WO2023088062A1 - 厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物 - Google Patents

厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物 Download PDF

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WO2023088062A1
WO2023088062A1 PCT/CN2022/128028 CN2022128028W WO2023088062A1 WO 2023088062 A1 WO2023088062 A1 WO 2023088062A1 CN 2022128028 W CN2022128028 W CN 2022128028W WO 2023088062 A1 WO2023088062 A1 WO 2023088062A1
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hypoxic
enyl
amino
honokiol
magnolol
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French (fr)
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张平平
刘晔
张玉英
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北京红惠新医药科技有限公司
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Priority to AU2022394648A priority Critical patent/AU2022394648A1/en
Priority to CA3238861A priority patent/CA3238861A1/en
Priority to EP22894599.4A priority patent/EP4385505A1/en
Publication of WO2023088062A1 publication Critical patent/WO2023088062A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the technical field of biomedicine, in particular to a use of magnolol and/or honokiol aromatic ring amino-substituted derivatives for anti-hypoxic/hypoxic injury and a pharmaceutical composition.
  • Magnolol and honokiol are the main active ingredients of the traditional Chinese medicine Magnolia officinalis, which are usually obtained through structural modification of the traditional Chinese medicine Magnolia officinalis extract.
  • the chemical structural formulas of magnolol and honokiol are as follows:
  • High altitude hypoxia poses a potential threat to the health of humans living in this area for a long time.
  • the heart is one of the organs with the highest oxygen consumption in the body.
  • Sufficient oxygen supply is required to maintain the vitality and function of the heart.
  • Exposure to low-pressure hypoxic environment due to the reduction of oxygen partial pressure, reduces the oxygen supply to the heart, resulting in cardiac dysfunction, thereby inducing some cardiovascular diseases, such as myocardial infarction (MI) and pulmonary hypertension-induced Right ventricle (RV) dysfunction, and even sudden cardiac death (suddencardiac death, SCD).
  • MI myocardial infarction
  • RV pulmonary hypertension-induced Right ventricle
  • SCD sudden cardiac death
  • the brain is another organ with high oxygen consumption in the body, and its tolerance to hypoxia is extremely low.
  • a low-pressure hypoxic environment will cause irreversible damage to the brain.
  • the atmospheric pressure and partial pressure of oxygen will drop rapidly after the people living in the plain enter the plateau, the blood oxygen saturation of the body will also drop rapidly, and the tissue will soon be in a state of hypoxia.
  • the body will produce acute mountain reaction, palpitations, chest tightness, chest pain, dizziness, dyspnea, etc., and even acute pulmonary edema, etc., even life-threatening.
  • the main purpose of the present invention is to provide a kind of magnolol and/or honokiol aromatic ring amino substituted derivatives anti-hypoxic/hypoxic injury application and pharmaceutical composition, to solve the existing problems of anti-hypoxic drugs The problem of indirect onset and slow onset of effect.
  • a kind of anti-hypoxia/hypoxic damage application of magnolol and/or honokiol aromatic ring amino derivatives is provided, the magnolol and/or Honokiol aromatic ring amino substitution derivatives are compounds or salts thereof shown in general formula I:
  • R 1 and R 4 are each independently selected from C 1 -C 8 hydrocarbon groups, R 2 and R 3 are each independently selected from hydrogen or hydroxyl, and R 2 and R 3 are not hydrogen or hydroxyl at the same time;
  • R 5 is selected from any one of H, C 1 -C 12 acyl groups, the remaining acyl moiety of a single amino acid after condensation of a carboxyl group, and the remaining acyl moiety of a polypeptide after condensation of a carboxyl group;
  • R 6 is selected from hydrogen, C 1 Any one of ⁇ C 8 hydrocarbon groups.
  • the C 1 to C 8 hydrocarbon groups in R 1 , R 4 and R 6 are each independently selected from any one of C 1 to C 8 alkyl groups and C 1 to C 8 alkenyl groups, preferably
  • the C 1 -C 8 alkyl group is selected from any one of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.
  • C 1 -C 8 alkenyl groups are selected from vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-ene pent-2-enyl, pent-3-enyl, pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl , Hex-5-enyl, Hep-1-enyl, Hep-2-enyl, Hep-3-enyl, Hep-4-enyl, Hep-5-enyl, Hep-6-enyl, In oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl, oct-7-enyl any kind.
  • C 1 -C 12 acyl group is selected from any one of formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, and octanoyl.
  • the above-mentioned single amino acid is selected from lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, 6-hydroxynorleucine, glycine, Any one of histidine, arginine, proline, glutamic acid, aspartic acid, serine threonine, tyrosine, cystine or cysteine.
  • polypeptide is a peptide formed by a plurality of single amino acids, preferably the molecular weight of the polypeptide is ⁇ 2500Da.
  • magnolol and/or honokiol aromatic ring amino-substituted compounds are salts of compounds shown in general formula I, one or more of the salable amino groups carried by R are in the form of salts,
  • the acid used for salt formation is pharmaceutically acceptable acids such as hydrochloric acid, oxalic acid or fumaric acid.
  • the above-mentioned magnolol and/or honokiol aromatic ring amino-substituted derivatives are any one or more of the following compounds: 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]amino-2,4'-dihydroxy-1,1'-biphenyl and its salts Salt, 3′,5-diallyl-3-[(S)-3-phenyl-2-amino-1-propionyl]amino-2,4′-dihydroxy-1,1′- Biphenyl and its hydrochloride, 3′,5-diallyl-3-[(R)-2,6-di
  • anti-hypoxic/hypoxic injury drugs are administered by injection, oral administration, implantation or direct filling of lesion sites.
  • an anti-hypoxic/hypoxic injury pharmaceutical composition comprises magnolol and/or honokiol aromatic ring amino-substituted Derivatives or salts thereof and pharmaceutically acceptable carriers; wherein the derivatives of magnolol and/or honokiol aromatic ring amino substitutions are the above-mentioned magnolol and/or honokiol aromatic ring amino substitutions derivative.
  • the derivatives having the structure shown in the above general formula I can be used to prepare anti-hypoxic/hypoxic injury drugs, quickly and effectively improve the oxygen-carrying capacity of red blood cells, and to prevent and treat erythrocytes caused by hypoxia in the external environment.
  • Diseases such as altitude sickness
  • ventilation and/or ventilation dysfunction diseases caused by various self-reasons such as central nervous system disorders, bronchi, lung lesions, etc.
  • self-reasons such as central nervous system disorders, bronchi, lung lesions, etc.
