CN110698411A - 4- (aminoalkyl) phthalazine-1-ketone compounds, preparation method and application thereof - Google Patents
4- (aminoalkyl) phthalazine-1-ketone compounds, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel 4- (aminoalkyl) phthalazine-1-ketone 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 related diseases of a nervous system, wherein the diseases comprise but are not limited to vascular dementia, Alzheimer disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a novel 4- (aminoalkyl) phthalazin-1-ketone compound (I), a preparation method thereof, a medicinal composition and application thereof in preparing medicaments for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, Alzheimer disease, Parkinson disease, Huntington's disease, HIV (human immunodeficiency virus) -related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma 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. The clinical manifestations of AD include hypomnesis, hypo-orientation, thought and judgment, and reduced and even appeared daily life capacityThe abnormal mental behavior symptoms and the like cause great nursing difficulty for patients and bring heavy burden to the society and families. Currently approved drugs for the treatment of light/moderate AD are 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, 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, studies have shown that the patient has a decreased acetylcholine level in the brain,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. 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 compounds also being 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. A large number of clinical studies have proved that AChE inhibitors can effectively relieve the symptoms of AD patients, and the short-term treatment effect is positive; therefore, when designing multi-target anti-AD drugs, the AChE inhibitory activity of the compound (inhibiting the enzyme is important for improving the symptoms of AD patients) is usually required to be kept, and one or more other targets or functions with pharmacological synergistic effect are added on the basis of the inhibition activity, so as to achieve the multi-target AD therapeutic effect [ 1, yellow Shufang and the like ] research progress of multi-target Alzheimer disease therapeutic drugs, China pharmaceutical chemistry journal 2011, 21(6): 433-434; 2. luo Sten et al, research progress of treating Alzheimer's disease by multi-target small molecule inhibitors, China journal of drug chemistry 2011, 21(6): 442-443). Obviously, the design and the discovery have 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 4- (aminoalkyl) phthalazin-1-one compound (I) and pharmaceutically acceptable salts thereof;
the invention also aims to disclose a preparation method of the 4- (aminoalkyl) phthalazin-1-one compound (I) and pharmaceutically acceptable salts thereof;
the invention also discloses a pharmaceutical composition containing the 4- (aminoalkyl) phthalazin-1-one compound (I) and pharmaceutically acceptable salts thereof;
the invention also aims to disclose that the 4- (aminoalkyl) phthalazin-1-one compounds (I) and the pharmaceutically acceptable salts thereof have multi-target effect and can be used for preparing the drugs for treating and/or preventing related diseases of the nervous system, including but not limited to vascular dementia, Alzheimer disease, Parkinson disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and other diseases.
The chemical structural general formula of the 4- (aminoalkyl) phthalazin-1-one compound (I) provided by the invention is as follows:
in the formula: r1Is represented by- (CH)2)n-NR4R5N represents 1-12, R4Representation H, C1~C12An alkyl group; r5Is represented by C1~C12Alkyl, benzyl or substituted benzyl; NR (nitrogen to noise ratio)4R5Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position by C1~C12Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl or substituted benzyl in the 4-position, piperazinyl, piperidinyl substituted by C in the 4-position1~C12Piperazinyl substituted with alkyl, piperazinyl substituted at the 4-position with benzyl or substituted benzyl; r1Is also shown
M represents 0-10, R6Representation H, C1~C12Alkyl, benzyl or substituted benzyl; r2And R3Each independently represents H, OH, SH, C1~C12Alkyl radical, C1~C12Alkoxy, CN, halogen, NR7R8Or C1~C12An alkylthio group; r7And R8Each independently representing H, C1~C12An alkyl group; NR (nitrogen to noise ratio)7R8Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r2And R3At any possible position of the phenyl ring. The term "halogen" as defined above means F, Cl, Br or I; "substituted benzyl" refers to benzyl groups on the phenyl ring substituted with 1 to 4 groups selected from the group consisting of: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR9R10Trifluoromethyl, trifluoromethoxy, amino, hydroxy or cyano, R9And R10Each independently represents C1~C12Alkyl radical, NR9R10But also tetrahydropyrrolyl, morpholinyl or piperidinyl, these substituents being in any possible position of the phenyl ring.
