Use and pharmaceutical compositions of aromatic amino-substituted derivatives of magnolol and / or honokiol in preventing hypoxic / anoxic injury

Abstract

The present invention provides the use of aromatic ring amino-substituted derivatives of magnolol and / or honokiol in anti-hypoxia / hypoxia injury, and a pharmaceutical composition thereof. The aromatic ring amino-substituted derivatives of magnolol and / or honokiol of the present invention are compounds represented by general formula I or salts thereof. The derivatives having the structure represented by the above general formula I are useful for preparing anti-hypoxia / hypoxia injury drugs, and can provide novel drugs for preventing and treating diseases, and can solve the problems of current anti-hypoxia / hypoxia injury drugs exerting their effects indirectly and taking effect slowly. [Formula 1] JPEG2024539707000016.jpg94170 (in general formula I, R1 and R4 are each independently selected from C1 to C8 hydrocarbyl, R2 and R3 are each independently selected from hydrogen or hydroxy, and R2 and R3 are not simultaneously hydrogen or hydroxy, and R5 is H, C1 to C8 hydrocarbyl, 12 acyl, the remaining acyl moiety after carboxyl condensation of a single amino acid, and the remaining acyl moiety after carboxyl condensation of a polypeptide, and R6 is any one selected from hydrogen and C1 to C8 hydrocarbyl.

Description

[Technical Field]

[0001] This application is based on and claims priority from a Chinese application bearing Chinese Patent Number 202111402114.5 and filed on November 19, 2021, the disclosure of which is incorporated herein in its entirety.

[0002] The present invention relates to the technical field of biomedicine, specifically to the use and pharmaceutical compositions of aromatic ring amino-substituted derivatives of magnolol and / or honokiol in anti-hypoxic / anoxic injury. [Background technology]

[0003] Magnolol and honokiol are the main active ingredients of Magnolia officinalis, a traditional Chinese herbal medicine, and are usually obtained by modifying the structure of an extract of Magnolia officinalis, a traditional Chinese herbal medicine. The chemical structural formulas of magnolol and honokiol are as follows: [ka]

[0004] In 1930, Sugii of Japan first isolated magnolol (Chinese Herbal Medicine; 2005, 36, 10, 1591-1594) from the bark of Magnolia officinalis (Huang Bao) in China. In 1989, Meng Lizhen et al. of China also isolated honokiol (Chinese Herbal Medicine; 1989, 11(8):223) from Magnolia officinalis (Huang Bao). Magnolol and honokiol have a wide range of pharmacological activities, including antibacterial, anti-inflammatory, antitumor, muscle relaxant, cholesterol-lowering, and anti-aging effects (Chinese Herbal Medicine; 2005, 36, 10, 1591-1594). The drugs used herein are aromatic amino-substituted derivatives of magnolol and honokiol, and there are currently no reports of their use in the treatment of hypoxic / anoxia injury.

[0005] High-altitude hypoxia (HAH) poses a potential threat to the health of people living in this region for extended periods. The heart is one of the organs with the highest oxygen consumption in the body, and a sufficient oxygen supply is required to maintain cardiac vitality and function. Exposure to a hypobaric / hypoxic environment reduces the oxygen supply to the heart due to a decrease in oxygen partial pressure, leading to impaired cardiac function and cardiovascular diseases such as myocardial infarction (MI), right ventricular (RV) dysfunction induced by pulmonary artery hypertension, and sudden cardiac death (SCD). The brain, another organ with a high oxygen consumption, has extremely low tolerance to hypoxia, and a hypobaric / oxygen-deficient environment can cause irreversible brain damage. In recent years, the number of people heading to plateaus has increased. When people who live on the plains suddenly enter the plateau, the rapid drop in atmospheric pressure and oxygen partial pressure causes a rapid drop in the body's blood oxygen saturation, and the tissues quickly become hypoxic. This causes a series of physiological and pathological changes in the body, resulting in acute alpine reactions, which can cause palpitations, chest tightness, chest pain, dizziness, and difficulty breathing. In severe cases, acute pulmonary edema can occur, which can be life-threatening.

[0006] Currently, antioxidative medications include Chinese herbal medicines such as Rhodiola rosea, Angelica sinensis, and ginseng, which have relatively reliable therapeutic effects but are slow to take effect, and Western medicines such as acetazolamide, dexamethasone, and aminophylline tablets, which can alleviate symptoms caused by oxygen deficiency, but cannot directly increase blood oxygen saturation in the body and prevent or resist damage caused by hypoxic / oxygen deficiency environments. Summary of the Invention [Problem to be solved by the invention]

[0007] The main objective of the present invention is to provide a pharmaceutical composition and use of aromatic ring amino-substituted derivatives of magnolol and / or honokiol in anti-hypoxic / hypoxia injury, in order to solve the problems of current anti-hypoxic / hypoxia drugs, such as indirect effect and slow onset of action. [Means for solving the problem]

