CN108727352B - Piperidine alkane carbamoyl phthalide compounds, preparation method and application thereof - Google Patents
Piperidine alkane carbamoyl phthalide compounds, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel piperidine carbaldehyde phthalide compound (I) and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing neurodegenerative related diseases, wherein the novel piperidine carbaldehyde phthalide compound (I) and the pharmaceutically acceptable salts thereof comprise but are not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV (human immunodeficiency virus) -related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a novel piperidine carbaldehyde phthalide compound (I), a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing neurodegenerative related diseases, including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV (human immunodeficiency virus) -related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and the like.
Background
Alzheimer's disease (AD, senile dementia) is a degenerative disease of the central nervous system mainly caused by progressive cognitive impairment and memory impairment, and the incidence of Alzheimer's disease is on the rise year by year, and is a high-grade disease second to cardiovascular diseases and cancers, and is the fourth cause of death in advanced countries such as europe and america. According to the report of the world health organization, 10% of the elderly over 65 years old have intellectual disability, wherein one half of the elderly have dementia, and the incidence rate of the elderly over eighty-five years old is nearly 50%. The number of AD patients in China is about 600- > 700 thousands, and the morbidity exceeds 5%. With the accelerated aging process of the global population, the incidence rate of the Disease is in a clear rising trend, and according to the global influence of Alzheimer's Disease published in 2013 in 12 months by Alzheimer's Disease International: 2013-2050 reports indicate that AD will become the biggest health challenge worldwide for decades in the future, and by 2030, the number of patients will rise from 4400 ten thousand in 2013 to 7600 ten thousand, and by 2050, the number will reach 1.35 hundred million which is surprising. 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. An approved drug for the treatment of light/moderate AD is acetylcholinesterase(AChE) inhibitors, and for the treatment of severe ADN-methyl-D-an aspartate (NMDA) receptor antagonist. 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, headache, nausea, hepatotoxicity, inappetence, frequent defecation and the like, so that the long-term curative effect is not ideal. Therefore, the development of AD therapeutic drugs with a novel mechanism of action is urgently needed clinically.
AD is a disease caused by various factors, the pathogenesis of the AD is complex, the pathogenesis of the AD is not completely clarified so far, but researches show that the acetylcholine level in the brain of a patient is reduced,βOverproduction and deposition of amyloid, platelet aggregation in cerebral vessels, metabolic disorders of metal ions, Ca2+Imbalance of balance,tauNeurofibrillary tangles caused by protein hyperphosphorylation, glutamate receptor hyperactivity, large amounts of Reactive Oxygen Species (ROS) and free radicals produced by oxidative stress, and various factors such as neuroinflammatory responses play important roles 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 andN-methyl-DAspartate 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.
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 to form a complex network regulation and control system in the occurrence and development process of AD. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of AD is the current necessity. Based on the above results, researchers have proposed a "multi-target-directed drugs" (MTDLs) strategy to develop anti-neurodegenerative drugs. So-called "multi-target drugs"Refers to that a single chemical entity acts on a plurality of targets in a disease network simultaneously, and the action on each target can generate a synergistic effect, so that the total effect is larger than the sum of each single effect, and the medicine is also called as 'multifunctionality' or 'multipotent' medicine. 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. Designs and finds that the compound has the effects of inhibiting acetylcholinesterase and inhibitingβMulti-target AD therapeutics that are associated with excessive amyloid production and deposition, antioxidant stress, anti-platelet aggregation, and anti-neuritic response remain important research targets.
Disclosure of Invention
The invention aims to disclose a piperidine carbaldehyde phthalide compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims to disclose a preparation method of the piperidine alkane carbamoyl phthalide compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims to disclose a pharmaceutical composition containing the piperidine carbaldehyde phthalide compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims to disclose the piperidine alkane carbamoyl phthalide compound (I) and the pharmaceutically acceptable salt thereof have multi-target effect, and can be used for preparing the drugs for treating and/or preventing neurodegenerative related diseases, including but not limited to vascular dementia, Alzheimer disease, Parkinson disease, Huntington disease, HIV related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases.
