CN115974854A - Phenolenyl phthalide pyrazolones compound and preparation method and application thereof - Google Patents
Phenolenyl phthalide pyrazolones compound and preparation method and application thereof Download PDFInfo
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- CN115974854A CN115974854A CN202310109772.8A CN202310109772A CN115974854A CN 115974854 A CN115974854 A CN 115974854A CN 202310109772 A CN202310109772 A CN 202310109772A CN 115974854 A CN115974854 A CN 115974854A
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- compound
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- pyrazolones
- phthalide
- phenolalkenylphthalein
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Abstract
The invention discloses a phenol alkenyl phthalide pyrazolone compound (I), a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing related diseases of a nervous system, wherein the compounds include but are not limited to vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, lewy body dementia, parkinson disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, nerve injury and other diseases caused by brain trauma;
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a phenolalkenylphthalein pyrazolone compound (I), a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing related diseases of a nervous system, wherein the related diseases of the nervous system comprise vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, lewy body dementia, parkinson disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and other diseases.
Background
Neurodegenerative diseases refer to a general term for diseases caused by chronic progressive degeneration of central nervous tissue, including Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's Disease (HD), amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and the pathogenesis of which is closely related to oxidative stress, neuroinflammation, and corresponding injury. Oxidative stress is mediated by Reactive Oxygen Species (ROS) radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, among others. Under normal physiological conditions, the ROS production level and the body antioxidant capacity are in a dynamic balance state, when the ROS production exceeds the cell antioxidant capacity, oxidative stress (Oxidative stress) occurs, and the brain is particularly sensitive to the Oxidative stress, so that various nervous system diseases are induced. In addition, researches show that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like are closely related to oxidative stress and neuroinflammation of the body.
Vascular Dementia (VD) is a clinical syndrome of intellectual and cognitive dysfunction caused by various types of cerebrovascular diseases, including ischemic cerebrovascular diseases, hemorrhagic cerebrovascular diseases, acute and chronic hypoxic cerebrovascular diseases, etc. Due to the complex pathogenesis of vascular dementia, no medicine capable of blocking the disease development exists at present, and the clinical treatment mainly aims at improving the blood circulation and the brain metabolism of the brain and strengthening the brain nutrition.
Alzheimer's disease (senile dementia, AD) is a degenerative disease of the central nervous system mainly involving progressive cognitive impairment and memory impairment, and its incidence rate is on the rise year by year, and it is a high-grade disease second to cardiovascular disease and cancer. With the accelerated aging process of the global population, the incidence rate of the disease is in a remarkably rising trend. It is estimated that more than 5000 million people suffer from dementia worldwide, the total amount of treatment and care cost exceeds 1 trillion dollars in 2018, and the number of patients will increase to 1.52 billion by 2050. Because AD is clinically manifested as hypomnesis, orientation ability, thinking and judgment ability, reduction of daily life ability, even abnormal mental behavior symptoms, and the like, the nursing difficulty of patients is large, and the heavy burden is brought to the society and families. Currently approved drugs for the treatment of light/moderate AD are acetylcholinesterase (AChE) inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists for the treatment of severe AD. Clinical application shows that the medicines can relieve AD symptoms by improving the acetylcholine level in a patient body or inhibiting excitotoxicity of excitatory amino acid, but cannot effectively prevent or reverse the course of disease, and can cause severe toxic and side effects such as hallucinations, consciousness chaos, dizziness, nausea, hepatotoxicity and the like, so that the long-term curative effect is not ideal. Therefore, there is an urgent clinical need to develop a novel therapeutic agent for AD that has both improved symptoms and altered course of disease.
AD is a disease caused by various factors, the pathogenesis of the AD is complex, and the pathogenesis of the AD is not completely clarified so far. However, the research shows that the patient has decreased acetylcholine level in brain, excessive generation and deposition of beta-amyloid protein, and platelet aggregation in cerebral blood vesselsDisorder of metabolism of metal ions and Ca 2+ 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 found a large number of drugs with high activity and high selectivity to a target by using the traditional "one drug one target" drug design strategy, such as: cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and the like. However, 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.