[0008] To achieve the above object, one aspect of the present invention provides the use of an aromatic ring amino-substituted derivative of magnolol and / or honokiol in anti-hypoxic / anoxia injury, wherein the aromatic ring amino-substituted derivative of magnolol and / or honokiol is a compound represented by general formula I or a salt thereof. [ka] (In general formula I, R1 and R4 are each independently selected from C1 to C8 hydrocarbyl, R2 and R3 are each independently selected from hydrogen or hydroxy, and R2 and R3 are not simultaneously hydrogen or hydroxy, and R5 is H, C1 to C8 12 acyl, the remaining acyl moiety after carboxyl condensation of a single amino acid, and the remaining acyl moiety after carboxyl condensation of a polypeptide, and R6 is any one selected from hydrogen and C1 to C8 hydrocarbyl.

[0009] Furthermore, the C1-C8 hydrocarbyl in R1, R4, and R6 is each independently any one selected from C1-C8 alkyl and C1-C8 alkenyl, and preferably, the C1-C8 alkyl is any one selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0010] Furthermore, the C1-C8 alkenyl is any one selected from vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl, oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl, and oct-7-enyl.

[0011] Furthermore, the above C1 to C 12 The acyl is any one selected from formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, and octanoyl.

[0012] Furthermore, the single amino acid is any one selected from lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, 6-hydroxynorleucine, glycine, histidine, arginine, proline, glutamic acid, aspartic acid, serine, threonine, tyrosine, cystine, and cysteine.

[0013] Furthermore, the polypeptide is a peptide formed from a plurality of single amino acids, and preferably, the molecular weight of the polypeptide is 2500 Da or less.

[0014] Furthermore, when the aromatic ring amino-substituted compound of magnolol and / or honokiol is a salt of a compound represented by general formula I, one or more of the salt-forming amino groups possessed by R5 is in the form of a salt, and the acid for salt formation is a pharmaceutically acceptable acid such as hydrochloric acid, oxalic acid, or fumaric acid.

[0015] Furthermore, the aromatic ring amino-substituted derivatives of magnolol and / or honokiol include 3',5-diallyl-3-amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3- Acetamide -2,4'-dihydroxy-1,1'-biphenyl, 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-3-phenyl-2-amino-1-propionyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(R)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-6-hydroxy-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-3-methyl-2-amino-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, and 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.

[0016] Furthermore, the administration route of the anti-hypoxic / anoxia injury drug is injection, oral administration, implantation or direct application to the lesion site.

[0017] According to another aspect of the present invention, there is provided an anti-hypoxic / anoxia injury pharmaceutical composition comprising an aromatic ring amino-substituted derivative of magnolol and / or honokiol or a salt thereof, and a pharmaceutically acceptable carrier, wherein the aromatic ring amino-substituted derivative of magnolol and / or honokiol is said aromatic ring amino-substituted derivative of magnolol and / or honokiol. [Effects of the Invention]

[0018] According to the technical solution of the present invention, the derivative having the structure represented by the general formula I is useful for preparing anti-hypoxia / anoxia injury drugs that can rapidly and effectively improve the oxygen carrying capacity of red blood cells, and provides a novel drug for preventing and treating diseases caused by hypoxia in the external environment (e.g., altitude sickness) and ventilation and / or ventilatory dysfunction diseases caused by various internal causes (e.g., central nervous system diseases, bronchial and pulmonary diseases, etc.), thereby solving the problems of conventional anti-hypoxia / anoxia injury drugs, such as indirect effects and slow onset of action.

[0019] The drawings in the specification that form a part of this application are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their descriptions are used to explain the present invention and are not intended to unduly limit the present invention. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows the effect of Compound 1 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) in SD rats before and after 24 hours of hypoxic treatment in Example 1 according to the present invention. [Figure 2] FIG. 1 shows the effect of Compound 1 on the respiratory rate (RR) of SD rats before and after 24 hours of hypoxic treatment in Example 1 according to the present invention. [Figure 3] This figure shows the effects of intravenous injection of Compound 2 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) in rats 24 hours before hypoxia treatment, and 1 hour, 6 hours, and 24 hours after hypoxia treatment in Example 2 of the present invention. [Figure 4] FIG. 1 is a graph showing the effect of intravenous injection of Compound 2 on the respiratory rate (RR) of SD rats before 24 hours of hypoxic treatment, and after 6 hours and 24 hours of hypoxic treatment in Example 2 according to the present invention. [Figure 5] FIG. 1 shows the effect of intravenous injection of Compound 2 on lung tissue damage in SD rats 24 hours after hypoxia treatment in Example 2 according to the present invention. [Figure 6]FIG. 1 shows the effect of intragastric administration of Compound 2 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) before and after 24 hours of hypoxia treatment in Example 3 according to the present invention. [Figure 7] FIG. 1 shows the effect of intragastric administration of Compound 2 on the respiratory rate (RR) of rats before and after 24 hours of hypoxic treatment in Example 3 according to the present invention. [Figure 8] FIG. 1 shows the effect of Compound 3 on blood oxygen saturation (SO 2 ) in SD rats before and after 24 hours of hypoxic treatment in Example 4 according to the present invention. [Figure 9] FIG. 1 shows the effect of Compound 3 on the respiratory rate (RR) of rats before and after 24 hours of hypoxic treatment in Example 4 according to the present invention. [Figure 10] FIG. 1 shows the effect of Compound 4 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) in SD rats before and after 24 hours of hypoxic treatment in Example 5 according to the present invention. [Figure 11] FIG. 1 shows the effect of Compound 4 on the respiratory rate (RR) of rats before and after 24 hours of hypoxic treatment in Example 5 according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0021] It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without causing any contradiction. The present invention will be described in detail below in combination with the embodiments with reference to the drawings.

