embodiment, the present invention provides the use of any compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the prevention or treatment of a radiation-induced brain injury of a subject.

[0046] In another embodiment, the present invention provides a method for preventing or treating radiation-induced brain injury in a subject, comprising administering to the subject in need a therapeutically effective amount of any compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any compound of Formula I or a pharmaceutically acceptable salt thereof.

[0047] In another embodiment, the present invention provides a pharmaceutical composition comprising any compound of Formula I or a pharmaceutically acceptable salt of the present invention, or any compound of Formula I or a pharmaceutically acceptable salt of the present invention, for the prevention or treatment of radiation-induced brain injury.

[0048] In any of the above embodiments, in a preferred embodiment, the compound is YC-6.

[0049] In any of the above embodiments, in a preferred embodiment, the radiation dose for the radiation-induced brain injury is 50 Gy or more, for example, 50 Gy to 100 Gy, for example, 50 Gy to 90 Gy, 50 Gy to 80 Gy, 50 Gy to 70 Gy, 50 Gy to 60 Gy, 60 Gy to 100 Gy, 60 Gy to 90 Gy, 60 Gy to 80 Gy, 60 Gy to 70 Gy, 70 Gy to 100 Gy, 70 Gy to 90 Gy, 70 Gy to 80 Gy, 80 Gy to 100 Gy, 80 Gy to 90 Gy, or 90 Gy to 100 Gy. In any of the above embodiments, in a preferred embodiment, the radiation dose for the radiation-induced brain injury is 100 Gy or less. For example, the radiation dose for radiation-induced brain injury is 50 Gy, 55 Gy, 60 Gy, 65 Gy, 70 Gy, 75 Gy, 80 Gy, 85 Gy, 90 Gy, 95 Gy, or 100 Gy. In other embodiments, the radiation dose for radiation-induced brain injury is less than 50 Gy. In other embodiments, the radiation dose for radiation-induced brain injury is higher than 100 Gy.

[0050] In any of the above embodiments, in a preferred embodiment, the radiation-induced brain injury is gamma-ray radiation-induced brain injury, such as cobalt-60 gamma rays. In any of the above embodiments, in another embodiment, the radiation-induced brain injury is brain injury induced by alpha rays, beta rays, gamma rays, X-rays, neutrons, electron beams, proton beams, particle beams, and combinations thereof. Conventional X-ray machines are used to treat superficial tumors. High-energy X-rays produced by various accelerators can treat tumors in any location, and are particularly effective in treating deep tumors.

[0051] In any of the above embodiments, the radiation-induced brain injury is acute, early-delayed-reaction, or late-delayed-reaction type, and is preferably late-delayed-reaction type radiation-induced brain injury. Based on imaging findings and characteristics, the late-delayed-reaction type can be divided into non-lesional stage, edematous stage, necrotic stage, and cystic stage, and each stage may appear simultaneously or sequentially in different parts of the brain of the same patient. (1) Non-lesional stage: The patient does not have a lesion visible on imaging, but has clinical findings of brain injury including brain injury symptoms that newly occur after radiotherapy, such as headache, cognitive impairment, epileptic seizures, and neurological dysfunction (numbness in the limbs, etc.). (2) Edematous stage: Head imaging reveals that the brain injury lesion is mainly characterized by white matter edema and has an indistinct border. (3) Necrotic stage: Localized necrosis is seen in the brain tissue lesion, which may be accompanied by hemorrhage or exudation, the signal is heterogeneous on head MRI, and enhancement is seen on contrast-enhanced CT scans. (4) Cystic stage: Patient head MRI shows clear boundaries of the radiation-induced brain injury lesion, indicating cystic changes, with signals similar to those of free water, regardless of the presence or absence of compression effect. Cystic lesions may remain stable for a long period, but can rapidly increase in size, leading to brain herniation, and the patient may experience decreased consciousness, stupor, or even death. In preferred embodiments, the radiation-induced brain injury is the edematous or necrotic stage of late-stage delayed-response radiation-induced brain injury.

[0052] Therefore, in some preferred embodiments of the present invention, the radiation-induced brain injury is brain injury induced by gamma-ray radiation of 50 Gy or more, for example, brain injury induced by gamma-ray radiation of 50 Gy or 60 Gy. In some preferred embodiments of the present invention, the radiation-induced brain injury is gamma-ray early-delayed-response type or late-delayed-response type radiation-induced brain injury, for example, gamma-ray late-delayed-response type radiation-induced brain injury. In some preferred embodiments of the present invention, the radiation-induced brain injury is the edematous or necrotic phase of gamma-ray late-delayed-response type radiation-induced brain injury.

