WO2011091692A1 - Utilisation d'un benzoate et de ses dérivés - Google Patents

Utilisation d'un benzoate et de ses dérivés Download PDF

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WO2011091692A1
WO2011091692A1 PCT/CN2010/079918 CN2010079918W WO2011091692A1 WO 2011091692 A1 WO2011091692 A1 WO 2011091692A1 CN 2010079918 W CN2010079918 W CN 2010079918W WO 2011091692 A1 WO2011091692 A1 WO 2011091692A1
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Prior art keywords
dihydroxybenzoate
tetradecyl
group
mmol
dihydroxy
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PCT/CN2010/079918
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English (en)
Chinese (zh)
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戚建华
胡永洲
曾苏
韩峰
罗燕
高丽娟
孙恺悦
王广法
李金优
陈玲
李林
向兰
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浙江大学
南京医科大学
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Priority to CN2010800626231A priority Critical patent/CN103118677A/zh
Publication of WO2011091692A1 publication Critical patent/WO2011091692A1/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention is in the field of pharmaceuticals and relates to the use of benzoic acid esters and derivatives thereof in neurological diseases and anti-cerebral aging diseases.
  • Alzheimer's disease With the aging of the social population, the prevalence of neurodegenerative diseases, especially Alzheimer's disease, has increased significantly, which has become the fourth leading cause of adult death. In particular, China's population is aging. At present, the number of patients with Alzheimer's disease, including Alzheimer's disease and vascular dementia, has exceeded 5 million, accounting for about 1/4 of the world's total cases. The lack of effective preventive and therapeutic measures has made Alzheimer's disease a serious impact on social stability and development. Therefore, the development of effective new drugs for the prevention and treatment of neurodegenerative diseases such as senile dementia is a medical problem that is urgently needed in the world. Book
  • the main target for clinical treatment of Alzheimer's disease drugs is the cholinergic nervous system, such as acetylcholine and acetylcholinesterase inhibitors: tacrine, rivastigmine tartrate, and huperzine A), donepezil (donepezil) and the like.
  • these drugs can only partially replace the cholinergic nervous system function, temporarily improving cognitive function, and can not prevent and delay the progression of neurodegenerative diseases.
  • the long-term use of the effect is gradually reduced, with side effects. Therefore, the development of new drugs against brain aging and prevention of neurodegenerative diseases has become the focus of current research.
  • Nerve growth factor is the first biologically active peptide that has important regulatory effects on the growth, development, differentiation and function maintenance of nerves. It is the most important neurotrophic factor. Especially in the process of nervous system diseases, neurotrophic factors have important protective effects on nerve cells and nerve regeneration. Neurotrophic factors can prevent or reduce nerve atrophy, neurodegeneration, and promote nerve repair after trauma.
  • NGF mimi CS neurotrophic factor mimics
  • Chinese herbal medicine is the material basis of traditional Chinese medicine, and it is a cornucopia of natural active organic compounds. China has thousands of years of Chinese medicine civilization, and it has a lot of valuable local medicine. Because the utilization of Chinese herbal medicine resources is convenient, it is very important to study its new ingredients and new activities. Studies have shown that Chinese medicine has a significant effect on Alzheimer's disease, the most famous of which is the alkaloid-huperzine A extracted from Huperzia serrata. It is an anti-independent intellectual property developed by the Institute of Materia Medica, Chinese Academy of Sciences. Drugs for senile dementia. It mainly inhibits acetylcholinesterase activity, reduces glutamate-induced neuronal cell death, and has anti-beta-like peptide neurotoxicity and antioxidant activity.
  • Gentian alias: bitter grass, gallbladder. Excavated in the spring and autumn seasons, washed and dried. Sexual taste, bitterness, cold. Liver, gallbladder Jing. Introduced in the 2005 edition of the Pharmacopoeia, the function and function of gentian: heat and dampness, diarrhea and biliary fire. For damp heat jaundice, vaginal itching, under the belt, strong, eczema itching, red eyes, deafness, hypochondriac pain, mouth pain, convulsions.
  • the object of the present invention is to provide a preparation method and application of a benzoic acid ester and a derivative thereof in view of the deficiencies of the prior art.
  • the object of the present invention is achieved by the following technical solutions: a benzoate and a derivative thereof for use in the preparation of a medicament for preventing and treating neurodegenerative diseases and anti-cerebral aging, the benzoate and The derivative has the following structural formula:
  • R is a linear, branched, saturated and unsaturated alkyl group having from 1 to 30 carbon atoms, an aliphatic ring or a derivative thereof; and R 5 are each independently selected from the group consisting of hydrogen, a hydroxyl group, a carboxyl group, and an aldehyde group.
  • X is selected from C(0)0, OC(0), C(0)NH, NHC(0), C(0), CH 2 , S ⁇ 0.