[0022] As described in the background art, conventional anti-oxidant drugs have problems such as indirect effects and slow onset of action. To solve these problems, the present invention provides the use and pharmaceutical compositions of aromatic ring amino-substituted derivatives of magnolol and / or honokiol in anti-hypoxic / hypoxia injury.

[0023] In a representative embodiment of the present application, there is provided the use of an aromatic ring amino-substituted derivative of magnolol and / or honokiol in anti-hypoxic / anoxia injury, wherein the aromatic ring amino-substituted derivative of magnolol and / or honokiol is a compound represented by general formula I or a salt thereof. [ka] (In general formula I, R1 and R4 are each independently selected from C1 to C8 hydrocarbyl, R2 and R3 are each independently selected from hydrogen or hydroxy, and R2 and R3 are not simultaneously hydrogen or hydroxy, and R5 is H, C1 to C8 12 acyl, the remaining acyl moiety after carboxyl condensation of a single amino acid, and the remaining acyl moiety after carboxyl condensation of a polypeptide, and R6 is any one selected from hydrogen and C1 to C8 hydrocarbyl.

[0024] The derivatives having the structure represented by the above general formula I are useful for preparing anti-hypoxia / anoxia injury drugs that can rapidly and effectively improve the oxygen-carrying capacity of red blood cells, and provide novel drugs for preventing and treating diseases caused by hypoxia in the external environment (e.g., altitude sickness) and ventilation and / or ventilatory dysfunction diseases caused by various internal causes (e.g., central nervous system diseases, bronchial and pulmonary diseases, etc.), thereby solving the problems of conventional anti-hypoxia / anoxia injury drugs, such as indirect effects and slow onset of action.

[0025] In order to further improve the synthesis efficiency of aromatic ring amino-substituted derivatives of magnolol and / or honokiol and widen the scope of their use in the preparation of anti-hypoxic / anoxic injury drugs, preferably, the C1-C8 hydrocarbyl in the above R1, R4 and R6 is each independently any one selected from C1-C8 alkyl and C1-C8 alkenyl, and preferably, the C1-C8 alkyl is any one selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, more preferably propyl.

[0026] R1 and R4 are located at the para-position or ortho-position of the hydroxy of each benzene ring, respectively, and their electronic and spatial effects affect the reactivity of each site on the benzene ring, so that the sites such as the hydroxy and hydroxy ortho-positions of each benzene ring have high reactivity and can easily obtain an excellent antihypoxic / anoxia drug. Preferably, the C1-C8 alkenyl is vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-alkenyl, pent-1-enyl, pent-2-enyl, enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl, oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl, and oct-7-enyl.

[0027] In order to further improve the ease of synthesis of the aromatic ring amino-substituted derivatives of magnolol and / or honokiol, preferably, R1 and R4 are each independently allyl.

[0028] Preferably, the above C1 to C 12 The acyl is any one selected from formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, and octanoyl. The above acyl is easily available and more easily exerts its antihypoxia / anoxia activity. Furthermore, it is preferably C1 to C 12 Acyl is acetyl.

[0029] In one embodiment of the present application, the single amino acid is any one selected from lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, 6-hydroxynorleucine, glycine, histidine, arginine, proline, glutamic acid, aspartic acid, serine, threonine, tyrosine, cystine, and cysteine.

[0030] The above amino acids are easily available, and most of them are amino acids necessary for the human body, so they are economical and safe. In order to further enhance the beneficial effects of the aromatic ring amino-substituted derivatives of magnolol and / or honokiol on the human body, such as anti-hypoxia / anoxia, the above amino acids are preferably lysine or methionine.

[0031] To further improve the drug activity when R5 is a polypeptide, the polypeptide is preferably a peptide formed from a plurality of the above single amino acids, and the molecular weight of the polypeptide is preferably 2500 Da or less.