Currently, two Monoamine oxidases (Monoamine oxidases) have been identified and characterized in humans, including the two MAO-A and MAO-B subtypes, which are primarily responsible for the oxidative deamination of biogenic amines and Monoamine neurotransmitters, such as 5-hydroxytryptamine, dopamine, norepinephrine and phenylethylamine, to regulate their concentration and metabolism in brain and surrounding tissues. MAO-B is mainly distributed in the mitochondrial outer membrane of glial cells, takes Flavin Adenine Dinucleotide (FAD) as a coenzyme factor, and is a main enzyme for oxidative deamination of dopamine in the brain. In recent years, the expression level of MAO-B in the brain of AD or PD patients is abnormally increased, and the enzyme can not only destroy cholinergic neurons and promote the generation of Abeta plaques and neurofibrillary tangles, but also obviously reduce the dopamine content in the brain; in addition, H is also produced simultaneously with catalytic deamination of MAO-B 2 O 2 H is generated 2 O 2 Can be combined with endogenous Cu 2+ 、Fe 2+ The plasma generates hydroxyl radicals through Fenton reaction (Fenton reaction), and the hydroxyl radicals can damage lipid, protein and nucleic acid, thereby causing mitochondrial dysfunction and finally causing death of cerebral neuron cells. Therefore, the effect of inhibiting the deamination of MAO-B can not only improve the content of dopamine in brain, but also achieve the effects of resisting oxidative stress and protecting nerves by reducing the generation of free radicals and active oxygen; in addition, research finds that the MAO-B inhibition can also increase the content of phenethylamine in brain, and the release of dopamine and the inhibition of dopamine can be stimulated by the phenethylamineAnd (4) reuptake. Therefore, the discovery of selective inhibitors of MAO-B is of great interest for the treatment and/or prevention of neurological related diseases.
In recent years, with the continuous elucidation of the pathogenic mechanism of neurodegenerative diseases, the occurrence and development of neurodegenerative diseases are found to have the characteristics of multi-mechanism and multi-factor action, and different mechanisms are mutually associated and influenced, so that a complex network regulation and control system in the occurrence and development process of the diseases is formed. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of neurodegenerative diseases is the current necessity. Based on the above results, researchers have proposed a "multi-target-directed drug" strategy to develop anti-neurodegenerative 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 each single effect. The main differences between the multi-target 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 development of a neurodegenerative disease-resistant therapeutic drug having a novel chemical structure, a novel action mechanism, a multi-target action and low toxic and side effects is an important direction at present.
Disclosure of Invention
The invention aims to disclose a phenol alkenyl phthalide pyrazolone compound (I).
The invention also aims to disclose a preparation method of the phenol alkenyl phthalide pyrazolone compound (I).
The invention also aims to disclose a pharmaceutical composition containing the phenolalkenylphthalein pyrazolone compound (I).
The invention also aims to disclose that the phenolalkenylphthalein pyrazolone compound (I) has multi-target effect and can be used for preparing medicines for treating and/or preventing related diseases of the nervous system, including but not limited to vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, lewy body dementia, parkinson disease, huntington disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like.
The general chemical structure formula of the phenolalkenyl phthalein pyrazolones compound (I) disclosed by the invention is as follows:
in the formula: x represents O, S or NH; r 1 Is propargyl or C 2 ～C 12 Alkenyl, wherein the olefinic bond in the alkenyl is at R 1 Any possible position of (a), but the 3-position of the phthalide parent nucleus is a saturated carbon; r is 2 And R 3 Each independently represents H, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, CF 3 、CF 3 O、R 4 CONH, CN or NR 5 R 6 These substituents are at any possible position on the phenyl ring on which the ortho-hydroxyphenyl group is located; r 4 Is represented by C 1-4 An alkyl group; r is 5 And R 6 Each independently represents H or C 1-4 An alkyl group; NR (nitrogen to noise ratio) 5 R 6 Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; the compound is in R configuration, S configuration or a mixture of R and S configurations in any proportion; the "halogen" refers to F, cl, br or I.
