CN112552232B - Pyridone hexa-alkynylamine modified derivative and preparation method and application thereof - Google Patents
Pyridone hexa-alkynylamine modified derivative and preparation method and application thereof Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention is aThe modified derivatives of pyridone hexa-alkynylamine as shown in formula (I), pharmaceutically acceptable salts thereof, a preparation method thereof and application of the modified derivatives of pyridone hexa-alkynylamine or pharmaceutically acceptable salts thereof in preparing medicaments for preventing or treating related diseases, particularly Alzheimer's disease and Parkinson's disease by inhibiting monoamine oxidase, chelating metallic iron ions, resisting A beta and resisting oxidation. The invention synthesizes a series of novel single-molecule multi-target anti-AD active compounds, innovatively combines a pyridone derivative with iron ion chelating activity and propargylamine with MAO-B inhibitory activity, has obvious advantages for Alzheimer's disease with complex pathogenesis, and the combined molecules are far superior to CP20 (deferiprone) in the aspect of iron ion chelating activity.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to a pyridone hexa-alkynylamine modified derivative which has both iron ion chelating capacity and monoamine oxidase B inhibition function and can resist intracerebral A beta aggregation and oxidation under the synergistic effect of nitrogen propynyl and a pyridone derivative, a preparation method thereof and application thereof in preparing medicaments for treating diseases such as Alzheimer's disease.
Background
Alzheimer's Disease (AD) is a neurodegenerative disease that affects the physical and mental health of millions of elderly people worldwide, causing patients to exhibit symptoms such as memory impairment and cognitive decline. With the global aging progressing, it is expected that the number of people with AD will increase to 1.31 billion by 2050.
The cause of AD is a mystery. Case analysis indicates that the etiology of AD is closely related to extracellular beta-amyloid (a β), intracellular neurofibrillary tangles (NFT), glial activation, inflammation, and mitochondrial disease. To date, the only four clinically available drugs, donepezil (Donepezil), galantamine (Galantamine), rivastigmine (Rivastigmine) and Memantine (Memantine), are ineffective in completely curing the disease. In recent years, the drawbacks of drugs directed to N-methyl-D-aspartate (NMDA) or acetylcholinesterase (AChE) have gradually emerged and the study of AD treatment regimens has gradually shifted from single-target combination therapy to multi-target therapy. Targeted Drugs (MTD).
With the continuous and intensive research on the pathological mechanism of AD, researchers find that the level of metal ions in the brain of a patient is 3-7 times that of a normal person. There is increasing evidence that a disturbance in the homeostasis of biological metals interferes with the normal degradation of Amyloid Precursor Protein (APP), resulting in the production of interfering factors in humans, which promote the conversion of APP into insoluble monomeric amyloid β (a β). These metals will further bind to the monomeric a β, promoting its aggregation into age spots. In addition, high iron content promotes NFT accumulation. Transition metal cations, particularly iron ions, of varying valency states also catalytically generate Reactive Oxygen Species (ROS) by electron transfer when their valency state is changed. ROS are also considered the root cause of oxidative damage in the AD brain. Thus, modulation of iron ion levels in the brain is a potential therapeutic strategy for the treatment of AD.
Also, studies have shown that levels of monoamine oxidase (MAOs) also exist in the brain of AD patients, especially MAO-B. Under physiological conditions, MAOs catalyze the oxidative deamination of monoamine neurotransmitters into aldehydes. The neurotoxic products of MAO-B catalysis, such as hydrogen peroxide, promote the formation of ROS and cause neuronal damage. Therefore, the development of MAO-B inhibitors is considered as a potential option for the treatment of AD.
Therefore, the development of the multi-target iron chelating agent with MAO-B inhibitory activity, anti-Abeta and anti-oxidation has great research prospect in the research and development of the multi-target anti-AD active compound.
Disclosure of Invention
In order to solve the problems, the invention designs a pyridone hexa-alkynylamine modified derivative with potential anti-AD activity, iron chelation and MAO-B inhibition activity and multi-target potential anti-Alzheimer's disease based on computer-aided drug design, quasi-drug 5 rules, multi-platform prediction through blood brain barrier and other means, a preparation method thereof and application of the pyridone hexa-alkynylamine modified derivative or medicinal salt thereof in preparation of drugs for preventing or treating related diseases, especially Alzheimer's disease and Parkinson's disease by inhibiting monoamine oxidase, chelating metallic iron ions, resisting A beta and resisting oxidation.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides a pyridone hexa-alkynylamine modified derivative shown as a formula (I) and a pharmaceutically acceptable salt thereof:
in formula (I):
R 1 is H or C 1 -C 6 A linear or branched alkyl group;
R 2 is H, C 1 -C 6 Straight or branched alkyl, F, CF 3 、OH、OCH 3 、CHOHCH 3 、COOH、COOCH 3 Or (CH) 2 ) m1 OH，m 1 ＝1-6；
R 3 Is H, C 1 -C 6 Straight or branched alkyl F, CF 3 、OH、OCH 3 、CHOHCH 3 COOH or COOCH 3 ；
R 4 Is C 1 -C 16 Straight or branched alkyl, C 2 -C 16 Straight-chain or branched alkynyl, C 2 -C 16 Straight-chain or branched alkenyl, (CH) 2 )m 2 X、
Wherein X is C 3 -C 10 Cycloalkyl groups of (a); m is 2 ＝0-6；
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently H, CH 3 、Cl、Br、F、I、CF 3 、CN、NH 2 、NO 2 、OH、OCH 3 、CH(CH 3 ) 2 Or C (CH) 3 ) 3 ；
n 1 Or n 2 Is CH 2 Number of (2), n 1 Or n 2 Taking 1-6.
