Application of ligustrazine nitrone derivative in preparation of medicine for preventing or treating muscle strength reduction or function loss caused by nerve injury

Abstract

The invention provides application of ligustrazine nitrone derivatives or pharmaceutically acceptable salts thereof in preparation of drugs for preventing or treating muscle strength reduction or function loss caused by nerve injury. The ligustrazine nitrone derivative has a structure as shown in the following general formula (I), and in the general formula (I), R1 and R3 are respectively and independently C1-C6 alkyl; r2 is a C1-C6 alkyl group or # imgabs 0 #; r < 4 > and R < 5 > are respectively and independently sec-butyl, isobutyl, tertiary butyl, cyclopentyl or cyclohexyl. The C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl or n-amyl. # imgabs1 #

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology and relates to the use of ligustrazine nitrone derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating muscle strength decline or function loss caused by nerve damage. Background Art

[0002] Muscle strength refers to the amount of force that can be generated by one or more muscle groups. Muscle weakness caused by limited neuromuscular input or failure of signal transmission at the neuromuscular junction leads to many functional losses and increased mortality in motor neuron disease. ALS is a disease characterized by progressive muscle weakness or functional loss caused by obvious nerve damage. It usually begins with muscle twitching and weakness in the arms or legs, or slurred speech. Usually within three to five years after the onset of symptoms, the muscle capacity required to control movement, speaking, eating, and breathing is gradually lost, eventually paralyzing the muscles required for breathing, and the patient dies of respiratory failure. Throughout the course of the disease, the patient will always maintain a clear consciousness and good skin sensation. This symptom is like a person being gradually frozen, and can only watch his or her body gradually die, but is powerless to do anything. Therefore, ALS is considered to be "a terminal illness more cruel than cancer."

[0003] Slowing down the progression of the disease is very important, and treatments that improve muscle function performance are also beneficial to patients. However, for muscle strength loss or functional loss caused by nerve damage (such as ALS), there are currently no clinically available drugs that can statistically improve the patient's muscle strength level. An article published by Mitsumoto H et al. in the top international academic journal "The Lancet Neurology" shows that in the past decade, at least 18 drugs have been tested in large-scale Phase II or Phase III clinical trials, but none of them showed positive results (Lancet Neurol. 2014 Nov;13(11):1127-1138.). The reason is that at this stage we know very little about the pathogenic mechanism of this type of disease. In addition, animal models are usually difficult to simulate the patient's actual disease state. A large number of drugs that have shown certain efficacy in animal experiments have not shown efficacy in corresponding clinical studies, such as coenzyme Q10 (Kaufmann P, Thompson JL, Levy G, Buchsbaum R, Shefner J, Krivickas LS, Katz J, Rollins Y, Barohn RJ, Jackson CE, Tiryaki E, Lomen-Hoerth C, Armon C, Tandan R, Rudnicki SA, Rezania K, Sufit R, PestronkA, Novella SP, Heiman-Patterson T, Kasarskis EJ, Pioro EP, Montes J, ArbingR, Vecchio D, Barsdorf A, Mitsumoto H, Levin B; QALS Study Group. Phase IItrial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol. 2009 Aug;66(2):235-44.); levomontracetam (Cudkowicz M, Genge A, Maragakis N, Petri S, van den Berg L, Aho VV, Sarapohja T, Kuoppamäki M, Garratt C, Al-Chalabi A; REFALS investigators.口服左西孟旦治疗肌萎缩侧索硬化症患者的安全性和有效性(REFALS研究):一项随机、双盲、安慰剂对照的3期试验。《柳叶刀·神经病学》。2021年10月;20(10):821 - 831。)、地普拉米索(Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA; EMPOWER研究人员。地普拉米索与安慰剂治疗肌萎缩侧索硬化症患者的疗效比较(EMPOWER):一项随机、双盲、3期试验。《柳叶刀·神经病学》。2013年11月;12(11):1059 - 67。)、吡格列酮(Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S, Kassubek J, Fischer W, Steiner F, Lindauer E, Otto M, Dreyhaupt J, Grehl T, Hermann A, Winkler AS, Bogdahn U, Benecke R, Schrank B, Wessig C, Grosskreutz J, Ludolph AC; GERP ALS研究组。吡格列酮联合利鲁唑治疗肌萎缩侧索硬化症的随机、双盲、安慰剂对照试验。《公共科学图书馆·综合》。2012年;7(6):e37885。(), ozanezumab (Meininger V, Genge A, van den Berg LH, Robberecht W, Ludolph A, Chio A, Kim SH, Leigh PN, Kiernan MC, Shefner JM, Desnuelle C, Morrison KE, Petri S, Boswell D, Temple J, Mohindra R, Davies M, Bullman J, Rees P, Lavrov A; NOG112264 Study Group. Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017 Mar;16(3):208-216.), vitamin E (Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, Hager C, Ludolph AC, Becker G, Osterhage J, Jost WH, Schrank B, Stein C, Kostopulos P, Lubik S, Wekwerth K, Dengler R, Troeger M, Wuerz A, Hoge A, Schrader C, Schimke N, Krampfl K, Petri S, Zierz S, Eger K, Neudecker S, Traufeller K, Sievert M, Neundörfer B, Hecht M; German vitamin E / ALS Study Group. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm (Vienna). 2005 May;112(5):649-60.). The relevant Chinese Guidelines (2012 Edition) and Expert Consensus (2022 Edition) issued by the Chinese Society of Neurology clearly pointed out that in animal experiments, although a number of drugs have shown certain efficacy in the treatment of animal models, such as creatine, high-dose vitamin E, coenzyme Q10, lithium carbonate, ciliary neurotrophic factor, insulin-like growth factor, lamotrigine, etc., they have not been proven to be effective in clinical studies (Chinese Journal of Neurology, 2012, 45(7): 531-533; Chinese Journal of Neurology, 2022, 55(6): 581-588.). . Summary of the invention