[0053] In any of the above embodiments, the subject has a tumor, for example, a nervous system tumor (e.g., brain tumor, medulloblastoma, neuroblastoma, pituitary tumor) or a head and neck tumor. The term "head and neck tumor" mainly includes three types depending on the location: cervical tumors, otolaryngological tumors, and oral and maxillofacial tumors. Cervical tumors include, for example, thyroid tumors; otolaryngological tumors include, for example, nasopharyngeal cancer, laryngeal cancer, paranasal sinus cancer, etc.; and oral and maxillofacial tumors include, for example, oral cancer (tongue cancer, gingival cancer, buccal mucosa cancer, maxillary sinus cancer, tonsil cancer, etc.).

[0054] In some embodiments, the present invention provides a method for preventing or treating radiation-induced brain injury, particularly early-delayed-response or late-delayed-response radiation-induced brain injury, the method comprising administering to a subject undergoing radiotherapy any of the compounds of Formula I or a pharmaceutically acceptable salt thereof, the administration of which is carried out immediately after radiotherapy and completed before the onset of radiation-induced brain injury.

[0055] In some embodiments, the present invention provides a method for preventing or treating acute radiation-induced brain injury, comprising administering a compound of formula I of the present invention (e.g., YC-6) or a pharmaceutically acceptable salt thereof to a subject undergoing radiotherapy, wherein the administration is performed immediately after radiotherapy and terminated before the onset of acute radiation-induced brain injury. For example, the administration is performed immediately after radiotherapy and continues for up to 10 days. For example, the administration is started on the same day after radiotherapy and continues for 1 to 10 days, for example, 1 to 7 days, 1 to 5 days, 1 to 3 days, 3 to 10 days, 3 to 7 days, 3 to 5 days, 5 to 10 days, or 5 to 7 days. For example, the administration is started on the same day after radiotherapy and continues for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0056] In some embodiments, the present invention provides a method for preventing or treating early-delayed-reaction radiation-induced brain injury, comprising administering a compound of formula I of the present invention (e.g., YC-6) or a pharmaceutically acceptable salt thereof to a subject undergoing radiotherapy, wherein the administration is performed immediately after radiotherapy and terminated before the onset of early-delayed-reaction radiation-induced brain injury. For example, the administration is performed immediately after radiotherapy and continues for up to one month. For example, the administration is started on the same day after radiotherapy and continues for 1 to 30 days, e.g., 5 to 30 days, 10 to 30 days, 10 to 25 days, 5 to 25 days, 5 to 20 days, 10 to 15 days, 15 to 20 days, or 10 to 20 days. For example, the administration is started on the day following radiotherapy and continues for 1, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.

[0057] In some embodiments, the present invention provides a method for preventing or treating late-stage radiation-induced brain injury, comprising administering a compound of formula I of the present invention (e.g., YC-6) or a pharmaceutically acceptable salt thereof to a subject undergoing radiotherapy, wherein the administration is performed immediately after radiotherapy and terminated before the onset of late-stage radiation-induced brain injury. For example, the administration is performed immediately after radiotherapy and continues for up to six months. For example, the administration is started on the same day as the radiotherapy and continues for 5 to 180 days, for example, 5 to 150 days, 5 to 120 days, 5 to 90 days, 5 to 60 days, 5 to 30 days, 10 to 150 days, 10 to 120 days, 10 to 90 days, 10 to 60 days, 10 to 30 days, 15 to 150 days, 15 to 120 days, 15 to 90 days, 15 to 60 days, 15 to 30 days, 20 to 150 days, 20 to 120 days, 20 to 90 days, 20 to 60 days, 20 to 30 days, 5 to 30 days, 10 to 30 days, 10 to 25 days, 5 to 25 days, 5 to 20 days, 10 to 15 days, 15 to 20 days, or 10 to 20 days. For example, the administration is started on the day following radiotherapy and continues for 1, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 45, 60, 75, 90, 105, 120, 150, or 180 days. [Examples]

[0058] This study investigates the prophylactic or therapeutic effects of YC-6 on BRI at the animal level using a gamma knife-induced localized radiation-induced brain injury model in C57BL / 6 mice. As the results show, prophylactic administration of YC-6 at 60 mg / kg / day for two weeks, followed by a drug-free period until week eight, significantly reduced the volume of brain lesions. This indicates that short-term administration of YC-6 has a "post-protective" effect, and eight weeks of YC-6 administration tended to further reduce the volume of brain lesions, mitigating brain tissue damage caused by gamma irradiation without affecting body weight. YC-6 reduces the volume of RBI lesions, mitigates brain tissue damage caused by gamma irradiation, and has a good prophylactic or therapeutic effect on RBI.

