CN115317474A - Application of benzoylguanidine derivative in preparation of medicine for preventing and treating nervous system diseases or cardiovascular system diseases - Google Patents

Application of benzoylguanidine derivative in preparation of medicine for preventing and treating nervous system diseases or cardiovascular system diseases Download PDF

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CN115317474A
CN115317474A CN202111456827.XA CN202111456827A CN115317474A CN 115317474 A CN115317474 A CN 115317474A CN 202111456827 A CN202111456827 A CN 202111456827A CN 115317474 A CN115317474 A CN 115317474A
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acid
system diseases
cells
nervous system
preparation
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郝杰杰
于广利
白董慧
李海花
孙伟之
李春霞
管华诗
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Ocean University of China
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Ocean University of China
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides an application of a benzoyl guanidine derivative in preparing a medicament for preventing and treating nervous system diseases or cardiovascular system diseases. The benzoyl guanidine derivative comprises compounds ML-1, ML-2, ML-3, ML-4, ML-5, ML-6, ML-7 and ML-8, and has the following structural formula. The new-structure benzoyl guanidine derivative has simple preparation method, can protect nerve cells, myocardial cells and vascular endothelial cells, and has good safety, thereby having important development significance.

Description

Application of benzoylguanidine derivative in preparation of medicine for preventing and treating nervous system diseases or cardiovascular system diseases
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of a benzoylguanidine derivative in preparation of a medicine for preventing and treating nervous system diseases or cardiovascular system diseases.
Background
Phosphodiesterases are a member of the enzyme family, and 11 PDE enzyme families (PDE 1-PDE 11) are known to date, which differ in their substrate specificity (cAMP, cGMP or both) and their dependence on other substrates (e.g. calmodulin). Inhibition of different types of PDE isozymes leads to intracellular accumulation of cAMP and/or cGMP, which can be useful in the treatment of different inflammation-related diseases. PDE4 is mainly distributed in various inflammatory cells, such as mast cells, macrophages, eosinophils, lymphocytes and epithelial cells, and can increase intracellular concentration by inhibiting enzyme activity, which can help to reduce the damage of inflammatory reaction to the body. The major PDE isozymes are also type 4 in cells important for allergic inflammation (lymphocytes, mast cells, eosinophils, macrophages). Therefore, inhibition of PDE4 with appropriate inhibitors is considered an important starting point for the treatment of a variety of allergy-induced diseases. PDE4 inhibitors have been developed as anti-inflammatory agents, such as roflumilast, mainly for the treatment of inflammation of the lung, especially asthma and chronic obstructive pulmonary disease; difamilast is used in the treatment of atopic dermatitis; and apremilast is used in the treatment of psoriatic arthritis.
Meanwhile, an important feature of PDE4 inhibitors is the inhibition of the release of tumor necrosis factor (TNF-. Alpha.) from inflammatory cells. TNF- α is an important proinflammatory cytokine affecting a variety of biological processes, which can be released from activated local cells, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. TNF- α itself has an activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, which in turn release different tissue-destructive mediators. TNF- α causes increased levels of other proinflammatory cytokines such as GM-CSF (granulocyte-macrophage colony stimulating factor) or interleukin-8 in monocytes, macrophages and T lymphocytes. TNF- α plays a key role in a variety of diseases such as respiratory inflammation, joint inflammation, endotoxic shock, tissue rejection, AIDS and a variety of other immune disorders, as TNF- α promotes inflammation and catabolic effects. Therefore, PDE4 inhibitors are also useful in the treatment of TNF- α related disorders.
Obstructive Pulmonary Disease (COPD) is a collective term for a group of chronic airflow obstructive diseases that combine the different syndromes of chronic bronchitis with symptoms of productive cough and progressive and irreversible lung function deterioration. The course of the disease is episodic and is often complicated by bacterial infections. At present, the western medicines for treating chronic obstructive pulmonary disease mainly comprise bronchodilators including theophylline, beta 2 agonist and anticholinergic drugs, and are matched with oxygen therapy, antibiotics, hormones, auxiliary ventilation and the like for symptomatic treatment. But the antibiotic is easy to have drug resistance and toxic and side effects after long-term use, and patients with repeated infection often adopt high-grade antibiotic, which is expensive and difficult to bear by patients; hormones have strong side effects. New therapeutic approaches to attack inflammatory mediators, proteases or adhesion molecules may be very promising.
