CN108299181B - Bis-o-hydroxyacetophenone twin drug compound and preparation method and application thereof - Google Patents
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- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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Abstract
The invention relates to a bis-o-hydroxyacetophenone twin drug compound and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry, wherein 2-hydroxyacetophenone derivatives are used as starting materials and react under the conditions of proper solvent and alkali to generate the bis-o-hydroxyacetophenone twin drug compound connected by different linkers, the compound has multiple-effect functions and is expected to be applied to drugs for treating and/or preventing neurodegenerative related diseases, and the neurodegenerative related diseases comprise Alzheimer disease, Parkinson disease, Huntington disease, HIV (human immunodeficiency virus) related dementia, multiple sclerosis, progressive lateral sclerosis, vascular dementia, neuropathic pain, glaucoma and the like, thereby laying a foundation for effectively treating related senile diseases and improving the healthy living level of residents.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a bis-o-hydroxyacetophenone twin drug compound and a preparation method and application thereof.
Background
Alzheimer's Disease (AD) is one of the most prevalent diseases in the elderly. The report on global Alzheimer's disease 2015 issued by the International Association for Alzheimer's Disease (ADI) states that over 4600 million people worldwide have dementia 2015, and it is predicted that 1.315 million people worldwide will suffer from dementia 2050, with the incidence of Chinese dementia reaching 6.61%. With the growing life of everyone, the disease has developed into a major burden for society and health care system, and has brought a heavy mental and economic stress to society, patients and family members. Therefore, the research and development of novel senile dementia treatment drugs are of great significance. From a market perspective, the international association for alzheimer's disease predicts that global sales of therapeutic drugs for dementia will reach $ 6000 billion by 2050 years; in China, with the rapid increase of the incidence rate of senile dementia, the market of the medicines is rapidly expanded.
AD is a chronic, multi-etiology, multi-node involved complex neurodegenerative disease characterized by progressive memory and cognitive impairment, and its major pathologies are Senile Plaque (SP) formed by the massive deposition of β -amyloid peptide (Α β), Neurofibrillary tangle (NFT) formed by hyperphosphorylation of tau protein, accompanied by apoptosis of neurons and degeneration of synapses, etc. In recent years, many researchers have been working on the molecular and cellular level to reveal the pathogenesis of AD, proposing various hypotheses such as: cholinergic neuronal damage, amyloid deposition, tau hyperphosphorylation, inflammation, free radical oxidation, metal ion imbalance, etc., and therefore, new therapeutic approaches and approaches developed for these pathogenesis would be expected to alleviate and improve the condition of AD patients. At present, the clinically effective drugs for treating AD are mainly divided into two types: (1) based on the cholinergic hypothesis that the neurotransmitter acetylcholine is deficient, leading to cognitive dysfunction, acetylcholinesterase inhibitors are used to increase acetylcholine levels in the brain of patients, such as: tacrine, Donepezil, Ravastigmine, Galantamine; (2) N-methyl-D-aspartate (NMDA) receptor inhibitors are used to reduce glutamate damage to nerve cells, such as: memantine Hydrochloride. However, long-term clinical use indicates that the drugs can relieve the symptoms of AD in a short period of time, but cannot fundamentally and effectively prevent or reverse the course of disease, and can also cause classical cholinergic toxicity, such as hallucinations, confusion, dizziness, nausea, hepatotoxicity, inappetence, frequent stools and the like. Therefore, the development of AD therapeutic drugs with a novel mechanism of action is urgently needed clinically.
The etiology of AD is complex, and the pathogenesis of AD has not been completely clarified yet, but researches show that the acetylcholine level in the brain of patients is reduced, the beta-amyloid is excessively generated and deposited, the metal ion metabolism is disturbed, and Ca is generated2+Imbalance of balance, neurofibrillary tangles caused by hyperphosphorylation of tau-protein, excessive glutamate receptor activity, large amounts of Reactive Oxygen Species (ROS) and free radicals produced by oxidative stress, and neuroinflammatory responses play an important role in the pathogenesis of AD. In view of the above pathogenic factors, researchers have adopted the traditional "one drug one target" drug design strategy to find a large number of drugs with high activity and high selectivity to a certain target, such as: cholinesterase inhibitors, NMDA receptor antagonists and the like, and the drugs have the problems of single action target, more toxic and side effects in clinical use, poor long-term curative effect on AD patients and the like.