[0032] In one embodiment of the present application, when the aromatic ring amino-substituted compounds of magnolol and / or honokiol are salts of the compounds represented by general formula I, one or more of the salt-forming amino groups possessed by R5 are in the form of a salt, and the acid for salt formation is a pharmaceutically acceptable acid such as hydrochloric acid, oxalic acid, or fumaric acid.

[0033] When the aromatic ring amino-substituted compounds of magnolol and / or honokiol are pharmaceutically acceptable salts of the compounds represented by general formula I, they have good water solubility and are easier to use.

[0034] In some embodiments, the aromatic ring amino-substituted derivatives of magnolol and / or honokiol are preferably 3',5-diallyl-3-amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3- Acetamide-2,4'-dihydroxy-1,1'-biphenyl, 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-3-phenyl-2-amino-1-propionyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(R)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-6-hydroxy-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-3-methyl-2-amino-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, and 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.

[0035] Particularly, the aromatic ring amino-substituted derivatives of magnolol and / or honokiol are preferably 3',5-diallyl-3-amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3- Acetamide In the case of 3-(2,4'-dihydroxy-1,1'-biphenyl, 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, it is advantageous to improve the antioxidative properties of the aromatic ring amino substituted derivatives of magnolol and / or honokiol.

[0036] In order to enhance the practical utility of the aromatic ring amino-substituted derivatives of magnolol and / or honokiol, the administration route of the anti-hypoxic / anoxia injury drug is preferably injection, oral administration, implantation or direct application to the lesion.

[0037] In another exemplary embodiment of the present application, there is provided an anti-hypoxic / anoxia injury pharmaceutical composition, which comprises an aromatic ring amino-substituted derivative of magnolol and / or honokiol or a salt thereof, and a pharmaceutically acceptable carrier, wherein the aromatic ring amino-substituted derivative of magnolol and / or honokiol is an aromatic ring amino-substituted derivative of magnolol and / or honokiol represented by the above general formula I.

[0038] The derivatives having the structure represented by the above general formula I are useful for preparing anti-hypoxia / anoxia injury drugs that can rapidly and effectively improve the oxygen-carrying capacity of red blood cells, and provide novel drugs for preventing and treating diseases caused by hypoxia in the external environment (e.g., altitude sickness) and ventilation and / or ventilatory dysfunction diseases caused by various causes (e.g., central nervous system diseases, bronchial and pulmonary diseases, etc.), thereby solving the problems of conventional anti-hypoxia / anoxia injury drugs, such as indirect effects and slow onset of action.

[0039] The beneficial effects of the present invention will be described below with reference to specific examples and comparative examples.

[0040] The aromatic ring amino-substituted derivatives of magnolol and / or honokiol used in the following examples can all be prepared by routes known in the prior art, such as the route described in Patent CN103113264A.

[0041] Anti-hypoxia / anoxia injury experiments Example 1 3',5-diallyl-3-amino-2,4'-dihydroxy-1,1'-biphenyl (English name: 3',5-diallyl-3-amino-[1,1'-biphenyl]-2,4'-diol, Compound 1) [ka]

[0042] 1. Experimental Method 1. Preparation of test substance: An appropriate amount of Compound 1 was weighed out, and an appropriate amount of solvent 2% DMSO+2% Tween 80+physiological saline was added to prepare a solution of the desired concentration (0.58 mg / mL). 2. Animal model: SPF grade SD male rats, weighing 220-240g, treated with hypoxia (oxygen content 11%). 3. Experimental grouping: hypoxia control group, 4 animals per group; hypoxia treatment group, 4 animals per group. 4. Administration method: One intravenous injection per rat in the hypoxia treatment group before hypoxia treatment. 5. Blood gas analysis: For each group, blood (approximately 0.5 mL) was collected from the femoral artery 24 hours before and 24 hours after hypoxia treatment, and blood gas analysis was performed. The results are shown in Table 1. [Table 1] 6. Respiratory rate: The respiratory rate of the rats was assessed at the time of blood collection. 7. Data statistics: Data analysis was performed using GraphPad, and the results were expressed as mean ± standard deviation (Mean ± SD). Data analysis was performed using a one-way analysis of variance (T-test), with P<0.05 indicating a statistical difference.

[0043] 2. Experimental results 1. The results of blood gas analysis are shown in Figure 1 (i.e., the effect of Compound 1 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) in SD rats before and after 24 hours of hypoxia treatment). 1) There were no significant differences in the blood gas analysis results between animals in each group 24 hours before hypoxia treatment. 2) After 24 hours of hypoxia treatment, the blood oxygen tension (p=0.0012) and blood oxygen saturation (p=0.019) in the 0.58 mg / kg group were significantly higher than those in the control group.

[0044] 2. Respiratory rate is shown in Figure 2 (i.e., the effect of Compound 1 on respiratory rate (RR) in SD rats before and after 24 hours of hypoxia treatment). 1) There was no significant difference in the respiratory rate of animals in each group 24 h before hypoxia treatment. 2) After 24 hours of hypoxia treatment, the respiratory rate of the treated group was significantly lower than that of the control group (p<0.05).