[0004] In order to solve the problems in the prior art, the present invention provides the use of ligustrazine nitrone derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating muscle strength decline or function loss caused by nerve damage.

[0005] Use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating muscle strength loss or functional loss caused by nerve damage; the ligustrazine nitrone derivative has the following general formula (I): (I) Wherein, R1 and R3 are each independently C1-C6 alkyl; R2 is C1-C6 alkyl or R4 and R5 are each independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl. The C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

[0006] According to one embodiment of the present invention, the ligustrazine nitrone derivative is nitrone oxadiazine or TN-2, and the specific structure is as follows:

[0007] Nitronazine TN-2.

[0008] The present invention provides a method for alleviating diseases related to muscle strength decline or function loss caused by nerve damage in patients, comprising administering a ligustrazine nitrone derivative (such as nitrazine or TN-2) or a pharmaceutically acceptable salt thereof to patients in need thereof.

[0009] According to one embodiment of the present invention, the muscle strength loss or function loss caused by nerve damage is the muscle strength loss or function loss caused by ALS.

[0010] According to one embodiment of the present invention, the muscles with decreased muscle strength or function loss are biceps brachii, triceps brachii, deltoid, pectoralis major, forearm flexors, thenar muscles, hypothenar muscles, tongue muscles, facial muscles, laryngeal muscles, neck muscles, trapezius muscles, sternocleidomastoid muscles, extensor digitorum communis, first interosseous muscles, abductor pollicis longus, abductor pollicis brevis, extensor index digitorum, thoracic paraspinal muscles, respiratory muscles, etc.

[0011] According to one embodiment of the present invention, the main symptoms of muscle strength decline or function loss caused by nerve damage are decreased ability in grip, speech, drooling, swallowing, handwriting, cutting food and using tableware, dressing and hygiene, dyspnea, orthopnea, impaired respiratory function, etc.