  • R is a linear, branched, saturated and unsaturated alkyl group having from 6 to 22 carbon atoms, an aliphatic ring or a derivative thereof.
  • benzoate and its derivative are: ethyl 2, 3-dihydroxybenzoate, amyl 2, 3-dihydroxybenzoate, octyl 2, 3-dihydroxybenzoate, 2, Ethyl 3-dihydroxybenzoate, dodecyl 2,3-dihydroxybenzoate, tetradecyl 2,3-dihydroxybenzoate, cetyl 2,3-dihydroxybenzoate, 2, Octadecyl 3-dihydroxybenzoate, eicosanyl 2,3-dihydroxybenzoate, behenyl 2,3-dihydroxybenzoate, triacontyl 2,3-dihydroxybenzoate , tetradecyl 2,6-dihydroxybenzoate, eicosanyl 2,6-dihydroxybenzoate, tetradecyl 2,4-dihydroxybenzoate, 4,4-dihydroxybenzoic acid Alkyl ester, tetradecyl 3,4,5-trihydroxybenzoate,
  • the beneficial effects of the invention are as follows: (1) 2,3-dihydroxybenzoate compound (ABG-001) has no toxic effect in oral or intraperitoneal administration, and the compound can rapidly enter the brain through the blood-brain barrier. Regulating the function of the cranial nervous system; (2) The results of animal pharmacology experiments prove that the 2,3-dihydroxybenzoate compound of the present invention can promote the regeneration of neurons in the adult brain, anti-brain aging, and prevent ⁇ -amyloid polypeptide The neurotoxicity, reduction of acetylcholinesterase activity, has the effect of preventing and treating senile dementia and anti-brain aging.
  • Figure 1 is a dose-dependent relationship diagram of compound ABG-001 promoting neurite elongation in PC12 cells
  • Figure 2 is a photomicrograph of neurites of PC 12 cells after 48 hours of addition of ABG-001, where a is 1% DMSO as a negative control; b is NGF 40 ng/ml as a positive control; c is ABG- 001 (1 ⁇ ) ;
  • FIG. 3 shows that ABG-001 has the role of a nerve growth factor, (a) is the expression of hippocampal nerve growth factor, and (b) is the number of newborn neurons;
  • Figure 4 shows that ABG-001 treatment promotes nerve regeneration and migration after cerebral ischemia
  • FIG. 5 shows that ABG-001 can pass the blood-brain barrier
  • Figure 6 shows that ABG-001 promotes adult nerve regeneration through the blood-brain barrier, where (a) is the number of newborn neurons, (b) is the length of the new neurons, and (c) is the differentiation of the new neurons. ;
  • FIG. 7 shows that ABG-001 has anti-brain aging effects, in which (a) is the number of newborn neurons, and (b), (c) and (d) are Morris water maze test plots, (e), (0 , (g) and (h) are the biochemical indicators of oxidative stress in mice;
  • Figure 8 shows that ABG-001 has anti-cerebral aging effects, wherein (a) is the total number of times of the Y-maze,
  • Figure 9 shows the Morris water maze test after ABG-001 treatment for ⁇ damage and ⁇ damage
  • FIG 10 shows that ABG-001 treatment can improve nerve regeneration in ⁇ lesions (APP/PS1 mice), where (a) is the number of newborn neurons, (b) is the length of the neonatal nerve, and (c) Acetylcholinesterase (AChE) activity map.
  • 2,3-dihydroxybenzoate compounds can cause a high proportion of PC12 cells to undergo neurite elongation, indicating that 2,3-dihydroxybenzoate has a very similar NGF activity and has been developed to prevent senile dementia.
  • the value of the therapeutic drug A series of benzoate derivatives were designed and synthesized using 2,3-dihydroxybenzoate as a lead, and their in vitro activity studies were extensively carried out to find the structure-activity relationship of the substances. It would be important to find a compound with potentially superior activity and/or lower toxicity and to prevent and treat neurodegenerative and anti-cerebral aging diseases such as Alzheimer's disease.
  • R is a linear, or branched, or saturated and unsaturated alkyl group having from 1 to 30 carbon atoms, or an aliphatic ring, or a derivative thereof, especially C 6 to C 22 ;
  • ⁇ R 5 are each independently selected from the group consisting of hydrogen, hydroxy, carboxy, aldehyde, ester, fluoro, chloro, bromo, iodo, decyl, amino, amide, cyano, nitro, sulfonyl, trifluoromethyl, Propenyl, alkyl, alkoxy, substituted benzyl, substituted phenyl, aryl, heteroaryl, glycosyl and amino acid residues;
  • X is selected from C (0) 0, OC ( 0), C (0) NH, NHC (0), C (0), CH 2, S and 0.