[0045] From the above data, it was found that a single injection of 0.58 mg / kg of compound 1 significantly increased the blood oxygen tension and blood oxygen saturation and significantly reduced the respiratory rate in SD rats 24 hours after hypoxia treatment, thereby exerting an anti-hypoxia / anoxia injury effect.

[0046] Example 2 3',5-Diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'- Biphenyl Dihydrochloride (English name: (S)-2,6-diamino-N-(3',5-diallyl-2,4'-dihydroxy-[1,1'-biphenyl]-3-yl)hexanamide dihydrochloride, Compound 2 [ka]

[0047] 1. Experimental Method 1. Preparation of test substance: An appropriate amount of Compound 2 was weighed out, and an appropriate amount of sodium chloride injection (0.9%) was added to prepare a solution of the desired concentration (0.25 mg / kg and 1 mg / kg). 2. Animal model: SPF grade SD male rats, weighing 220-240g, treated with hypoxia (oxygen content 11%). 3. Experimental grouping: hypoxia control group, 4 animals per group; hypoxia treatment group, 4 animals per group. 4. Administration method: One intravenous injection per rat in the hypoxia treatment group before hypoxia treatment. 5. Blood gas analysis: For each group, blood (approximately 0.5 mL) was collected from the femoral artery 24 hours before and 24 hours after hypoxia treatment, and blood gas analysis was performed. The results are shown in Table 2. [Table 2] 6. Respiratory rate: The respiratory rate of the rats was assessed at the time of blood collection. 7. H&E staining Paraffin sections were prepared, stained, and pathologically analyzed using lung tissues from the hypoxia-treated (24h) control group and the hypoxia-treated (24h) group (dose 1 mg / kg). 1) Dewaxing of paraffin sections with water: The sections were immersed in xylene I for 20 min, xylene II for 20 min, absolute ethanol I for 5 min, absolute ethanol II for 5 min, and 75% alcohol for 5 min, and finally washed with tap water. 2) Hematoxylin staining: The sections were placed in hematoxylin staining solution and stained for 3 to 5 minutes, then washed with tap water, differentiated in differentiation solution, washed again with tap water, blued with blue solution, and finally rinsed with running water. 3) Eosin staining: The sections were dehydrated in 85% and 95% graded alcohols, one after the other, for 5 minutes each, and then placed in eosin staining solution for 5 minutes. 4) Dehydration and blocking: The sections were immersed in absolute ethanol I for 5 min, absolute ethanol II for 5 min, absolute ethanol III for 5 min, xylene I for 5 min, and xylene II for 5 min, cleared, and finally blocked with neutral balsam. 5) Microscopic examination was performed and images were collected and analyzed. 6) Judging the results: The nuclei were blue and the cytoplasm was red. 8. Data statistics: Data analysis was performed using GraphPad, and the results were expressed as mean ± standard deviation (Mean ± SD). One-way analysis of variance (T-test) was used for data analysis, and P<0.05 indicated statistical significance.

[0048] 2. Experimental results 1. Blood gas analysis is shown in Figure 3 (i.e., the effect of intravenous injection of Compound 2 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) in rats before 24 hours of hypoxia treatment, and after 1 hour, 6 hours, and 24 hours of hypoxia treatment). 1) There were no significant differences in the blood gas analysis results between animals in each group 24 hours before hypoxia treatment. 2) One hour after hypoxia treatment, the blood oxygen tension of the 0.25 mg / kg group was higher than that of the control group, but the difference was not significant (p=0.059). The blood oxygen saturation of the treated group was higher than that of the control group, and the difference was significant (p=0.023). 3) Six hours after hypoxia treatment, the blood oxygen partial pressure (p=0.018) and blood oxygen saturation (p=0.015) of the 0.25 mg / kg group were significantly higher than those of the control group. 4) Six hours after hypoxia, the blood oxygen tension in the 1 mg / kg group was significantly higher than that in the control group (p=0.003). The blood oxygen saturation in the 1 mg / kg group was also significantly higher than that in the control group (p=0.0012). 5) 24 hours after hypoxia treatment, the blood oxygen partial pressure (p=0.0012) and blood oxygen saturation (p=0.001) of the 1 mg / kg group were significantly higher than those of the control group.

[0049] 2. Respiratory rate is shown in Figure 4 (i.e., the effect of intravenous injection of Compound 2 on respiratory rate (RR) in SD rats before 24 hours of hypoxia treatment, and after 6 hours and 24 hours of hypoxia treatment). 1) There was no significant difference in the respiratory rate of animals in each group 24 h before hypoxia treatment. 2) After 6 or 24 hours of hypoxic treatment, the respiratory rate of the treated group was significantly lower than that of the control group (p<0.05).