Preferably, R 1 、R 2 Or R 3 Each independently is H or C 1 -C 4 A linear or branched alkyl group; r 4 Is C 1 -C 4 Straight or branched alkyl, C 2 -C 4 Straight-chain or branched alkynyl or
Wherein, Y 1 、Z 1 Each independently H, CH 3 、Cl、F、CF 3 、OCH 3 ，n 1 Or n 2 Is 1-3.
Preferably, R 1 Is CH 3 ；R 2 And R 3 Is H; r 4 Is a benzyl group,
n 1 Or n 2 Preferably 1.
Specifically, the modified derivative of pyridone hexa-alkynylamine shown in the formula (I) is one of the following compounds:
specifically, the pharmaceutically acceptable salt is hydrochloride of the pyridone hexa-alkynylamine modified derivative shown in the formula (I).
The invention also provides a preparation method of the pyridone hexa-alkynylamine modified derivative shown as the formula (I), and the synthesis thought is as follows: firstly, taking a compound of a formula 1 as a raw material, and carrying out a series of reactions to obtain an intermediate shown in a formula 4; synthesizing a compound shown in a formula 5 by using different substituted amine derivatives as raw materials, splicing the intermediate shown in the formula 4 and the intermediate shown in the formula 5 together through reaction to obtain a compound shown in a formula 6, and finally performing deprotection to obtain a target compound shown in a formula (I).
Specifically, the method comprises the following steps:
(1) Dissolving a compound shown as a formula 4 in an organic solvent A, adding a compound shown as a formula 5 and an alkaline substance B, reacting at 30-80 ℃ for 24-48h, and after the reaction is finished, carrying out aftertreatment treatment on an obtained reaction liquid C to obtain a compound shown as a formula 6; the mass ratio of the compound of formula 4 to the compound of formula 5 to the basic substance B is 1; the alkaline substance B is one or a mixture of any more of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine, preferably triethylamine;
(2) Dissolving the compound of formula 6 obtained in the step (1) in anhydrous dichloromethane to obtain 0.01-0.04 mmol/mL of anhydrous dichloromethane solution of the compound of formula 6, and slowly dropwise adding boron trichloride (BCl) into the anhydrous dichloromethane solution of the compound of formula 6 at-78-0 ℃ under the protection of nitrogen 3 ) After the dropwise addition of the anhydrous dichloromethane solution is finished, continuously stirring for 1-3h, adding methanol X for quenching, transferring to room temperature, continuously stirring for reaction for 12-24h, and carrying out post-treatment B on the obtained reaction liquid D to obtain a compound shown in a formula (I); the mass ratio of the compound shown in the formula 6 to the boron trichloride is 1:1-5 (preferably 1:2-3); the volume of the methanol X is 15-40 mL/mmol (preferably 20-35 mL/mmol) based on the amount of the intermediate substance of the formula 6; the methanol X is also methanol, which is defined herein as methanol X for convenience of description only, without special meaning;
in the formulae 4 to 6 or the formula (I), n 1 、n 2 Is CH 2 Number of (2), n 1 Or n 2 Each is 1-6;
R 1 is H, C 1 -C 6 A linear or branched alkyl group;
R 2 is H, C 1 -C 6 Straight or branched alkyl F, CF 3 、OH、OCH 3 、CHOHCH 3 、COOH、COOCH 3 Or (CH) 2 ) m1 OH，m 1 ＝1-6；
R 3 Is H, C 1 -C 6 Straight or branched alkyl F, CF 3 、OH、OCH 3 、CHOHCH 3 COOH or COOCH 3 ；
R 4 Is C 1 -C 16 Straight or branched alkyl, C 2 -C 16 Straight-chain or branched alkynyl, C 2 -C 16 Straight-chain or branched alkenyl, (CH) 2 ) m2 X、
Wherein X is C 3 -C 10 Cycloalkyl groups of (a); m is 2 ＝0-6；
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently H, CH 3 、Cl、Br、F、I、CF 3 、CN、NH 2 、NO 2 、OH、OCH 3 、CH(CH 3 ) 2 Or C (CH) 3 ) 3 。
Preferably, R 1 、R 2 Or R 3 Each independently is H or C 1 -C 4 A linear or branched alkyl group; r 4 Is C 1 -C 4 Straight or branched alkyl, C 2 -C 4 Straight-chain or branched alkynyl or
Wherein, Y 1 、Z 1 Each independently H, CH 3 、Cl、F、CF 3 、OCH 3 ，n 1 Or n 2 Is 1-3.
Preferably, R 1 Is CH 3 ；R 2 And R 3 Is H; r 4 Is a benzyl group,
n 1 Or n 2 Preferably 1.
Preferably, the modified pyridone hexaalkynylamine derivative of formula (I) is one of the following compounds:
preferably, the organic solvent a in step (1) is one or a mixture of any several of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide, and is preferably acetonitrile.
Further, in the step (1), the amount of the organic solvent A added is 10 to 20mL/mmol based on the amount of the compound of formula 4.
Further, in the step (1), the reaction condition is preferably that the reaction is carried out for 30-40h at 50-70 ℃.
Further, the post-treatment A in the step (1) is as follows: the reaction solution C was concentrated under reduced pressure, subjected to silica gel column chromatography, and gradient-eluted with a mixed solution of dichloromethane: methanol = 30.