  • the acid is a substituted benzoic acid or a linear, or branched, or saturated and unsaturated alkyl group having 1 to 30 carbon atoms, or an aliphatic ring, or a derivative thereof, particularly a C 6 -C 22 fatty acid; a linear or branched chain having from 1 to 30 carbon atoms, or a saturated and unsaturated alkyl group, or an aliphatic ring, or a derivative thereof, particularly a C 6 to C 22 fatty alcohol; the phenol is a substituted phenol;
  • the dehydrating agent is concentrated sulfuric acid, diisopropylcarbodiimide or dicyclohexylcarbodiimide;
  • the solvent is a protic solvent methanol, ethanol or tetrahydrofuran, or an aprotic solvent dichloromethane, chloroform, benzene, toluene, two Toluene, dimethyl sulfoxide or acetonitrile; the m
  • reaction solution is cooled to 0 ° C, 1 mol of hydrochloric acid per liter of hydrochloric acid solution is slowly added, and the reaction solution is extracted with diethyl ether. The organic phase is washed successively with 1 mol of diluted hydrochloric acid, saturated sodium hydrogencarbonate solution and saturated brine. Drying with anhydrous magnesium sulfate, concentrating, and purifying by silica gel column chromatography to obtain an alcohol compound.
  • the inert gas is nitrogen or argon;
  • the solvent is anhydrous diethyl ether or tetrahydrofuran;
  • the aldehyde is a substituted benzaldehyde;
  • the brominated alkane is a linear or branched, saturated or unsaturated brominated alkane having from 1 to 30;
  • the temperature can be from -80 to 50 degrees;
  • the molar ratio of brominated alkane to magnesium is 1:1 to 1:10;
  • the molar ratio of the brominated alkane to the substituted benzaldehyde is from 1:1 to 1:10.
  • the alcohol compound is completely dissolved in a solvent, and the oxidizing agent is slowly added. After the reaction is completed, the mixture is concentrated under reduced pressure. The obtained concentrate is diluted with ethyl acetate, and washed with 1 mol of diluted hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine. Drying with anhydrous magnesium sulfate, concentrating, and purifying by silica gel column chromatography to obtain a ketone compound.
  • the solvent may be tetrahydrofuran, dichloromethane, acetone, chloroform, dimethyl sulfoxide or acetonitrile;
  • the oxidizing agent may be chromium trioxide, manganese dioxide, dimethyl sulfoxide, periodate or N-methylmorpholine oxide.
  • the molar ratio of alcohol to oxidant is from 1:1 to 1:10.
  • the phenol is a substituted phenol, a substituted naphthol
  • the alcohol is a linear or branched, saturated or unsaturated fatty alcohol having from 1 to 30 carbon atoms
  • the azo reagent may be diethyl azodicarboxylate or azodicarboxylic acid.
  • the phosphine reagent may be triphenylphosphine, triisopropylphosphine, tri-p-tolyl Phosphine, triethylphosphine, tributylphosphine or tricyclohexylphosphine;
  • solvent is protic solvent methanol or ethanol, or aprotic solvent tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, xylene, dimethyl sulfoxide Or acetonitrile;
  • the molar ratio of phenol to alcohol is 1:20
  • the molar ratio of phenol to azo reagent is 1 : 0.2 ⁇ 1:20
  • the molar ratio of phenol to phosphine reagent is 1:0.2 ⁇ 1
  • the object of the present invention is the use of benzoic acid esters and derivatives thereof for the preparation of a medicament for the treatment of Alzheimer's disease and anti-cerebral aging diseases.
  • the present invention further provides a pharmaceutical composition for treating senile dementia and anti-brain aging, the pharmaceutical composition comprising a physiologically effective amount of a benzoate and a derivative thereof (I) and a pharmaceutically acceptable carrier or Thinner.
  • the weight ratio of the benzoate and its derivative (I) shown in the drug is from 0.1% to 90% by weight.
  • the pharmaceutically acceptable carrier as used herein refers to a conventional pharmaceutical carrier in the pharmaceutical field, such as a diluent, an excipient, etc., a filler such as starch, sucrose, microcrystalline cellulose, etc.; a binder such as starch slurry, hydroxy Propylene, gelatin, polyethylene glycol, etc.; wetting agents such as magnesium stearate, micronized silica gel, polyethylene glycol, etc.; absorption enhancer polysorbate, lecithin, etc., surfactant poloxamer, fatty acid Yamanite, polysorbate, etc., and other adjuvants such as flavoring agents, sweeteners and the like may also be added to the composition.
  • a conventional pharmaceutical carrier in the pharmaceutical field such as a diluent, an excipient, etc., a filler such as starch, sucrose, microcrystalline cellulose, etc.; a binder such as starch slurry, hydroxy Propylene, gelatin, polyethylene glycol,
  • the benzoate derivatives of the present invention can be administered in unit dosage form for enteral and parenteral administration, including oral, intramuscular, and subcutaneous.