The chemical structural general formula of the piperidine carbaldehyde phthalide compound (I) provided by the invention is as follows:
in the formula: x represents O, NR6Or S; r2And R3Each independently represents H, OH, SH, C1~C12Alkyl radical, C1~C12Alkoxy, CN, halogen, NR4R5Or C1~C12An alkylthio group; r4And R5Each independently representing H, C1~C12An alkyl group; NR (nitrogen to noise ratio)4R5Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r2And R3Can be arranged at any possible position of a benzene ring; r1Representation H, C1~C12Alkyl, benzyl or substituted benzyl; r6Representation H, C1~C12Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; m represents 0 to 6; n represents 0 to 12; the compound isRThe configuration,SConfiguration or racemate; the term "halogen" as defined above means F, Cl, Br, or I; "substituted phenyl" or "substituted benzyl" refers to phenyl or benzyl substituted on the phenyl ring with 1-4 groups selected from the group consisting of: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR7R8Trifluoromethyl, trifluoromethoxy, nitro, amino, carboxyl, hydroxy, cyano, R7And R8Each independently represents C1~C12Alkyl radical, NR7R8Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; these substituents may be in any possible position on the phenyl ring.
The piperidine alkyl phthalide compound (I) provided by the invention can be prepared by the following method:
taking corresponding carboxyalkyl phthalide compound raceme or optical isomer (1) and piperidine-4-alkylamine compound (2) as initial raw materials, reacting in a proper solvent and in the presence of a condensing agent to obtain corresponding piperidine carbaldehyde phthalide compound (I) raceme or optical isomer; or separating the corresponding racemate of the piperidine carbaldehyde phthalide compound (I) by utilizing a conventional chiral HPLC chromatography to obtain a corresponding optical isomer; the reaction formula is as follows:
in the formula: x, R1、R2、R3M and n are defined as the chemical structural general formula of the piperidine carbaldehyde phthalide compound (I).
For the above synthetic route, the specific preparation method is described as follows:
the condensing agent used in the reaction is: chloroformic acid C1-8Fatty alcohol ester compounds (such as ethyl chloroformate, tert-butyl chloroformate and benzyl chloroformate),NEthoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), carbodiimide-based compounds (e.g. DCC, EDCI), diethyl cyanophosphate (DEPC), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride (DMTMM) wherein the anion in DMTMM is chloro, bromo, perchlorate, fluoroborate, methane sulfonate, benzene sulfonate, p-toluene sulfonate, camphor sulfonate, amino sulfonate, preferably the condensing agent is: ethyl chloroformate, Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), or DMTMM; the solvent used in the reaction is: water, C1-6Alcohol, C3-8Aliphatic ketones, C5-10Aliphatic alkanes (e.g. n-hexane, n-heptane, etc.),N,NDimethylformamide, ethers (e.g. diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), C1-6Fatty acids with C1-6Esters formed from aliphatic alcohols, halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1, 2-dichloroethane, o-dichlorobenzene, etc.), aromatic or substituted aromatic hydrocarbons (e.g. benzene, toluene), acetonitrile, preferably in the form of: tetrahydrofuran, tetrahydrofuran,N,N-dimethylformamide, water, dichloromethane, isopropanol, acetone,Ethyl acetate, toluene; a carboxyalkyl phthalide compound racemate or an optical isomer (1): piperidin-4-alkylamine compound (2): the molar charge ratio of the condensing agent is 1.0: 1.0-9.0: 1.0-9.0, and the preferable molar feed ratio is 1.0: 1.0-4.0: 1.0 to 5.0; the condensation reaction temperature is 0-130 ℃, and the preferable reaction temperature is 0-50 ℃; the condensation reaction time is 30 minutes to 48 hours, and the preferable reaction time is 1 to 20 hours.
The piperidine carbaldehyde phthalide compound (I) obtained by the method contains amino which is basic, and can be prepared into pharmaceutically acceptable salts thereof by a pharmaceutically conventional salt forming method with any suitable acid, wherein the acid is as follows: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Fatty carboxylic acid (such as formic acid, acetic acid, propionic acid, etc.), oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), camphorsulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.