The phenol alkenyl phthalide pyrazolone compound (I) disclosed by the invention can be prepared by the following method: taking a corresponding 4-hydroxy benzopyran-2-ketone compound (1) as an initial raw material, and reacting the initial raw material with a racemic or chiral 6-hydrazino-3-substituted phthalide compound (2) in a solvent to obtain a phenolalkenyl phthalide pyrazolone compound (I); the reaction formula is as follows:
in the formula: x, R 1 、R 2 And R 3 Definition of (1) and phenolalkenylphthalein pyrazolonesThe chemical structural general formulas of the compounds (I) are the same.
For the above synthetic route, the specific preparation method is described as follows:
the solvent used in the reaction is: c 1-6 Fatty alcohol, C 1-6 Fatty acid, C 1-6 Fatty acids with C 1-6 Esters formed from fatty alcohols, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, benzene, toluene, xylene or chlorobenzene, preferably in the form of solvents: n, N-dimethylformamide, toluene, xylene or chlorobenzene; 4-hydroxybenzopyran-2-ones (1): the molar charge ratio of the 6-hydrazino-3-substituted phthalide compound (2) is 1.0: 1.0-5.0, and the preferable molar feed ratio is 1.0:1.0 to 2.0; the reaction temperature is between room temperature and 180 ℃, and the preferable reaction temperature is between 80 and 140 ℃; the reaction time is 1 to 72 hours, preferably 4 to 30 hours.
The starting materials of the present invention, 4-hydroxybenzopyran-2-ones (1) and 6-hydrazino-3-substituted phthalides (2), can be prepared by techniques common in the art, including but not limited to the methods disclosed in the following documents: 1. k.a. nolan, et al.j.med.chem.2009,52,7142-7156; 2. x.qiang, et al.bioorg.med.chem.lett.2017,27,718-722.
The pharmaceutical composition disclosed by the invention comprises one or more phenolalkenylphthalein pyrazolones (I) 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 pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, or animal targeted by a researcher or physician; the term "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 phenol alkenyl phthalide pyrazolone compound (I) as an active component accounts for 2-99.5% of the total weight.
The invention discloses a phenol alkenyl phthalide pyrazolone compound (I) which is subjected to the following biological activity screening:
(1) Inhibitory activity of phenolalkenylphthalein pyrazolones (I) on monoamine oxidase B
Recombinant human MAO-B was prepared in 75. Mu.g/mL sample using 100mM potassium phosphate buffer, pH 7.4. Adding 20 mu L of a compound solution to be detected and 80 mu L of monoamine oxidase into a black 96 pore plate, uniformly mixing, incubating for 15min at a dark place at 37 ℃, adding 200 mu M Amplex Red reagent, 2U/mL horseradish peroxidase and 2mM benzylamine to initiate reaction, incubating for 20min at 37 ℃, and measuring the fluorescence emission intensity at 590nm on a multifunctional microplate reader by using a fixed excitation wavelength of 545nm, wherein potassium phosphate buffer solution is used for replacing MAO-B as a blank; the inhibition rate of the compound for inhibiting monoamine oxidase is calculated by the following formula: 100- (IF) i )/(IF c ) 100 of the formula, IF i And IF c The difference between the fluorescence intensity in the presence and absence of inhibitor and the fluorescence intensity of the blank, respectively. Each compound was assayed in 3 replicates each, each experiment being independently repeated three times. Selecting five to six concentrations of the compound, measuring the enzyme inhibition rate, performing linear regression by using the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate, and obtaining the molar concentration when the 50% inhibition rate is obtained as the IC of the compound 50 . The determination result shows that the phenolalkenyl phthalein pyrazolones (I) disclosed in the embodiment of the invention have obvious inhibition effect on MAO-B, and IC thereof 50 0.06. Mu.M to 23.2. Mu.M (for example, 0.18. Mu.M for example compounds 1-1 to 13, 0.91. Mu.M for example compounds 1-2 to 13, and 1.57. Mu.M for example compounds 1-3 to 13); further research on structure-activity relationship discovers that 'OH' on a benzene ring where an o-hydroxyphenyl group is located in a molecule of the phenol-based alkenyl phthalide pyrazolone compound (I) is replaced by 'H', the MAO-B inhibitory activity of the obtained corresponding compound is greatly reduced, and IC (integrated Circuit) is shown 50 The values were all greater than 30. Mu.M.