In recent years, with the continuous elucidation of the pathogenic mechanism of AD, the occurrence and development of AD have the characteristics of multi-mechanism and multi-factor action, and different mechanisms are mutually associated and influenced, so that a network regulation system with complex occurrence and development processes of AD is formed. Based on the above results, researchers have proposed a "multi-target-directed drugs (MTDLs)" strategy to develop anti-neurodegenerative disease drugs. By "multi-target drug" is meant that a single chemical entity acts on multiple targets in a disease network simultaneously, and the effect on each target can produce a synergistic effect such that the total effect is greater than the sum of the individual effects, such drugs are also referred to as "Multifunctional" or "Multipotential" drugs. The main differences of the multi-target point medicine and the multi-medicine combined application and the compound medicine are as follows: can reduce the dosage, improve the treatment effect, avoid the interaction between the medicaments and the toxic and side effect caused by the interaction, have uniform pharmacokinetic characteristic, and are convenient to use, and the like. Therefore, the research and development of the neurodegenerative disease resisting treatment drug which has a novel chemical structure, a novel action mechanism, a multi-target effect and low toxic and side effects not only meets the urgent need of the social aging process, but also has good market prospect.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a bis-o-hydroxyacetophenone twin compound; the second purpose is to disclose a preparation method of the bis-o-hydroxyacetophenone twin drug compound; the third purpose is to provide a pharmaceutical composition containing the bis-o-hydroxyacetophenone twin drug compound or pharmaceutically acceptable salt thereof; the purpose is to disclose the application of the bis-2-hydroxyacetophenone twin drug compound in preparing the drugs for treating and/or preventing neurodegenerative related diseases.
A bis-o-hydroxyacetophenone twin drug compound has a chemical structural general formula:
wherein R represents-H, -OH, -F, -Cl, -Br, -I, C1-4Alkyl radical, C1-4Any one, two or three of alkoxy, trifluoromethyl, trifluoromethoxy, nitro and cyano substituent groups;
linker is (CH)2)n、[(CH2)nNH(CH2)n]m or (CH)2)nCONH(CH2)nNHCO(CH2) n, wherein n and m are both 1-12.
The invention also provides a preparation method of the bis-o-hydroxyacetophenone twin drug compound, which comprises the following steps:
the method I comprises the following steps of taking a 2-hydroxyacetophenone derivative as a starting material, and reacting the starting material with a dibromo compound under the alkaline condition formed by adding alkali in a solvent to obtain a bis-o-hydroxyacetophenone twin compound Ia as a product, wherein the chemical reaction equation is as follows:
in the second method, a 2-hydroxyacetophenone derivative is used as an initial raw material and reacts with dibromoalkylamine under the alkaline condition formed by adding alkali in a solvent to obtain a product bis 2-hydroxyacetophenone twin drug compound Ib, and the chemical reaction equation is as follows:
taking a 2-hydroxyacetophenone derivative as an initial raw material, reacting with ethyl bromoalkanoate under the alkaline condition formed by adding alkali in a solvent, then performing hydrolysis reaction under the alkaline condition formed by adding alkali, adjusting the pH to 2 to obtain a 2-hydroxyacetophenone-O-alkyl acid derivative, and reacting with alkyldiamine under the condition of a condensing agent to obtain a product bis 2-hydroxyacetophenone twin drug compound Ic, wherein the chemical reaction equation is as follows:
wherein n and/or m in the molecule of the dibromo compound, the dibromoalkylamine, the ethyl bromoalkanoate and the alkyl diamine are 1-12.
Further, the solvent is C3-8Aliphatic ketone, N-dimethylformamide, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C1-6Fatty acids with C1-6Ester formed by fatty alcohol, dichloromethane, chloroform, 1, 2-dichloroethane, benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, acetonitrile, dimethyl sulfoxide and pyridine.
Further, the base used in the alkaline condition is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate, C1-6One or more of fatty acid alkali metal salt, piperidine, tetrahydropyrrole, triethylamine, tributylamine, trioctylamine, pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine and tetrabutylammonium hydroxide.
Further, the condensing agent is one or more of EDCI, HOBT, DCC, DMAP and Katt condensing agent.
Further, in the first method, the molar ratio of the 2-hydroxyacetophenone derivative to the dibromo compound to the alkali is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20 ℃ to 130 ℃, and the reaction time is 1-72 hours;
in the second method, the molar ratio of the 2-hydroxyacetophenone derivative to the dibromoalkylamine compound to the alkali is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20-130 ℃, and the reaction time is 1-72 hours;
in the third method, the molar ratio of the 2-hydroxyacetophenone derivative to the ethyl bromoalkanoate to the alkali is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20-130 ℃, and the reaction time is 1-72 hours; the molar ratio of the 2-hydroxyacetophenone-O-alkyl acid to the alkyl diamine to the condensing agent is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20 ℃ to 130 ℃, and the reaction time is 1-72 hours.
The invention also claims a pharmaceutical composition which comprises the bis-o-hydroxyacetophenone twin drug compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
Further, the pharmaceutically acceptable salt is a bis-o-hydroxyacetophenone twin drug compound and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and C1-6Fatty carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C1-6Alkyl sulfonic acid, camphor sulfonic acid, benzene sulfonic acid or p-toluene sulfonic acid.