Further, the concentration of boron trichloride in the anhydrous dichloromethane solution of boron trichloride in the step (2) is 0.05 to 0.15mmol/mL (preferably 0.08 to 0.13 mmol/mL)
Further, the post-treatment B in the step (2) is as follows: and distilling the obtained reaction liquid D under reduced pressure to remove the solvent, and recrystallizing with a mixed solvent of methanol and diethyl ether to obtain the compound shown in the formula (I), wherein the volume ratio of the methanol to the diethyl ether in the mixed solvent of the methanol and the diethyl ether is 1:5.
Further, in the step (2), the reaction temperature is preferably from-20 to-40 ℃.
In addition, the compound represented by formula 4 according to the present invention is specifically prepared as follows:
s1: dissolving hydroxypyrone shown in formula 1, benzyl bromide and an alkaline substance E in an organic solvent M, reacting at 25-90 ℃ for 2-12h, after the reaction is finished, concentrating the obtained reaction solution G under reduced pressure to obtain a solid, washing with water, and drying to obtain a compound shown in formula 2; the amount ratio of the hydroxypyrone shown in the formula 1, the benzyl bromide and the alkaline substance E is 1:1-5:1-4 (preferably 1:1-3:2-4); the alkaline substance E is one or a mixture of any more of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine, preferably potassium carbonate or sodium hydroxide, and more preferably potassium carbonate.
S2: dissolving the intermediate shown in the formula 2 in an organic solvent H, adding the compound shown in the formula 7 and an alkaline substance A, reacting for 1-5H at 30-80 ℃, and after the reaction is finished, carrying out aftertreatment C on the obtained reaction liquid J to obtain a compound shown in the formula 3; the mass ratio of the compound of the formula 2 and the formula 7 to the alkaline substance A is 1:1-4:1-4 (preferably 1:2-4:2-4); the compound of formula 7 is one of the following compounds: c 1 -C 6 Linear or branched aliphatic amines, ammonia; the alkaline substance A is one or a mixture of any more of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine, preferably potassium carbonate or sodium hydroxide, and more preferably sodium hydroxide; when the compound of the formula 7 is ammonia, the compound participates in the reaction in the form of ammonia water with the mass fraction of 25-28%;
s3: dropwise adding thionyl chloride (AR, the purity is more than or equal to 99.0%) into the intermediate shown in the formula 3, reacting at the temperature of 20-50 ℃ for 1-5h, and after the reaction is finished, carrying out aftertreatment D on obtained reaction liquid K to obtain the intermediate shown in the formula 4; the amount ratio of the intermediate represented by the above formula 3 to the thionyl chloride is 1:1 to 5 (preferably 1:1 to 3).
In formulae 1 to 4, n 2 Is CH 2 Number of (2), n 2 Taking 1-6;
R 1 is H, C 1 -C 6 A linear or branched alkyl group;
R 2 is H, C 1 -C 6 Straight or branched alkyl, F, CF 3 、OH、OCH 3 、CHOHCH 3 、COOH、COOCH 3 Or (CH) 2 ) m1 OH，m 1 ＝1-6；
R 3 H, C 1 -C 6 Straight or branched alkyl F, CF 3 、OH、OCH 3 、CHOHCH 3 COOH or COOCH 3 ；
Further, the organic solvent M in S1 is one or a mixture of any more of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, toluene, dimethyl sulfoxide, dioxane, N-dimethylformamide, and N, N-dimethylacetamide, preferably acetone or ethanol, and more preferably ethanol.
Still further, the amount of the organic solvent M added is 1 to 3mL/mmol based on the amount of the hydroxypyrone represented by the formula 1.
Further, in S1, the reaction temperature is preferably 25 to 70 ℃ and the reaction time is preferably 3 to 8 hours.
Further, in S2, the organic solvent H is one or a mixture of any one of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, toluene, dimethyl sulfoxide, dioxane, N-dimethylformamide, and N, N-dimethylacetamide, and preferably ethanol.
Still further, the amount of the organic solvent H added is 1 to 3mL/mmol based on the amount of the intermediate represented by the formula 2.
Further, in S2, the reaction temperature is preferably 40 to 70 ℃ and the reaction time is preferably 2 to 4 hours.
Further, post-treatment C in S2 is: after the reaction was terminated, the reaction solution J was concentrated under reduced pressure, and the eluate containing the target product (detected by TLC plates) was collected by silica gel column chromatography (dichloromethane: methanol = 50.
Further, in S3, the reaction temperature is preferably 25 to 40 ℃ and the reaction time is preferably 2 to 4 hours.
Further, in S3, the amount of thionyl chloride (AR, purity. Gtoreq.99.0%) added is 1 to 5mL/mmol based on the amount of the intermediate represented by the above formula 3.
Further, the mode of post-processing D in S3 is: the reaction solution K is concentrated under reduced pressure to remove the solvent, and is recrystallized by using a mixed solvent of methanol and diethyl ether to obtain the compound shown in the formula 4. The volume ratio of the methanol to the ether in the mixed solvent of the methanol and the ether is 1:8.