[0059] (Experimental method) The animals are divided into groups. As shown in Table 1, the animals are randomly divided into four groups based on their weight. Refer to Figure 1 for the procedure of the experiment. [Table 1]

[0060] (Modeling method for localized radiation-induced brain damage caused by gamma-ray irradiation) The modeling method for localized radiation-induced brain damage by gamma-ray irradiation, as reported in the literature, was modified. Mice were anesthetized by intraperitoneal injection of 0.1% pentobarbital sodium solution, then fixed to a custom-made table, and their heads were scanned using an X-ray computed tomography (CT) scanner (radiation energy was 80kV, scanning range was 250mm, slice thickness and slice interval were 0.625mm, and pixel size was 0.49×0.49mm). Based on the scan results, the irradiation position and depth of gamma knife irradiation of the animals were determined. The mice and custom-made table were then placed in a stereotactic gamma-ray irradiation system and irradiated. The irradiation site was the left thalamus of the mouse, with the center of irradiation coordinates 2mm posterior to the frontal suture (AP), 2mm lateral to the left midline (L), and 2mm below the dura mater (dorsal-ventral DV). The radiation dose was 50Gy at the 50% isodose line, and the irradiation rate was approximately 1.7Gy / min. In the treatment group, 6 mg / mL of YC-6 was injected into the tail vein within 10 minutes of modeling, with a total dose of 10 mL / kg.

[0061] (Animal weight) Before and after modeling using gamma ray irradiation, weigh yourself once a week for eight weeks.

[0062] (Quantitative analysis of brain lesion volume using magnetic resonance imaging (MRI)) After 8 weeks of gamma-ray irradiation modeling, mice were rapidly anesthetized by induction with 3% isoflurane and maintained with 2% isoflurane. Each mouse was injected with 200 μL of contrast solution at a concentration of approximately 48 mg / mL before testing. Subsequently, T1-weighted scans of the mouse brain were performed using a 7T Bruker small animal magnetic resonance imaging (MRI) system. High signal intensity areas in the T1-weighted scan images represented cerebral edema lesions. The obtained T1-weighted DICOM images were imported into ITK-SNAP software, and all high signal intensity areas from the gamma knife irradiation region were extracted from the entire brain, particularly from the left (irradiated) hemisphere of several consecutive image slices, according to the software's operating instructions. All brain necrosis volume data was recorded and analyzed by dividing the image files through rapid and precise contrast adjustment (stepped threshold adjustment) and stepwise loading, and the volume of the lesion was calculated.

[0063] (Collection of animal brain tissue and embedding of sections) After MRI imaging, the animals were rapidly anesthetized by induction with 3% isoflurane, placed supine on a dissection table, their skin was incised, and their thoracic cavity was exposed. Approximately 30 mL of saline solution was perfused into each heart to flush out the blood from the blood vessels, the heads were decapitated, and the complete brain tissue was removed. This tissue was fixed in a 4% paraformaldehyde solution for 24 hours, then dehydrated with 30% sucrose for 48 hours. The cerebellum, olfactory bulb, and part of the forebrain were removed, and the remaining brain tissue was selected, embedded in OTC, and the sections were frozen. The brain tissue was then prepared into 20 μm thick sections in preparation for subsequent immunofluorescence staining.

[0064] (Immunofluorescence staining of GFAP, CC1, and MAG proteins in brain sections) Brain tissue sections were left to stand at room temperature for 15 minutes, and after returning to room temperature, they were immersed in PBS for 10 minutes to remove the OCT from the sections, and circles were made along the brain tissue to be stained using a water-repellent pen. Brain sections were blocked for 1 hour at room temperature using a blocking solution consisting of 1% BSA and 0.25% Triton X-100. The brain sections were then incubated overnight with primary antibodies in a refrigerator at 4°C. The dilutions were 1:500 for MAP2 antibody, 1:500 for GFAP antibody, 1:1000 for Iba1 antibody, 1:100 for CD68 antibody, 1:1000 for CC1 antibody, and 1:500 for MAG antibody. The brain sections are washed three times with PBS, each time for 10 minutes. The corresponding species' fluorescent secondary antibody was added and incubated at 37°C in the dark for 1 hour, with a dilution ratio of 1:1000 for the fluorescent secondary antibody. Wash three times with PBS, each time for 10 minutes. Add DAPI and stain again, then incubate at room temperature in the dark for 3-5 minutes. Wash the specimens three times with PBS, each time for 10 minutes, and then mount them using a mounting medium.

[0065] Using a confocal laser microscope, images of brain sections after immunofluorescence staining were obtained. Images of the same size were taken for each brain section, and the images were analyzed using ImageJ software. After background subtraction, the same threshold was applied to all images. Fields of view of the damaged lesion area of ​​the brain sections were selected, and the number of GFAP-positive cells, the number of CC-1-positive cells, and the fluorescence intensity of MAG per unit area were analyzed using the particle analysis function of ImageJ.