The invention further provides application of the bis-o-hydroxyacetophenone twin drug compound in preparation of drugs for treating and/or preventing neurodegenerative related diseases.
The invention has the beneficial effects that:
1. the bis-o-hydroxyacetophenone twin drug compound has obvious inhibition effect on MAO-A and MAO-B, and IC50 of the compound is 0.05-50 mu M; shows strong complexation effect on metal ions; has stronger antioxidant activity; the protective agent has obvious protective effect on PC12 cell damage induced by hydrogen peroxide under the concentration of 10 < -4 > mol/L to 10 < -7 > mol/L; under the concentration of 10 < -4 > mol/L to 10 < -7 > mol/L, the composition has obvious protective effect on SH-SY5Y cell injury induced by Abeta 1-42; has dose-dependent improving effect on mouse acquired dysmnesia caused by scopolamine.
2. The invention designs and prepares a multi-target compound with multiple-effect functions by taking a 2-hydroxyacetophenone derivative as a starting material based on a multi-target drug design strategy, and the compound is applied to drugs and is expected to treat and/or prevent neurodegenerative related diseases, wherein the neurodegenerative related diseases comprise Alzheimer disease, Parkinson disease, Huntington disease, HIV (human immunodeficiency Virus) related dementia, multiple sclerosis, progressive lateral sclerosis, vascular dementia, neuropathic pain, glaucoma and the like, thereby laying a foundation for effectively treating related senile diseases and improving the healthy living level of residents.
Detailed Description
The invention is further illustrated by the following specific examples.
Example 1 general method for preparing bis-o-hydroxyacetophenone twin compounds Ia
Adding 2.0mmol of 2-hydroxyacetophenone (1), 10mmol of corresponding dibromo compound (2), 3mmol of anhydrous potassium carbonate and 50ml of acetonitrile into a reaction bottle, uniformly stirring, heating, refluxing and stirring for reacting for 2.0-72 hours (tracking the reaction process by TLC); after the reaction is finished, the solvent is evaporated to dryness under reduced pressure, 80mL of deionized water is added, 200mL of dichloromethane is used for extraction for three times, organic layers are combined and washed by saturated sodium chloride, the mixture is dried and filtered by anhydrous sodium sulfate, the solvent is evaporated to dryness by the reduced-pressure bis 2-hydroxyacetophenone twin drug compound (Ia), and the residue is purified by column chromatography (petroleum ether: acetone: 100:1v/v) to obtain the corresponding bis 2-hydroxyacetophenone twin drug compound Ia with the yield of 15-65 percent1H-NMR、13C-NMR and ESI-MS confirmation: the purities of the obtained target substances are more than 97 percent through HPLC. The target prepared by the method has the following structure:
in the molecular structure of the bis-o-hydroxyacetophenone twin compound Ia, different R and different values of n are taken for testing, and the molecular structure of the obtained compound is shown in Table 1 through ESI-MS.
Table 1: testing of different substituents and n value
NMR was performed on some of the compounds in table 1 above, and the molecular structure and nuclear magnetic data of the corresponding compounds were as follows:
1、
target compound Ia-2:1H NMR:12.75(s,2H,2×OH),7.63(d,J＝8.8Hz,2H,2×Ar-H),6.46-6.43(m,4H,4×Ar-H),4.19(t,J＝6.0Hz,4H,2×OCH2),2.56(s,6H,2×CH3),2.32-2.26(m,2H,CH2).13C NMR:202.65,165.20,132.38,113.99,107.92,101.36,64.45,28.73,23.29.
2、
target compound Ia-3:1H NMR 12.73(s,2H,2×OH),7.63(d,J＝8.8Hz,2H,2×Ar-H),6.43(d,J＝12.4Hz,4H,4×Ar-H),4.07(s,4H,2×OCH2),2.56(s,6H,2×CH3),1.99-1.98(m,4H,2×CH2).13NMR 202.5(2C),165.4(2C),165.3(2C),132.3(2C),114.0(2C),107.9(2C),101.4(2C),67.7(2C),29.7,29.6,26.2,25.7.
3、
target compound Ia-4:1H NMR 12.75(s,2H,2×OH),7.62(d,J＝8.8Hz,2H,2×Ar-H),6.43(dd,J1＝6.8Hz,J2＝2.0Hz,2H,2×Ar-H),6.40(d,J＝2.4Hz,2H,2×Ar-H),4.02(t,J＝6.4Hz,4H,2×OCH2),2.55(s,6H,2×COCH3),1.91-1.83(m,4H,2×CH2),1.68-1.63(m,2H,CH2).13C NMR 202.6(2C),165.6(2C),165.2(2C),132.3(2C),113.8(2C),108.0(2C),101.3(2C),68.0(2C),28.7(2C),26.2(2C),22.6.