Further, the compound represented by formula 5 according to the present invention is prepared according to the following method:
adding different substituted amine derivatives and alkaline substances M into an organic solvent L, dissolving the compound shown in the formula 8 in an organic solvent D, placing the organic solvent D into a constant-pressure dropping funnel, dropping the mixture at the temperature of between 10 and 50 ℃ for reaction for 5 to 24 hours, and after the reaction is finished, carrying out aftertreatment E on the obtained reaction liquid P to obtain a compound shown in the formula 5; the mass ratio of the different substituted amine derivatives, the compound of formula 8 and the basic substance M is 1;
the different substituted amine derivative is one of the following compounds: c 1 -C 16 Linear or branched saturated aliphatic amine, C 2 -C 16 Straight-chain or branched alkynylamines, C 2 -C 16 Linear or branched enamines, H 2 N(CH 2 ) m2 X、
The alkaline substance M is one or a mixture of any more of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine, preferably potassium carbonate or triethylamine, and more preferably potassium carbonate;
H 2 N(CH 2 ) m2 x in X is C 3 -C 10 Cycloalkyl groups of (a); m is 2 ＝0-6；
In the case of the formulas 5 and 8,
R 4 is C 1 -C 16 Straight or branched alkyl, C 2 -C 16 Straight-chain or branched alkynyl, C 2 -C 16 Straight-chain or branched alkenyl, (CH) 2 ) m2 X、
Wherein X is C 3 -C 10 Cycloalkyl groups of (a); m is 2 ＝0-6；
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently H, CH 3 、Cl、Br、F、I、CF 3 、CN、NH 2 、NO 2 、OH、OCH 3 、CH(CH 3 ) 2 Or C (CH) 3 ) 3 ；n 1 Taking 1-6;
further, in the preparation method of the compound of formula 5, the organic solvent L or the organic solvent D is one or a mixture of any several of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide, and N, N-dimethylacetamide, and preferably N, N-dimethylformamide.
Further, the volume of the organic solvent L is 1-5 mL/mmol based on the amount of the different substituted amine derivatives; the volume of the organic solvent D is 1-5 mL/mmol based on the amount of the compound of formula 8.
Furthermore, the reaction condition is preferably 25-40 ℃, and the reaction time is preferably 10-20h.
Further, the post-treatment E is: adding ethyl acetate into the reaction liquid P, extracting for 3 times by using saturated saline solution, combining organic layers, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, finally performing silica gel column chromatography by using normal hexane: ethyl acetate =5:1 as an eluent, combining eluates containing a target compound (detected by a TLC point plate), and concentrating under reduced pressure to obtain an intermediate shown in a formula 5.
The invention also provides application of the pyridone hexa-alkynylamine modified derivative or pharmaceutically acceptable salt thereof in preparation of medicines for preventing or treating related diseases by inhibiting monoamine oxidase, chelating metallic iron ions, resisting A beta and resisting oxidation.
Preferably, the disease is alzheimer's disease or parkinson's disease.
Compared with the prior art, the invention has the beneficial effects that: the invention synthesizes a series of novel single-molecule multi-target anti-AD active compounds, innovatively combines a pyridone derivative with iron ion chelating activity and propargylamine with MAO-B inhibitory activity, has obvious advantages for Alzheimer's disease with complex pathogenesis, and the combined molecules are far superior to CP20 (deferiprone) in the aspect of iron ion chelating activity.
Detailed Description
The present invention will be further described with reference to specific examples, but the present invention is not limited to these examples.
Example 1
Preparation method of 1-methyl-2- ((benzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 1)
Kojic acid (12.78g, 90mmol), benzyl bromide (23.08g, 135mmol) and potassium carbonate (24.84g, 180mmol) are respectively added into a 500mL single-mouth bottle and reacted at 60 ℃ for 5h under the condition of taking ethanol as a solvent (250 mL), after the reaction is finished, the reaction system is decompressed and concentrated to obtain a light yellow solid crude product, and then the light yellow solid crude product is washed by water and dried to obtain a white solid (18.75 g), and the yield is 89.8%.
The above white solid (13.92g, 60mmol) was taken and dissolved in ethanol (150 mL), and sodium hydroxide (4.80g, 120mmol) and 9.30g of a methylamine aqueous solution (mass fraction: 40%; methylamine 120 mmol) were added and reacted at 50 ℃ for 2h, after the reaction was completed, the reaction solution was concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane: methanol = 50.
Placing the brown yellow solid (9.80g, 40mmol) in a 150mL single-neck bottle, slowly dropwise adding thionyl chloride (AR, the purity is more than or equal to 99.0 percent and 80 mL), stirring at 30 ℃ after dropwise adding, reacting for 2h, after the reaction is finished, concentrating the reaction solution under reduced pressure, and recrystallizing with a methanol/ether mixed solution (v: v = 1:8) to obtain an intermediate (9.21 g) of the formula 4, namely 1-methyl-2- (chloromethyl) -5-hydroxypyridine-4-one, wherein the yield is 87.5 percent.