The starting materials of the present invention, carboxyalkylphthalide racemate or optical isomer (1) and piperidine-4-alkylamine compound (2), can be prepared by techniques common in the art, including but not limited to the methods disclosed in the following documents: 1. matarlo j.et al.Biochemistry2015, 54(42), 6514 and 6524; 2. plum fruit, etc.Fine and fine And special chemicals2004, 12(12), 19-21；3、Guo L. et al.Syn. Commun.2004, 34(7), 1183-1189；4、Antonia D. M. et al.Beilstein J. Org. Chem.2015, 11, 2591-2599；5、Keller M. et al.Bioorg. Med. Chem.2015, 23(14), 3970-3990；6、Asadipour A. et al.Eur. J. Med. Chem.2013, 70, 623-630；7、Zonghua L. et al.J. Med. Chem.2013, 56(22), 9089-9099。
The pharmaceutical composition disclosed by the invention comprises one or more piperidine carbaldehyde phthalide compounds (I) or pharmaceutically acceptable salts thereof with effective treatment 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 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 piperidine carbaldehyde phthalide 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 piperidine carbaldehyde phthalide compound (I) and the pharmaceutically acceptable salt thereof disclosed by the invention are subjected to the following biological activity screening.
(1) Inhibitory activity of piperidinoalkane carbamoyl phthalide compound (I) on acetylcholinesterase and butyrylcholinesterase
Adding 1.0 mmol/L thioacetylcholine iodide or thiobutyrylcholine iodide (all purchased from Sigma company) 30 muL, PBS buffer solution of pH7.4 40 muL, compound solution to be detected 20 muL (DMSO content is less than 1%) and acetylcholinesterase 10 muL (5% homogenate supernatant of rat cortex, phosphate buffer solution of pH7.4 as homogenate medium) or butyrylcholinesterase (25% supernatant of rat serum, pH7.4 phosphate buffer solution as homogenate medium) solution into a 96-well plate in sequence, mixing uniformly after adding, incubating at 37 ℃ for 15min, adding 0.2% 5, 5' -dithio-bis (2-nitrobenzoic acid) (DTNB from Sigma) solution 30 μ L to each well for color development, measuring optical density (OD value) of each well at 405nm by a microplate reader, the inhibition rate of the compound to the enzyme (enzyme inhibition (%) = (1-sample group OD value/blank group OD value) × 100%) was calculated as compared with the blank wells to which the sample to be tested was not added; 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 compound50. The test result shows that the piperidine carbaldehyde phthalide compound (I) disclosed in the embodiment of the invention is acetylcholineThe esterases all have obvious inhibiting effect, and the IC thereof50Is 2.0X 10-3nM to 10.0 mu M, the chiral configuration has no significant influence on the inhibition of the activity of acetylcholinesterase; the determination result also shows that the inhibitory activity of the piperidinoalkane carbamoyl phthalide compound (I) on acetylcholinesterase is obviously higher than that of butyrylcholinesterase (the selectivity is more than 100 times), which indicates that the compound disclosed by the invention has a selective inhibitory effect on acetylcholinesterase and indicates that the compound has low toxicity on peripheral systems. In addition, the measurement results also show that the IC of AChE inhibition by the clinically used rivastigmine50IC for butyrylcholinesterase inhibition at 10.5 μ M50Is 2.6 mu M; and IC of acetylcholinesterase inhibition by control Compound (II) (Y in the chemical formula represents O, NH or S, respectively) and control Compound (III) shown below50Are all larger than 100 mu M;
(2) antioxidant activity of piperidinoalkylcarbamoylphthalides (I) (ORAC-FL method)