[0012] Muscle strength refers to the maximum force that one or more muscle groups can produce. Upper limb grip strength has been widely recognized as an evaluation index of muscle strength. Grip strength is directly related to the biceps, triceps, deltoid, pectoralis major, forearm flexors, thenar, and hypothenar. In addition, studies have confirmed that grip strength is significantly correlated with parameters such as lower limb strength, quadriceps torque, and gastrocnemius muscle cross-sectional area, and is linearly correlated with the ability to perform activities of daily living. The handgrip dynamometer is the most commonly used tool for testing grip strength.

[0013] The ligustrazine nitrone derivatives of the present invention can improve, maintain or slow down the deterioration of muscle strength (e.g., grip strength, medullary function, respiratory function, etc.) of subjects with decreased muscle strength or functional loss caused by nerve damage. In some embodiments, these methods can more significantly lead to improvements in the subject's upper limb strength compared to other muscle groups.

[0014] Nerve damage may cause a decline in medullary function, mainly involving the tongue muscles, trapezius muscles, sternocleidomastoid muscles, etc., which may cause speech problems and dysphagia, which directly affects the patient's quality of life.

[0015] In terms of respiratory function, forced vital capacity (FVC), dyspnea, orthopnea, and respiratory function impairment scores can be used to monitor the response of patients and / or subjects to treatment with decreased muscle strength or functional loss caused by nerve damage. The ligustrazine nitrone derivatives of the present invention can be used for the degeneration of respiratory muscle strength and / or deterioration of lung function caused by nerve damage. The method provided by the present invention can improve or maintain the respiratory muscle and / or lung function of the subject, or slow down the deterioration of the respiratory muscle and / or lung function of the subject. The respiratory muscle and / or lung function of the subject can be evaluated by any suitable method described herein or known in the art. For example, respiratory function scores (dyspnea, orthopnea, impaired respiratory function) and medullary function scores (speech, swallowing, drooling) can be assessed by the ALSFRS-R scale. ALSFRS-R is a scale for assessing ALS (rating 0-4) known in the art, which is used to determine the assessment of the subject's ability and independence in its functional activities.

[0016] The use of the ligustrazine nitrone derivative or its pharmaceutically acceptable salt in the present invention in the preparation of a pharmaceutical preparation for preventing or treating decreased muscle strength or loss of function is characterized in that an oral preparation mainly prepared with the ligustrazine nitrone derivative is administered in the form of a unit dose, and the amount of the ligustrazine nitrone derivative contained in the preparation can effectively treat, prevent, and prevent muscle strength or function loss, reduce its risk, delay its occurrence and / or delay its progression, and the range is about 100-5000 mg of ligustrazine nitrone derivative per day, such as about 300-4000 mg of ligustrazine nitrone derivative per day, about 600-3000 mg of ligustrazine nitrone derivative per day, and about 1200-2400 mg of ligustrazine nitrone derivative per day.

[0017] According to one embodiment of the present invention, the pharmaceutically acceptable salt of the present invention can be a salt of a ligustrazine nitrone derivative formed with an acid, such as a salt formed with the following acids: hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, hexanoic acid, hydroiodic acid, nitric acid, sulfuric acid, salicylic acid, oxalic acid, malonic acid, tartaric acid, stearic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, cinnamic acid, 2-naphthalenesulfonic acid, succinic acid, D-gluconic acid, dodecyl sulfuric acid, pyrosulfuric acid, pyruvic acid, cyclopentanepropionic acid, citric acid, lactic acid or aspartic acid.

[0018] According to one embodiment of the present invention, the ligustrazine nitrone derivative (such as nitrone nitrone or TN-2) as an active pharmaceutical ingredient can be formulated into a pharmaceutical composition (pharmaceutical preparation) using a pharmaceutically acceptable carrier.

[0019] According to one embodiment of the present invention, the pharmaceutical composition is in any form suitable for oral, sublingual, topical inhalation (nasal spray), rectal, intramuscular, intradermal, subcutaneous or intravenous administration. Oral administration is preferred.