(2) Anti-platelet aggregation activity of phenolalkenyl phthalein pyrazolone compound (I)
3 male rabbits were taken, locally anesthetized with lidocaine, and blood was taken from total carotid artery by surgical separation, and 3.8% sodium citrate 1:9 anticoagulating, centrifuging at 500r/min for 10min to obtain Platelet Rich Plasma (PRP), centrifuging the rest at 3000r/min to obtain Platelet Poor Plasma (PPP), and performing platelet aggregation experiment by turbidimetry. Adding 240 mu L of PRP and 30 mu L of test drugs with different concentrations into a measuring tube, incubating for 5 minutes, respectively taking 30 mu L of Adenosine Diphosphate (ADP) (the final concentration is 10 mu mol/L) as an inducer, and observing and recording the maximum aggregation rate within 5 minutes; the inhibition (%) of each test compound was calculated using physiological saline (NS) as a control. The determination result shows that the phenol alkenyl phthalide pyrazolone compound (I) disclosed in the embodiment of the invention has a remarkable inhibition effect on platelet aggregation induced by ADP, the inhibition rate of the compound is 30.5-83.6% at the concentration of 33.0 mu M, and the inhibition rate of the compound is more than 50.0% at the concentration of 100.0 mu M; the positive controls butylphthalide and aspirin were 9.3% and 12.5% inhibition at a concentration of 33.0 μ M, respectively.
(3) Antioxidant activity of phenolalkenylphthalein pyrazolones (I) (ORAC-FL method)
The measurements were carried out with reference to the methods reported in the literature (Qiang, X.M.et al.Eur.J Med.chem.2014,76, 314-331), namely: 6-hydroxy-2, 5,7, 8-tetramethylchromane-2-carboxylic acid (Trolox) was made into a solution of 10-80. Mu. Mol/L with PBS buffer solution of pH7.4, fluorescein (fluorescein) was made into a solution of 250nmol/L with PBS buffer solution of pH7.4, and 2,2' -azobisisobutylamidine dihydrochloride (AAPH) was made into a solution of 40mmol/L with PBS buffer solution of pH7.4 before use. The compound solution and the fluorescein solution were added to a 96-well plate at 50-10. Mu. Mol/L, mixed well, incubated at 37 ℃ for 15min, and AAPH solution was added to make the total volume per well 200. Mu.L, mixed well, immediately placed in a Varioskan Flash Multimode Reader (Thermo Scientific) instrument, and continuously measured at 485nm excitation wavelength and 535nm emission wavelength for 90min. Calculating the area AUC under the fluorescence attenuation curve, wherein 1-8 mu mol/L Trolox is used as a standard, a sample to be detected is not added as a blank, the antioxidant activity result of the compound is expressed as the equivalent of the Trolox, and the calculation formula is as follows: [ (AUC Sample-AUC blank)/(AUC Trolox-AUC blank) ] × [ (concentration of Trolox/concentration of Sample) ], 3 replicates per compound were assayed, each experiment being independently repeated three times. The determination result shows that the antioxidant activity of the phenolalkenyl phthalein pyrazolone compound (I) disclosed in the embodiment of the invention is 0.96-3.6 times of that of Trolox, which indicates that the compound has stronger antioxidant activity. Further research finds that 'OH' on a benzene ring where an ortho-hydroxyphenyl group is located in a molecule of the phenol-based alkenyl phthalide pyrazolone compound (I) in the embodiment is replaced by 'H', so that the antioxidant activity of the obtained corresponding compound is remarkably reduced, and the antioxidant activity of the corresponding compound is at least reduced by 1.5-6.0 times, which indicates that the 'OH' on the benzene ring where the ortho-hydroxyphenyl group is located has a serious influence on the antioxidant activity of the compound; in addition, the research also finds that the chiral center of the phenol alkenyl phthalide pyrazolone compound (I) has no influence on the antioxidant activity of the compound.