  • Figure 1 shows the effect of compound 1 on blood oxygen partial pressure (PO 2 ) and blood oxygen saturation (SO 2 ) in SD rats before and after 24 hours of hypoxic treatment in Example 1 of the present invention. picture;
  • Fig. 2 shows before hypoxic treatment 24h and after hypoxic treatment 24h in embodiment 1 of the present invention, compound 1 is to SD rat respiratory rate (RR) influence figure;
  • Figure 3 shows the effect of intravenous injection of compound 2 on blood oxygen partial pressure (PO 2 ) and blood oxygen saturation ( Influence diagram of SO 2 );
  • Figure 4 shows the effect of intravenous injection of Compound 2 on SD rat respiratory rate (RR) before hypoxic treatment 24h and hypoxic treatment 6h and 24h in Example 2 of the present invention
  • Figure 5 shows the effect of intravenous injection of compound 2 on lung tissue damage in SD rats after hypoxic treatment in Example 2 of the present invention for 24 hours;
  • Fig. 6 shows the effects of intragastric administration of compound 2 on blood oxygen partial pressure (PO 2 ) and blood oxygen saturation (SO 2 ) before and after 24 hours of hypoxic treatment in Example 3 of the present invention ;
  • Fig. 7 shows before hypoxic treatment 24h and after hypoxic treatment 24h in embodiment 3 according to the present invention, the figure of the impact of gavage Compound 2 on rat respiratory rate (RR);
  • Fig. 8 shows the effect of compound 3 on blood oxygen saturation (SO 2 ) of SD rats before and after 24 hours of hypoxic treatment in Example 4 of the present invention
  • Fig. 9 shows the graph of the influence of compound 3 on the respiratory rate (RR) of rats before hypoxic treatment 24h and after hypoxic treatment 24h in Example 4 of the present invention
  • Figure 10 shows the effect of compound 4 on blood oxygen partial pressure (PO 2 ) and blood oxygen saturation (SO 2 ) in SD rats before and after 24 hours of hypoxic treatment in Example 5 of the present invention diagram;
  • Fig. 11 shows the effect of compound 4 on the respiratory rate (RR) of rats before and after 24 hours of hypoxic treatment in Example 5 of the present invention.
  • the existing anti-hypoxic drugs have the problem of indirect onset and slow onset of effect.
  • the present invention provides a kind of magnolol and/or honokiol aromatic ring amino-substituted Anti-hypoxic/hypoxic damage application and pharmaceutical composition of derivatives.
  • magnolol and/or honokiol aromatic ring amino substitution derivatives are compounds or salts thereof shown in general formula I:
  • R 1 and R 4 are each independently selected from C 1 -C 8 hydrocarbon groups, R 2 and R 3 are each independently selected from hydrogen or hydroxyl, and R 2 and R 3 are not hydrogen or hydroxyl at the same time;
  • R 5 is selected from any one of H, C 1 -C 12 acyl groups, the remaining acyl moiety of a single amino acid after condensation of a carboxyl group, and the remaining acyl moiety of a polypeptide after condensation of a carboxyl group;
  • R 6 is selected from hydrogen, C 1 Any one of ⁇ C 8 hydrocarbon groups.
  • Derivatives with the structure shown in the above general formula I can be used to prepare anti-hypoxic/hypoxic damage drugs, quickly and effectively improve the oxygen-carrying capacity of red blood cells, and prevent and treat diseases caused by low oxygen in the external environment (such as altitude sickness) and Ventilation and/or ventilation dysfunction diseases caused by various self-reasons (such as central nervous system disorders, bronchi, lung lesions, etc.) provide new drug options to solve the indirect onset and onset of current anti-hypoxic/hypoxic drugs. Slow and so on.
  • R1 , C 1 -C 8 hydrocarbon groups in R 4 and R 6 are each independently selected from any one of C 1 -C 8 alkyl groups, C 1 -C 8 alkenyl groups, preferably C 1 -C 8
  • the alkyl group is selected from any one of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, more preferably propyl.
  • R 1 and R 4 are respectively located at the para-position or ortho-position of the hydroxyl group of each benzene ring, and their electronic effects and steric effects will affect the reactivity of each site on the benzene ring.
  • the site has higher reactivity, so that it is easier to obtain excellent anti-hypoxia/hypoxia drugs, preferably the above-mentioned C 1 to C 8 alkenyl is selected from vinyl, propenyl, allyl, but-1- Alkenyl, 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, Hep-1-enyl, Hep-2-enyl, Hep-3-enyl, Hept-4-enyl, hept-5-en
  • R 1 and R 4 are independently allyl groups.
  • the aforementioned C 1 -C 12 acyl group is selected from any one of formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, and octanoyl.
  • the above acyl groups are relatively easy to obtain, and are more likely to exert their anti-hypoxia/hypoxia activity.
  • the acyl groups with C 1 -C 12 are preferably acetyl groups.
  • the above-mentioned single amino acid is selected from lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, 6-hydroxy Any of norleucine, glycine, histidine, arginine, proline, glutamic acid, aspartic acid, serine threonine, tyrosine, cystine, or cysteine .
  • the above-mentioned types of amino acids are relatively easy to obtain, and most of the amino acids are the types required by the human body, which are more economical and safer.
  • the above-mentioned amino acid is lysine or methionine.
  • the above-mentioned polypeptide is a peptide formed by a plurality of the above-mentioned single amino acids, and the molecular weight of the polypeptide is preferably ⁇ 2500Da.
  • one of the salable amino groups carried by R One or more of them are in the form of salt, and the acid used for forming the salt is a pharmaceutically acceptable acid such as hydrochloric acid, oxalic acid or fumaric acid.
  • magnolol and/or honokiol aromatic ring amino-substituted compounds are pharmaceutically acceptable salts of the compound represented by the general formula I, the water solubility is good and the application is more convenient.
  • the above-mentioned magnolol and/or honokiol aromatic ring amino-substituted derivatives are any one or more of the following compounds: 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]amino-2,4′-dihydroxy-1,1′-biphenyl Benzene and its hydrochloride, 3′,5-diallyl-3-[(S)-3-phenyl-2-amino-1-propionyl]amino-2,4′-dihydroxy-1 , 1′-biphenyl and its hydrochloride, 3′,5-dial
  • the above-mentioned anti-hypoxic/hypoxic injury drugs are administered by injection, oral administration, implantation or direct filling of lesion sites .
  • an anti-hypoxic/hypoxic injury pharmaceutical composition in another typical embodiment of the present application, includes magnolol and/or honokiol Aryl ring amino substituted derivatives or their salts and a pharmaceutically acceptable carrier; wherein magnolol and/or honokiol aryl ring amino substituted derivatives are magnolol and/or honokiol shown in general formula I above Or honokiol aromatic ring amino substituted derivatives.
  • Derivatives with the structure shown in the above general formula I can be used to prepare anti-hypoxic/hypoxic damage drugs, quickly and effectively improve the oxygen-carrying capacity of red blood cells, and prevent and treat diseases caused by low oxygen in the external environment (such as altitude sickness) and Ventilation and/or ventilation dysfunction diseases caused by various self-reasons (such as central nervous system disorders, bronchi, lung lesions, etc.) provide new drug options to solve the indirect onset and onset of current anti-hypoxic/hypoxic drugs. Slow and so on.