The 4- (aminoalkyl) phthalazin-1-ketone compound (I) provided by the invention can be prepared by the following method:
taking a corresponding 3-bromophenylphthalide compound (1) as an initial raw material, and reacting with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine phthalide salt compound (2); the obtained compound 2 and corresponding aminoalkyl aldehyde compound (3) are subjected to Wittig reaction in proper solvent under alkaline condition to obtain corresponding compound (4)E/ZA configuration mixture which can directly react with hydrazine hydrate in a proper solvent without separation and purification to prepare a corresponding 4- (aminoalkyl) phthalazin-1-one compound (I); or of the compound (4)E/ZSeparating and purifying the mixture by silica gel column chromatography to obtain corresponding compoundsEIs of the formulaZThe compound (4) with the formula configuration can be respectively reacted with hydrazine hydrate in a proper solvent to prepare the corresponding 4- (aminoalkyl) phthalazin-1-one compound (I); the reaction formula is as follows:
in the formula: r1、R2And R3The definition of (A) is the same as the chemical structural general formula of the 4- (aminoalkyl) phthalazin-1-one compound (I).
For the above synthetic route, the specific preparation method is described as follows:
step A): reacting the 3-bromophenylphthalide compound (1) with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine phthalide salt compound (2); wherein, the solvent used in the reaction is: c3-8An aliphatic ketone,N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1, 4-dioxane, ethylene glycol dimethyl ether or C5-8The alkane is preferably 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene or 1, 4-dioxane, the molar charge ratio of the 3-bromophenylphthalide compound (1) to the triphenylphosphine is 1.0: 1.0 ~ 10.0.0, the preferred molar charge ratio is 1.0: 1.0 ~ 5.0.0, the reaction temperature is 40 ~ 150 ℃, the preferred reaction temperature is 60 ~ 120 ℃, and the reaction time is 1 ~ 120 hours, the preferred reaction time is 2 ~ 72 hours.
Step B): the 3-triphenylphosphine phthalide salt compound (2) obtained in the step A) and the corresponding amine alkyl aldehyde compound (3) are subjected to Wittig reaction in a proper solvent under the alkaline condition to obtain the corresponding compound (4)E/ZA mixture of configurations; wherein, the solvent used in the reaction is: c1-8Fatty alcohol, C3-8Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 4-dioxane, benzene, toluene, acetonitrile or C5-8Alkanes, preferred solvents are: chloroform, dichloromethane, acetone, acetonitrile, tetrahydrofuran or toluene; the base used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, C1-8Alkali metal salts of alcohols, organic tertiary or quaternary amines (e.g. triethylamine, tributylamine, trioctylamine, pyridine, tert-butyl amine, tert-butyl,N-methylmorpholine,NMethylpiperidine, triethylenediamine, tetrabutylammonium hydroxide), the preferred bases being: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; 3-triphenyl radicalsThe molar charge ratio of the phosphine phthalide salt compound (2) to the amine alkyl aldehyde compound (3) to the alkali is 1.0: 1.0 ~ 10.0.0: 1.0 ~ 10.0.0, the preferred molar charge ratio is 1.0: 1.0 ~ 3.0.0: 1.0 ~ 5.0.0, the reaction temperature is 0 ~ 120 ℃, the preferred reaction temperature is room temperature ~ 100 ℃ and the reaction time is 20 minutes ~ 48 hours, and the preferred reaction time is 1 ~ 24 hours.