Chronic inflammation, dominated by neutrophils, is found in the bronchi independently of bacterial infections that are concurrent with the disease. In addition to this, mediators and enzymes released by neutrophils are responsible for the structural changes observed in the respiratory tract (emphysema). Therefore, inhibition of neutrophil activity is a reasonable starting point for preventing or delaying COPD progression (lung function parameter regression). An important stimulus for the activation of granulocytes is the proinflammatory cytokine TNF- α. TNF- α is currently known to stimulate neutrophil oxygen free radicals. PDE4 inhibitors can be very effective in inhibiting the release of TNF-alpha by a variety of cells and thus inhibit neutrophil activity. The nonspecific PDE inhibitor pentoxifylline is capable of inhibiting the production of oxygen radicals and the ability of neutrophils to phagocytose.
In addition, asthma is also a common respiratory disease, which is a chronic airway inflammation involved by various cells, particularly mast cells, eosinophils and T lymphocytes, and has become a major chronic disease that seriously threatens public health. At present, the western medicine treatment mode of asthma mostly depends on bronchodilators or oxygen inhalation to relieve symptoms, and the treatment is not carried out aiming at the pathogenesis of asthma. The mode of treating symptoms and root causes is easy to cause dependence and repeated attack, has side effects and can seriously affect the normal life of patients.
Although PDE4 inhibitors are known to have shown beneficial pharmacological effects, such inhibitors have adverse effects that cause diarrhea, nausea, and the like. Therefore, the research of novel specific inhibitors to overcome these adverse reactions becomes one of the hot spots of inhibitor drug research. The natural traditional Chinese medicine derivative is a treasury discovered by a lead compound for developing new medicines, a novel inhibitor is searched from the treasury, and the natural traditional Chinese medicine derivative has important significance for developing an inhibitor anti-inflammatory medicine with high curative effect and small side effect.
Disclosure of Invention
The invention provides an application of a benzoylguanidine derivative in preparing a medicament for preventing and treating nervous system diseases or cardiovascular system diseases. The benzoylguanidine derivatives have novel structures, and pharmacological experiments prove that the benzoylguanidine derivatives have the effects of inhibiting phosphodiesterase activity and protecting nerve cells, myocardial cells and vascular endothelial cells.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
the invention provides application of a benzoylguanidine derivative in preparing a medicament for preventing and treating nervous system diseases or cardiovascular system diseases, wherein the benzoylguanidine derivative with a novel structure comprises compounds ML-1, ML-2, ML-3, ML-4, ML-5, ML-6, ML-7 and ML-8, and the structural formulas are respectively as follows:
Figure BDA0003386885420000031
further, the preparation method of the new-structure benzoylguanidine derivative comprises the following steps:
condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid serving as an initial raw material with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc under the action of diisopropylcarbodiimide, recrystallizing methanol, removing a Boc protecting group under the action of trifluoroacetic acid, dissolving saturated sodium bicarbonate to separate out a solid, filtering, and recrystallizing with ethanol to obtain compounds ML-5 and ML-6;
or 3-cyclopentanyloxy-4-alkoxy benzoic acid is used as a starting material, dissolved in dichloromethane, condensed with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc, added with a condensing agent for complete reaction, filtered, vacuum-distilled, recrystallized under glacial methanol, and then the Boc protecting group is removed under the action of trifluoroacetic acid to obtain compounds ML-1 and ML-2;
or 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentyloxy-4-alkoxybenzoic acid reacts with thionyl chloride in a tetrahydrofuran solvent to obtain an active intermediate, wherein the reaction temperature is 20-120 ℃, and the reaction time is 1-24 hours; and reacting the Boc protected 4-guanidino-1-butylamine (or 4-guanidino-1-propylamine) with sodium hydroxide in a dichloromethane solution to obtain activated amino anions at the reaction temperature of 0-100 ℃ for 1-10 hours, slowly adding an active intermediate into the activated amino anions for 1-24 hours, then removing the Boc protecting group from a dichloromethane and trifluoroacetic acid mixed solution, and recrystallizing the obtained crude product with ethyl acetate to obtain the compounds ML-7, ML-8, ML-3 and ML-4.
Further: the new-structure benzoyl guanidine derivative also comprises pharmaceutically acceptable salts thereof, and can be obtained by a method of neutralizing alkali with inorganic acid or organic acid.