4、
target compound Ia-5:1H NMR 12.74(s,2H,2×OH),7.62(d,J＝8.8Hz,2H,2×Ar-H),6.43(d,J＝9.2Hz,2H,2×Ar-H),6.40(s,2H,2×Ar-H),4.01(t,J＝6.0Hz,4H,2×OCH2),2.55(s,6H,2×CH3),1.83-1.81(m,4H,2×CH2),1.54-1.53(m,4H,2×CH2).13C NMR 202.5(2C),165.6(2C),165.3(2C),132.3(2C),113.8(2C),108.0(2C),101.3(2C),68.0(2C),28.9(2C),26.2(2C),25.7(2C).
5、
target compound Ia-7:1H NMR 12.67(s,2H,2×OH),7.53(d,J＝8.8Hz,2H,2×Ar-H),6.34(d,J＝8.8Hz,2H,2×Ar-H),6.33-6.31(m,2H,2×Ar-H),3.91(t,J＝6.8Hz,4H,2×OCH2),2.47(s,6H,2×CH3),1.75-1.68(m,4H,2×CH2),1.43-1.37(m,4H,2×CH2),1.33-1.28(m,4H,2×CH2),1.20-1.18(m,4H,2×CH2).13NMR 201.4(2C),164.7(2C),164.3(2C),131.2(2C),112.8(2C),107.0(2C),100.3(2C),67.3(2C),30.9(2C),28.7(2C),28.3(2C),27.9(2C).
6、
target compound Ia-8:1H NMR 12.76(s,2H,2×OH),7.62(d,J＝8.8Hz,2H,2×Ar-H),6.43(dd,J1＝6.8Hz,J2＝2.4Hz,2H,2×Ar-H),6.40(d,J＝2.4Hz,2H,2×Ar-H),3.99(t,J＝6.4Hz,4H,2×OCH2),2.56(s,6H,2×CH3),1.83-1.76(m,4H,2×CH2),1.62-1.58(m,4H,2×CH2),1.47-1.42(m,4H,2×CH2),1.33-1.31(m,6H,3×CH2).13NMR 202.5(2C),165.7(2C),165.3(2C),132.3(2C),113.7(2C),108.0(2C),101.2(2C),68.4(2C),29.4(2C),29.2(2C),28.9(2C),26.2(2C),25.9(3C).
7、
target compound Ia-10:1H NMR 12.74(s,2H,2×OH),7.62(d,J＝8.8Hz,2H,2×Ar-H),6.43(d,J＝8.8Hz,2H,2×Ar-H),6.40-6.39(m,2H,2×Ar-H),3.98(t,J＝6.8Hz,4H,2×OCH2),2.55(s,6H,2×CH3),1.80-1.76(m,4H,2×CH2),1.45-1.42(m,4H,2×CH2),1.30-1.28(m,4H,2×CH2),1.29-1.27(m,12H,6×CH2).13NMR 202.5(2C),165.8(2C),165.3(2C),132.3(2C),113.7(2C),108.0(2C),101.3(2C),68.4(2C),29.7(2C),29.5(2C),29.3(2C),28.9(2C),26.2(2C),25.9(2C).
example 2 general method for preparing bis-o-hydroxyacetophenone twin compound (Ib)
Adding 2.0mmol of 2-hydroxyacetophenone (1), 10mmol of corresponding dibromoalkylamine compound (3), 5mmol of anhydrous potassium carbonate and 20ml of acetonitrile into a reaction bottle, uniformly stirring, heating, refluxing and stirring for reacting for 2.0-72 hours (tracking the reaction process by TLC); after the reaction is finished, the solvent is evaporated to dryness under reduced pressure, 80mL of deionized water is added, 200mL of dichloromethane is used for extraction for three times, organic layers are combined and washed by saturated sodium chloride, the mixture is dried and filtered by anhydrous sodium sulfate, the solvent is evaporated to dryness by the reduced-pressure bis 2-hydroxyacetophenone twin drug compound (Ib), and the residue is purified by column chromatography (petroleum ether: acetone: 100:1v/v) to obtain the corresponding bis 2-hydroxyacetophenone twin drug compound (Ib), the yield is 10-55%, and the chemical structures are all subjected to chemical structure extraction1H-NMR、13C-NMR and ESI-MS confirmation: the purities of the obtained target substances are more than 97 percent through HPLC. The target structure prepared by the above method is as followsThe following:
in the molecular structure of the bis-o-hydroxyacetophenone twin compound Ib, different Rs and different values of n are adopted for testing, and the molecular structure of the obtained compound is shown in Table 2 through ESI-MS.