(4) Complexation of phenolalkenylphthaleinpyrazolone compound (I) with metal ions
Dissolving CuCl with methanol 2 ·2H 2 O、ZnCl 2 、FeSO 4 、AlCl 3 And a to-be-detected compound, preparing a solution of 75 mu mol/L, adding 100 mu L of the to-be-detected compound solution and 100 mu L of the metal ion solution into a 96-well plate, uniformly mixing, standing for 30min at room temperature, recording an ultraviolet absorption curve of the mixture in a range of 200-600nm on a Varioskan Flash Multimode 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 to-be-detected compound by taking 100 mu L of the to-be-detected compound solution and 100 mu L of methanol mixed solution as references. The determination result shows that the phenolalkenyl phthalein pyrazolone compound (I) disclosed in the embodiment of the invention has a complexing effect on the metal ions; and the 'OH' on the benzene ring of the ortho-hydroxyphenyl group in the structure is replaced by 'H', and the obtained corresponding compound has almost no complexing effect with the metal ions (the maximum absorption peak intensity of the mixed solution of the compound to be detected and the metal ions has no obvious change, and the maximum absorption peak has no red shift phenomenon). The research shows that the 'OH' on the benzene ring of the ortho-hydroxyphenyl group has obvious influence on the metal ion complexing action of the compound.
(5) Inhibitory Activity of Phenolenylphthalide pyrazolones (I) on neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Preparing BV-2 cells in logarithmic growth phaseInoculating the cell suspension into a 96-well plate, setting at 37 ℃,5% CO 2 Culturing for 24h in a cell culture box, changing to 90 μ L of fresh serum-free culture solution after the cells adhere to the wall, respectively adding 10 μ L of each concentration compound to be tested, pre-incubating for 30min, and setting a blank control group for each concentration of 3 parallel holes; then with or without LPS at 37 ℃ and 5% CO 2 Continuously culturing for 24h in a cell culture box, adding MTT solution, incubating for 4h at 37 ℃, discarding supernatant, adding 200 mu L DMSO solution into each hole, slightly oscillating for 10min, measuring OD (optical density) at 490nm by using an enzyme-labeling instrument, calculating the average value of OD (optical density) values measured by different concentrations of each tested sample, and calculating the cell survival rate according to the following companies: cell survival (%) = administration group OD mean/control group OD mean × 100%. The test result shows that all the phenol alkenyl phthalide pyrazolones (I) disclosed in the embodiment of the invention do not show cytotoxicity (the inhibition rate is less than that of the compound) under the concentration of not more than 25 mu M<10％)。
(b) Influence of phenol alkenyl phthalide pyrazolones (I) on NO release of BV-2 cells induced by LPS
Preparing BV-2 cells in logarithmic growth phase into cell suspension, inoculating into 96-well plate, placing at 37 deg.C, and 5% CO 2 Culturing for 24h in a cell culture box, changing to 90 μ L of fresh serum-free culture solution after the cells adhere to the wall, respectively adding 10 μ L of each concentration compound to be tested, pre-incubating for 30min, and setting a blank control group for each concentration of 3 parallel holes; then stimulated with LPS (1.0. Mu.g/ml), set at 37 ℃ and 5% CO 2 And (3) continuously culturing