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-: 6-hydroxy-2, 5,7, 8-tetramethylchromane-2-carboxylic acid (C)Trolox) The solution was adjusted to 10 to 80. mu. mol/L with PBS buffer solution of pH7.4, the solution was adjusted to 250 nmol/L with fluorescein (fluorescein) and PBS buffer solution of pH7.4, and the solution was adjusted to 40 mmol/L with PBS buffer solution of pH7.4 before use of 2, 2' -azobisisobutylamidine dihydrochloride (AAPH). Adding 50-10 mu mol/L of 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 (Thermo Scientific) instrument, and continuously measuring for 90 min under 485 nm excitation wavelength and 535 nm emission wavelength. Calculating the area AUC under the fluorescence attenuation curve, wherein the area AUC is 1-8 [ mu ] mol/LTroloxAs a standard, taking no sample to be tested as a blank, and the antioxidant activity of the compoundThe result is expressed asTroloxThe formula of the equivalent of (a) is: [ (AUC Sample-AUC blank)/(AUCTrolox-AUC blank)] ×[(concentration of Trolox/concentration of sample)]Each compound was assayed in 3 replicates each, each set of experiments was independently repeated three times. The determination result shows that the antioxidant activity of the piperidine carbaldehyde phthalide compound (I) disclosed in the embodiment of the invention isTrolox0.2-2.0 times of the total amount of the compound, which shows that the compound has stronger antioxidant activity; the antioxidant activity of the rivastigmine measured under the same condition is less than that of the rivastigmineTrolox0.1 times of.
(3) Piperidine carbaldehyde phthalide compound (I) to Aβ 1-42Inhibitory Activity of self-aggregation
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-: pretreated Aβ 1-42Preparing stock solution by DMSO, and diluting the stock solution to 50 mu M by PBS buffer solution with pH7.4 before use; preparing a to-be-detected compound into 2.5 mM stock solution by using DMSO (dimethyl sulfoxide), diluting the stock solution to a corresponding concentration by using a PBS (phosphate buffer solution) with the pH of 7.4 before use, and taking 20 mu L of Aβ 1-42Solution of compound to be detected of +20 muL, and 20 muL of Aβ 1-42Incubating the solution +20 μ L of PBS buffer (containing 2% DMSO) in a 96-well plate at 37 ℃ for 24h, adding 160 μ L of 50mM glycine-NaOH buffer (pH = 8.5) containing 5 μ M thioflavin T, and immediately after shaking for 5s, measuring fluorescence values by using a multifunctional microplate reader at an excitation wavelength of 446 nm and an emission wavelength of 490 nm; a. theβ 1-42+ the fluorescence value of the test compound is recorded as IFi，Aβ 1-42The fluorescence value of + PBS buffer was designated as IFcThe fluorescence value of the buffer solution containing only PBS was designated as IF0Compounds inhibiting Aβ 1-42The inhibition rate of self-aggregation is: 100- (IF)i-IF0)/(IFc-IF0) 100, x; selecting five to six concentrations of the compound, and determining the inhibition rate; each compound was tested in triplicate at each concentration, with curcumin as a positive control. The measurement result shows that the piperidine carbaldehyde phthalide compound (I) disclosed in the embodiment of the invention is opposite to the Aβ 1-42Self-assembly allHas obvious inhibiting activity on A at the concentration of 20.0 mu Mβ 1-42The inhibition rate of self-aggregation is between 30.0 and 60.0 percent; and anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, and the above control compound (II) (Y in the chemical structural formula represents O, NH or S, respectively) and control compound (III) were added to A at a concentration of 25.0 μ Mβ 1-42The inhibition rate of self-aggregation is less than 10%.