  • the route of administration of the compound can also be intravenous. Injections include intravenous, intramuscular, subcutaneous and acupoint injections.
  • compositions of the present invention can be prepared according to conventional methods of manufacture in the pharmaceutical arts, e.g., by mixing the active ingredient with one or more carriers, and then bringing it into such preparation.
  • the dosage form can be a solid preparation, a capsule or a liquid preparation, including tablets, capsules, dispersible tablets, oral liquids, large infusions, small needles, freeze-dried powder needles.
  • the benzoate and its derivative of the present invention have remarkable nerve growth factor-like activity, have neuroprotective and anti-cerebral aging effects, and can be obtained in the prevention of neurodegenerative diseases such as Alzheimer's disease and anti-brain aging. application.
  • the benzoate compound of the present invention exhibits remarkable NGF in the in vitro screening model PC12 cells of Alzheimer's disease Mimics activity. It is of great practical significance to use such compounds as a lead to optimize the structure and to conduct basic research for the development of new drugs for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease.
  • the benzoate and its derivative of the present invention can pass the blood-brain barrier and have high-efficiency neurotrophic effects.
  • the benzoic acid esters and derivatives thereof according to the present invention have anti-brain aging and the effects of preventing and treating senile dementia.
  • the synthesis method is the same as the compound I -4, and the reaction charge is: (170 mg, 1 mmol) 3,4,5-trihydroxybenzoic acid, (428 mg, 2 mmol) tetradecanol, (250 mg, 1.2 mmol) Cyclohexylcarbodiimide, 15 ml of tetrahydrofuran afforded 176 mg as a white solid.
  • the synthesis method is the same as the compound I -4, and the reaction charge is: (182 mg, l mmol) 2,3-dimethoxybenzoic acid, (428 mg, 2 mmol) tetradecanol, (250 mg, 1.2 mmol) Cyclohexylcarbodiimide, 15 ml of tetrahydrofuran afforded 162 mg as a white solid.
  • the synthesis method is the same as the compound I -4, and the reaction charge is: (182 mg, l mmol) 2,3-dimethoxybenzoic acid, (540 mg, 2 mmol) stearyl alcohol, (250 mg, 1.2 mmol) Cyclohexylcarbodiimide, 15 ml of tetrahydrofuran afforded a white solid, 170 mg.
  • the synthesis method is the same as the compound I -23, and the reaction charge is: (182 mg, 1 mmol) 2,3-dimethoxybenzoic acid, (230 mg, l Methyl)tetradecylamine, (135 mg, 1 mmol) 1-hydroxybenzotriazole hydrate, (250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml of tetrahydrofuran afforded 305 mg as a white solid.
  • the synthesis method is the same as the compound I-23, and the reaction charge is: (312 mg, 2 mmol) 3,4-dimethoxyaniline, (465 mg, 2 mmol) myristic acid, (135 mg, 1 mmol) 1-hydroxybenzene
  • the triazole hydrate, (450 mg, 2.2 mmol) of dicyclohexylcarbodiimide, 30 ml of tetrahydrofuran afforded 560 mg of white solid.
  • Tetradecanic acid (2.28 g, 0.01 mol) was dissolved in 30 ml of thionyl chloride, refluxed under nitrogen overnight, and excess SOCl 2 was distilled off under reduced pressure to give tetradecyl chloride.
  • 2 ml of 1,2-dimethoxybenzene was dissolved in 20 ml of carbon disulfide, and A1C1 3 (1.4 g, 10 mmol) was added portionwise with stirring. After the addition, the mixture was stirred for another 15 minutes, and the acid chloride was added dropwise, and stirring was continued for 4 hours. After the reaction is completed, the reaction will be Pour the solution into 30 ml of ice water until the reddish brown color disappears.
  • the synthesis method is the same as the compound 1-35, and the reaction charge is: (100 mg, 0.29 mmol) of compound 1 -23, (37 mg, 0.3 mmol) of DMAP, (0.6 ml) acetic anhydride, 2 ml of dry pyridine to obtain a pale yellow liquid 1 10 mg.
  • the synthesis method is the same as the compound I -4, and the reaction charge is: o-diphenol (110 mg, 1 mmol), eicosanoic acid (310 mg, 1 mmol), dicyclohexylcarbodiimide (250 mg, 1.2 mmol), 15 ml of tetrahydrofuran afforded 391 mg of a white solid.
  • the synthesis method is the same as the compound I -4, and the reaction charge is: o-trisphenol (126 mg, 1 mmol), myristic acid (456 mg, 2 mmol), dicyclohexylcarbodiimide (250 mg, 1.2 mmol), 15 ml of tetrahydrofuran afforded 120 mg of a white solid.