  • magnolol and/or honokiol aromatic ring amino-substituted derivatives used in the following examples can be prepared by known routes in the prior art, such as the route in patent CN103113264A.
  • test substance Weigh an appropriate amount of compound 1, add an appropriate amount of solvent 2% DMSO+2% Tween80+physiological saline, and prepare a solution with the desired concentration (0.58 mg/mL).
  • Animal model male SD rats of SPF grade, body weight 220-240 g, treated with hypoxia (oxygen content is 11%).
  • hypoxic treatment control group 4 rats in each group
  • hypoxic treatment administration group 4 rats in each group.
  • Blood gas analysis blood (about 0.5 mL) was collected from the femoral artery of each group before and after 24 hours of hypoxic treatment, and blood gas analysis was performed. Refer to Table 1 for details.
  • Respiratory rate The respiratory rate of the rats was assessed at the time of blood collection.
  • the respiratory rate is as shown in Figure 2 (i.e. before the hypoxic treatment for 24 hours and after the hypoxic treatment for 24 hours, the effect of compound 1 on the respiratory rate (RR) of SD rats):
  • test substance Weigh an appropriate amount of compound 2, add an appropriate amount of sodium chloride injection (0.9%), and prepare solutions with required concentrations (0.25 mg/kg and 1 mg/kg).
  • Animal model male SD rats of SPF grade, body weight 220-240 g, treated with hypoxia (oxygen content is 11%).
  • hypoxic treatment control group 4 rats in each group
  • hypoxic treatment administration group 4 rats in each group.
  • Blood gas analysis blood (about 0.5 mL) was collected from the femoral artery of each group before and after hypoxic treatment for 24 hours, and blood gas analysis was performed. See Table 2 for details.
  • Respiratory rate The respiratory rate of the rats was assessed at the time of blood collection.
  • the lung tissues of the hypoxic treatment (24h) control group and the hypoxic treatment (24h) administration group were taken for paraffin section preparation, staining, and case analysis.
  • Paraffin sections were dewaxed to water: put the sections in xylene I for 20 minutes, xylene II for 20 minutes, absolute ethanol I for 5 minutes, absolute ethanol II for 5 minutes, 75% alcohol for 5 minutes, and finally washed with tap water.
  • Hematoxylin staining the slices were stained with hematoxylin solution for 3-5 minutes, then washed with tap water, differentiated in the differentiation solution, washed with tap water again, the blue solution returned to blue, and finally rinsed with running water.
  • Eosin staining the sections were dehydrated in 85% and 95% gradient alcohols for 5 minutes each, and stained in eosin staining solution for 5 minutes.
  • the respiratory rate is as shown in Figure 4 (i.e. before the hypoxic treatment 24h and after the hypoxic treatment 6h and 24h, the impact of intravenous injection of compound 2 on the respiratory rate (RR) of SD rats):
  • medium-sized alveolar wall thickening (black arrow 8) can be seen in the lung tissue, accompanied by a small amount of inflammatory cell infiltration (red arrow 9); eosinophilic interstitial fluid infiltration can be seen in a small amount of bronchial lumen out (yellow arrow 10); a small amount of vascular muscularization, smooth muscle cell proliferation, tube wall hypertrophy, and lumen narrowing (blue arrow 11).
  • the administration group can alleviate the symptoms of pulmonary edema, alveolar wall thickening, inflammatory cell infiltration, neutrophil infiltration, vascular muscularization, smooth muscle cell hyperplasia, tube wall hypertrophy and luminal stenosis. Tissue damage from oxygen (hypoxia).
  • a single intravenous injection of 0.25mg/kg and 1mg/kg of compound 2 can increase the blood oxygen partial pressure and blood oxygen saturation in SD rats treated with hypoxia for 1h, 6h and 24h; a single intravenous injection of 1mg Compound 2/kg can significantly reduce the respiratory rate of SD rats treated with hypoxia for 6h and 24h; a single intravenous injection of 1mg/kg compound 2 can significantly reduce the damage to lung tissue in SD rats treated with hypoxia for 24h . Accordingly, injection of compound 2 can effectively resist hypoxic/hypoxic injury by increasing blood oxygen carrying capacity.
  • test substance Weigh an appropriate amount of compound 2, add an appropriate amount of sodium chloride injection (0.9%), and prepare a solution with a desired concentration (40 mg/kg).
  • Animal model male SD rats of SPF grade, body weight 220-240 g, treated with hypoxia (oxygen content is 11%).
  • hypoxic treatment control group 4 rats in each group
  • hypoxic treatment administration group 4 rats in each group.
  • Blood gas analysis blood (about 0.5 mL) was collected from the femoral artery of each group before and after 24 hours of hypoxic treatment, and blood gas analysis was performed, see Table 3 for details.
  • Respiratory rate The respiratory rate of the rats was assessed at the time of blood collection.
  • the respiratory rate is as shown in Figure 7 (before hypoxic treatment for 24 hours and after hypoxic treatment for 24 hours, the impact of gavage compound 2 on the respiratory rate (RR) of rats):
  • test substance Weigh an appropriate amount of compound 3, add an appropriate amount of sodium chloride injection (0.9%), and prepare a solution with the desired concentration (0.93 mg/kg).
  • Animal model male SD rats of SPF grade, body weight 220-240 g, treated with hypoxia (oxygen content is 11%).
  • hypoxic treatment control group 4 rats in each group
  • hypoxic treatment administration group 4 rats in each group.
  • Blood gas analysis Blood (about 0.5 mL) was collected from the femoral artery of each group before and after 24 hours of hypoxic treatment, and blood gas analysis was performed. Refer to Table 4 for details.
  • hypoxic treatment control group Take blood once 24 hours before hypoxic treatment; take blood once 24 hours after hypoxic treatment
  • Hypoxic treatment administration group 0.93 Take blood once 24 hours before hypoxic treatment; take blood once 24 hours after hypoxic treatment
  • test substance Weigh an appropriate amount of compound 4, add an appropriate amount of solvent 2% DMSO+2% Tween80+physiological saline, and prepare a solution with the desired concentration (0.67 mg/kg).
  • Animal model male SD rats of SPF grade, body weight 220-240 g, treated with hypoxia (oxygen content is 11%).
  • hypoxic treatment control group 4 rats in each group
  • hypoxic treatment administration group 4 rats in each group.
  • Blood gas analysis Blood (about 0.5 mL) was collected from the femoral artery before and after 24 hours of hypoxic treatment, and blood gas analysis was performed, see Table 5 for details.
  • Respiratory rate The respiratory rate of the rats was assessed at the time of blood collection.