for 24h in the cell culture box, taking cell culture supernatants of different treatment groups, adding a Griess reagent I with the same volume and a Griess reagent II with the same volume, carrying out a dark reaction at room temperature for 10min, and measuring absorbance at 540nm to detect the level of NO in the cell supernatants (the specific operation is carried out according to the instruction of the NO detection kit). Test results show that all the phenolalkenylphthalein pyrazolones (I) disclosed in the embodiment of the invention show stronger inhibition on the generation of BV-2 cell NO induced by LPS (the inhibition rate at the concentration of 5.0 mu M is more than 32.3%) in the concentration range of 0.5 mu M to 25 mu M, and have obvious dose-effect relationship; indicating that the compound (I) has remarkable anti-neuritis activity.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
Example 1 general procedure for the preparation of Phenolenylphthalide pyrazolones (I)
Adding corresponding 4-hydroxybenzopyran-2-ketone compound (1) (2.0 mmol), 6-hydrazino-3-substituted phthalide compound (2) (3.0 mmol) and toluene (60 ml) into a reaction bottle, and then heating, refluxing and stirring for reaction for 4.0-24.0 hours (tracking the reaction process by TLC); after the reaction is finished, the solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane-ethyl acetate =20: 1v/v), so that the corresponding phenol alkenyl phthalide pyrazolone compound (I) is obtained, the yield is 35.7% -66.5%, and the chemical structures are all purified by a chromatographic column 1 H-NMR、 13 The purity of the target substance is more than 96.0 percent by HPLC determination through C-NMR and ESI-MS confirmation. The target prepared by the method has the following structure:
of partial compounds 1 The H-NMR data are as follows:
1 HNMR(DMSO-d 6 ):12.50(brs,1H),10.16(s,1H),8.24(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),8.17(s,1H),7.88(d,J＝8.4Hz,1H),7.29(d,J＝2.4Hz,1H),6.88-6.82(m,2H),6.25(s,1H),5.83(t,J＝8.4Hz,1H),3.76(s,3H),3.06(m,2H),2.83(s,1H)；
1 HNMR(CDCl 3 ):9.44(s,1H),8.25(s,1H),8.13(d,J＝8.4Hz,1H),7.47(d,J＝9.4Hz,1H),6.94(s,2H),6.66(s,1H),5.75-5.65(m,1H),5.48(t,J＝6.0Hz,1H),5.15-5.09(m,2H),3.91(s,2H),3.74(s,3H),2.17-2.59(m,2H)；
1 HNMR(CDCl 3 ):9.51(s,1H),8.30(s,1H),8.20(dd,J 1 ＝8.4 Hz,J 2 ＝2.0 Hz,1H),7.50(d,J＝8.4Hz,1H),7.03-6.97(m,2H),6.71(s,1H),5.84-5.74(m,1H),5.51-5.48(m,1H),5.01-4.93(m,2H),3.97(s,2H),3.80(s,3H),2.07-2.02(m,3H),1.84-1.73(m,1H),1.52-1.38(m,6H)；
1 HNMR(CDCl 3 ):9.51(s,1H),8.31(s,1H),8.14(d,J＝8.4 Hz,1H),7.59(d,J＝8.4 Hz,1H),7.04-6.98(m,2H),6.73(s,1H),5.93-5.86(m,1H),5.25(s,1H),5.22-5.11(m,2H),3.97(s,2H),3.81(s,3H),1.28(s,3H),0.97(s,3H)；
1 HNMR(DMSO-d 6 ):12.59(s,1H),10.46(s,1H),8.21(s,1H),8.19(s,1H),7.75(d,J＝8.0 Hz,1H),7.54(s,1H),7.02(d,J＝8.0 Hz,1H),6.82(d,J＝8.0 Hz,1H),6.14(s,1H),5.89-5.82(m,1H),5.55(s,1H),5.15-5.07(m,2H),2.27(s,3H),1.19(s,3H),0.99(s,3H)；
1 HNMR(CDCl 3 ):9.84(s,1H),8.25(s,1H),8.08(d,J＝8.4 Hz,1H),7.53(d,J＝8.4 Hz,1H),7.34(t,J＝8.0 Hz,1H),7.18(s,1H),7.02(s,1H),6.92(t,J＝7.6 Hz,1H),5.86-5.79(m,1H),5.18(s,1H),5.15-5.04(m,2H),3.94(s,2H),1.21(s,3H),1.18(s,3H)。
Claims (9)
1. a kind of phenol group alkenyl phthalide pyrazolone compounds is characterized in that the chemical structural general formula of the compounds is shown as (I):