[0020] According to one embodiment of the present invention, the "acceptable carrier" means one that is compatible with other ingredients of the formulation and not harmful to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to those skilled in the art.

[0021] If appropriate, the preparation is preferably in discrete dosage units and can be prepared by any method well known in the pharmaceutical field. All methods include the following steps: mixing the active ingredient with one or more pharmaceutically acceptable carriers, and then forming the product into the desired preparation if necessary. The pharmaceutical composition can be formulated into the following dosage forms: tablets, granules, fine granules, powders, capsules, capsules, soft capsules, pills, oral solutions, syrups, chewable tablets, sugar-coated tablets, effervescent tablets, drops, suspensions, rapidly dissolving tablets, rapidly dispersible oral tablets, sustained-release tablets, sustained-release capsules, enteric-coated tablets or enteric-coated capsules, etc.

[0022] According to one embodiment of the present invention, the desired dose of the oral pharmaceutical formulation of the present invention may be conveniently provided once a day or as divided doses administered at appropriate intervals (eg, two, three or more doses a day).

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0024] As used herein, the terms "subject" and "patient" are used interchangeably. A subject or patient is a human patient or human subject. The terms "for example" and "such as" and their grammatical equivalents, unless expressly stated otherwise, should be understood to follow the phrase "without limitation" or "and without limitation".

[0025] As used herein, the term "therapeutically effective amount" or "pharmaceutically effective amount" refers to the amount of an active compound or agent that elicits the medical response in a human body that a physician or other clinician is seeking. A therapeutically or pharmaceutically effective amount of a compound is at least the minimum amount necessary to ameliorate, alleviate, mitigate, delay, reduce, relieve or cure a disease, disorder or syndrome, or one or more of its symptoms, signs or causes.

[0026] The term "treatment" includes therapeutic treatment of patients who have developed the condition. Therapeutic treatment can be symptomatic treatment to alleviate the symptoms of the specific indication, or causal treatment to reverse or partially reverse the condition of the indication or stop or slow the progression of the disease. Therefore, the compositions and methods of the present invention can be used as therapeutic treatment for example for a period of time as well as for chronic treatment.

[0027] The terms "prophylactic treatment," "preventive therapy," and "prevention" are used interchangeably and include treating a patient at risk of developing the above-mentioned conditions, thereby reducing said risk. As used herein, the term "treat" also refers to delaying or ameliorating or preventing the progression (i.e., the known or expected progression of the disease), severity, and / or duration of a disease as a result of the administration of one or more therapies; or delaying or ameliorating or preventing the progression of one or more symptoms, clinical manifestations, observations, or measurements; or preventing or slowing a negative progression of a pathological assessment (i.e., "managing" but not "curing" a condition). Implementation

[0028] The present invention is described in detail below by specific examples. It is pointed out that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Unless otherwise specified, the parts described in the present invention are all parts by weight, and the percentages are all mass percentages. In the examples of the present invention, n represents the number of subjects participating in the test.

[0029] Example 1 Clinical Trial The present invention adopts a multi-center, randomized, double-blind, placebo parallel controlled design.

[0030] Test subjects: Patients diagnosed with ALS (all signed informed consent).

[0031] Subjects were randomly assigned (1:1:1) to receive nitrofenamide 600 mg, 1200 mg, or placebo twice daily for 180 days. A total of 148 subjects were included in the FAS set, of which 50 subjects received placebo (Placebo), 46 subjects received nitrofenamide 600 mg / time (twice a day), and 52 subjects received nitrofenamide 1200 mg / time (twice a day).

[0032] The maximum grip strength of the subjects was tested using an electronic handgrip dynamometer (electronic handgrip tester). The results showed that nitrazepam statistically improved the grip strength of the subjects. The baseline of the placebo group was 16.13 kg, and the relative baseline change after 180 days of treatment was -7.60 kg; the baseline of the 600 mg group was 14.53 kg, and the relative baseline change after 180 days of treatment was -6.53 kg, which was 13.95% higher than the placebo group; the baseline of the 1200 mg group was 16.51 kg, and the relative baseline change after 180 days of treatment was -5.14 kg, which was 32.37% higher than the placebo group (p=0.037).