  • a single injection of 0.67 mg/kg compound 4 can significantly increase blood oxygen partial pressure and blood oxygen saturation after 24 hours of hypoxic treatment in SD rats, significantly reduce respiratory rate, and thus play an anti-hypoxic/hypoxic injury effect.
  • the magnolol and/or honokiol aromatic ring amino-substituted derivatives of the present application are used in the preparation of anti-hypoxic/hypoxic damage drugs, which can significantly play a role in anti-hypoxic/hypoxic damage. effect.
  • Derivatives with the structure shown in the above general formula I can be used to prepare anti-hypoxic/hypoxic damage drugs, quickly and effectively improve the oxygen-carrying capacity of red blood cells, and prevent and treat diseases caused by low oxygen in the external environment (such as altitude sickness) and Ventilation and/or ventilation dysfunction diseases caused by various self-reasons (such as central nervous system disorders, bronchi, lung lesions, etc.) provide new drug options to solve the indirect onset and onset of current anti-hypoxic/hypoxic drugs. Slow and so on.

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Abstract

本发明提供了一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物。该厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为通式I所示化合物或其盐：通式I 通式I中，R 1和R 4各自独立地选自C 1～C 8的烃基，R 2和R 3各自独立地选自氢或羟基，且R 2和R 3不同时为氢或羟基；R 5选自H、C 1～C 12的酰基、单一氨基酸在羧基发生缩合后的剩余酰基部分、多肽在羧基发生缩合后的剩余酰基部分中的任意一种；R 6选自氢、C 1～C 8的烃基中的任意一种。上述通式I所示结构的衍生物可用于制备抗低氧/缺氧损伤药物，为预防和治疗疾病提供新的药物选择，解决当前抗低氧/缺氧药物间接性起效、起效慢等问题。

Description

厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物
本申请是以CN申请号为202111402114.5，申请日为2021年11月19日的中国申请为基础，并主张其优先权，该CN申请的公开内容再次作为整体引入本申请中。
技术领域
本发明涉及生物医药技术领域，具体而言，涉及一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物。
背景技术
厚朴酚以及和厚朴酚是中国传统中药厚朴的主要活性成分，通常由传统中药厚朴提取物经过结构改造而获得，厚朴酚以及和厚朴酚的化学结构式分别如下：
Figure PCTCN2022128028-appb-000001
1930年日本杉井首先从中国厚朴树皮中分离得到了厚朴酚(中草药；2005，36，10，1591-1594)。1989年中国的孟丽珍等也从厚朴分离到和厚朴酚(中成药：1989，11(8)：223.)。厚朴酚以及和厚朴酚具有抗菌、抗炎、抗肿瘤、肌肉松弛、降胆固醇和抗衰老等广泛的药理作用(中草药；2005，36，10，1591-1594)。本文中所用药物为厚朴酚与和厚朴酚芳环氨基取代类衍生物，目前尚无用于抵抗低氧/缺氧损伤的报道。
高原低氧环境(high altitude hypoxia，HAH)对长期生活在该地区的人类的健康构成了潜在威胁。心脏是机体中耗氧量较高的器官之一，维持心脏的活力和机能需要充足的氧气供应。暴露于低压低氧环境中，由于氧分压的降低，使得供应心脏的氧气减少，造成心脏功能紊乱，从而诱发一些心血管疾病的发生，如心肌梗死(myocardial infarction，MI)和肺动脉高压诱发的右心室(right ventricle，RV)功能障碍，甚至出现心脏性猝死(suddencardiac death，SCD)。大脑是机体另外一个耗氧量较高的器官，对缺氧的耐受性极低，低压缺氧环境会引起大脑不可逆性损伤。近年来，随着奔赴高原的人数日益增加，居住在平原的人急进入高原后，大气压及氧分压的迅速降低，机体的血氧饱和度也随之快速降低，组织很快处于缺氧状态，进而导致机体发生一系列的生理和病理的改变，机体会产生急性高山反应，出现心悸，胸闷、胸痛、头晕、呼吸困难等，重者甚至会发生急性肺水肿等情况，甚至危及生命。
目前，抗缺氧药物中的中药有红景天、当归、人参等，其疗效较为确切、但起效较慢；西药有乙酰唑胺、***、氨茶碱片等，这些药物虽然对缺氧症状有缓解作用，但不能直接地提高体内血氧饱和度进而实现预防和抵抗低氧/缺氧环境引起的损伤。
发明内容
本发明的主要目的在于提供一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物，以解决现有抗缺氧药物存在的间接性起效、起效慢的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途，该厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为通式I所示化合物或其盐：
Figure PCTCN2022128028-appb-000002
通式I中，R 1和R 4各自独立地选自C 1～C 8的烃基，R 2和R 3各自独立地选自氢或羟基，且R 2和R 3不同时为氢或羟基；R 5选自H、C 1～C 12的酰基、单一氨基酸在羧基发生缩合后的剩余酰基部分、多肽在羧基发生缩合后的剩余酰基部分中的任意一种；R 6选自氢、C 1～C 8的烃基中的任意一种。
进一步地，上述R 1、R 4和R 6中的C 1～C 8的烃基各自独立地选自C 1～C 8的烷基、C 1～C 8的烯基中的任意一种，优选C 1～C 8的烷基选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基中的任意一种。
进一步地，上述C 1～C 8的烯基选自乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3-烯基、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基、 辛-1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基、辛-7-烯基中的任意一种。