Benzylamine (0.21g, 2mmol), potassium carbonate (0.41g, 3mmol) and N, N-dimethylformamide (10 mL) were added to a 50mL single-neck flask, and then a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (3 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and after completion of the reaction, ethyl acetate (15 mL) was added, and extraction was performed with 20mL × 3 saturated saline, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the eluate containing the target compound (obtained by TLC plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.10 g) with a yield of 69.0%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.27g, 1.04mmol) and triethylamine (0.11g, 1.04mmol) to the above bright yellow transparent liquid (0.10g, 0.69mmol) in a 50mL single-necked flask in this order and reacting at 60 ℃ for 36 hours with acetonitrile (12 mL) as a reaction solvent, the reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.18g, 0.48mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (0.96 mL, available from Sahn chemical technology Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with an anhydrous dichloromethane solution (10 mL) and placed in a constant-pressure dropping funnel under N 2 Under protection, slowly dropwise adding the diluted dropwise boron trichloride solution at-30 ℃, continuously stirring for 2h while keeping the temperature after dropwise adding, adding 10mL of methanol for quenching under the condition of low temperature, then transferring to room temperature, continuously stirring for reaction for 12h, finally concentrating the reaction solution under reduced pressure, and recrystallizing with a methanol/ether (v: v = 1:5) mixed solution to obtain a white solid a1 (0.13 g) with the yield of 96.0%.
m.p.173-175℃；ESI-HRMS:m/z calcd for C 17 H 18 N 2 O 2 [M+H]+:283.1441；found:283.1438； 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.28(s,1H),7.42(s,1H),7.33(d,J＝4.4Hz,3H),7.31–7.24(m,1H),4.04(s,3H),3.86(s,2H),3.70(s,2H),3.38(t,J＝2.4Hz,1H),3.27(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.26,146.27,144.67,137.54,133.98,129.53,128.89,128.03,114.74,77.94,65.39,57.48,53.90,43.53,41.75.
Example 2
Preparation method of 1-methyl-2- ((3-chlorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 2)
3-chlorobenzylamine (0.28g, 2mmol), potassium carbonate (0.55g, 4mmol) and N, N-dimethylformamide (10 mL) were added to a 50mL single-neck flask, and then a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (2 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and after completion of the reaction, ethyl acetate (20 mL) was added, and extraction was performed with 20 mL. Times.3 saturated saline, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate 5:1 was performed), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.14 g) with a yield of 77.8%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1mmol) and triethylamine (0.10g, 1mmol) obtained in the reaction in example 1 to a 50mL single vial and reacting at 60 ℃ for 36 hours using acetonitrile (16 mL) as a reaction solvent, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.12g, 0.29mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (0.87 mL, available from Saen chemical technology Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with an anhydrous dichloromethane solution (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain white solid a2 (0.80 g) with the yield of 87.0%.
m.p.177-179℃；ESI-HRMS:m/z calcd for C 17 H 17 ClN 2 O 2 [M+H]+:317.1051；found:317.1050； 1 H NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.29(s,1H),7.40(s,1H),7.38–7.28(m,3H),4.05(s,3H),3.86(s,2H),3.71(s,2H),3.41(t,J＝2.4Hz,1H),3.29(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.24,146.24,144.65,140.41,133.98,133.51,130.76,129.05,128.12,127.97,114.71,80.23,77.95,56.86,54.04,43.52,41.93.
Example 3
Preparation method of 1-methyl-2- ((3-fluorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 3)
3-fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.34g, 2.5 mmol) and N, N-dimethylformamide (9 mL) were added to a 50mL single-neck flask, and a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (3 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, and extracted with 20mL × 3 saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to give a bright yellow transparent liquid (0.11 g) with a yield of 67.5%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1mmol) and triethylamine (0.15g, 1.5mmol) obtained by the reaction in example 1 to a 50mL single-necked flask, and reacting at 60 ℃ for 36 hours using acetonitrile (16 mL) as a reaction solvent, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.15g, 0.38mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.14 mL, available from Sahn chemical Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with an anhydrous dichloromethane solution (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a3 (0.09 g) with the yield of 78.9%.
m.p.185-187℃；ESI-HRMS:m/z calcd for C 17 H 17 FN 2 O 2 [M+H]+:301.1347；found:301.1349； 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.28(s,1H),7.43–7.34(m,2H),7.21–7.06(m,3H),4.04(s,3H),3.86(s,2H),3.71(s,2H),3.40(t,J＝2.4Hz,1H),3.28(d,J＝2.6Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ162.67(d, 1 J C-F ＝263.4Hz),160.25,146.38,144.62,140.84(d, 3 J C-F ＝7.3Hz),133.98,130.82(d, 3 J C-F ＝8.3Hz),125.42(d, 4 J C-H ＝2.4Hz),115.89(d, 2 J C-F ＝21.1),114.80(d, 2 J C-F ＝20.9),114.62,80.23,77.89,56.91,54.02,43.51,41.93.
Example 4
Preparation method of 1-methyl-2- ((4-methylbenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 4)
4-methylbenzylamine (0.24g, 2mmol), potassium carbonate (0.28g, 2mmol) and N, N-dimethylformamide (8 mL) were charged into a 50mL single-neck flask, a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (4 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, the mixture was stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (20 mL) was added, the mixture was extracted with 20mL × 3 saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate =5:1 elution), the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to give a bright yellow transparent liquid (0.12 g), and the yield was 75.5%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1mmol) and triethylamine (0.15g, 1.5mmol) obtained by the reaction in example 1 to a 50mL single-necked flask, and reacting at 60 ℃ for 36 hours using acetonitrile (20 mL) as a reaction solvent, the reaction mixture was concentrated, and the reaction mixture was purified by silica gel column chromatography (dichloromethane: methanol = 30.