Further: the inorganic acid comprises hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; the organic acid includes carboxylic acid, thioacid, sulfonic acid, acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, pamoic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1, 2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, or naphthalene-2-sulfonic acid.
Further: the new structure of the benzoyl guanidine derivative also comprises D type, L type or D, L-mixture.
Further: the new structure of the benzoyl guanidine derivative also comprises diastereoisomer thereof.
The invention also provides application of the new-structure benzoylguanidine derivative in preparing a medicament for preventing and treating nervous system diseases or cardiovascular system diseases.
Further: the new structure of the benzoylguanidine derivative canCan inhibit Abeta aggregates and/or CoCl 2 Induced nerve cell and/or myocardial cell damage, or vascular endothelial cell damage induced by effectively reversing oxidized low-density lipoprotein ox-LDL, thereby achieving the effect of protecting nerve cells or cardiovascular cells.
Further: the cardiovascular diseases comprise arteriosclerosis, heart failure, angina and ischemic injury caused by myocardial cell or vascular endothelial cell injury; the nervous system diseases include Alzheimer's disease, amnesia, dementia, apoplexy, schizophrenia, depression, anxiety and Parkinson's disease caused by nerve cell injury.
Further: the nervous system disease or cardiovascular system disease further comprises memory loss, intermittent claudication, hyperlipidemia, hyperglycemia, benign prostatic hyperplasia, pollakiuria, nocturia, incontinence, urinary calculus induced striated pain, and sexual dysfunction.
Further: the medicine can be tablet, oral liquid, aerosol, pill, capsule, granule, unguent, dripping pill, syrup, powder, granule, tincture, powder for injection or injection.
Further: the medicament is administered orally, parenterally, intravenously, transdermally, topically, by inhalation, and intranasally.
Further: the dosage of the drug is a single dose administered once a day, or is divided into two or more doses each of 0.001-500mg per day.
Further: the medicament also comprises at least one of an adjuvant, a carrier and an additive.
Further: the carrier comprises calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methyl cellulose, talc, highly dispersed silicon dioxide, silicone oil, stearic acid, gelatin, agar, vegetable or animal fats and oils, polyethylene glycol.
Further: the adjuvants include sweeteners, flavoring agents, preservatives, stabilizers, wetting agents, osmotic agents, emulsifiers, coating agents, cosolvents, salts for controlling osmotic pressure or for buffering, sugars or sugar alcohols and/or viscosity regulators.
Further: the additive comprises tartrate and citrate buffer, ethanol and complexing agent.
Further: for viscosity control, the additives can also use liquid polyethylene oxide, microcrystalline cellulose, polyvinylpyrrolidone, dextran or gelatin.
Further: oil suspensions for parenteral or topical application may contain synthetic or semi-synthetic oils of vegetable origin, including liquid fatty acid esters thereof having from 8 to 22 carbon atoms in the fatty acid chain, including palmitic, lauric, tridecanoic, margaric, stearic, eicosanoic, myristic, behenic, pentadecanoic, linoleic, elaidic, basilic, erucic or oleic acid, which are esterified with mono-and trihydric alcohols having from 1 to 6 carbon atoms, including methanol, ethanol, propanol, butanol, pentanol or isomers thereof, ethylene glycol or glycerol; the fatty acid ester includes Miglyole, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG-6 decanoic acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleate, ethyl oleate, waxy fatty acid esters such as synthetic duck tail gland fat, isopropyl esters of coconut oil fatty acids, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, fatty acid esters of polyhydric alcohols; silicone or fatty alcohols including isotridecanol, 2-octyldodecanol, cetostearyl or oleyl alcohol, oleic acid and vegetable oils including castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil can also be used.
Further: as solvents, gel formers and cosolvents, water or alcohols are used including ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalates, adipates, propylene glycol, glycerol, dipropylene glycol, tripropylene glycol, waxes, methyl cellosolve, esters, wulin, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydroxypyran, cyclohexanone.
Further: as film-forming agents, cellulose ethers which are soluble or swellable in water and organic solvents are used, including hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches, sodium carboxymethylcellulose, polyacrylic acid, polyisobutylene acid and salts thereof, sodium pullulan hemiglycolate, alginic acid or propylene glycol alginate vinegar as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
Further: as other adjuvants, glycerol, paraffin of different viscosity, triethanolamine, collagen, allantoin, novantisolysure can also be used.