Table 2: testing of different substituents and n value
EXAMPLE 3 general procedure for preparation of bis-o-hydroxyacetophenone twin compound (Ic)
Adding 2.0mmol of 2-hydroxyacetophenone (1), 10mmol of corresponding ethyl bromoalkanoate (4), 5mmol of anhydrous potassium carbonate and 20ml of acetonitrile into a reaction bottle, uniformly stirring, heating, refluxing and stirring for reacting for 2.0-72 hours (tracking the reaction process by TLC); after the reaction is finished, the solvent is evaporated to dryness under reduced pressure, 80mL of deionized water is added, 200mL of dichloromethane is used for extraction for three times, organic layers are combined and washed by saturated sodium chloride, the mixture is dried and filtered by anhydrous sodium sulfate, the solvent is evaporated to dryness by reduced pressure of the ferulic amide-O-alkyl acid ethyl ester, the residue is purified by column chromatography (petroleum ether: acetone is 100:1v/v) to obtain the corresponding ferulic amide-O-alkyl acid ethyl ester, then 20mL of methanol and 10mmol of 30% LiOH solution are added, after the TLC detection reaction is finished, adjusting pH to 2 with 10% HCl, precipitating light yellow solid, filtering, recrystallizing the filter cake with ethanol, to obtain a key intermediate, namely the ferulic amide-O-alkyl acid (5), and finally, adding 2.0mmol (5) of the intermediate, 2.0mmol (6) of diamine derivative, 3.0mmol EDCI, 3.0mmol HOBT and 10mL tetrahydrofuran into a reaction bottle, and stirring at room temperature for reaction for 24 hours (tracking the reaction process by TLC); after the reaction, the solvent was evaporated to dryness under reduced pressure, 80mL of deionized water was added, extraction was carried out three times with 200mL of methylene chloride, and the organic layers were combinedWashing with saturated sodium chloride, drying and filtering with anhydrous sodium sulfate, decompressing the bis 2-hydroxyacetophenone twin drug compound (Ic) to dryness, purifying the residue by column chromatography (petroleum ether: acetone: 100:1v/v) to obtain the corresponding bis 2-hydroxyacetophenone twin drug compound (Ic), with the yield of 30-75%, and the chemical structures are all obtained by1H-NMR、13C-NMR and ESI-MS confirmation: the purities of the obtained target substances are more than 97 percent through HPLC. The target prepared by the method has the following structure:
in the molecular structure of the bis-o-hydroxyacetophenone twin compound Ic, different R and different values of n are taken for testing, and the molecular structure of the obtained compound is shown in Table 3 through ESI-MS.
Table 3: testing of different substituents and n value
The bis-o-hydroxyacetophenone twin drug compound (I) obtained by the method contains amino in the molecule, the amino is basic, and pharmaceutically acceptable salts thereof can be prepared by any suitable acid through a pharmaceutically conventional salt forming method.
The pharmaceutical composition disclosed by the invention comprises one or more bis-o-hydroxyacetophenone twin compounds (I) or pharmaceutically acceptable salts thereof with a therapeutically effective amount, and the pharmaceutical composition can further contain one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of a drug or agent that elicits a biological or medicinal response in a tissue, system, or animal targeted by a researcher or physician; the composition refers to a product formed by mixing more than one substance or component; the "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or vehicle, such as: liquid or solid fillers, diluents, excipients, solvents or encapsulating substances, which carry or transport certain chemical substances. The ideal proportion of the pharmaceutical composition provided by the invention is that the bis-o-hydroxyacetophenone twin drug compound (I) or the pharmaceutically acceptable salt thereof is taken as an active ingredient and accounts for 2-99.5% of the total weight.
The bis-o-hydroxyacetophenone twin drug compound (I) or pharmaceutically acceptable salt thereof disclosed by the invention is subjected to the following biological activity screening.
(1) Inhibitory activity of bis-o-hydroxyacetophenone twin compound (I) on monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B)
Test of inhibitory Activity against MAO-A: taking 100 mu L of 225 mu M kynuramine solution, adding 100 mu L of compound solution to be detected with different concentrations and 300 mu L of MAO-A solution with 25 mu g/mL to ensure that the total volume of A reaction system is 500 mu L, uniformly mixing, incubating at 37 ℃ for 20min, adding 400 mu L of NaOH solution with 2mol/L and 1000 mu L of water to stop reaction, centrifuging at 16000g for 10min, taking supernatant, and measuring fluorescence intensity at an excitation wavelength of 310nm and an emission wavelength of 400 nm; dissolving 4-hydroxyquinoline in 500. mu.L of potassium phosphate buffer, adding 2mol/L of NaOH solution 400. mu.L and water 1000. mu.L, establishing a standard curve under the same conditions, plotting the initial rate of oxidation of kynuramine by GraphPad Prism against the logarithm of the concentration of the inhibitor, drawing a dose-dependent S-curve, and calculating the IC of the compound for inhibiting monoamine oxidase50The S-curve was plotted with at least six inhibitor concentrations of three different orders of magnitude, each experiment being independently repeated three times.