Into a 100mL single-necked flask were charged the oily liquid (0.13g, 0.34mmol) and anhydrous dichloromethane (15 mL), and 1.0mol/L of boron trichloride was added(1.02 mL, available from Sahn Chemicals Ltd., batch No.: GK130009, dichloromethane as solvent) was diluted with anhydrous dichloromethane (10 mL) and placed in an isobaric dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after dripping, adding 10mL of methanol at low temperature for quenching, transferring to room temperature and continuously stirring for reacting for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a4 (0.08 g) with the yield of 79.5%.
m.p.190-192℃；ESI-HRMS:m/z calcd for C 18 H 20 ClN 2 O 2 [M+H]+:297.1598；found:297.1581； 1 H NMR(400MHz,DMSO-d 6 )δ11.08(s,1H),8.26(s,1H),7.38(s,1H),7.21(d,J＝8.0Hz,2H),7.13(d,J＝7.8Hz,2H),4.03(s,3H),3.83(s,2H),3.64(s,2H),3.36(t,J＝2.4Hz,1H),3.25(d,J＝2.4Hz,2H),2.28(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ160.23,146.41,144.64,137.20,134.46,133.97,129.51,129.45,114.68,77.99,77.88,57.22,53.81,43.51,41.63,21.20.
Example 5
Preparation method of 1-methyl-2- ((4-fluorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 5)
4-fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.55g, 4mmol) and N, N-dimethylformamide (9 mL) were added to a 50mL single-neck flask, and then a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (4 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and after completion of the reaction, ethyl acetate (15 mL) was added, and extraction was performed with 20mL × 3 saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate 5:1 was eluted), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.13 g) with a yield of 79.7%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1mmol) and triethylamine (0.20g, 2mmol) obtained in the reaction in example 1 to a 50mL single vial, followed by reaction at 60 ℃ for 36 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.15g, 0.38mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.11 mL, available from Sahn chemical Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with an anhydrous dichloromethane solution (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a5 (0.10 g) with the yield of 87.7%.
m.p.188-190℃；ESI-HRMS:m/z calcd for C 17 H 17 FN 2 O 2 [M+H]+:301.1347；found:301.1345； 1 H NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.29(s,1H),7.42(s,1H),7.41–7.35(m,2H),7.18–7.12(m,2H),4.03(s,3H),3.85(s,2H),3.68(s,2H),3.39(t,J＝2.4Hz,1H),3.26(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ162.02(d, 1 J C-F ＝242Hz),160.28,146.32,144.66,133.99,133.03,131.50(d, 3 J C-F ＝8.2Hz),115.63(d, 2 J C-F ＝21.1Hz)114.70,80.14,77.92,56.64,53.85,43.52,41.75.
Example 6
Preparation method of 1-methyl-2- ((4-chlorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 6)
4-chlorobenzylamine (0.28g, 2mmol), potassium carbonate (0.41g, 3mmol) and N, N-dimethylformamide (10 mL) were charged into a 50mL single-neck flask, a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (3 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, the mixture was stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, extraction was performed with 20 mL. Times.3 saturated saline, the organic layers were combined, dried with sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate =5:1 elution), the eluate containing the target compound (obtained by TLC spot plate) was collected, concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g), and the yield was 66.7%.
After the reaction was completed for 36 hours at 60 ℃ by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1 mmol) and triethylamine (0.10g, 1mmol) obtained in the reaction of example 1 to a 50mL single-necked flask, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.15g, 0.37mmol) and anhydrous methylene chloride (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.11 mL, obtained from Sahn chemical Co., ltd., batch No.: GK130009, solvent: methylene chloride) was diluted with anhydrous methylene chloride (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a6 (0.11 g) with the yield of 93.8%.
m.p.187-189℃；ESI-HRMS:m/z calcd for C 17 H 17 ClN 2 O 2 [M+H]+:317.1051；found:317.1054； 1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H),8.30–8.23(m,1H),7.45–7.33(m,6H),4.03(s,3H),3.84(s,2H),3.68(s,2H),3.38(t,J＝2.4Hz,1H),3.26(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.28,146.19,144.68,136.62,133.94,132.55,131.38,128.84,114.66,78.01,77.86,56.64,53.88,43.57,41.80.
Example 7
Preparation method of 1-methyl-2- ((2-chlorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 7)
2-chlorobenzylamine (0.56g, 4 mmol), potassium carbonate (1.10g, 8mmol) and N, N-dimethylformamide (20 mL) were added to a 50mL single-neck flask, and a solution of 3-bromopropyne (0.24g, 2mmol) in N, N-dimethylformamide (8 mL) was slowly dropped into the reaction solution through a constant-pressure dropping funnel, and stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (30 mL) was added, and extracted with 30 mL. Times.4 saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.26 g) with a yield of 72.2%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.395 mmol) and triethylamine (0.20g, 2mmol) obtained in the reaction in example 1 to a 50mL single-necked flask, using acetonitrile (25 mL) as a reaction solvent, and reacting at 60 ℃ for 36 hours, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.16g, 0.39mmol) and anhydrous dichloromethane (15 mL) were charged in a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.18 mL, available from Saen chemical technology Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 And (2) slowly adding the diluted boron trichloride solution dropwise at-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise addition is finished, adding 10mL of methanol at low temperature for quenching, transferring to room temperature, continuously stirring for reacting for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a7 (0.09 g) with the yield of 72.8%.
m.p.190-192℃；ESI-HRMS:m/z calcd for C 17 H 17 ClN 2 O 2 [M+H]+:317.1051；found:317.1056； 1 H NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),8.29(s,1H),7.49–7.40(m,2H),7.36–7.28(m,2H),4.02(s,3H),3.89(s,2H),3.77(s,2H),3.42(t,J＝2.4Hz,1H),3.31(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.23,146.18,144.73,135.08,133.99,133.97,131.90,130.03,129.87,127.74,115.04,78.04,77.99,54.34,54.14,43.38,41.98.