And further: surfactants, emulsifiers or wetting agents can also be included in the medicament, including sodium lauryl sulfate, fatty alcohol ether sulfates, disodium N-lauryl- β -iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbate, cetyl alcohol, lecithin, glycerol stearate, polyoxyethylene stearate, alkylphenol polyglycol ether, ethoxylated cetyl trimethylammonium or alkyl or dialkyl polyglycol ether orthophosphoric acid ethanolamine salt; stabilizers include montmorillonite or colloidal silica; antioxidants including tocopherol or butylated hydroxyanisole; preservatives include parabens.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the novel-structure benzoylguanidine derivative prepared by the invention has a novel structure, and pharmacological experiments prove that the novel-structure benzoylguanidine derivative can inhibit nerve cell injury induced by Abeta (amyloid beta) aggregates or CoCl 2 Induced anoxic injury of nerve cells or myocardial cells, and effectively reverse ox-LDL injury of vascular endothelial cells, thereby increasing the activity of the nerve cells or the myocardial cells, avoiding the injury of the vascular endothelial cells by oxidized low-density lipoprotein, and achieving the effect of protecting the nerve cells or the cardiovascular cells. The new-structure benzoyl guanidine derivative has good treatment effect on various diseases, has good safety and further development priceThe value is obtained.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples.
Example 1: synthesis of benzoyl guanidine derivative benzyl ester compound
1. Synthesis of the general Compound 4-guanidinobutane-3-cyclopropylmethoxy-4-difluoromethoxybenzyl
Taking commercially available 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as a starting material, dissolving 35g of the commercially available 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid in 100mL of anhydrous dichloromethane, stirring to fully dissolve the commercially available 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, adding 60g of dimethylaminopyridine p-toluenesulfonate in batches, adding 32.5g of Boc-protected 4-guanidino-1-butanol after the solution is clarified, stirring to dissolve the solution, adding 38.5g of diisopropylcarbodiimide, stirring overnight at room temperature, performing TLC detection reaction, filtering off insoluble substances by suction, distilling under reduced pressure to remove dichloromethane, adding frozen glacial methanol in advance until white crystals are separated out, and filtering to obtain about 25.3g of a white powdery crystal precursor. The precursor compound was taken at 4.0mM, and 1:1 in 10mL of a mixed solution of dichloromethane and trifluoroacetic acid, and reacting at room temperature for 5 hours, and determining whether the reaction is completed by TLC. Distilling under reduced pressure to remove dichloromethane, washing with petroleum ether for 3 times, adding appropriate amount of saturated NaHCO 3 Adjusting the pH of the solution to 8-11, precipitating a solid, and then filtering to obtain 4-guanidinobutane-3-cyclopropa methoxy-4-difluoromethoxybenzyl methyl ester, namely a representative product ML-5, wherein the data of a nuclear magnetic resonance hydrogen spectrum and a carbon spectrum are as follows:
Figure BDA0003386885420000071
compound ML-5 Hydrogen Spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ8.29(s,1H),7.58(s,2H),7.41(s,2H),7.06(s,2H),6.60(s,4H),6.05(s,2H),4.40(s,2H),4.30(s,2H),3.94(s,4H),3.57(s,2H),1.83(s,2H),1.50(s,2H),1.10(s,1H),0.47(s,2H),0.23(s,2H).
compound ML-5 carbon Spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.37(s),156.86(s),153.61(s),149.68(s),125.82(s),124.84(s),124.56(s),119.05(s),118.56(s),74.00(s),66.74(s),41.46(s),27.93(s),27.36(s),10.70(s),7.85(s).
2. the compounds ML-6, ML-1 and ML-2 can be synthesized by the classical acid-alcohol condensation method, which is as follows:
Figure BDA0003386885420000072
compound ML-6 hydrogen spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ8.31(s,2H),7.61(s,4H),7.44(s,4H),7.09(s,4H),6.63(s,8H),6.10(s,4H),4.42(s,4H),4.30(s,4H),3.95(s,8H),3.58(s,4H),2.00(s,3H),1.11(s,1H),0.51(s,4H),0.17(s,4H).
compound ML-6 carbon Spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.37(s),156.86(s),153.61(s),149.68(s),125.82(s),124.84(s),124.56(s),119.05(s),118.56(s),74.00(s),62.55(s),38.88(s),30.61(s),10.70(s),7.85(s).