Compounds were tested for MAO-B inhibitory activity: the procedure was identical to MAO-A, except that kynuramine was added at A concentration of 150. mu.M, and the procedure and performance were unchanged.
The determination result shows that the bis 2-hydroxyacetophenone twin compound (I) disclosed in the embodiment of the invention has obvious inhibition effect on MAO-A and MAO-B, and IC thereof500.05-50 μ M and 0.05-50 μ M, respectively, while the IC of Rasagiline, A positive control drug, on MAO-B and MAO-A inhibition500.028. mu.M and 0.58. mu.M.
(2) Determination of complexation of bis-o-hydroxyacetophenone twin compound (I) and metal ions
Dissolving CuCl with methanol2.2H2O、ZnCl2、FeSO4.7H2O、AlCl3And a compound to be detected, preparing a solution of 75 mu mol/L, adding 100 mu L of the solution of the compound to be detected and 100 mu L of the metal ion solution into a 96-well plate, uniformly mixing, standing for 30 minutes at room temperature, recording an ultraviolet absorption curve within the range of 200-600nm on a multifunctional microplate reader, and observing the red shift phenomenon of the maximum absorption peak and the intensity of the maximum absorption peak of the mixed solution of the metal ion and the compound to be detected by taking 100 mu L of the solution of the compound to be detected and 100 mu L of methanol mixed solution as comparison. The determination result shows that the bis 2-hydroxyacetophenone twin compounds (I) disclosed in the embodiment of the invention all show strong complexation effect on metal ions.
(3) Antioxidant activity of bis-o-hydroxyacetophenone twin compounds (I) (ORAC-FL method)
6-hydroxy-2, 5,7, 8-tetramethyl chromane-2-carboxylic acid (Trolox) is prepared into 10-80. mu. mol/L solution by using PBS buffer solution with pH7.4, fluorescein (florescensin) is prepared into 250nmol/L solution by using PBS buffer solution with pH7.4, and 2, 2' -azobisisobutylamidine dihydrochloride (AAPH) is prepared into 40mmol/L solution by using PBS buffer solution with pH7.4 before use. Adding 50-10 mu mol/L compound solution and fluorescein solution into a 96-well plate, mixing uniformly, incubating for 15min at 37 ℃, adding AAPH solution to make the total volume of each well 200 mu L, mixing uniformly, immediately placing in a Varioskan Flash Multimode Reader, and continuously measuring for 90min under 485nm excitation wavelength and 535nm emission wavelength. And calculating the area AUC under the fluorescence attenuation curve, wherein 1-8 mu mol/L Trolox is taken as a standard, a blank is taken without adding a Sample to be tested, the antioxidant activity result of the compound is expressed as the equivalent of the Trolox, the calculation formula is [ (AUC Sample-AUC blank)/(AUC Trolox-AUC blank) ]/[ (concentration of Trolox/concentration of Sample) ], each compound is measured for 3 replicate holes, and each group of experiments is independently repeated for three times. The determination result shows that the antioxidant activity disclosed in the embodiment of the invention is 1.0-5.0 times of that of Trolox, which indicates that the compound has strong antioxidant activity.
(4) The bis-o-hydroxyacetophenone twin drug compound (I) prepared by the invention is H pair2O2Screening for protective Effect of induced PC12 cell injury
PC12 cells were cultured in DMEM containing 10% calf serum at 1X 105Inoculating the culture medium at a density of 100 mL/well on a 96-well culture plate, and then adding a medium containing 5% CO2Culturing in a constant temperature incubator at 37 ℃. After 24 hours of incubation, the corresponding concentration of compound (final concentration 10) was added to the group administered-5mol/L，10-6mol/L)10 mL/well, preincubated for 2 hours (10. mu.L/well PBS was added to the control and lesion groups, respectively, to keep their volumes equal). After PC12 cells were incubated for 2 hours, 100 μm of H was added to the administration group and the injured group, respectively2O2The wound healing agent was added at 10. mu.L/well (10. mu.L/well PBS to the control group), and after 30 minutes, the culture medium of each group was changed to RPMI1640 culture medium without calf serum, and the culture medium was cultured in a constant temperature incubator for 24 hours, and the volume of the culture medium was considered to be 100. mu.L/well. After further incubation for 24 hours, each group was stained for viable cells by adding 5mg/mL MTT 100. mu.L/well. After 3 hours, 100 μ L of 100% DMSO stop buffer was added to each group, and the mixture was dissolved and mixed well. OD values were measured at 490nm for each group, and the test results were repeated 3 times and counted by Duncan's test method, and the values of each group are expressed as mean ± s.e.m., based on 100% of the control group, and the values of the administration group and the injured group are expressed as percentages of the control group.