Step C): directly reacting the compound (4) mixture obtained in the step B) with hydrazine hydrate in a proper solvent without separation and purification to obtain a corresponding 4- (aminoalkyl) phthalazin-1-one compound (I); wherein, the solvent used in the reaction is: c1-6Fatty alcohol, C3-8Aliphatic ketones, C1-6Fatty acid, C1-6Fatty acids with C1-6Esters formed by aliphatic alcohols, ethers (such as diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and the like), benzene, toluene or xylene, aliphatic hydrocarbons (such as hexane, heptane, octane and the like), preferably solvent tetrahydrofuran, methanol, ethanol or isopropanol, the molar charge ratio of the compound (4) to hydrazine hydrate is 1.0: 1.0 ~ 10.0, preferably 1.0: 1.0 ~ 3.0.0, the reaction temperature is ~ 150 ℃, preferably ~ 120 ℃, the reaction time is 30 minutes ~ 48 hours, preferably 1 ~ 24 hours.
The side chain of the molecule of the 4- (aminoalkyl) phthalazin-1-one compound (I) obtained by the method contains amino which is basic, and the pharmaceutically acceptable salt thereof can be prepared by any suitable acid through a pharmaceutically conventional salt forming method, wherein the acid is as follows: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C1-6Aliphatic carboxylic acids (e.g. formic acid, acetic acid, propionic acid, etc.), trifluoroacetic acid, stearic acid, pamoic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C1-6Alkyl sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 1, 4-butanedisulfonic acid.
Starting Material of the inventionThe-3-bromophenylphthalide compound (1) and the aminoalkylaldehyde compound (3) can be prepared by techniques common in the art, including, but not limited to, the methods disclosed in the following documents: 1. guidong Z.et al.WO2011130478A1；2、Sakamoto F.et al.Chem. Pharm. Bull.1983, 31(8), 2698-2707；3、Chunzhi Z.et al.Chinese Journal of Organic Chemistry2014, 34, 1881-1888；4、Sugimoto H.et al.US 5100901；5、Mingyu W.et al.European Journal of Medicinal Chemistry2016, 121, 864-879。
The pharmaceutical composition disclosed by the invention comprises one or more 4- (aminoalkyl) phthalazin-1-one 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 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 4- (aminoalkyl) phthalazin-1-one compound (I) or the pharmaceutically acceptable salt thereof is taken as an active component and accounts for 2 to 99.5 percent of the total weight.
The 4- (aminoalkyl) phthalazin-1-one compound (I) and the pharmaceutically acceptable salt thereof disclosed by the invention are subjected to the following biological activity screening.
(1) Inhibitory Activity of 4- (aminoalkyl) phthalazin-1-ones (I) on Acetylcholinesterase and Butyrylcholinesterase
To a 96-well plate, 30. mu.L of thioacetylcholine iodide or thiobutyrylcholine iodide (each obtained from Sigma), 40. mu.L of PBS buffer solution at pH7.4, 20. mu.L of a test compound solution (DMSO content: less than 1%), and 10. mu.L of acetylcholinesterase (5% homogenate supernatant of rat brain cortex, phosphate buffer solution at pH 7.4) were sequentially addedHomogenization medium) or butyrylcholinesterase (rat serum 25% supernatant, ph7.4 phosphate buffer as homogenization medium), after adding and mixing, incubating for 15min at 37 ℃, adding 0.2% 5, 5' -dithio-bis (2-nitrobenzoic acid) (DTNB, purchased from Sigma) solution 30 μ L to each well for color development, measuring optical density (OD value) of each well at 405nm with a microplate reader, and calculating the inhibition rate of the compound on the enzyme (enzyme inhibition rate (%) = (1-sample group OD value/blank group OD value) × 100%) compared with blank wells without the sample to be measured; 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 4- (aminoalkyl) phthalazin-1-one compound (I) disclosed in the embodiment of the invention has obvious inhibition effect on acetylcholinesterase and IC thereof50The value is 0.11 nM ~ 10.0.0 mu M, and the inhibitory activity of the 4- (aminoalkyl) phthalazin-1-one compound (I) on acetylcholinesterase is obviously