(4) Antiplatelet aggregation activity of piperidine alkane carbamyl phthalide compound (I)
3 male rabbits were taken, locally anesthetized with lidocaine, and subjected to surgical isolation of carotid artery for blood collection, and 3.8% sodium citrate 1: 9 anticoagulating, centrifuging at 500r/min for 10 min 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. 240 mu L of PRP and 30 mu L of test drugs with different concentrations are added into a measuring tube, incubation is carried out for 5 minutes, 30 mu L of Adenosine Diphosphate (ADP) (the final concentration is 10 mu mol/L), 30 mu L of thrombin (the final concentration is 0.5U/mL) and 30 mu L of Arachidonic Acid (AA) (the final concentration is 1.0 mmol/L) are respectively used as inducers, and the maximum aggregation rate within 5 minutes is observed and recorded. The inhibition (%) of each test compound was calculated using physiological saline (NS) as a control. The determination result shows that the piperidine carbaldehyde phthalide compound (I) disclosed in the embodiment of the invention has obvious inhibition effect on platelet aggregation induced by ADP, thrombin and AA, and the inhibition rate is 15.0-40.0%. And anti-AD drugs widely used clinically: the inhibition rates of the donepezil, the rivastigmine, the memantine hydrochloride and the control compound (III) on the platelet aggregation are all less than 5.0 percent; the control compound (II) (Y in the chemical structural formula represents O, NH or S respectively) has an inhibition rate of 8.2-12.0% on platelet aggregation.
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 piperidinoalkylcarbamoylphthalides (I)
Adding 1.0 mmol of carboxyalkylphthalide compound racemate or optical isomer (1), 1.3 mmol of piperidine-4-alkylamine compound (2) and 25 mL of tetrahydrofuran into a reaction bottle, stirring uniformly, adding 2.0 mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), stirring at room temperature for reaction for 2.0-20.0 hours (tracking the reaction process by TLC), evaporating the solvent under reduced pressure after the reaction is finished, adding 50 mL of dichloromethane into the residue, washing the residue with deionized water, saturated sodium carbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, drying the organic layer with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography (eluent: dichloromethane: methanol = 20-30: 1 v/v) to obtain the corresponding piperidinoalkylcarbamoylphthalide compound (I), the yield is 60.0-95.0%, and the chemical structures are all through1H-NMR、13C-NMR and ESI-MS confirmation; the purities of the obtained target substances are more than 97.0 percent through HPLC. The target prepared by the method has the following structure:
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Example 2 general method for salt formation of piperidinoalkylcarbamoylphthalide (I) with acid
Adding 1.0 mmol of piperidine carbaldehyde phthalide compound (I) obtained in the embodiment 1 and 25 ml of acetone into a reaction bottle, uniformly stirring, adding 4.0 mmol of corresponding acid, heating, refluxing, stirring, reacting for 20 minutes, cooling to room temperature after the reaction is finished, removing the solvent by reduced pressure evaporation, recrystallizing the residue with acetone, and filtering the separated solid to obtain the salt of piperidine carbaldehyde phthalide compound (I), wherein the chemical structure of the salt is shown in the specification1H NMR and ESI-MS.
Claims (8)
1. A piperidine alkane carbamoyl phthalide compound or pharmaceutically acceptable salt thereof is characterized in that the chemical structural general formula of the compound is shown as (I):
in the formula: x represents O, NR6Or S; r2And R3Each independently represents H, OH, SH, C1~C12Alkyl radical, C1~C12Alkoxy, CN, halogen, NR4R5Or C1~C12An alkylthio group; r4And R5Each independently representing H, C1~C12An alkyl group; NR (nitrogen to noise ratio)4R5Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r2And R3Can be arranged at any possible position of a benzene ring; r1Representation H, C1~C12Alkyl, benzyl or substituted benzyl; r6Representation H, C1~C12Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; m represents 0 to 6; n represents 0 to 12; the compound isRThe configuration,SConfiguration or racemate; the term "halogen" as defined above means F, Cl, Br, or I; "substituted phenyl" or "substituted benzyl" refers to phenyl or benzyl groups on the phenyl ring substituted with 1-4 groups selected from the group consisting of: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR7R8Trifluoromethyl, trifluoromethoxy, nitro, amino, carboxyl, hydroxy, cyano, R7And R8Each independently represents C1~C12Alkyl radical, NR7R8Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; these substituents may be in any possible position on the phenyl ring.
2. The piperidinoalkylcarbamoylphthalide or a pharmaceutically acceptable salt thereof of claim 1, wherein the pharmaceutically acceptable salt is a mixture of said piperidinoalkylphthalide with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Fatty carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Salts of alkylsulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.