Example 8
Preparation method of 1-methyl-2- ((2-methoxybenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 8)
2-methoxybenzylamine (0.82g, 6 mmol), potassium carbonate (1.66g, 12mmol) and N, N-dimethylformamide (30 mL) were added to a 50mL single-neck flask, a solution of 3-bromopropyne (0.36g, 3 mmol) in N, N-dimethylformamide (12 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, the mixture was stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (40 mL) was added, the mixture was extracted with 40 mL. Times.3 saturated saline, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate =5:1 elution), the eluate containing the target compound (obtained by TLC spot plate) was collected, concentrated under reduced pressure to give a bright yellow transparent liquid (0.42 g), and the yield was 80.0%.
After the reaction was completed for 36 hours at 60 ℃ by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridine-4-one (0.39g, 1.5mmol) and triethylamine (0.15g, 1.5mmol) obtained by the reaction in example 1 to a 50mL single-neck flask, the reaction solution was concentrated, and the eluate containing the objective compound (obtained by TLC spot plate) was collected and concentrated to obtain a yellow oily liquid (0.25 g) in a yield of 62.2% under reduced pressure by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15 mL) were charged in a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.11 mL, available from Sahn chemical technology Co., ltd., batch No.: GK130009, solventDichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a8 (0.09 g) with the yield of 78.0%.
m.p.136-138℃；ESI-HRMS:m/z calcd for C 18 H 20 N 2 O 3 [M+H]+:313.1547；found:313.1550； 1 H NMR(400MHz,DMSO-d 6 )δ11.20(s,1H),8.31(s,1H),7.40(s,1H),7.26(t,J＝7.3Hz,2H),7.02–6.85(m,2H),4.03(s,3H),3.87(s,2H),3.73(s,3H),3.65(s,2H),3.39(s,1H),3.30(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.21,158.03,146.07,144.75,134.00,131.03,129.62,124.85,120.64,115.13,111.44,78.13,77.84,55.81,54.09,51.56,43.37,42.00.
Example 9
Preparation method of 1-methyl-2- ((4-trifluoromethylbenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 9)
4-trifluoromethylbenzylamine (0.35g, 2mmol), potassium carbonate (0.48g, 3.5 mmol) and N, N-dimethylformamide (9 mL) were added to a 50mL single-neck flask, and a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (4 mL) was slowly added dropwise to the reaction solution through a constant-pressure dropping funnel, followed by stirring at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, extraction was performed with 20mL × 3 saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.15 g) with a yield of 70.4%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.27g, 1.02mmol) and triethylamine (0.21g, 2.04mmol) obtained in the reaction of example 1 to a 50mL single-neck flask, using acetonitrile (20 mL) as a reaction solvent, and reacting at 60 ℃ for 36 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane: methanol =30:1 to 15.
The oily liquid (0.17g, 0.39mmol) and anhydrous dichloromethane (15 mL) were charged in a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.17 mL, available from Saen chemical technology Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a9 (0.11 g) with the yield of 80.6%.
m.p.194-196℃；ESI-HRMS:m/z calcd for C 18 H 17 F 3 N 2 O 2 [M+H]+:351.1315；found:351.1318； 1 H NMR(400MHz,DMSO-d 6 )δ11.13(s,1H),8.27(s,1H),7.69(d,J＝8.1Hz,2H),7.57(d,J＝8.0Hz,2H),7.41(s,1H),4.05(s,3H),3.89(s,2H),3.80(s,2H),3.42(t,J＝2.4Hz,2H),3.30(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.28,146.41,144.63,142.84,133.94,130.12,128.51(q, 2 J C-F ＝94.9),124.72(d, 1 J C-F ＝270.2),125.69(d, 4 J C-F ＝3.7),114.57,78.00,77.90,56.94,54.10,43.52,42.08.
Example 10
Preparation method of 1-methyl-2- ((3,5-difluorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 10)
3,5-difluorobenzylamine (0.29g, 2mmol), potassium carbonate (0.55g, 4mmol) and N, N-dimethylformamide (10 mL) were added to a 50mL single-neck flask, a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, extraction was performed with 20mL × 3 saturated saline, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the target compound (obtained by TLC spot) was collected, concentrated under reduced pressure to give a bright yellow transparent liquid (0.14 g), and the yield was 77.3%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 0.99mmol) and triethylamine (0.10g, 0.99mmol) obtained in the reaction of example 1 to a 50mL single-necked flask, and reacting at 60 ℃ for 36 hours using acetonitrile (18 mL) as a reaction solvent, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane: methanol =30:1 to 15.
The oily liquid (0.17g, 0.42mmol) and anhydrous methylene chloride (15 mL) were charged in a 100mL single-neck flask, and 1.0mol/L of boron trichloride (1.26 mL, obtained from Sahn chemical technology Co., ltd., batch No.: GK130009, solvent: methylene chloride) was diluted with anhydrous methylene chloride (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a10 (0.11 g) with the yield of 82.3%.
m.p.183-185℃；ESI-HRMS:m/z calcd for C 17 H 16 F 2 N 2 O 2 [M+H]+:319.1253；found:319.1256； 1 H NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.30(s,1H),7.42(s,1H),7.17–7.09(m,1H),7.09–7.02(m,2H),4.04(s,3H),3.87(s,3H),3.73(s,2H),3.39(t,J＝2.4Hz,1H),3.31(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ162.83(dd, 1 J C-F ＝244.8, 3 J C-F ＝13.2),160.27,146.28,144.64,142.78(t, 3 J C-F ＝9Hz),133.99,114.57,112.18(dd, 2 J C-F ＝24.8Hz, 4 J C-F ＝11.9Hz),103.39(t, 2 J C-F ＝51.2),80.27,77.93,56.65,54.03,43.53,42.11.