higher than that on butyrylcholinesterase (the selectivity is more than 100 times), which shows that the compound disclosed by the invention has selective inhibitory effect on acetylcholinesterase and has small toxicity on peripheral systems50IC for butyrylcholinesterase inhibition at 10.5 μ M50Is 2.6 mu M; IC of control Compound (II) and control Compound (III) for acetylcholinesterase inhibition as shown below50Are each greater than 150 μ M, and a control compound (IV) (R in its structure)1、R2And R3The definition of (A) is the same as the chemical structural general formula of the 4- (aminoalkyl) phthalazin-1-ketone compound (I), and the IC of the compound for inhibiting the acetylcholinesterase50The values are 2-10 times higher than those of corresponding 4- (aminoalkyl) phthalazin-1-ones (I) with the same substituents;
(2) antioxidant activity of 4- (aminoalkyl) phthalazin-1-ones (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 10-80. mu. mol/L with PBS buffer solution of pH7.4, the solution was adjusted to 250 nmol/L with PBS buffer solution of pH7.4 for fluorescein (fluorescein), and the solution was adjusted to 40 mmol/L with PBS buffer solution of pH7.4 for 2, 2' -azobisisobutylamidine dihydrochloride (AAPH) before use. The compound solution and the fluorescein solution were added to a 96-well plate at 50-10. mu. mol/L, mixed, incubated at 37 ℃ for 15min, and AAPH solution was added to make the total volume per well 200. mu.L, mixed, immediately placed in a Varioskan Flash Multimode Reader (Thermo Scientific) instrument, and continuously measured at 485 nm excitation wavelength and 535 nm emission wavelength for 90 min. Calculating the area AUC under the fluorescence decay curve, wherein the area AUC is 1-8 mu mol/LTroloxAs a standard, taking a sample not to be tested as a blank, and expressing the antioxidant activity result of the compound asTroloxThe formula of the equivalent of (a) is: [ (AUC Sample-AUCblank)/(AUCTrolox-AUC blank)]×[(concentration ofTrolox/concentration ofsample)]Each compound was assayed in 3 replicates each, each set of experiments was independently repeated three times. The test result shows that the antioxidant activity of the 4- (aminoalkyl) phthalazin-1-one compound (I) disclosed in the embodiment of the invention isTrolox0.5-4.0 times of the total amount of the compound, which shows that the compound has stronger antioxidant activity. In addition, the assay results also show that the antioxidant activity of the 4- (aminoalkyl) phthalazin-1-one compounds (I) is also significantly higher than that of the corresponding control compounds (IV) with the same substituents (n =3,p<0.05）。
(3) 4- (aminoalkyl) phthalazin-1-ones (I) to Aβ 1-42Inhibitory Activity of self-aggregation
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-: pretreated Aβ 1-42Stock solutions were prepared in DMSO, and diluted to 50. mu.M in PBS buffer, pH7.4, before use; test compounds were prepared in 2.5 mM stock solutions in DMSO and used prior to usePBS buffer (pH7.4) was diluted to the corresponding concentration, and 20. mu.L of A was takenβ 1-42Solution + 20. mu.L of test Compound solution, 20. mu.L of Aβ 1-42Solution +20 μ L PBS buffer (containing 2% DMSO) in 96-well plates, incubated at 37 ℃ for 24h, then 160 μ L of 50mM glycine-NaOH buffer (pH = 8.5) containing 5 μ M thioflavin T was added, and fluorescence was measured immediately after shaking for 5s with a multifunctional plate reader at 446 nm excitation wavelength and 490 nm emission wavelength; 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 4- (aminoalkyl) phthalazin-1-one compounds (I) disclosed in the embodiment of the invention are Aβ 1-42The self-aggregation has obvious inhibitory activity on A at the concentration of 20.0 mu Mβ 1-42The inhibition rate of self-aggregation is between 25.0 and 65.0 percent; and anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, and the above control compound (II) and control compound (III) were administered to A at a concentration of 25.0 μ Mβ 1-42The inhibition rate of self-aggregation is less than 10%.