进一步地，上述C 1～C 12的酰基选自甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、庚酰基、辛酰基中的任意一种。
进一步地，上述单一氨基酸选自赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、6-羟基正亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、丝氨酸苏氨酸、酪氨酸、胱氨酸或半胱氨酸中的任意一种。
进一步地，上述多肽为多个单一氨基酸形成的肽，优选多肽的分子量≤2500Da。
进一步地，当上述厚朴酚和/或和厚朴酚芳环氨基取代类化合物为通式I所示化合物的盐时，R 5携带的可成盐氨基中的一个或多个为盐形式，成盐用的酸为盐酸、草酸或富马酸等药学上可接受的酸。
进一步地，上述厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为以下化合物中的任意一种或多种：3′，5-二烯丙基-3-氨基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-乙酰胺基-2，4′-二羟基-1，1′-联苯、3′，5-二烯丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-3-苯基-2-氨基-1-丙酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(R)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-6-羟基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-3-甲基-2-氨基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、和3′，5-二丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐。
进一步地，上述抗低氧/缺氧损伤药物的给药方式为注射、口服、埋植或直接填充病灶部位。
根据本发明的另一方面，提供了一种抗低氧/缺氧损伤药物组合物，该抗低氧/缺氧损伤药物组合物包括厚朴酚和/或和厚朴酚芳环氨基取代类衍生物或其盐以及在药学上可接受的载体；其中厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为上述的厚朴酚和/或和厚朴酚芳环氨基取代类衍生物。
应用本发明的技术方案，具有上述通式I所示结构的衍生物可用于制备抗低氧/缺氧损伤药物，快速有效地提高红细胞携氧能力，为预防和治疗因外环境低氧引起的疾病(如高原病)以及各种自身原因(如中枢神经***疾患，支气管、肺病变等)引起的通气和/或换气功能障碍性疾病提供新的药物选择，解决当前抗低氧/缺氧药物间接性起效、起效慢等问题。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了根据本发明的实施例1中低氧处理24h前以及低氧处理24h后，化合物1对SD大鼠血氧分压(PO 2)和血氧饱和度(SO 2)的影响图；
图2示出了根据本发明的实施例1中低氧处理24h前以及低氧处理24h后，化合物1对SD大鼠呼吸频率(RR)的影响图；
图3示出了根据本发明的实施例2中低氧处理24h前以及低氧处理1h、6h和24h后，静脉注射化合物2对大鼠血氧分压(PO 2)和血氧饱和度(SO 2)的影响图；
图4示出了根据本发明的实施例2中低氧处理24h前以及低氧处理6h和24h后，静脉注射化合物2对SD大鼠呼吸频率(RR)的影响；
图5示出了根据本发明的实施例2中低氧处理24h后，静脉注射化合物2对SD大鼠肺组织损伤的影响图；
图6示出了根据本发明的实施例3中低氧处理24h前以及低氧处理24h后，灌胃化合物2对血氧分压(PO 2)和血氧饱和度(SO 2)的影响图；
图7示出了根据本发明的实施例3中低氧处理24h前以及低氧处理24h后，灌胃化合物2对大鼠呼吸频率(RR)的影响图；
图8示出了根据本发明的实施例4中低氧处理24h前以及低氧处理24h后，化合物3对SD大鼠血氧饱和度(SO 2)的影响图；
图9示出了根据本发明的实施例4中低氧处理24h前以及低氧处理24h后，化合物3对大鼠呼吸频率(RR)的影响图；
图10示出了根据本发明的实施例5中低氧处理24h前以及低氧处理24h后，化合物4对SD大鼠血氧分压(PO 2)和血氧饱和度(SO 2)的影响图；以及
图11示出了根据本发明的实施例5中低氧处理24h前以及低氧处理24h后，化合物4对大鼠呼吸频率(RR)的影响图。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
如背景技术所分析的，现有抗缺氧药物存在间接性起效、起效慢的问题，为解决该问题，本发明提供了一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途及药物组合物。
在本申请的一种典型的实施方式中，提供了一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途，该厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为通式I所示化合物或其盐：
Figure PCTCN2022128028-appb-000003
通式I中，R 1和R 4各自独立地选自C 1～C 8的烃基，R 2和R 3各自独立地选自氢或羟基，且R 2和R 3不同时为氢或羟基；R 5选自H、C 1～C 12的酰基、单一氨基酸在羧基发生缩合后的剩余酰基部分、多肽在羧基发生缩合后的剩余酰基部分中的任意一种；R 6选自氢、C 1～C 8的烃基中的任意一种。
具有上述通式I所示结构的衍生物可用于制备抗低氧/缺氧损伤药物，快速有效地提高红细胞携氧能力，为预防和治疗因外环境低氧引起的疾病(如高原病)以及各种自身原因(如中枢神经***疾患，支气管、肺病变等)引起的通气和/或换气功能障碍性疾病提供新的药物选择，解决当前抗低氧/缺氧药物间接性起效、起效慢等问题。
为进一步地提高厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的合成效率，从而进一步地开拓其在用于制备抗低氧/缺氧损伤药物中的用途，优选上述R 1、R 4和R 6中的C 1～C 8的烃基各自独立地选自C 1～C 8的烷基、C 1～C 8的烯基中的任意一种，优选C 1～C 8的烷基选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基中的任意一种，进一步地优选为丙基。
R 1和R 4分别位于各苯环羟基的对位或邻位，其电子效应和空间效应会影响苯环上各位点的反应活性，为尽可能使各苯环上的羟基及羟基邻位等位点具有较高的反应活性，以便更容易得到具有优良的抗低氧/缺氧药物，优选上述C 1～C 8的烯基选自乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3烯基、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基、辛-1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基、辛-7-烯基中的任意一种。
为进一步地提高厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的合成便利性，优选上述R 1和R 4分别独立地为烯丙基。
优选上述C 1～C 12的酰基选自甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、庚酰基、辛酰基中的任意一种。以上酰基相对容易获得，且更易于发挥其抗低氧/缺氧活性，进一步地，优选为C 1～C 12的酰基为乙酰基。