The results of the assay show that the compounds disclosed in the examples of the present invention are 10-4mol/L～10-7The protective effect on the PC12 cell injury induced by the hydrogen peroxide is obvious under the mol/L concentration.
(5) The bis-o-hydroxyacetophenone twin drug compound (I) prepared by the invention is paired with Abeta1-42Screening for protective Effect of induced SH-SY5Y cell Damage
SH-SY5Y cells were cultured in 100U.mL of 10% fetal bovine serum-1DMEM complete medium of penicillin, 100mg.L-1 streptomycin at 37 ℃ with 5% CO2Culturing in a constant-temperature incubator. And 2d, carrying out passage once, and taking cells in a logarithmic growth phase for testing. Abeta 1-42 is dissolved in buffer solution and incubated at 4 ℃ for 48h for aging. SH-SY5Y with 1X 105Inoculating the cells/mL in a 96-well culture plate at a density of one cell/mL, incubating at 37 ℃ for 12h, changing a blank control group cell culture solution into a serum-free DMEM culture solution, continuously incubating for 48h after the model group and the compound group to be tested use the serum-free DMEM culture solution containing 5 mu mol.L-1, adding 5mg/mL and MTT solution into each group, incubating at 37 ℃ for 4h, removing the culture medium, adding 150 mu LDMSO into each well, fully dissolving and uniformly mixing. OD values were measured at 490nm for each group, and the test results were repeated 3 times and counted by Duncan's test method, and the values of each group are expressed as mean ± s.e.m., based on 100% of the control group, and the values of the administration group and the injured group are expressed as percentages of the control group.
The results of the assay show that the compounds disclosed in the examples of the present invention are 10-4mol/L～10-7For Abeta at mol/L concentration1-42The induced SH-SY5Y cell injury has obvious protective effect.
(6) The influence of the bis-o-hydroxyacetophenone twin compound (I) on cognitive dysfunction in an A beta-induced rat dementia model.
Wistar rats (10 weeks old) weigh about 280, and are randomized: control group and dementia model group, animals in the dementia model group were anesthetized with sodium pentobarbital (40mg/kg, i.p.), fixed on I-C type rat stereotaxic apparatus, sterilized conventionally, skin was incised, bregma was exposed, and aggregate Abeta was slowly injected into left hippocampal area of rat with microsyringe1-425.0 μ L, leave the needle for 5 minutes to allow the A β to diffuse sufficiently, and then slowly withdraw the needle to suture the wound. The control group was given an equal volume of saline. On the day of a β injection, the dementia-molding group rats were randomly divided into 5 groups: model group, high (8mg/kg), medium (4mg/kg), low (2mg/kg), dosage group and positive control group of donepezil (5mg/kg), 8 per group, and intragastric administration (equal volume of solvent is given to control group and model group) for 1 time in 1 day for 4 weeks; the learning and memory capacity of rats was measured by Morris water maze procedure at week 3 of the administration. The measurement result shows that the latent period of the Morris water maze test of the dementia model group is obviously prolonged compared with the control group (P)<0.01); the latency of the drug high and medium dose group is significantly shortened (P) compared with that of the dementia model group<0.01), whereas the drug low dose group and donepezil group had a somewhat shortened tendency of latency without significant difference (P) compared to the dementia model group<0.05)。
(7) The SPF grade ICR male mice affected by the bis-o-hydroxyacetophenone twin compound (I) on mouse memory acquisition disorder caused by scopolamine are 25-30g, and are randomly divided into: normal group, model group, test drug high and low dose groups (5.0, 2.5mg/kg), 10 animals per group. The tested medicine is given by one-time intragastric administration, the solvent of 0.5 percent CMC-Na is given to the blank group and the model group, and the administration volumes are both 0.1ml/10 g; injecting normal saline into abdominal cavity of normal group mice 45min after administration, and injecting scopolamine (5mg/kg) into other groups of animals, wherein the administration volume is 0.1ml/10 g; after 30min of molding, the mice were placed in the non-electrostimulated Y maze for behavioral testing. During testing, a mouse is placed at the tail end of one arm, the mouse freely passes through the maze for 8min, the times of entering each arm and the alternation times are recorded, and the alternation rate is calculated according to the following formula: the alternation rate is [% alternation/(total number of entries-2) ] × 100, the results are expressed as mean ± standard deviation, and the differences between groups are analyzed by one-way variance.
The test result shows that under the experimental condition, the compound disclosed by the invention has a dose-dependent improvement effect on acquiring dysmnesia of mice caused by scopolamine, and has statistical difference (p is less than 0.01) compared with a model group.
The above embodiments are illustrative, and the scope of the present invention is not limited thereto. It will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention, and such changes and modifications are intended to be within the scope of the invention.