  • NGF neuronal degeneration
  • PC 12 cells have the general characteristics of nerve cells, under the action of NGF, PC12 cells will stop dividing, grow protrusions, and transform into neuron-like cells. Therefore, a compound which can cause PC12 cells to transform into neuron-like cells has an application value for preventing and treating neurodegenerative diseases such as senile dementia.
  • PC 12 cells Culture of PC 12 cells: Connect 20 ⁇ 10 4 PC 12 cells in a 100 mm culture dish containing 10 ml DMEM medium (containing 10% horse serum, 5% fetal bovine serum), and replace the culture once every two days. Base, another three days to succeed. First with Wash the cells twice with PBS, add 10 ml of PBS to the culture dish, incubate in a 37 ° C, 5% C0 2 incubator for 10 minutes, purge, transfer to a 15 ml disposable centrifuge tube, and centrifuge the blood cells. Count on the count board. Add 24 ml of serum-containing DMEM medium to each well of the 24-well cell culture plate. After counting the cells, connect 2> ⁇ 10 4 cells per well, and incubate in a C0 2 incubator for 24 hours.
  • DMEM medium containing 10% horse serum, 5% fetal bovine serum
  • DMSO was used as a negative control
  • NGF 40 ng was used as a positive control
  • Compound I was configured to a different concentration of DMSO solution.
  • the original medium of each well of a 24-well cell plate was replaced with 1 ml of a DMEM solution containing 1% DMSO and a sample (without serum), and then placed in a 37 V, 5% C0 2 incubator.
  • the morphological changes of the cells were observed every 24 hours and 6 consecutive days under an inverted microscope, and the neurite differentiation rate of the cells (the ratio of the number of cells whose neurites were longer than the diameter of the cell body to the total number of cells in the field of view) was recorded, about 100 per field of view.
  • 3 were randomly selected, averaged, and statistically plotted.
  • Figure 1 shows the change of neurite differentiation rate of PC 12 cells with dose increase after 48 hours of addition of compound ABG-001.
  • C 1% DMS0 is a negative control; NGF C40ng/ml) is a positive control, compound ABG- The concentration unit of 001 is ⁇ .
  • Figure 2 is a photomicrograph of neurites of PC 12 cells after 48 hours of addition of compound ABG-001, Figure a, 1% DMSO as a negative control; Figure b, NGF 40 ng/ml as a positive control; Figure c, Compound ABG The concentration of -001 is 1 ⁇ . 2-2:
  • 1,25 ( ⁇ ) 2 Vitamin D3 can induce the expression of nerve growth factor (NGF) by activating its receptor.
  • NGF nerve growth factor
  • let-hydroxylase knockout mice showed reduced expression of NGF and hippocampal neuronal regeneration compared with wild-type mice.
  • Supplementation with 1,25(OH) 2 vitamin D3 or NGF improved neurological regeneration in let-hydroxylase knockout mice.
  • a 12-week-old target knockout let-hydroxylase gene mouse was selected as an experimental animal model of adult NGF deficiency. (This lab was developed in cooperation with McGill University, Canada) Experimental procedure: 12-week old let-hydroxylase knockout mice were injected intraperitoneally with BU. After 10 days, brain tissue was fixed by perfusion of 4% paraformaldehyde through the left ventricle, and BrdU immunostaining was performed to label newborn neurons. ABG-001 is dissolved in
  • Oral administration was carried out in 99.5% ethanol, followed by dilution with physiological saline.
  • FIG. 3 Compared with the NGF treatment group (intraventricular administration), ABG-001 intraperitoneal administration can effectively improve the nerve regeneration function of let-hydroxylase knockout mice;
  • Figure 3 (a) It can be seen that the expression of nerve growth factor (NGF) in the hippocampus of let-hydroxylase knockout mice (-/-) is significantly lower than that of wild-type mice (+/+); as can be seen from Figure 3 (b) Compared with wild-type mice, the survival of hippocampal neonatal neurons in hydroxylase knockout mice was reduced.
  • NGF treatment Intraventricular administration
  • ABG-001 treatment (abdominal administration) can effectively ameliorate the neuroregeneration disorder caused by NGF deficiency.
  • EXPERIMENTAL RESULTS (Fig. 4): ABG-001 administration promotes the survival of new neurons and migration to the striatum in the brain injury area after cerebral ischemia, and is easy to restore the nervous system function after ischemic brain injury.
  • Example 3 ABG-001 acute high-dose oral, long-term oral and intraperitoneal administration did not show toxicity
  • ICR mice body weight 22g ⁇ 25g, 5 males and 5 females, purchased from Experimental Animal Center of Zhejiang University).
  • ABG-001 is less soluble in water.
  • (1) Dissolve ABG-001 in 99.5% ethanol, then add 1% Tween 80, diluted with physiological saline to the use concentration (the final concentration of ethanol is less than 2%).