3. A process for the preparation of a piperidinoalkane carbamoyl phthalide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, which is characterized in that the compound is prepared by the following method:
in the formula: x, R1、R2、R3The definitions of m and n are the same as the general chemical structure formula of the piperidine carbaldehyde phthalide compound (I);
taking corresponding carboxyalkyl phthalide compound raceme or optical isomer (1) and piperidine-4-alkylamine compound (2) as initial raw materials, reacting in a proper solvent and in the presence of a condensing agent to obtain corresponding piperidine carbaldehyde phthalide compound (I) raceme or optical isomer; or separating the corresponding racemate of the piperidine carbaldehyde phthalide compound (I) by utilizing the conventional chiral HPLC chromatography to obtain the corresponding optical isomer.
4. The process for preparing piperidinoalkylcarbamoylphthalide or a pharmaceutically acceptable salt thereof according to claim 3, wherein the condensing agent used in the reaction is: chloroformic acid C1-8Fatty alcohol ester compounds,NEthoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl cyanophosphate, 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride.
5. The process for preparing piperidinoalkylcarbamoylphthalide or a pharmaceutically acceptable salt thereof according to claim 3, wherein the solvent used in the reaction is: water, C1-6Alcohol, C3-8Aliphatic ketones, C5-10Aliphatic alkane,N,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, o-xyleneDichlorobenzene, benzene, toluene, acetonitrile.
6. The process for producing a piperidinoalkylcarbamoylphthalide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the carboxyalkylphthalide compound is racemic or in the form of the optical isomer (1): piperidin-4-alkylamine compound (2): the molar charge ratio of the condensing agent is 1.0: 1.0-9.0: 1.0 to 9.0; the condensation reaction temperature is 0-130 ℃; the condensation reaction time is 30 minutes to 48 hours.
7. A pharmaceutical composition comprising a piperidinoalkylcarbamoylphthalide compound or a pharmaceutically acceptable salt thereof according to any of claims 1-2, and one or more pharmaceutically acceptable carriers or excipients.
8. Use of the piperidinoalkane carbamoyl phthalide compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of neurodegenerative-related diseases: vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, or glaucoma.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05247022A (en) * | 1990-07-10 | 1993-09-24 | Tsumura & Co | New phthalide and brain function improver containing the same as active ingredient |
| CN1330069A (en) * | 2000-06-28 | 2002-01-09 | 中国医学科学院药物研究所 | Substituted 2-benzo [c] furanone compound, its preparing process and medicinal composition containing it |
| CN101455661A (en) * | 2008-11-19 | 2009-06-17 | 中国科学院上海有机化学研究所 | Use of 3-substituted phthalide and the analogue |
| CN106432161A (en) * | 2016-07-19 | 2017-02-22 | 四川大学 | 3-Alkyl-5,6-dioxo-substituted phthalide compounds, and preparation method and use thereof |
-
2018
- 2018-04-03 CN CN201810285408.6A patent/CN108727352B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05247022A (en) * | 1990-07-10 | 1993-09-24 | Tsumura & Co | New phthalide and brain function improver containing the same as active ingredient |
| CN1330069A (en) * | 2000-06-28 | 2002-01-09 | 中国医学科学院药物研究所 | Substituted 2-benzo [c] furanone compound, its preparing process and medicinal composition containing it |
| CN101455661A (en) * | 2008-11-19 | 2009-06-17 | 中国科学院上海有机化学研究所 | Use of 3-substituted phthalide and the analogue |
| CN106432161A (en) * | 2016-07-19 | 2017-02-22 | 四川大学 | 3-Alkyl-5,6-dioxo-substituted phthalide compounds, and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-β-amyloid aggragation and neuroprotective properties for the treatment of Alzheimers disease;Yan Li et al.;《European Journal of Medicinal Chemistry》;20161005;第126卷;第762-775页 * |
| DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimers therapy;Xiaoming Qiang et al.;《Bioorganic & Medicinal Chemistry Letters》;20170117;第27卷;第718-722页 * |
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