Figure BDA0003386885420000081
compound ML-1 hydrogen spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ7.61(s,1H),7.44(s,1H),6.90(s,1H),6.73(s,1H),6.48(s,2H),4.30(d,J＝15.8Hz,2H),3.83(s,3H),3.68(s,1H),3.58(s,1H),2.05(s,1H),1.84(s,2H),1.78(s,1H),1.71(s,1H),1.61(s,1H),1.51(s,1H).
compound ML-1 carbon Spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.37(s),156.86(s),156.67(s),148.08(s),123.16(s),122.49(s),117.64(s),117.01(s),83.94(s),66.74(s),56.83(s),41.46(s),33.43(s),27.93(s),27.36(s),24.08(s).
Figure BDA0003386885420000082
compound ML-2 hydrogen spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ7.61(s,1H),7.44(s,1H),6.90(s,1H),6.14(s,1H),6.09(s,2H),5.07(s,1H),4.30(s,1H),4.20(s,1H),3.83(s,3H),3.58(s,1H),2.05(s,1H),2.00(s,1H),1.78(s,1H),1.71(s,1H),1.61(s,1H).
compound ML-2 carbon spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.37(s),156.86(s),156.67(s),148.08(s),123.16(s),122.49(s),117.64(s),117.01(s),83.94(s),62.55(s),56.83(s),38.88(s),33.43(s),30.61(s),24.08(s).
example 2: synthesis of benzoylguanidine derivative benzamide compound
1. Synthesis of the representative Compound 3-Cyclopentyloxy-N-4-guanidinobutane-4-methoxybenzylamine
2.83g NaH was added to 50mL of dry tetrahydrofuran, and Boc-protected 4-guanidino-1-butylamine (78.2 mM) was slowly added thereto and reacted at room temperature for 1.5 hours; dissolving 3-cyclopentanyloxy-4-methoxybenzoic acid (33.1 mM) in 200mL dry tetrahydrofuran, and slowly adding 8.6mL SOCl dropwise under ice-bath condition 2 After the completion of the addition, the mixture was refluxed for 6 hours, the solvent was distilled off, and the mixture was dissolved in 65mL of anhydrous tetrahydrofuran, and then the mixture was slowly dropped into the above reaction system at room temperature to react at 50 ℃ for 6 hours. Cooled to room temperature, 300mL of water was added and extracted 3 times with 150mL of acetate, the combined organic phases were dried over anhydrous sodium sulfate and then 1:1, reacting at room temperature for 6 hours, determining whether the reaction is finished deprotection or not by TLC (thin layer chromatography), then distilling off the solvent under reduced pressure to obtain a crude product, recrystallizing the crude product by ethyl acetate to obtain a representative compound 3-cyclopentanyloxy-N-4-guanidinobutane-4-methoxybenzamide, namely a compound ML-3, wherein the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound are as follows:
Figure BDA0003386885420000091
compound ML-3 Hydrogen Spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ7.61(s,1H),7.49(s,1H),7.02(s,1H),6.63(s,2H),6.15(s,1H),5.94(s,1H),4.46(s,1H),4.36(s,1H),3.83(s,3H),3.58(s,2H),3.30(s,2H),2.06(s,1H),1.78(s,1H),1.71(s,1H),1.61(s,1H),1.55(s,2H),1.49(s,2H).
compound ML-3 carbon spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.82(s),156.86(s),153.51(s),148.80(s),128.31(s),122.37(s),116.54(s),113.88(s),83.94(s),56.83(s),41.49(d,J＝7.6Hz),33.43(s),27.39(s),24.08(s).
2. using the classical acid-amine condensation method described above, compounds ML-7, ML-8, ML-4 can be synthesized as follows:
Figure BDA0003386885420000092
compound ML-7 hydrogen Spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ8.35(s,1H),7.57(s,2H),7.45(s,2H),7.12(s,2H),6.74(s,2H),6.47(s,4H),6.06(s,2H),3.99(s,2H),3.94(s,4H),3.56(s,4H),3.28(s,4H),1.54(s,6H),1.48(s,2H),1.10(s,1H),0.47(s,2H),0.19(s,2H).
compound ML-7 carbon spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.82(s),156.86(s),153.70(s),147.81(s),128.59(s),124.84(s),121.58(s),118.99(s),118.56(s),74.00(s),41.49(d,J＝7.6Hz),27.39(s),10.70(s),7.85(s).