在本申请的一种实施例中，上述单一氨基酸选自赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、6-羟基正亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、丝氨酸苏氨酸、酪氨酸、胱氨酸或半胱氨酸中的任意一种。
上述种类的氨基酸相对容易获得，且氨基酸多为人体所需种类，经济型和安全性更好。为进一步地提高上述厚朴酚和/或和厚朴酚芳环氨基取代类衍生物对人体抗低氧/缺氧的有益效果，优选上述氨基酸为赖氨酸或蛋氨酸。
为进一步地提高R 5为多肽时其具有的药物活性，优选上述多肽为多个上述单一氨基酸形成的肽，优选多肽的分子量≤2500Da。
在本申请的一种实施例中，当上述厚朴酚和/或和厚朴酚芳环氨基取代类化合物为通式I所示化合物的盐时，R 5携带的可成盐氨基中的一个或多个为盐形式，成盐用的酸为盐酸、草酸或富马酸等药学上可接受的酸。
当上述厚朴酚和/或和厚朴酚芳环氨基取代类化合物为通式I所示化合物的药学上可接受的盐时，其水溶性好，应用更方便。
在一些实施例中，优选上述厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为以下化合物中的任意一种或多种：3′，5-二烯丙基-3-氨基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-乙酰胺基-2，4′-二羟基-1，1′-联苯、3′，5-二烯丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-3-苯基-2-氨基-1-丙酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(R)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-6-羟基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-3-甲基-2-氨基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、和3′，5-二丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐。
特别地，当优选厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为3′，5-二烯丙基-3-氨基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-乙酰胺基-2，4′-二羟基-1，1′-联苯、3′，5-二烯丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐时，更有利于提高厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗缺氧性。
为提高上述厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的实用性，优选上述抗低氧/缺氧损伤药物的给药方式为注射、口服、埋植或直接填充病灶部位。
在本申请的另一种典型的实施方式中，提供了一种抗低氧/缺氧损伤药物组合物，该抗低氧/缺氧损伤药物组合物包括厚朴酚和/或和厚朴酚芳环氨基取代类衍生物或其盐以及在药学上可接受的载体；其中厚朴酚和/或和厚朴酚芳环氨基取代类衍生物为上述通式I所示的厚朴酚和/或和厚朴酚芳环氨基取代类衍生物。
具有上述通式I所示结构的衍生物可用于制备抗低氧/缺氧损伤药物，快速有效地提高红细胞携氧能力，为预防和治疗因外环境低氧引起的疾病(如高原病)以及各种自身原因(如中枢神经***疾患，支气管、肺病变等)引起的通气和/或换气功能障碍性疾病提供新的药物选择，解决当前抗低氧/缺氧药物间接性起效、起效慢等问题。
以下将结合具体实施例和对比例，对本申请的有益效果进行说明。
以下实施例中用到的厚朴酚和/或和厚朴酚芳环氨基取代类衍生物均可采用现有技术中的己知路线进行制备，比如可采用专利CN103113264A中的路线进行制备。
抗低氧/缺氧损伤实验：
实施例1
3′，5-二烯丙基-3-氨基-2，4′-二羟基-1，1′-联苯(英文名：3′，5-diallyl-3-amino-[1，1′-biphenyl]-2，4′-diol，化合物1)：
Figure PCTCN2022128028-appb-000004
一、实验方法
1.受试物的配制：称取适量化合物1，加入适量溶剂2％DMSO+2％Tween80+生理盐水，配制成所需浓度(0.58mg/mL)溶液。
2.动物模型：SPF级SD雄性大鼠，体重220～240g，低氧(氧含量为11％)处理。
3.实验分组：低氧处理对照组，每组4只；低氧处理给药组，每组4只。
4.给药方式：低氧处理前向低氧处理给药组各大鼠单次静脉注射给药。
5.血气分析：各组分别在低氧处理24h前和低氧处理24h后股动脉取血(约0.5mL)，进行血气分析，具体参照表1。
表1
Figure PCTCN2022128028-appb-000005
Figure PCTCN2022128028-appb-000006
6.呼吸频率：取血时评估大鼠呼吸频率。
7.数据统计：采用GraphPad进行数据分析，结果以平均值±标准差(Mean±SD)表示，数据分析采用单因素方差分析-T-test，P＜0.05表示具有统计学差异。
二、实验结果
1.血气分析结果如图1所示(即低氧处理24h前以及低氧处理24h后，化合物1对SD大鼠血氧分压(PO 2)和血氧饱和度(SO 2)的影响)：
1)低氧处理24h前，各组动物血气分析结果无明显差异。
2)低氧处理24h时后，给药0.58mg/kg组的血氧分压(p＝0.0012)和血氧饱和度(p＝0.019)显著高于对照组。
2.呼吸频率如图2所示(即低氧处理24h前以及低氧处理24h后，化合物1对SD大鼠呼吸频率(RR)的影响)：
1)低氧处理24h前，各组动物呼吸频率无明显差异。
2)低氧处理24h后，给药组的呼吸频率低于对照组，差异明显(p＜0.05)。
由以上数据可知，单次注射0.58mg/kg化合物1能够显著增加SD大鼠低氧处理24h后的血氧分压和血氧饱和度，显著减少呼吸频率，从而起到抗低氧/缺氧损伤作用。
实施例2
3′，5-二烯丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-二联苯·二盐酸盐(英文名(S)-2，6-diamino-N-(3′，5-diallyl-2，4′-dihydroxy-[1，1′-biphenyl]-3-yl)hexanamide dihydrochloride，化合物2)：
Figure PCTCN2022128028-appb-000007
一、实验方法
1.受试物的配制：称取适量化合物2，加入适量氯化钠注射液(0.9％)，配制成所需浓度(0.25mg/kg和1mg/kg)溶液。
2.动物模型：SPF级SD雄性大鼠，体重220～240g，低氧(氧含量为11％)处理。
3.实验分组：低氧处理对照组，每组4只；低氧处理给药组，每组4只。
4.给药方式：低氧处理前向低氧处理给药组各大鼠单次静脉注射给药。
5.血气分析：各组分别在低氧处理24h前和低氧后股动脉取血(约0.5mL)，进行血气分析，具体参照见表2。
表2
Figure PCTCN2022128028-appb-000008
6.呼吸频率：取血时评估大鼠呼吸频率。
7.H&E染色：
取低氧处理(24h)对照组和低氧处理(24h)给药组(剂量1mg/kg)肺组织进行石蜡切片制备、染色、病例分析。
1)石蜡切片脱蜡至水：依次将切片放入二甲苯I中20min、二甲苯II中20min、无水乙醇I中5min、无水乙醇II中5min、75％酒精中5min，最后自来水洗。