[0050] 3. Pathological analysis of paraffin sections of lung tissue is shown in Figure 5 (i.e., effect of intravenous injection of Compound 2 on lung tissue damage in SD rats 24 h after hypoxia treatment). In control group 1, lung tissue clearly showed widespread alveolar wall thickening (black arrow 1), small amounts of vascular muscularization, smooth muscle cell proliferation, vascular wall hypertrophy, and luminal narrowing (yellow arrow 3), accompanied by inflammatory cell infiltration (red arrow 2), and occasionally small focal infiltration of inflammatory cells around the bronchi (blue arrow 4).

[0051] In control group 2, small amounts of inflammatory cell infiltration (black arrow 6) were clearly observed in the alveolar walls of the lung tissue, widespread pulmonary edema was observed, and uniform eosinophilic tissue fluid exudation was observed in the alveolar spaces (yellow arrow 7).

[0052] In the treated group 1, the lung tissue clearly showed a medium area of ​​alveolar wall thickening (black arrow 8) accompanied by a small amount of inflammatory cell infiltration (red arrow 9), a small amount of eosinophilic tissue fluid exudation into the bronchial lumen (yellow arrow 10), and a small amount of vascular muscularization, smooth muscle cell proliferation, vascular wall hypertrophy, and luminal narrowing (blue arrow 11).

[0053] In Group 2, lung tissue clearly showed mild thickening of large areas of alveolar walls (black arrow 12) with a small amount of inflammatory cell infiltration (red arrow 13), as well as a small amount of vascular muscularization, smooth muscle cell proliferation, vascular wall hypertrophy, and luminal narrowing (blue arrow 14).

[0054] From the above, compared to the control group, the treatment group was able to reduce tissue damage caused by hypoxia (oxygen deficiency), such as pulmonary edema, alveolar wall thickening, inflammatory cell infiltration, neutrophil infiltration, vascular muscularization, smooth muscle cell proliferation, vascular wall hypertrophy, and luminal narrowing.

[0055] These data suggest that a single intravenous injection of compound 2 at 0.25 mg / kg and 1 mg / kg increased blood oxygen tension and blood oxygen saturation in SD rats 1, 6, and 24 hours after hypoxia treatment, a single intravenous injection of compound 2 at 1 mg / kg significantly decreased respiratory rate in SD rats 6 and 24 hours after hypoxia treatment, and a single intravenous injection of compound 2 at 1 mg / kg significantly reduced lung tissue damage in SD rats 24 hours after hypoxia treatment. These results suggest that injection of compound 2 can effectively inhibit hypoxia / anoxia injury by effectively increasing blood oxygen transport.

[0056] Example 3 3',5-Diallyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'- Biphenyl Dihydrochloride (English name: (S)-2,6-diamino-N-(3',5-diallyl-2,4'-dihydroxy-[1,1'-biphenyl]-3-yl)hexanamide dihydrochloride, Compound 2 [ka]

[0057] 1. Experimental Method 1. Preparation of test substance: An appropriate amount of Compound 2 was weighed, and an appropriate amount of sodium chloride injection (0.9%) was added to prepare a solution of the desired concentration (40 mg / kg). 2. Animal model: SPF grade SD male rats, weighing 220-240g, treated with hypoxia (oxygen content 11%). 3. Experimental grouping: hypoxia control group, 4 animals per group; hypoxia treatment group, 4 animals per group. 4. Administration method: One intragastric administration to each rat in the hypoxia treatment group before hypoxia treatment. 5. Blood gas analysis: For each group, blood (approximately 0.5 mL) was collected from the femoral artery 24 hours before and 24 hours after hypoxia treatment, and blood gas analysis was performed. The results are shown in Table 3. [Table 3] 6. Respiratory rate: The respiratory rate of the rats was assessed at the time of blood collection. 7. Data statistics: Data analysis was performed using GraphPad, and the results were expressed as mean ± standard deviation (Mean ± SD). Data analysis was performed using a one-way analysis of variance (T-test), with P<0.05 indicating a statistically significant difference.

[0058] 2. Experimental results 1. Blood gas analysis is shown in Figure 6 (effects of intragastric administration of Compound 2 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) before and after 24 hours of hypoxia treatment). 1) There were no significant differences in the blood gas analysis results between animals in each group 24 hours before hypoxia treatment. 2) 24 hours after hypoxia treatment, the blood oxygen partial pressure (p=0.036) and blood oxygen saturation (p=0.016) of the 40 mg / kg group were significantly higher than those of the control group.

[0059] 2. Respiratory rate is shown in Figure 7 (effect of intragastric administration of Compound 2 on respiratory rate (RR) in rats before and after 24 hours of hypoxia treatment). 1) There was no significant difference in the respiratory rate of animals in each group 24 h before hypoxia treatment. 2) After 24 hours of hypoxia treatment, the respiratory rate of the treated group was significantly lower than that of the control group (p<0.05).