Figure BDA0003386885420000101
compound ML-8 Hydrogen Spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ8.54(s,1H),7.55(d,J＝60.0Hz,4H),7.16(s,2H),6.63(s,4H),6.10(s,2H),6.00(s,2H),4.45(s,2H),3.96(s,4H),3.58(s,2H),3.42(s,2H),1.90(s,2H),1.11(s,1H),0.49(s,2H),0.16(s,2H).
compound ML-8 carbon Spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.82(s),156.86(s),153.70(s),147.81(s),128.59(s),124.84(s),121.58(s),118.99(s),118.56(s),74.00(s),39.20(s),38.35(s),28.44(s),10.70(s),7.85(s).
Figure BDA0003386885420000102
compound ML-4 hydrogen spectrum: 1 H NMR(400MHz,DMSO-d 6 )δ7.55(d,J＝60.0Hz,2H),7.02(s,1H),6.32(d,J＝11.6Hz,3H),6.06(s,1H),4.57(s,1H),4.22(s,1H),3.83(s,3H),3.58(s,1H),3.42(s,1H),2.06(s,1H),1.90(s,1H),1.70(t,J＝42.3Hz,6H),1.61(s,3H),1.61(s,1H).
compound ML-4 carbon spectrum: 13 C NMR(101MHz,DMSO-d 6 )δ166.82(s),156.86(s),153.51(s),148.80(s),128.31(s),122.37(s),116.54(s),113.88(s),83.94(s),56.83(s),39.20(s),38.35(s),33.43(s),28.44(s),24.08(s).
example 3: protective effect of new-structure benzoylguanidine derivative on A beta aggregate-induced nerve cell injury
The inhibition effect of the compound prepared in example 1 on the nerve cell cytotoxicity induced by the Abeta is observed by taking the cell viability without adding the Abeta 1-42 as a negative control, and the specific implementation steps are as follows: inoculating PC12 cells into MEM complete culture solution, culturing in 96-well plate, incubating in constant temperature cell incubator for 24 hr, adding the A beta protein oligomer, adding the compound solution to each well after 2 hr, adding the same amount of sterile water to the model group, and incubating for 24 hr. After completion, the cell viability was measured by the MTT method. Each time three replicates were performed and the experiment was repeated three times.
The results are shown in table 1, and after treatment at the administration concentration of 10 μmol/L, the compounds of the present invention all have good nerve cell protection effects, and have obvious inhibition effects on A β aggregate induced nerve cell damage. Therefore, the new-structure benzoylguanidine derivatives of the present invention are useful for the treatment and prevention of diseases associated with neuroprotection.
Table 1: results of protecting neuronal cells with Compounds
Group of Cell survival rate (%)
Model set 42±2.8
ML-1 78±2.7
ML-2 82±2.5
ML-3 80±2.3
ML-4 75±2.1
ML-5 93±2.6
ML-6 81±2.9
ML-7 75±2.2
ML-8 91±3.2
Example 4: novel structure of benzoylguanidine derivative p-CoCl 2 Protective action for inducing hypoxia injury of nerve cell and cardiac muscle cell
With no addition of CoCl 2 Cell viability of induced nerve cells PC12 and cardiomyocytes H9C2 was negative control, and the compound prepared in example 1 was observed against induced CoCl 2 The specific implementation steps of the generated inhibition effect of the hypoxia injury of the nerve cells and the cardiac muscle cells are as follows: inoculating PC12 and H9C2 cells into MEM or DMEM complete culture solution, culturing in 96-well plate, incubating in constant temperature cell incubator for 24 hr, adding pre-dissolved CoCl-containing solution 2 2h of the injury liquidThereafter, each compound solution was added to each well of each compound group at a concentration of 50. Mu. Mol/L, and the model group was added with an equal amount of sterile water and incubated in the incubator for another 48 hours. After completion, the cell viability was measured by the MTT method. Each time three replicates were performed and the experiment was repeated three times.
As shown in tables 2 and 3, the compounds of the present invention have a superior effect of protecting both nerve cells and myocardial cells from hypoxic injury after treatment at a dosage concentration of 50. Mu. Mol/l. Therefore, the new-structure benzoyl guanidine derivative of the present invention is suitable for treating and preventing diseases related to damage of nerve cells and cardiovascular system.