[0066] (Statistical methods for data) Data are presented as mean ± standard error (Mean ± SEM). Statistical analysis and graph creation were performed using Graphpad Prism 7.0 software. If the data satisfies normality and equal variances, one-way ANOVA was used, and Tukey's test was employed for group comparisons. If the data did not satisfy normality or equal variances, a nonparametric test (Kruskal-Wallis H-rank sum test) was used, and uncorrected Dunn's test was employed for group comparisons. Two-way ANOVA was used for analyzing changes in body weight data at different time points for each animal group, and Tukey's multiple comparisons test was employed for group comparisons.

[0067] Example 1: YC-6 significantly reduces the volume of gamma-ray-induced radiation-induced brain damage. In this study, after 8 weeks of modeling with gamma-ray irradiation, MRI images of the mouse brain showed the appearance of severe lesions (white signal areas) in the brain tissue of the gamma knife irradiation area. Prophylactic administration of YC-6 was performed from the day of modeling with gamma knife irradiation. MRI images showed that when YC-6 was administered for only 2 weeks and then discontinued until week 8, the volume of the lesions was significantly reduced, indicating that short-term administration of YC-6 has a "post-protective" effect. Administration of YC-6 for 8 weeks tended to be more effective in reducing the volume of lesions than short-term administration of YC-6, suggesting that YC-6 can mitigate brain tissue damage caused by gamma-ray irradiation. See Table 2 and Figures 2A and 2B for results. [Table 2]

[0068] Example 2: YC-6 suppresses astrocyte activation after radiation-induced brain injury. Glial fibrillary acidic protein (GFAP) is a marker of astrocyte activation, and since astrocyte proliferation is generally accompanied by increased GFAP expression, GFAP is often used as a biomarker for astrocyte proliferation. When the central nervous system is damaged, astrocytes are in an "activated" state, and their morphology, number, and biological function change, transforming them from benign "quiescent astrocytes" to "reactive astrocytes."

[0069] In this study, after 8 weeks of gamma knife irradiation, astrocytes were found to be significantly activated in the thalamic region of the lesion. GFAP expression increased, the number of astrocytes increased, cell size increased, and many long, branching projections were observed from the cell body. 8 weeks of YC-6 administration significantly suppressed astrocyte activation; see Table 3 and Figures 3A and 3B for results. [Table 3]

[0070] Example 3: YC-6 suppresses the decrease of oligodendrocytes and restores MAG levels. Oligodendrocytes are obtained through the proliferation and differentiation of oligodendrocyte precursor cells. Their main function is to enclose neuronal axons, forming an insulating myelin sheath structure, supporting the rapid transmission of bioelectrical signals, and maintaining and ensuring the normal function of neurons. Interruption of their proliferation and differentiation leads to damage to the central nervous system. CC-1 (APC) is a marker of maturing oligodendrocytes. Myelin-associated glycoprotein (MAG) is expressed by oligodendrocytes and Schwann cells of the peripheral nervous system. It is localized in the innermost layer of the myelin sheath that is in direct contact with the axon and is involved in myelin formation and maintenance of its integrity by mediating the interaction between glial cells and axons.

[0071] After 8 weeks of gamma knife irradiation, the CC1 immunofluorescence staining signal decreased, and MAG levels declined. This was accompanied by a significant decrease in the number of oligodendrocytes maturing in the thalamic region of the lesion, suggesting that there was a lesion in the myelin sheath structure of the axons after BRI. 8 weeks of YC-6 administration significantly suppressed the decrease in oligodendrocytes, restored MAG levels, and protected the myelin sheath. See Tables 4 and 5 and Figures 4A and 4B for results. [Table 4] [Table 5]

Claims

1. Formula I in the manufacture of pharmaceuticals for preventing or treating radiation-induced brain injury 【Chemistry 1】 (Equation I) [In the formula, R １ H, -CN, fluorine, chlorine, C １～１０ C substituted with alkyl groups, fluorine, or chlorine １～１０ alkyl group, C １～１０ C substituted with alkoxy groups, fluorine, or chlorine １～１０ Alkoxy groups and C ３～１０ Selected from cycloalkyl groups] The use of the compound or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the radiation dose for radiation-induced brain injury is 50 Gy or more.

3. The use according to claim 1 or 2, wherein the radiation-induced brain injury is gamma-ray radiation-induced brain injury.

4. The use according to any one of claims 1 to 3, wherein the radiation-induced brain injury is an early-delayed reaction type or a late-delayed reaction type radiation-induced brain injury.

5. The use according to any one of claims 1 to 3, wherein the radiation-induced brain injury is the edema or necrotic phase of late-stage delayed-response radiation-induced brain injury.

6. R １ is H, -CHCH ２ CH ３ , -CH(CH ３ ) ２ , -CH(CH ２ ) ３ CH ３ or -CH(CH ３ )(CH ２ ) ３ CH(CH ３ ) ２ The use according to claim 1, wherein it is such.

7. R １ The use described in claim 1, wherein is H.

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