[0060] These data indicate that a single intragastric administration of 40 mg / kg of Compound 2 significantly increased blood oxygen tension and blood oxygen saturation and reduced respiratory rate in SD rats 24 hours after hypoxia. This indicates that intragastric administration of Compound 2 effectively improves blood oxygen transport capacity and thereby effectively suppresses hypoxia / anoxia injury.

[0061] Example 4 2-amino-N-(3',5-diallyl-2,4'-dihydroxy-[1,1'-biphenyl]-3-yl)-4-(methylthio)butanamide hydrochloride (Compound 3) [ka]

[0062] 1. Experimental Method 1. Preparation of test substance: An appropriate amount of Compound 3 was weighed, and an appropriate amount of sodium chloride injection (0.9%) was added to prepare a solution of the desired concentration (0.93 mg / kg). 2. Animal model: SPF grade SD male rats, weighing 220-240g, treated with hypoxia (oxygen content 11%). 3. Experimental grouping: hypoxia control group, 4 animals per group; hypoxia treatment group, 4 animals per group. 4. Administration method: One intravenous injection per rat in the hypoxia treatment group before hypoxia treatment. 5. Blood gas analysis: For each group, blood (approximately 0.5 mL) was collected from the femoral artery 24 hours before and 24 hours after hypoxia treatment, and blood gas analysis was performed. The results are shown in Table 4. [Table 4] 7. Data statistics: Data analysis was performed using GraphPad, and the results were expressed as mean ± standard deviation (Mean ± SD). Data analysis was performed using a one-way analysis of variance (T-test), with P<0.05 indicating a statistically significant difference.

[0063] 2. Experimental results 1. Blood gas analysis is shown in Figure 8 (effect of Compound 3 on blood oxygen saturation (SO2) in SD rats before and after 24 hours of hypoxia treatment). 1) There were no significant differences in the blood gas analysis results between animals in each group 24 hours before hypoxia treatment. 2) After 24 hours of hypoxia treatment, the blood oxygen saturation (p=0.06) of the 0.93 mg / kg group was higher than that of the control group.

[0064] 2. Respiratory rate is shown in Figure 9 (effect of Compound 3 on respiratory rate (RR) in rats before and after 24 hours of hypoxic treatment). 1) There was no significant difference in the respiratory rate of animals in each group 24 h before hypoxia treatment. 2) After 24 hours of hypoxia treatment, the respiratory rate of the treated group was significantly lower than that of the control group (p<0.05).

[0065] From the above data, it was found that a single intravenous injection of 0.93 mg / kg of compound 3 increased the blood oxygen saturation and significantly reduced the respiratory rate in SD rats 24 hours after hypoxia treatment, thereby exerting an anti-hypoxic / anoxia injury effect.

[0066] Example 5 3',5-Diallyl-3- Acetamide -2,4'-Dihydroxy-1,1'-biphenyl (English name: N-(3',5-diallyl-2,4'-dihydroxy-[1,1'-biphenyl]-3-yl)acetamide, Compound 4 [ka]

[0067] 1. Experimental Method 1. Preparation of test substance: An appropriate amount of Compound 4 was weighed, and an appropriate amount of solvent 2% DMSO+2% Tween 80+physiological saline was added to prepare a solution of the desired concentration (0.67 mg / kg). 2. Animal model: SPF grade SD male rats, weighing 220-240g, treated with hypoxia (oxygen content 11%). 3. Experimental grouping: hypoxia control group, 4 animals per group; hypoxia treatment group, 4 animals per group. 4. Administration method: One intravenous injection per rat in the hypoxia treatment group before hypoxia treatment. 5. Blood gas analysis: Blood (approximately 0.5 mL) was collected from the femoral artery 24 hours before and 24 hours after hypoxia treatment, and blood gas analysis was performed. The results are shown in Table 5. [Table 5] 6. Respiratory rate: The respiratory rate of the rats was assessed at the time of blood collection. 7. Data statistics: Data analysis was performed using GraphPad, and the results were expressed as mean ± standard deviation (Mean ± SD). Data analysis was performed using a one-way analysis of variance (T-test), with P<0.05 indicating a statistically significant difference.

[0068] 2. Experimental results 1. Blood gas analysis is shown in Figure 10 (effect of Compound 4 on blood oxygen partial pressure (PO2) and blood oxygen saturation (SO2) in SD rats before and after 24 hours of hypoxia treatment). 1) There were no significant differences in the blood gas analysis results between animals in each group 24 hours before hypoxia treatment. 2) 24 hours after hypoxia treatment, the blood oxygen partial pressure (p=0.023) and blood oxygen saturation (p=0.0023) of the 0.67 mg / kg group were higher than those of the control group.

[0069] 2. Respiratory rate is shown in FIG. 11 (effect of Compound 4 on respiratory rate (RR) of rats before and after 24 hours of hypoxic treatment). 1) There was no significant difference in the respiratory rate of animals in each group 24 h before hypoxia treatment. 2) After 24 hours of hypoxia treatment, the respiratory rate of the treated group was significantly lower than that of the control group (p<0.05).