Claims (9)
1. A bis-o-hydroxyacetophenone twin drug compound is characterized in that the chemical structure general formula is as follows:
wherein R represents-OH, -F, -Cl, -Br, -I, C1-4Alkyl radical, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, nitro andany one of cyano substituents;
linker is (CH)2)n、[(CH2)nNH(CH2)n]m or (CH)2)nCONH(CH2)nNHCO(CH2) n, wherein n and m are both 1-12.
2. The method for preparing the bis-o-hydroxyacetophenone twin compound as claimed in claim 1, wherein: the preparation method comprises the following steps:
the method I comprises the following steps of taking a 2-hydroxyacetophenone derivative as a starting material, and reacting the starting material with a dibromo compound under the alkaline condition formed by adding alkali into a solvent to obtain a bis-o-hydroxyacetophenone twin drug compound (I-a), wherein the chemical reaction equation is as follows:
in the second method, a 2-hydroxyacetophenone derivative is used as an initial raw material and reacts with dibromoalkylamine under the alkaline condition formed by adding alkali in a solvent to obtain a product bis-2-hydroxyacetophenone twin drug compound (I-b), and the chemical reaction equation is as follows:
taking a 2-hydroxyacetophenone derivative as a starting material, reacting with ethyl bromoalkanoate under the alkaline condition formed by adding alkali in a solvent, then performing hydrolysis reaction under the alkaline condition formed by adding alkali, adjusting the pH to be =2 to obtain a 2-hydroxyacetophenone-O-alkyl acid derivative, and reacting with alkyldiamine under the condition of a condensing agent to obtain a product, namely a bis 2-hydroxyacetophenone twin drug compound (I-c), wherein the chemical reaction equation is as follows:
wherein n and/or m in the molecule of the dibromo compound, the dibromoalkylamine, the ethyl bromoalkanoate and the alkyl diamine are 1-12.
3. The method for preparing the bis-o-hydroxyacetophenone twin compound as claimed in claim 2, wherein: the solvent is C3-8Aliphatic ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C1-6Fatty acids with C1-6Ester formed by fatty alcohol, one or more of dichloromethane, chloroform, 1, 2-dichloroethane, benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, dimethyl sulfoxide and pyridine.
4. The method for preparing the bis-o-hydroxyacetophenone twin compound as claimed in claim 2, wherein: the alkali used in the alkaline condition is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal or alkaline earth metal bicarbonate, C1-6Fatty acid alkali metal salt, piperidine, tetrahydropyrrole, triethylamine, tributylamine, trioctylamine, pyridine, and the like,N-methylmorpholine,NOne or more of methylpiperidine, triethylenediamine and tetrabutylammonium hydroxide.
5. The method for preparing the bis-o-hydroxyacetophenone twin compound as claimed in claim 2, wherein: the condensing agent is one or more of EDCI, HOBT, DCC, DMAP and Carter condensing agents.
6. The method for preparing the bis-o-hydroxyacetophenone twin compound as claimed in claim 2, wherein: in the first method, the molar ratio of the 2-hydroxyacetophenone derivative to the dibromo compound to the alkali is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20 ℃ to 130 ℃, and the reaction time is 1-72 hours;
in the second method, the molar ratio of the 2-hydroxyacetophenone derivative to the dibromoalkylamine compound to the alkali is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20-130 ℃, and the reaction time is 1-72 hours;
in the third method, the molar ratio of the 2-hydroxyacetophenone derivative to the ethyl bromoalkanoate to the alkali is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20-130 ℃, and the reaction time is 1-72 hours; the molar ratio of the 2-hydroxyacetophenone-O-alkyl acid to the alkyl diamine to the condensing agent is 1.0:1.0-50.0:1.0-100.0, the reaction temperature is-20 ℃ to 130 ℃, and the reaction time is 1-72 hours.
7. A pharmaceutical composition characterized by: the bis-o-hydroxyacetophenone twin compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, together with one or more pharmaceutically acceptable carriers or excipients.
8. A pharmaceutical composition according to claim 7, wherein: the pharmaceutically acceptable salt is a bis-o-hydroxyacetophenone twin drug compound, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and C1-6Fatty carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C1-6Alkyl sulfonic acid, camphor sulfonic acid, benzene sulfonic acid or p-toluene sulfonic acid.
9. Use of the bis-o-hydroxyacetophenone twin compound according to claim 1 in the preparation of a medicament for the treatment and/or prevention of neurodegenerative-related diseases.
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| GB1340512A (en) * | 1970-01-21 | 1973-12-12 | Fisons Ltd | Production of esters of chromone-2-carboxylic acids |
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| GB1340512A (en) * | 1970-01-21 | 1973-12-12 | Fisons Ltd | Production of esters of chromone-2-carboxylic acids |
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