  • DMSO dimethyl sulfoxide
  • Acute poisoning test 20 ICR male mice of 4 weeks old, male and female, were randomly divided into control group and 5g/kg treatment group.
  • the compound ABG-001 dissolved in 1% Tween-80 was orally administered at 5 g/kg for one week.
  • the mental state of the animals was observed every day, and the body weight and food intake were measured.
  • the limbs of the mice contracted and the amount of exercise decreased.
  • Table 2 shows that compared with the saline control group, the ABG-001 treatment group did not show weight gain/decrease (including the weight of each organ), nor did breathing (50 to 60 times/min) and heart rate ( 305 to 400 beats/min), abnormality of mean arterial pressure (210 mmHg), and symptoms such as lethargy, mania, and abnormal motor behavior.
  • TP total protein
  • ALB albumin
  • GLOB globulin
  • ALT aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • DBIL direct bilirubin
  • CHE acetylcholinesterase
  • ABG-001 was administered by intraperitoneal injection (10 mg/kg/day) for 60 consecutive days or by oral administration (10 mg/kg/day) (administered as saline as a control group).
  • Abdominal anesthesia with 10% chloral hydrate was used to record respiration, heart rate, and mean arterial pressure. Blood is then taken from the left ventricle for testing of hematology and blood biochemical indicators. And take the internal organs to take observations of histology.
  • Table 4 shows that there was no weight gain/decrease (including the weight of each organ) in the ABG-001 treated group compared with the saline control group. There were also no abnormalities in breathing (50 to 60 beats/min), heart rate (305 to 400 beats/min), average arterial pressure (210 mmHg), and lethargy, arrogance, and abnormal motor behavior.
  • organ coefficient organ weight / weight
  • Example 7 2 7 4 98 6 Table 5 TP (total protein), ALB (albumin), GLOB (globulin), ALT (alanine aminotransfer) Enzyme), AST (aspartate aminotransferase), TBIL (total bilirubin), DBIL (direct bilirubin), CHE (acetylcholinesterase).
  • TP total protein
  • ALB albumin
  • GLOB globulin
  • ALT alanine aminotransfer
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • DBIL direct bilirubin
  • CHE acetylcholinesterase
  • Example 5 Theoretical analysis and preliminary experimental results indicate that all of the other compounds in Example 1 also have similar effects as ABG-001.
  • Example 5 ABG-001 can promote the regeneration of brain neurons through the blood-brain barrier (Fig. 6)
  • mice used BrdU (5-bromodeoxyuridine) to label mitotic cells and found that neural stem cells of adult mammalian hippocampus can differentiate into neuronal-neurogenesis.
  • Neonatal neurons in the dentate gyrus of adult hippocampus are similar to mature granulosa cells and can establish synaptic connections with synaptic plasticity in CA3 neurons.
  • Adult neurogenesis can replace neuronal death due to natural aging or disease, maximizing brain function and structural integrity.
  • Studies have shown that the reduction of nascent cytokines in the aged brain (neural neonatal decline) is associated with senile cognitive decline. This study focused on the effects of ABG-001 on neurogenesis (mainly including neural stem cell proliferation, survival, differentiation).
  • ABG-001 was dissolved in 99.5% ethanol or dimethyl sulfoxide, and then diluted intraperitoneally with tea oil or diluted with physiological saline for oral administration.
  • FIG. 6 Experimental results (Fig. 6): Oral or intraperitoneal administration of ABG-001 can promote the proliferation of hippocampal dentate gyrus neural stem cells (a), promote the growth of new neurons (b), and promote the differentiation of stem cells into neurons (c). Tip ABG-001 has God Through nutrition.
  • Example 7 Theoretical analysis and preliminary experimental results indicate that all of the other compounds in Example 1 also have similar effects as ABG-001.
  • Example 6 ABG-001 has anti-aging effect ( Figure 7)
  • Mammals obtain galactose from lactose, which is hydrolyzed in the body to produce glucose and galactose, while galactose is rapidly digested into glucose in the liver. Excess galactose is reduced to galactitol by aldose reductase catalysis. Galactose is a metabolic end product that cannot be further catabolized and accumulates, increasing the osmotic pressure of cells, leading to cell swelling, dysfunction and metabolic disorders, which eventually lead to aging of the body.
  • D-gal galactose-induced aging animal models D-gal causes rat embryonic brain neurons to develop degenerative changes such as slow growth, neurite outgrowth, and increased mortality.
  • D-gal leads to a decrease in the number of in vitro division algebras in rat lung fibroblasts, a decrease in G2-M phase cells, an increase in G-G1 phase cells, and a slower cell proliferation rate in the diploid fibroblast dividing cycle. D-gal inhibits cell growth and development and reduces the number of divisions, accelerating cell senescence.