Table 2: effect of Compounds on hypoxia-induced nerve injury
Figure BDA0003386885420000111
Figure BDA0003386885420000121
Table 3: protective effect of compound on cardiovascular cells caused by hypoxia
Group of Cell survival rate (%)
Model set 52±3.1
ML-1 74±2.0
ML-2 77±1.7
ML-3 80±2.5
ML-4 85±2.8
ML-5 93±2.2
ML-6 85±2.4
ML-7 90±3.2
ML-8 91±3.4
Example 5: inhibition of oxidative low-density lipoprotein (ox-LDL) -induced vascular endothelial cell damage by new-structure benzoylguanidine derivatives
HUVEC of vascular endothelial cells are inoculated in MEM complete culture solution, and the protective effect of the compound on vascular endothelial atherosclerosis injury induced by ox-LDL is observed by taking a group of non-oxidized low-density lipoprotein ox-LDL as a negative control. The method comprises the following specific steps: HUVEC cells were inoculated in MEM or DMEM complete medium, cultured in 96-well plates, incubated in a constant-temperature cell incubator for 24 hours, then added with an ox-LDL-containing induction solution dissolved in advance, and after 2 hours, 50. Mu.M of benzoylguanidine derivatives were added to each well, with the group without ox-LDL as a negative control. After completion, the content of IL-6 inflammatory factor was measured by ELISA.
The results are shown in Table 4, that the benzoyl guanidine derivatives can effectively inhibit the increase of IL-6 in vascular endothelial cells stimulated by oxidative low-density lipoprotein ox-LDL, and that the benzoyl guanidine derivatives with the novel structure are suitable for preventing and treating diseases related to vascular endothelial cell injury.
Table 4: inhibition of ox-LDL induced endothelial cell atheroma
Figure BDA0003386885420000122
Figure BDA0003386885420000131
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; such modifications and substitutions do not depart from the spirit and scope of the corresponding claims.

Claims (5)

1. The application of the benzoyl guanidine derivative in preparing medicine for preventing and treating nervous system diseases or cardiovascular system diseases is characterized in that the new-structure benzoyl guanidine derivative comprises compounds ML-1, ML-2, ML-3, ML-4, ML-5, ML-6, ML-7 and ML-8, and the structural formulas are respectively as follows:
Figure FDA0003386885410000011
2. use of the benzoylguanidine derivative according to claim 1 for the preparation of a medicament for the prevention and treatment of a disease of the nervous system or cardiovascular system, wherein the preparation method of the benzoylguanidine derivative comprises the steps of:
condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentanyloxy-4-alkoxybenzoic acid with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc, and removing the Boc protecting group under the action of trifluoroacetic acid to obtain compounds ML-5, ML-6, ML-1 or ML-2;
or condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentanyloxy-4-alkoxybenzoic acid with Boc-protected 4-guanidino-1-butylamine or 4-guanidino-1-propylamine, and then removing the Boc protecting group in a mixed solution of dichloromethane and trifluoroacetic acid to obtain compounds ML-7, ML-8, ML-3 or ML-4.
3. Use of the benzoylguanidine derivative according to claim 1 for the preparation of a medicament for the prevention and treatment of a neurological or cardiovascular disease, wherein the benzoylguanidine derivative is capable of inhibiting a β aggregates and/or CoCl 2 Induced nerve cell and/or myocardial cell damage, or vascular endothelial cell damage induced by effectively reversing oxidized low-density lipoprotein ox-LDL, thereby achieving the effect of protecting nerve cells or cardiovascular cells.
4. The use of the benzoylguanidine derivative according to claim 1 for the preparation of a medicament for the prevention and treatment of a disease of the nervous system or cardiovascular system, wherein the cardiovascular disease includes arteriosclerosis, heart failure, angina pectoris, ischemic injury caused by the injury of myocardial cells or vascular endothelial cells; the nervous system diseases include Alzheimer's disease, amnesia, dementia, apoplexy, schizophrenia, depression, anxiety and Parkinson's disease caused by nerve cell injury.
5. The application of the benzoylguanidine derivative according to claim 1, in the preparation of a medicament for preventing and treating nervous system diseases or cardiovascular system diseases, wherein the medicament is in the form of tablet, oral liquid, aerosol, pill, capsule, granule, paste, drop pill, syrup, powder, granule, tincture, powder injection or injection.
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