(4) Anti-platelet aggregation activity of 4- (aminoalkyl) phthalazin-1-one 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 500 r/min for 10 min to obtain Platelet Rich Plasma (PRP), centrifuging the rest at 3000 r/min to obtain Platelet Poor Plasma (PPP), and performing platelet aggregation experiment by turbidimetry. mu.L of PRP and 30. mu.L of the test drug at different concentrations were added to the assay tube and incubated for 5 minutes, and the maximal aggregation rate was observed and recorded within 5 minutes using 30. mu.L of Adenosine Diphosphate (ADP) (final concentration of 10. mu. mol/L), 30. mu.L of thrombin (final concentration of 0.5U/mL) and 30. mu.L of Arachidonic Acid (AA) (final concentration of 1.0 mmol/L) as inducers. The inhibition (%) of each test compound was calculated using physiological saline (NS) as a control. The determination result shows that the 4- (aminoalkyl) phthalazin-1-one compound (I) disclosed in the embodiment of the invention has a significant inhibition effect on platelet aggregation induced by ADP, thrombin and AA at a concentration of 33.0 mu M, and the inhibition rate is more than 15.0%. And anti-AD drugs widely used clinically: the inhibition rate of the donepezil, the rivastigmine, the memantine hydrochloride and the control compounds (II), (III) and (IV) on the platelet aggregation is less than 10.0 percent under the same concentration.
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 14 general procedure for the preparation of- (aminoalkyl) phthalazin-1-ones (I)
Adding 2.0 mmol of corresponding 3-bromide (1), 2.4 mmol of triphenylphosphine and 20 ml of toluene into a reaction bottle, heating, refluxing and stirring for reacting for 8-24.0 hours (tracking the reaction process by TLC); after the reaction is finished, cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake by toluene and petroleum ether in sequence, and drying to obtain the corresponding 3-triphenylphosphine salt compound (2), wherein the yield is 60.0-88.0%, and the chemical structures are all subjected to reaction1H-NMR confirmation;
adding 1.0mmol of the 3-triphenylphosphine salt compound (2), 1.2mmol of the amine alkyl aldehyde compound (3) and 30 ml of dichloromethane prepared in the previous step into a reaction bottle, stirring uniformly, adding 1.2mmol of triethylamine, and stirring at room temperature for reacting for 6.0-24.0 hours (tracking the reaction process by TLC); after the reaction, the solvent was evaporated under reduced pressure, 30 mL of deionized water was added to the residue, the pH of the reaction solution was adjusted to strong acidity with 10% hydrochloric acid aqueous solution, the pH of the reaction solution was adjusted to weak alkalinity with saturated sodium bicarbonate aqueous solution, and 120 mL of methylene chloride was used to divide the solution into three portionsExtracting, mixing organic layers, washing with saturated aqueous solution of sodium chloride, drying with anhydrous sodium sulfate, filtering, and vacuum evaporating to remove solvent to obtain residue of corresponding compound (4)E/ZThe yield of the configuration mixture is 80.0-98.0%, and the chemical structures of the configuration mixture are all through1H-NMR confirmation;
preparation of Compound (4) prepared in the above stepE/ZAdding the configured mixture 0.6 mmol, ethanol 15 ml and hydrazine hydrate 1.0mmol into a reaction bottle, heating, refluxing and stirring for reaction for 2.0-12.0 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: methanol = 20-30: 1 v/v) to obtain the corresponding 4- (aminoalkyl) phthalazin-1-one compound (I), wherein the yield is 70.0-90.0%, 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 97.0 percent through HPLC.