in the formula: x represents O, S or NH; r 1 Is propargyl, C 2 ～C 12 Alkenyl, wherein the olefinic bond in the alkenyl is at R 1 Any possible position of (a), but the 3-position of the phthalide parent nucleus is a saturated carbon; r 2 And R 3 Each independently represents H, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, CF 3 、CF 3 O、R 4 CONH, CN or NR 5 R 6 These substituents are in any possible position on the phenyl ring in which the ortho-hydroxyphenyl group is located; r is 4 Is represented by C 1-4 An alkyl group; r is 5 And R 6 Each independently represents H or C 1-4 An alkyl group; NR (nitrogen to noise ratio) 5 R 6 Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; the compound is in an R configuration, an S configuration or a mixture of the R configuration and the S configuration in any proportion; the "halogen" refers to F, cl, br or I.
2. The phenolalkenylphthalein pyrazolones according to claim 1, wherein R is 1 Represents propargyl, allyl, 1-alkenylbutyl, 1-alkenylpentyl, 1-alkenylhexyl, 1-alkenylheptyl, 3-dimethyl-1-allyl.
3. The phenolalkenylphthalein pyrazolones according to claim 1, wherein R is 2 And R 3 Each independently represents H, F, cl, br, methyl, methoxy, CF 3 、CF 3 O、CH 3 CONH、CN、NH 2 、N(CH 3 ) 2 Tetrahydropyrrolyl, morpholinyl or piperidinyl.
4. A process for the preparation of phenolalkenylphthalein pyrazolones according to any of claims 1 to 3, characterized in that they are obtainable by:
in the formula: x, R 1 、R 2 And R 3 The definition of (a) is the same as the general formula of the chemical structure of the phenol alkenyl phthalide pyrazolone compound (I);
taking the corresponding 4-hydroxy benzopyran-2-ketone compound (1) as an initial raw material, and reacting with a racemic or chiral 6-hydrazino-3-substituted phthalide compound (2) in a solvent to obtain the corresponding phenolalkenyl phthalein pyrazolone compound (I).
5. The method for producing the phenolalkenylphthalein pyrazolones compound according to claim 4, wherein the solvent used in the reaction is: c 1-6 Fatty alcohol, C 1-6 Fatty acid, C 1-6 Fatty acids with C 1-6 Ester formed by aliphatic alcohol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, benzene, toluene and xyleneOr chlorobenzene.
6. The process for producing the phenolalkenylphthalein pyrazolones according to claim 4, wherein the 4-hydroxybenzopyran-2-ones compound (1): the molar charge ratio of the 6-hydrazino-3-substituted phthalide compound (2) is 1.0:1.0 to 5.0.
7. The method for producing the phenolalkenylphthalylphthalide pyrazolone compound according to claim 4, wherein the reaction temperature is room temperature to 180 ℃; the reaction time is 1 to 72 hours.
8. A pharmaceutical composition comprising the phenolalkenylphthalein pyrazolones according to any of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
9. Use of the phenolalkenylphthalein pyrazolones according to any one of claims 1 to 3 in the preparation of a medicament for the treatment and/or prevention of neurological diseases, such neurological diseases being: vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with Lewy bodies, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage due to brain trauma.
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| CN116003391A (en) * | 2023-02-14 | 2023-04-25 | 四川大学 | O-hydroxyphenylphthalazinone compound as well as preparation method and application thereof |
| CN116003391B (en) * | 2023-02-14 | 2024-07-09 | 四川大学 | O-hydroxyphenylphthalazinone compound as well as preparation method and application thereof |
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