  • D-gal galactose (100 mg/kg/day) was administered intraperitoneally for 60 days. After 6 weeks, the mice were slow-moving, with dark coats and thin bodies, showing obvious signs of aging, proving that the aging model was successfully established. After 20 days of D-gal galactose injection, ABG-001 was orally administered (0.1, 5.0, 10.0 mg/kg/day) or intraperitoneally (0.1, 0.5, 5 mg/kg/day). When D-gal was injected for 30 days, BrdU (5-bromodeoxyuridine, 50.0 mg/kg) was administered 4 times at intervals of 6 hours.
  • BrdU-positive (BrdU + ) cells in the hippocampal DG region were examined to determine the effect of ABG-001 on neonatal cell survival and maturation (28-day-brown U + cells).
  • the effect of ABG-001 on the growth of neonatal neurons was observed by immunostaining with Doublecortin (DCX).
  • mice were sacrificed on the 2nd day after the last administration, and the hippocampus and cerebral cortex were taken out to measure glutathione peroxidase (GSH2Px), superoxide dismutase (SOD), and monoamine oxidase (monoamine oxidase).
  • GSH2Px glutathione peroxidase
  • SOD superoxide dismutase
  • MAO monoamine oxidase
  • T-ACO total anti-oxidation competence
  • SAM R1 (6-week-old males, 18 each) and SAM P8 (9-week-old males, 18 each) were purchased from the First affiliated Hospital of Tianjin Medical University.
  • SAM P8 mice are a rapidly aging animal model.
  • Experimental procedure SAM P8 9-month-old mice were randomly divided into 3 groups, control group (1% Tween 80 saline), low dose (lmg/kg) group and high dose (3 mg/kg) group, each group 6 only.
  • SAM R1 six-week-old mice served as a youth control group for normal aged mice. Each group was intraperitoneally injected with 1% Tween 80 saline or ABG-001 daily for two weeks. Detection of learning and spatial memory functions.
  • Y-maze experiment Spontaneous alternation behavior can be assessed using the Y-maze experiment.
  • Y-maze is a black Y-shaped three-part radiant lost box, consisting of 3 arms and a connecting zone. The three arms are at an angle of 120° to each other, each arm is 38.5 cm long, 8 cm wide and 3.5 cm wide. , 12 cm high, one arm can be selected as the starting arm. Each mouse was released from the end of the fixed arm, and the mice were allowed to move freely for 8 minutes, and the order of each arm was recorded. Three consecutive entries into the three different arms were defined as alternating arms (eg ABC, ACB, BAC, BCA, CAB, CBA).
  • alternating arms eg ABC, ACB, BAC, BCA, CAB, CBA
  • the calculation of the alternate arm rate is: 1 (number of errors / total number of times 2) ⁇ 100%. In addition, the total number of arms can be determined.
  • (2) Novel object discrimination experiment The novel object discrimination experiment is based on the ability of rodents to distinguish familiar and novel objects. The device used was a white uncovered box (length X width X height: 40 x 20 x 18 cm). First, there is no object in the box. Each time the mouse is released from the same position, let it move freely for 5 minutes to adapt to the environment, called the adaptation period, for two days. The third day is the familiarization period and the test period.
  • Familiarization period After placing two identical objects, put the mouse in, freely move for 5 minutes, and count the mouse nose as less than 2 cm from the object or on the recognized object, and record the two pairs.
  • Test period After 1 hour interval, replace with two different objects (one of which is the same object as the familiar period (0, the other is a novel object (n)), let it move freely for 5 minutes, and record the mouse pair Familiar with the exploration time of the object f and the exploration time of the novel object n.
  • the familiar period and the test period are combined by two kinds of objects and positions according to random numbers.
  • the calculation formula of the cognitive index is the time n/total exploration of the novel object. Time n+f.
  • Example 7 ABG-001 has the effect of preventing and treating senile dementia (Fig. 9)
  • Sprague-Dawley (SD) rats (20 males and females) weighing 200 g to 250 g were purchased from Jiangsu Experimental Animal Center.
  • the osmotic pump (osmotic minipump: Alzet 2002; Alze, CA) is connected to the cannula and fixed in the lateral ventricle of one side (0.3mm behind the anterior iliac crest, 1mm on the right side, deep) 2.5mm).
  • ⁇ ( 1 _42) was perfused into the lateral ventricle for 2 weeks (100 pM/day).
  • the stability of the AD model was verified by observing the deposition of ⁇ , spatial memory function, and cholinergic system function.
  • ABG-001 (0.5-1.0 mg/kg) was administered intraperitoneally for 14 consecutive days starting on the 2nd day after ⁇ (1 _42) perfusion.
  • a water maze test was performed on the 7th day after ⁇ ⁇ -4 2 ) perfusion to examine the spatial memory function. The trajectory of the rat was recorded and the staging latency was calculated.