[0070] A single injection of 0.67 mg / kg of compound 4 significantly increased the blood oxygen tension and blood oxygen saturation and significantly reduced the respiratory rate in SD rats 24 hours after hypoxia treatment, thereby exerting an anti-hypoxia / anoxia injury effect.

[0071] From the above, it was found that the aromatic ring amino-substituted derivatives of magnolol and / or honokiol of the present invention can be used to prepare anti-hypoxic / hypoxia injury drugs, which can exhibit significant anti-hypoxic / hypoxia injury effects.

[0072] As apparent from the above description, the above-described embodiment of the present invention provides the following technical effects. The derivatives having the structure represented by the above general formula I are useful for preparing anti-hypoxia / anoxia injury drugs that can rapidly and effectively improve the oxygen-carrying capacity of red blood cells, and provide novel drugs for preventing and treating diseases caused by hypoxia in the external environment (e.g., altitude sickness) and ventilation and / or ventilatory dysfunction diseases caused by various internal causes (e.g., central nervous system diseases, bronchial and pulmonary diseases, etc.), thereby solving the problems of conventional anti-hypoxia / anoxia injury drugs, such as indirect effects and slow onset of action.

[0073] The above is merely a preferred embodiment of the present invention, and is not intended to limit the present invention. Those skilled in the art can make various modifications and changes to the present invention. All modifications, equivalent replacements, improvements, etc. made without departing from the spirit and principle of the present invention shall be included in the patent scope of the present invention.

Claims

1. 1. Use of an aromatic ring amino-substituted derivative of magnolol and / or honokiol in the manufacture of a pharmaceutical composition for anti-hypoxic / anoxic injury, The use, characterized in that the aromatic ring amino-substituted derivative of magnolol and / or honokiol is a compound represented by general formula I or a salt thereof. 【Chemical 1】 (In the general formula I, R １ and R ４ are each independently any one selected from C 1 to C 8 alkyl and C 1 to C 8 alkenyl, and R ２ and R ３ are each independently selected from hydrogen or hydroxy, and R ２ and R ３ is not simultaneously hydrogen or hydroxy, and R ５ is H, C １ ~C １２ acyl, and the acyl moiety remaining after carboxyl condensation of a single amino acid; R ６ is selected from hydrogen, the single amino acid is any one selected from lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, 6-hydroxynorleucine, glycine, histidine, arginine, proline, glutamic acid, aspartic acid, serine, threonine, tyrosine, cystine, and cysteine; When the aromatic ring amino-substituted compound of magnolol and / or honokiol is a salt of the compound represented by the general formula I, one or more of the salt-forming amino groups possessed by R 5 are in the form of a salt, and the acid for salt formation is a pharmaceutically acceptable acid.

2. Said C １ ~C ８ alkyl is any one selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl; Said C １ ~C ８ 2. The use of claim 1 in preparing a pharmaceutical composition for treating hypoxic / anoxia injury, wherein alkenyl is selected from the group consisting of vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl, oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl, and oct-7-enyl.

3. Said C １ ~C １２ The use in the manufacture of a pharmaceutical composition for anti-hypoxia / anoxia injury according to claim 1 or 2, characterized in that acyl is any one selected from formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, and octanoyl.

4. The aromatic ring amino-substituted derivatives of magnolol and / or honokiol include 3',5-diallyl-3-amino-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-acetamido-2,4'-dihydroxy-1,1'-biphenyl, 3',5-diallyl-3-[(S)-2,6-diamino-1-hexanoyl] ... C-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-3-phenyl-2-amino-1-propionyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(R)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3 3. The use of the compound according to claim 1 or 2 in the preparation of a pharmaceutical composition for treating hypoxic / anoxic injury, characterized in that the compound is any one or more of the following compounds: 3',5-diallyl-3-[(S)-2-amino-6-hydroxy-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-2-amino-4-methylthio-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, 3',5-diallyl-3-[(S)-3-methyl-2-amino-1-butyryl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride, and 3',5-dipropyl-3-[(S)-2,6-diamino-1-hexanoyl]amido-2,4'-dihydroxy-1,1'-biphenyl and its hydrochloride.

5. Use in the manufacture of the anti-hypoxia / anoxia injury medicinal composition described in claim 1, characterized in that the administration method of the anti-hypoxia / anoxia injury drug is injection, oral administration, implantation or direct injection into the lesion.

6. A pharmaceutical composition for treating hypoxic / anoxia damage, comprising an aromatic ring amino-substituted derivative of magnolol and / or honokiol or a salt thereof, and a pharmaceutically acceptable carrier, wherein the aromatic ring amino-substituted derivative of magnolol and / or honokiol is the aromatic ring amino-substituted derivative of magnolol and / or honokiol described in claim 1.

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