2)苏木素染色：切片入苏木素染液染3～5min后自来水洗，分化液分化，再自来水洗，返蓝液返蓝，最后流水冲洗。
3)伊红染色：切片依次入85％、95％的梯度酒精脱水各5min，入伊红染液中染色5min。
4)脱水封片：切片依次放入无水乙醇I中5min、无水乙醇II中5min、无水乙醇III中5min、二甲I中5min、二甲苯II中5min至透明，最后采用中性树胶封片。
5)显微镜镜检，图像采集分析。
6)结果判读：细胞核呈蓝色，细胞质呈红色。
8.数据统计：采用GraphPad进行数据分析，结果以平均值±标准差(Mean±SD)表示，数据分析采用单因素方差分析-T-test，P＜0.05表示具有统计学差异。
二、实验结果
1.血气分析如图3所示(即低氧处理24h前以及低氧处理1h、6h和24h后，静脉注射化合物2对大鼠血氧分压(PO 2)和血氧饱和度(SO 2)的影响)：
1)低氧处理24h前，各组动物血气分析结果无明显差异。
2)低氧处理1h后后，给药0.25mg/kg组的血氧分压高于对照组，但差异不明显(p＝0.059)，给药组的血氧饱和度高于对照组，差异明显(p＝0.023)。
3)低氧处理6h后，给药0.25mg/kg组的血氧分压(p＝0.018)和血氧饱和度(p＝0.015)高于对照组，差异明显。
4)缺氧处理6h后，给药1mg/kg组的血氧分压高于对照组，差异明显(p＝0.003)，给药组的血氧饱和度高于对照组，差异明显(p＝0.0012)。
5)缺氧处理24h后，给药1mg/kg组的血氧分压(p＝0.0012)和血氧饱和度(p＝0.001)高于对照组，差异明显。
2.呼吸频率如图4所示(即低氧处理24h前以及低氧处理6h和24h后，静脉注射化合物2对SD大鼠呼吸频率(RR)的影响)：
1)低氧处理24h前，各组动物呼吸频率无明显差异。
2)低氧处理6h或24h后，给药组的呼吸频率低于对照组，差异明显(p＜0.05)。
3.肺组织石蜡切片病理分析，如图5所示(即低氧处理24h后，静脉注射化合物2对SD大鼠肺组织损伤的影响)：
由对照组1可知，肺组织可见大面积的肺泡壁增厚(黑色箭头1)，伴有炎性细胞浸润(红色箭头2)；少量的血管肌化，平滑肌细胞增生，管壁肥厚，管腔狭窄(黄色箭头3)；偶见支气管周围可见炎性细胞小灶性浸润(蓝色箭头4)。
由对照组2可知，肺组织可见肺泡壁上有少量的炎性细胞浸润(黑色箭头6)；大面积的肺水肿，肺泡腔内可见均质状的嗜酸性组织液渗出(黄色箭头7)。
由给药组1可知，肺组织可见中等面积的肺泡壁增厚(黑色箭头8)，伴有少量的炎性细胞浸润(红色箭头9)；少量的支气管的管腔内可见嗜酸性的组织液渗出(黄色箭头10)；少量的血管肌化，平滑肌细胞增生，管壁肥厚，管腔狭窄(蓝色箭头11)。
由给药组2可知，肺组织可见大面积的肺泡壁轻度增厚(黑色箭头12)，伴有少量的炎性细胞浸润(红色箭头13)；少量的血管肌化，平滑肌细胞增生，管壁肥厚，管腔狭窄(蓝色箭头14)。
综上，与对照组相比，给药组能够减轻肺水肿、肺泡壁增厚、炎性细胞浸润、中性粒细胞浸润、血管肌化、平滑肌细胞增生、管壁肥厚和管腔狭窄等低氧(缺氧)造成的组织损伤。
由以上数据可知单次静脉注射0.25mg/kg和1mg/kg化合物2均能够增加SD大鼠低氧处理1h、6h和24h后的血氧分压及血氧饱和度；单次静脉静脉注射1mg/kg化合物2均能够显著减少SD大鼠低氧处理6h和24h后的呼吸频率；单次静脉静脉注射1mg/kg化合物2，能够显著减少SD大鼠低氧处理24h后对肺组织造成的损伤。据此表明，注射化合物2可以通过增加血携氧量来有效抗低氧/缺氧损伤。
实施例3
3′，5-二烯丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-二联苯·二盐酸盐(英文名(S)-2，6-diamino-N-(3′，5-diallyl-2，4′-dihydroxy-[1，1′-biphenyl]-3-yl)hexanamide dihydrochloride，化合物2)：
Figure PCTCN2022128028-appb-000009
一、实验方法
1.受试物的配制：称取适量化合物2，加入适量氯化钠注射液(0.9％)，配制成所需浓度(40mg/kg)溶液。
2.动物模型：SPF级SD雄性大鼠，体重220～240g，低氧(氧含量为11％)处理。
3.实验分组：低氧处理对照组，每组4只；低氧处理给药组，每组4只。
4.给药方式：低氧处理前向低氧处理给药组各大鼠单次灌胃给药。
5.血气分析：各组分别在低氧处理24h前和低氧处理24后股动脉取血(约0.5mL)，进行血气分析，具体参见表3。
表3
Figure PCTCN2022128028-appb-000010
6.呼吸频率：取血时评估大鼠呼吸频率。
7.数据统计：采用GraphPad进行数据分析，结果以平均值±标准差(Mean±SD)表示，数据分析采用单因素方差分析-T-test，P＜0.05表示具有统计学差异。
二、实验结果
1.血气分析如图6所示(低氧处理24h前以及低氧处理24h后，灌胃化合物2对血氧分压(PO 2)和血氧饱和度(SO 2)的影响)：
1)低氧处理24h前，各组动物血气分析结果无明显差异。
2)低氧处理24h后，给药40mg/kg组的血氧分压(p＝0.036)和血氧饱和度(p＝0.016)高于对照组，差异明显。
2.呼吸频率如图7所示(低氧处理24h前以及低氧处理24h后，灌胃化合物2对大鼠呼吸频率(RR)的影响)：
1)低氧处理24h前，各组动物呼吸频率无明显差异。
2)低氧饲养24h后，给药组的呼吸频率低于对照组，差异明显(p＜0.05)。
由以上数据可知，单次灌胃给药40mg/kg化合物2能够显著增加SD大鼠低氧处理处理24h后的血氧分压及血氧饱和度，降低呼吸频率。据此表明，灌胃化合物2可以通过增加血携氧量来有效抗低氧/缺氧损伤。
实施例4
3′，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯·盐酸盐(英文名2-amino-N-(3′，5-diallyl-2，4′-dihydroxy-[1，1′-biphenyl]-3-yl)-4-(methylthio)butanamide hydro chloride，化合物3)：
Figure PCTCN2022128028-appb-000011
一、实验方法
1.受试物的配制：称取适量化合物3，加入适量氯化钠注射液(0.9％)，配制成所需浓度(0.93mg/kg)溶液。
2.动物模型：SPF级SD雄性大鼠，体重220～240g，低氧(氧含量为11％)处理。
3.实验分组：低氧处理对照组，每组4只；低氧处理给药组，每组4只。
4.给药方式：低氧处理前向低氧处理给药组各大鼠单次静脉注射给药。
5.血气分析：各组分别在低氧处理24h前和低氧处理24h后股动脉取血(约0.5mL)，进行血气分析，具体参照表4。
表4
组别 剂量浓度 血气分析时间
  (mg/kg)  
低氧处理对照组 - 低氧处理24h前取血一次；低氧处理24h后取血一次
低氧处理给药组 0.93 低氧处理24h前取血一次；低氧处理24h后取血一次
7.数据统计：采用GraphPad进行数据分析，结果以平均值±标准差(Mean±SD)表示，数据分析采用单因素方差分析-T-test，P＜0.05表示具有统计学差异。
二、实验结果
1.血气分析如图8所示(低氧处理24h前以及低氧处理24h后，化合物3对SD大鼠血氧饱和度(SO 2)的影响)：
1)低氧处理24h前，各组动物血气分析结果无明显差异。
2)低氧处理24h后，给药0.93mg/kg组的血氧饱和度(p＝0.06)高于对照组。
2.呼吸频率如图9所示(低氧处理24h前以及低氧处理24h后，化合物3对大鼠呼吸频率(RR)的影响)：
1)低氧处理24h时前，各组动物呼吸频率无明显差异。