  • 15 days after ⁇ ⁇ _ 42) perfusion brain tissue was fixed by perfusion of 4% paraformaldehyde through the left ventricle. After the paraffin is embedded, the hippocampus is serially sliced. After staining with 1% toluidine blue, the density of viable pyramidal cells in the CA1 region of the hippocampus was measured (the number of granule cells per mm length of the pyramidal cell layer).
  • ABG-001 treatment improves endogenous neurological regenerative disorders in Alzheimer's disease (AD)
  • AD Alzheimer's disease
  • AD brain hippocampus The neural stem cells of the adult mammalian hippocampal dentate gyrus can differentiate into neural cells called neurogenesis.
  • Adult nerves are thought to replace and repair neuronal loss due to natural aging or disease, maximizing the structure and function of the brain.
  • AD Alzheimer's disease
  • the study found that the differentiation ratio of precursor cells to neurons in AD brain hippocampus was significantly reduced, while the survival rate of newborn neurons was significantly reduced, and the neurite outgrowth of newborn neurons was abnormal.
  • APP/PS1 transgenic AD mice (10-month-old male and female mice) (purchased at the Animal Model Center of Nanjing University).
  • the effects of ABG-001 on neonatal differentiation were observed by immunostaining of neuron-specific nuclear protein (NeuN) and glial cells (GFAP).
  • Neuron-specific nuclear protein Neuron-specific nuclear protein
  • GFAP neuron-specific nuclear protein
  • Doublecortin is specifically expressed during the migration of neural precursor cells during the development of the central nervous system.
  • DCX a marker of neuronal precursor cells, can be used to study the proliferation and migration of neuronal precursor cells.
  • the growth of neonatal neuronal processes can be observed by DCX staining. Mice were sacrificed on the 2nd day after the last administration, and hippocampus was taken out to measure acetylcholinesterase (AChE) activity.
  • AChE acetylcholinesterase
  • Example 8 preparation method of ABG-001 tablet
  • Method Weigh the prescribed amount of ABG-001 and propylene glycol, add 500 mL of water for injection, stir to dissolve; add 0.1% activated carbon to the above solution, stir, leave for 15 minutes, decarburize the 5 micron titanium rod, and then pass the cartridge filter Fine filtration of 0. 45 micron and 0.22 micron microfiltration membrane; potting in a 10 ml ampoule and steam sterilization at 100 °C for 45 minutes, the injection of the invented ABG-001.

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Abstract

La présente invention concerne des utilisations d'un benzoate et de ses dérivés contre le vieillissement du cerveau et pour la prévention et le traitement de maladies neurodégénératives telles que la démence sénile et analogues. La présente invention a également pour objet la synthèse de toute une série du benzoate et de ses dérivés par un procédé chimique. Il s'est avéré par l'intermédiaire d'expériences in vitro d'activité cellulaire que le benzoate et ses dérivés synthétisés possèdent des activités pouvant se distinguer similaires aux facteurs de croissance des cellules nerveuses. Il s'est avéré par l'intermédiaire d'une expérience animale que le benzoate et ses dérivés n'induisent aucune réaction toxique au cours d'une administration orale ou cœliaque à long terme, qu'ils sont capables de traverser la barrière hémato-encéphalique et d'activer la régénération des neurones cérébraux.
PCT/CN2010/079918 2010-01-29 2010-12-17 Utilisation d'un benzoate et de ses dérivés WO2011091692A1 (fr)

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CN101817761B (zh) * 2010-01-29 2014-06-25 浙江大学 苯甲酸酯类衍生物及制备方法和应用
CN103340880B (zh) * 2013-05-13 2014-12-24 杭州耐奇睿生物医药科技有限公司 2,3-二羟基苯甲酸酯类化合物在制备治疗糖尿病的食品和药物中的应用
CN105085348B (zh) * 2014-05-20 2017-07-25 浙江大学 一种苯甲酸硫酯类化合物及其应用
CN106608824B (zh) * 2015-10-21 2019-12-20 复旦大学 芳酸酯类化合物及其制备方法和用途
CN108553456B (zh) * 2016-12-29 2020-09-15 天津中医药大学 苯甲酸及其衍生物的用途
CN109422858A (zh) * 2017-08-19 2019-03-05 中国铁道科学研究院铁道建筑研究所 一种接枝紫外吸收剂分子的多元醇
CN114292192A (zh) * 2022-01-17 2022-04-08 山东泓瑞医药科技股份公司 一种3,4-二甲氧基苯甲酸甲酯的合成方法
CN114956971A (zh) * 2022-05-24 2022-08-30 浙江禾本科技股份有限公司 一种制备灭螨醌中间体2-月桂酰基-1-萘酚及其类似物的方法

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