[0033] In addition, the test results show that nitrazepam can also improve the medullary function and respiratory function of the subjects. Take the 1200 mg group as an example. In terms of medullary function scores, the baseline of the placebo group was 11.0 points, and the relative baseline change after 180 days of treatment was -1.26 points; the baseline of the 1200 mg group was 11.4 points, and the relative baseline change after 180 days of treatment was -1.12 points, and the difference change rate relative to the placebo group increased by 11.11%. In terms of respiratory function scores, the baseline of the placebo group was 12.00 points, and the relative baseline change after 180 days of treatment was -1.21 points; the baseline of the 1200 mg group was 12.00 points, and the relative baseline change after 180 days of treatment was -0.96 points, and the difference change rate relative to the placebo group increased by 20.66%.

[0034] In the clinical trial, during the 12-week observation period before randomization, all subjects aged less than 65 years and whose ALSFRS-R score decreased by 1-2 points (≥1 and ≤2) had ALSFRS-R scores, forced vital capacity (%FVC) and muscle strength (grip strength) after 180 days of treatment as shown in Table 1, and medullary function scores and respiratory function scores as shown in Table 2.

[0035] Table 1 ALSFRS-R score, forced vital capacity (%FVC) and muscle strength (grip strength)

[0036] It can be clearly seen from Table 1 that nitrazepam significantly improved the subjects' ALSFRS-R scores, forced vital capacity (%FVC) and muscle strength decline. In terms of ALSFRS-R scores, the baseline score of the placebo group was 42.11 points, and the relative baseline change after 180 days of treatment was -5.72 points; the baseline score of the 600 mg group was 42.40 points, and the relative baseline change after 180 days of treatment was -5.04 points, which was 11.89% higher than the placebo group; the baseline score of the 1200 mg group was 42.30 points, and the relative baseline change after 180 days of treatment was -4.42 points, which was 22.90% higher than the placebo group. In terms of forced vital capacity (%FVC), the baseline value of the placebo group was 99.48%, and the relative change from baseline after 180 days of treatment was -14.46%; the baseline value of the 600 mg group was 98.34%, and the relative change from baseline after 180 days of treatment was -10.16%, and the difference change rate was increased by 29.67% compared with the placebo group; the baseline value of the 1200 mg group was 98.43%, and the relative change from baseline after 180 days of treatment was -9.06%, and the difference change rate was increased by 37.25% compared with the placebo group. In terms of muscle strength (grip strength), the baseline value of the placebo group was 18.51 kg, and the relative change from baseline after 180 days of treatment was -7.24 kg; the baseline value of the 600 mg group was 17.03 kg, and the relative change from baseline after 180 days of treatment was -4.74 kg, and the difference change rate was 34.67% higher than that of the placebo group; the baseline value of the 1200 mg group was 20.28 kg, and the relative change from baseline after 180 days of treatment was -3.62 kg, and the difference change rate was 50.14% higher than that of the placebo group (p=0.011).

[0037] Table 2. Medullary function score and respiratory function score

[0038] It can be clearly seen from Table 2 that nitrazepam significantly improved the subjects' medullary function scores and respiratory function scores. In terms of medullary function, the baseline score of the placebo group was 11.0 points, and the relative baseline change after 180 days of treatment was -1.02 points; the baseline score of the 600 mg group was 11.1 points, and the relative baseline change after 180 days of treatment was -0.67 points, which was 35.29% higher than the placebo group; the baseline score of the 1200 mg group was 11.4 points, and the relative baseline change after 180 days of treatment was -0.36 points, which was 64.71% higher than the placebo group (p=0.040). In terms of respiratory function, the baseline score of the placebo group was 12.00 points, and the relative change after 180 days of treatment was -0.71 points; the baseline score of the 600 mg group was 12.00 points, and the relative change after 180 days of treatment was -0.17 points, and the difference rate of change was 76.06% higher than that of the placebo group (p=0.040); the baseline score of the 1200 mg group was 12.00 points, and the relative change after 180 days of treatment was -0.11 points, and the difference rate of change was 85.92% higher than that of the placebo group (p=0.021).