2)低氧处理24h后，给药组的呼吸频率低于对照组，差异明显(p＜0.05)。
由以上数据可知，单次静脉注射0.93mg/kg化合物3，能够增加SD大鼠低氧处理24h后的血氧饱和度，显著减少呼吸频率，从而起到抗低氧/缺氧损伤作用。
实施例5
3′，5-二烯丙基-3-乙酰胺基-2，4′-二羟基-1，1′-联苯(英文名N-(3′，5-diallyl-2，4′-dihydroxy-[1，1′-biphenyl]-3-yl)acetamide，化合物4)：
Figure PCTCN2022128028-appb-000012
一、实验方法
1.受试物的配制：称取适量化合物4，加入适量溶剂2％DMSO+2％Tween80+生理盐水，配制成所需浓度(0.67mg/kg)溶液。
2.动物模型：SPF级SD雄性大鼠，体重220～240g，低氧(氧含量为11％)处理。
3.实验分组：低氧处理对照组，每组4只；低氧处理给药组，每组4只。
4.给药方式：低氧处理前向低氧处理给药组各大鼠单次静脉注射给药。
5.血气分析：分别在低氧处理24h前和低氧处理24h后股动脉取血(约0.5mL)，进行血气分析，具体参照表5。
表5
Figure PCTCN2022128028-appb-000013
6.呼吸频率：取血时评估大鼠呼吸频率。
7.数据统计：采用GraphPad进行数据分析，结果以平均值±标准差(Mean±SD)表示，数据分析采用单因素方差分析-T-test，P＜0.05表示具有统计学差异。
二、实验结果
1.血气分析如图10所示(低氧处理24h前以及低氧处理24h后，化合物4对SD大鼠血氧分压(PO 2)和血氧饱和度(SO 2)的影响)：
1)低氧处理24h前，各组动物血气分析结果无明显差异。
2)低氧处理24h后，给药0.67mg/kg组的血氧分压(p＝0.023)和血氧饱和度(p＝0.0023)高于对照组。
2.呼吸频率如图11所示(低氧处理24h前以及低氧处理24h后，化合物4对大鼠呼吸频率(RR)的影响)：
1)低氧处理24h前，各组动物呼吸频率无明显差异。
2)低氧处理24h后，给药组的呼吸频率低于对照组，差异明显(p＜0.05)。
单次注射0.67mg/kg化合物4能够显著增加SD大鼠低氧处理24h后的血氧分压和血氧饱和度，显著减少呼吸频率，从而起到抗低氧/缺氧损伤作用。
综上，可知通过本申请的厚朴酚和/或和厚朴酚芳环氨基取代类衍生物用于制备抗低氧/缺氧损伤药物中，能够显著地起到抗低氧/缺氧损伤作用。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
具有上述通式I所示结构的衍生物可用于制备抗低氧/缺氧损伤药物，快速有效地提高红细胞携氧能力，为预防和治疗因外环境低氧引起的疾病(如高原病)以及各种自身原因(如中枢神经***疾患，支气管、肺病变等)引起的通气和/或换气功能障碍性疾病提供新的药物选择，解决当前抗低氧/缺氧药物间接性起效、起效慢等问题。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种厚朴酚和/或和厚朴酚芳环氨基取代类衍生物的抗低氧/缺氧损伤用途，其特征在于，所述厚朴酚和/或所述和厚朴酚芳环氨基取代类衍生物为通式I所示化合物或其盐：
    Figure PCTCN2022128028-appb-100001
    所述通式I中，R 1和R 4各自独立地选自C 1～C 8的烃基，R 2和R 3各自独立地选自氢或羟基，且R 2和R 3不同时为氢或羟基；R 5选自H、C 1～C 12的酰基、单一氨基酸在羧基发生缩合后的剩余酰基部分、多肽在羧基发生缩合后的剩余酰基部分中的任意一种；R 6选自氢、C 1～C 8的烃基中的任意一种。
  2. 根据权利要求1所述的抗低氧/缺氧损伤用途，其特征在于，所述R 1、所述R 4和所述R 6中的所述C 1～C 8的烃基各自独立地选自C 1～C 8的烷基、C 1～C 8的烯基中的任意一种，优选所述C 1～C 8的烷基选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基中的任意一种。
  3. 根据权利要求2所述的抗低氧/缺氧损伤用途，其特征在于，所述C 1～C 8的烯基选自乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、丁-3-烯基、戊-1-烯基、戊-2-烯基、戊-3-烯基、戊-4-烯基、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基、己-5-烯基、庚-1-烯基、庚-2-烯基、庚-3-烯基、庚-4-烯基、庚-5-烯基、庚-6-烯基、辛-1-烯基、辛-2-烯基、辛-3-烯基、辛-4-烯基、辛-5-烯基、辛-6-烯基、辛-7-烯基中的任意一种。
  4. 根据权利要求1至3中的任一项所述的抗低氧/缺氧损伤用途，其特征在于，所述C 1～C 12的酰基选自甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、庚酰基、辛酰基中的任意一种。
  5. 根据权利要求1至4中的任一项所述的抗低氧/缺氧损伤用途，其特征在于，所述单一氨基酸选自赖氨酸、蛋氨酸、色氨酸、缬氨酸、丙氨酸、苯丙氨酸、亮氨酸、异亮氨酸、 6-羟基正亮氨酸、甘氨酸、组氨酸、精氨酸、脯氨酸、谷氨酸、天冬氨酸、丝氨酸苏氨酸、酪氨酸、胱氨酸或半胱氨酸中的任意一种。
  6. 根据权利要求1至5中的任一项所述的抗低氧/缺氧损伤用途，其特征在于，所述多肽为多个所述单一氨基酸形成的肽，优选所述多肽的分子量≤2500Da。
  7. 根据权利要求1至6中的任一项所述的抗低氧/缺氧损伤用途，其特征在于，当所述厚朴酚和/或和厚朴酚芳环氨基取代类化合物为所述通式I所示化合物的盐时，所述R 5携带的可成盐氨基中的一个或多个为盐形式，成盐用的酸为盐酸、草酸或富马酸等药学上可接受的酸。
  8. 根据权利要求1至7中的任一项所述的抗低氧/缺氧损伤用途，其特征在于，所述厚朴酚和/或所述和厚朴酚芳环氨基取代类衍生物为以下化合物中的任意一种或多种：3′，5-二烯丙基-3-氨基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-乙酰胺基-2，4′-二羟基-1，1′-联苯、3′，5-二烯丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-3-苯基-2-氨基-1-丙酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(R)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-6-羟基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-2-氨基-4-甲硫基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、3′，5-二烯丙基-3-[(S)-3-甲基-2-氨基-1-丁酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐、和3′，5-二丙基-3-[(S)-2，6-二氨基-1-己酰]胺基-2，4′-二羟基-1，1′-联苯及其盐酸盐。
  9. 根据权利要求1所述的抗低氧/缺氧损伤用途，其特征在于，所述抗低氧/缺氧损伤药物的给药方式为注射、口服、埋植或直接填充病灶部位。
  10. 一种抗低氧/缺氧损伤药物组合物，其特征在于，所述抗低氧/缺氧损伤药物组合物包括厚朴酚和/或和厚朴酚芳环氨基取代类衍生物或其盐以及在药学上可接受的载体；其中所述厚朴酚和/或所述和厚朴酚芳环氨基取代类衍生物为权利要求1所述的厚朴酚和/或和厚朴酚芳环氨基取代类衍生物。
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