The following target substances are prepared by the general method:
(1) when R is1Is represented by- (CH)2)n-NR4R5The target compound has the following structure:
note: in the table R4And R5When they share a single cell, they represent the substituent-NR4R5”；
Of partial compounds1The H-NMR data are as follows:
1H NMR (CDCl3): 10.39 (s, 1H), 7.79 (s, 1H), 7.30-7.26 (m, 5H), 7.04 (s,1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.66 (s, 2H), 3.15 (t,J= 7.2 Hz, 2H), 2.88(t,J= 7.2 Hz, 2H), 2.43 (s, 3H)；
1H NMR (CDCl3): 11.25 (s, 1H), 7.81 (s, 1H), 7.33-7.23 (m, 2H), 7.16 (s,1H), 6.92-6.85 (m, 2H), 4.05 (s, 3H), 3.95 (s, 3H), 3.82 (s, 3H), 3.74 (s,2H), 3.25 (t,J= 7.6 Hz, 2H), 2.96 (t,J= 7.6 Hz, 2H), 2.46 (s, 3H)；
1H NMR (CDCl3): 10.80 (s, 1H), 7.82 (s, 1H), 7.32-7.24 (m, 5H), 7.08 (s,1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.55 (s, 2H), 2.92 (t,J= 7.2 Hz, 2H), 2.50(t,J= 7.2 Hz, 2H), 2.24 (s, 3H), 1.89-1.81 (m, 2H), 1.75-1.69 (m, 2H)；
1H NMR (CDCl3): 11.00 (s, 1H), 7.83 (s, 1H), 7.33-7.19 (m, 5H), 7.06 (s,1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.62 (s, 2H), 2.89 (t,J= 7.2 Hz, 2H),2.57-2.50 (m, 4H), 1.85-1.77 (m, 2H), 1.69-1.63 (m, 2H), 1.06 (t,J= 7.2 Hz,3H)；
1H NMR (CDCl3): 10.75 (s, 1H), 7.81 (s, 1H), 7.40 (d,J= 7.2 Hz, 1H),7.29 (t,J= 7.2 Hz, 1H), 7.10 (s, 1H), 6.94 (t,J= 7.2 Hz, 1H), 6.88 (d,J= 8.4 Hz, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.81 (s, 3H), 3.79 (s, 2H), 2.95(t,J= 7.2 Hz, 2H), 2.69 (t,J= 7.2 Hz, 2H), 2.39 (s, 3H), 1.86-1.69 (m,4H)；
1H NMR (CDCl3): 10.87 (s, 1H), 7.82-7.75 (m, 2H), 7.29 (t,J= 7.2 Hz,1H), 7.17-7.08 (m, 3H), 4.06 (s, 2H), 4.05 (s, 3H), 4.04 (s, 3H), 2.94 (t,J= 7.2 Hz, 2H), 2.90-2.78 (m, 4H), 2.65 (s, 6H), 1.95-1.78 (m, 4H), 1.32-1.15(m, 3H)；
1H NMR (CDCl3): 10.75 (s, 1H), 7.81 (s, 1H), 7.23 (d,J= 8.4 Hz, 2H),7.08 (s, 1H), 6.66 (d,J= 8.4 Hz, 2H), 4.05 (s, 3H), 4.03 (s, 3H), 3.74 (s,2H), 2.93 (s, 6H), 2.92 (t,J= 7.2 Hz, 2H), 2.80-2.61 (m, 4H), 1.86-1.79 (m,4H), 1.22-1.18 (m, 3H)；
1H NMR (CDCl3): 12.37 (s, 1H), 7.62 (s, 1H), 7.28 (s, 1H), 3.99 (s, 3H),3.94 (s, 3H), 3.12-3.01 (m, 6H), 2.99-2.94 (m, 2H), 1.82-1.72 (m, 4H), 1.23-1.19 (m, 6H)；
1H NMR (CDCl3): 11.19 (s, 1H), 7.79 (s, 1H), 7.08 (s, 1H), 4.06 (s, 3H),4.05 (s, 3H), 2.98-2.92 (m, 2H), 2.78-2.67 (m, 6H), 2.00-1.84 (m, 8H), 1.71-1.55 (m, 2H)；
1H NMR (CDCl3): 11.15 (s, 1H), 7.81 (s, 1H), 7.08 (s, 1H), 4.05 (s, 3H),4.02 (s, 3H), 2.93 (t,J= 7.6 Hz, 2H), 2.72-2.50 (m, 8H), 2.48 (t,J= 7.6Hz, 2H), 2.34 (s, 3H), 1.86-1.79 (m, 2H), 1.70-1.66 (m, 2H)；
1H NMR (CDCl3): 10.86 (s, 1H), 7.82 (s, 1H), 7.40 (d,J= 7.2 Hz, 1H),7.28 (t,J= 7.2 Hz, 1H), 7.10 (s, 1H), 6.95 (t,J= 7.2 Hz, 1H), 6.88 (d,J= 8.0 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.83 (s, 3H), 3.76 (s, 2H), 2.90(t,J= 7.2 Hz, 2H), 2.61-2.55 (m, 2H), 2.37 (s, 3H), 1.86-1.78 (m, 2H),1.77-1.62 (m, 2H), 1.55-1.36 (m, 4H)；