[0039] In addition, compared with the placebo group, the subjects' writing ability and ability to use tableware also improved significantly. Take the 1200 mg group as an example. In terms of writing ability, the baseline of the placebo group was 3.27 points, and the relative baseline change after 180 days of treatment was -0.61 points; the baseline of the 1200 mg group was 3.38 points, and the relative baseline change after 180 days of treatment was -0.39 points, and the difference change rate increased by 36.07% relative to the placebo group. In terms of cutting food and using tableware, the baseline of the placebo group was 3.04 points, and the relative baseline change after 180 days of treatment was -0.94 points; the baseline of the 1200 mg group was 3.04 points, and the relative baseline change after 180 days of treatment was -0.33 points, and the difference change rate increased by 35.11% relative to the placebo group. In terms of clothing and personal hygiene, the baseline score of the placebo group was 3.00 points, and the relative change after 180 days of treatment was -0.87 points; the baseline score of the 1200 mg group was 2.92 points, and the relative change after 180 days of treatment was -0.75 points, which was an increase of 13.79% compared with the placebo group.

Claims

1. Use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating muscle strength loss or functional loss caused by nerve damage; the ligustrazine nitrone derivative has the following general formula (I): （I） in, R1 and R3 are each independently C1-C6 alkyl; R2 is C1-C6 alkyl or ; R4 and R5 are each independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

2. The use according to claim 1, characterized in that The ligustrazine nitrone derivative is nitrone oxazine or TN-2, and the specific structure is as follows: Nitronazine TN-2.

3. The use according to claim 2, characterized in that The muscle strength loss or function loss caused by nerve damage is the muscle strength loss or function loss caused by ALS.

4. The use according to any one of claims 1 to 3, characterized in that: The muscles with decreased muscle strength or function loss are one or more of the biceps brachii, triceps brachii, deltoid, pectoralis major, forearm flexors, thenar muscles, hypothenar muscles, tongue muscles, facial muscles, laryngeal muscles, neck muscles, trapezius muscles, sternocleidomastoid muscles, extensor digitorum common, first interosseous muscles, abductor pollicis longus, abductor pollicis brevis, extensor index digitorum, thoracic paraspinal muscles, and respiratory muscles.

5. The use according to any one of claims 1 to 3, characterized in that: The application is to improve one or more symptoms of the patient's grip strength, speech, drooling, swallowing, handwriting, cutting food and using tableware, dressing and hygiene, dyspnea, orthopnea, and impaired respiratory function.

6. The use according to any one of claims 1 to 3, characterized in that: The application is to administer a preparation containing a ligustrazine nitrone derivative in a unit dosage form, wherein the preparation contains a ligustrazine nitrone derivative that is effective in treating, preventing, and preventing muscle strength decline or function loss, reducing its risk, delaying its occurrence, and / or delaying its progression.

7. The use according to any one of claim 6, characterized in that The application is to administer 100-5000 mg of ligustrazine nitrone derivatives every day.

8. The use according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable salt is a salt formed by a ligustrazine nitrone derivative and an acid, wherein the acid is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, hexanoic acid, hydroiodic acid, nitric acid, sulfuric acid, salicylic acid, oxalic acid, malonic acid, tartaric acid, stearic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, cinnamic acid, 2-naphthalenesulfonic acid, succinic acid, D-gluconic acid, dodecyl sulfuric acid, pyrosulfuric acid, pyruvic acid, cyclopentanepropionic acid, citric acid, lactic acid or aspartic acid.

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