1H NMR (CDCl3): 10.49 (s, 1H), 7.88 (d,J= 7.2 Hz, 1H), 7.81 (s, 1H),7.34 (t,J= 7.2 Hz, 1H), 7.23-7.14 (m, 2H), 7.09 (s, 1H), 4.28 (s, 2H), 4.07(s, 3H), 4.05 (s, 3H), 3.08-2.87 (m, 6H), 2.65 (s, 6H), 1.83-1.45 (m, 4H),1.44-1.28 (m, 7H)。
(2) when R is1To represent
The target compound has the following structure:
of partial compounds1The H-NMR data are as follows:
1H NMR (CDCl3): 10.23 (s, 1H), 7.82 (s, 1H), 7.31-7.23 (m, 5H), 7.07 (s,1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.49 (s, 2H), 2.89-2.85 (m, 4H), 1.96-1.91(m, 2H), 1.81-1.76 (m, 2H), 1.69-1.66 (m, 3H), 1.40-1.36 (m, 2H), 1.28-1.25(m, 2H)。
EXAMPLE 24 preparation of salts of (aminoalkyl) phthalazin-1-ones with acids
Adding 3.0 mmol of the 4- (aminoalkyl) phthalazin-1-one compound (I) obtained in the example 1 and 25 ml of acetone into a reaction bottle, stirring uniformly, adding 8.0 mmol of corresponding acid, heating, refluxing, stirring and reacting for 20 minutes, cooling to room temperature after the reaction is finished, evaporating the solvent under reduced pressure, recrystallizing the residue by using acetone, and filtering the precipitated solid to obtain the salt of the 4- (aminoalkyl) phthalazin-1-one compound (I), wherein the chemical structure of the salt is shown in the specification1H NMR and ESI-MS.
Claims (8)
1. A4- (aminoalkyl) phthalazin-1-ketone compound or a pharmaceutically acceptable salt thereof is characterized in that the chemical structural general formula of the compound is shown as (I):
in the formula: r1Is represented by- (CH)2)n-NR4R5N represents 1-12, R4Representation H, C1~C12An alkyl group; r5Is represented by C1~C12Alkyl, benzyl or substituted benzyl; NR (nitrogen to noise ratio)4R5Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position by C1~C12Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl or substituted benzyl in the 4-position, piperazinyl, piperidinyl substituted by C in the 4-position1~C12Piperazinyl substituted with alkyl, piperazinyl substituted at the 4-position with benzyl or substituted benzyl; r1Is also shownM represents 0-10, R6Representation H, C1~C12Alkyl, benzyl or substituted benzyl; r2And R3Each independently represents H, OH, SH, C1~C12Alkyl radical, C1~C12Alkoxy, CN, halogen, NR7R8Or C1~C12An alkylthio group; r7And R8Each independently representing H, C1~C12An alkyl group; NR (nitrogen to noise ratio)7R8Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r2And R3At any possible position of the phenyl ring; the term "halogen" as defined above means F, Cl, Br or I; "substituted benzyl" refers to benzyl groups on the phenyl ring substituted with 1 to 4 groups selected from the group consisting of: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR9R10Trifluoromethyl, trifluoromethoxy, amino, hydroxy or cyano, R9And R10Each independently represents C1~C12Alkyl radical, NR9R10But also tetrahydropyrrolyl, morpholinyl or piperidinyl, these substituents being in any possible position of the phenyl ring.
2. The 4- (aminoalkyl) phthalazin-1-ones or the pharmaceutically acceptable salts thereof according to claim 1, characterized in that the pharmaceutically acceptable salts are such 4- (aminoalkyl) phthalazin-1-ones with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C1-6Aliphatic carboxylic acid, trifluoroacetic acid, stearic acid, pamoic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C1-6Salts of alkylsulfonic acids, camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1, 4-butanedisulfonic acid.
3. A process for the preparation of a compound of the 4- (aminoalkyl) phthalazin-1-one type or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2, characterized in that the compound is obtainable by:
in the formula: r1、R2And R3The definition of (A) is the same as the chemical structural general formula of the 4- (aminoalkyl) phthalazin-1-one compound (I);
step A): taking a corresponding 3-bromophenylphthalide compound (1) as an initial raw material, and reacting with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine phthalide salt compound (2);
step B): the 3-triphenylphosphine phthalide salt compound (2) obtained in the step A) and the corresponding amine alkyl aldehyde compound (3) are subjected to Wittig reaction in a solvent under the alkaline condition to obtain the corresponding compound (4)E/ZA mixture of configurations;
step C): directly reacting the compound (4) mixture obtained in the step B) with hydrazine hydrate in a proper solvent without separation and purification to obtain a corresponding 4- (aminoalkyl) phthalazin-1-one compound (I);
the 4- (aminoalkyl) phthalazin-1-one compound (I) obtained by the method contains amino in the molecule, the amino is basic, and the pharmaceutically acceptable salt can be prepared by any suitable acid through a pharmaceutically conventional salt forming method.
4. The process for preparing 4- (aminoalkyl) phthalazin-1-ones or pharmaceutically acceptable salts thereof as claimed in claim 3, wherein in step A), the reaction is carried out in the following solvent: c3-8An aliphatic ketone,N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1, 4-dioxane, ethylene glycol dimethyl ether or C5-8The molar charge ratio of the alkane, the 3-bromophenylphthalide compound (1) and the triphenylphosphine is 1.0: 1.0 ~ 10.0.0, the reaction temperature is 40 ~ 150 ℃, and the reaction time is 1 ~ 120 hours.
5. The process for preparing 4- (aminoalkyl) phthalazin-1-ones or pharmaceutically acceptable salts thereof as claimed in claim 3, wherein in step B), the reaction is carried out in the following solvent: c1-8Fatty alcohol, C3-8Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 4-dioxane, benzene, toluene, acetonitrile or C5-8An alkane; the base used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metalMetal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, C1-8Alkali metal salts of alcohols, triethylamine, tributylamine, trioctylamine, pyridine,N-methylmorpholine,NMethyl piperidine, triethylene diamine and tetrabutyl ammonium hydroxide, a 3-triphenylphosphine phthalide compound (2), an amine alkyl aldehyde compound (3), an alkali molar charge ratio of 1.0: 1.0 ~ 10.0.0: 1.0 ~ 10.0.0, a reaction temperature of 0 ~ 120 ℃ to 120 ℃, and a reaction time of 20 minutes to ~ 48 hours.
6. The process for preparing 4- (aminoalkyl) phthalazin-1-ones or pharmaceutically acceptable salts thereof as claimed in claim 3, wherein in step C), the reaction is carried out in the following solvent: c1-6Fatty alcohol, C3-8Aliphatic ketones, C1-6Fatty acid, C1-6Fatty acids with C1-6Ester formed by fatty alcohol, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, glycol dimethyl ether, benzene, toluene or xylene, the molar charge ratio of the compound (4) to hydrazine hydrate is 1.0: 1.0 ~ 10.0.0, the reaction temperature is ~ 150 ℃ at room temperature, and the reaction time is ~ 48 minutes and ~ hours.
7. A pharmaceutical composition comprising a 4- (aminoalkyl) phthalazin-1-one compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2 and one or more pharmaceutically acceptable carriers or excipients.
8. Use of a 4- (aminoalkyl) phthalazin-1-one 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 prophylaxis of neurological-related disorders: vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve damage due to brain trauma.
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