Example 11
Preparation method of 1-methyl-2- ((4-methoxybenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 11)
4-methoxybenzylamine (0.27g, 2mmol), potassium carbonate (0.55g, 4mmol) and N, N-dimethylformamide (9 mL) were added to a 50mL single-neck flask, and then a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, and extraction was performed with 20mL × 3 saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g) with a yield of 68.6%.
The bright yellow transparent liquid (0.11g, 0.63mmol) was taken out and charged into a 50mL single-neck flask, and 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.25g, 0.94mmol) and triethylamine (0.14g, 1.41mmol) obtained in the reaction of example 1 were added thereto, and the reaction mixture was reacted at 60 ℃ for 36 hours with acetonitrile (15 mL) as a reaction solvent, and after the reaction was completed, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane: methanol =30:1 to 15.
The oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.11 mL, available from Sahn chemical Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 Under protection, slowly adding diluted boron trichloride solution at-30 deg.C, heating, stirring at the same temperature for 2 hr, and adding at low temperatureAfter the reaction solution was concentrated, the reaction solution was recrystallized from a mixed solvent of methanol/ether (v: v = 1:5) to obtain a white solid a11 (0.10 g) with a yield of 86.6%.
m.p.158-160℃；ESI-HRMS:m/z calcd for C 18 H 20 N 2 O 3 [M+H]+:313.1547；found:313.1526； 1 H NMR(400MHz,DMSO-d 6 )δ11.22(s,1H),8.29(s,1H),7.42(s,1H),7.29–7.23(m,2H),6.92–6.85(m,2H),4.03(s,3H),3.85(s,2H),3.73(s,3H),3.65(s,2H),3.39(t,J＝2.4Hz,1H),3.27(d,J＝2Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.20,159.28,145.71,144.74,133.98,131.08,128.63,114.98,114.29,78.32,77.59,56.92,55.55,53.46,43.66,41.63.
Example 12
Preparation method of 1-methyl-2- ((2-methylbenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 12)
2-methylbenzylamine (0.24g, 2mmol), potassium carbonate (0.41g, 3mmol) and N, N-dimethylformamide (8 mL) were added to a 50mL single-neck flask, and a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (4 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, and extracted with 20 mL. Times.3 saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.11 g) with a yield of 69.2%.
After the reaction was completed by adding 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1mmol) and triethylamine (0.15g, 1.5mmol) obtained by the reaction in example 1 to a 50mL single-necked flask, and reacting at 60 ℃ for 36 hours using acetonitrile (20 mL) as a reaction solvent, the reaction mixture was concentrated, and the reaction mixture was purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.12g, 0.31mmol) and anhydrous dichloromethane (15 mL) were charged in a 100mL single-neck flask, and 1.0mol/L boron trichloride (0.93 mL, available from Saen chemical technology Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding diluted boron trichloride solution dropwise at-30 deg.C under protection, stirring for 2 hr, adding 10mL methanol at low temperature, transferring to room temperature, stirring for reaction for 12 hr, concentrating the reaction solution, and recrystallizing with methanol/diethyl ether (v: v = 1:5) mixed solvent to obtain white solid a12 (0.07 g) with yield of 76.3%
m.p.177-179℃；ESI-HRMS:m/z calcd for C 18 H 20 N 2 O 2 [M+H]+:297.1598；found:297.1599； 1 H NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),8.27(s,1H),7.37(s,1H),7.27(dd,J＝7.8,1.8Hz,1H),7.21–7.11(m,3H),3.97(s,3H),3.84(s,2H),3.68(s,2H),3.41(t,J＝2.4Hz,1H),3.26(d,J＝2.4Hz,2H),2.25(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ160.24,146.29,144.71,137.65,135.48,133.87,130.78,130.49,128.12,126.20,114.93,78.10,78.03,55.38,53.76,43.28,41.84,19.16.
Example 13
Preparation method of 1-methyl-2- ((3-methoxybenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 13)
3-methoxybenzylamine (0.27g, 2mmol), potassium carbonate (0.55g, 4mmol) and N, N-dimethylformamide (10 mL) were added to a 50mL single-neck flask, and then a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, and stirred at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, and extraction was performed with 20mL × 3 saturated brine, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (N-hexane: ethyl acetate = 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g) with a yield of 68.6%.
The bright yellow transparent liquid (0.11g, 0.63mmol) was taken out and put into a 50mL single-neck flask, and 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.25g, 0.94mmol) and triethylamine (0.20g, 2 mmol) obtained in the reaction in example 1 were added to the mixture, and the mixture was reacted at 60 ℃ for 36 hours, and after the reaction was completed, the reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.11 mL, available from Sahn chemical Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at the temperature of-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after the dropwise adding is finished, adding 10mL of methanol for quenching at low temperature, transferring to room temperature and continuously stirring for reaction for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a13 (0.09 g) with the yield of 78.0%.
m.p.159-161℃；ESI-HRMS:m/z calcd for C 18 H 20 N 2 O 3 [M+H]+:313.1547；found:313.1544； 1 H NMR(400MHz,DMSO-d 6 )δ11.13(s,1H),8.27(s,1H),7.39(s,1H),7.24(t,J＝7.8Hz,1H),6.90(dt,J＝7.5,1.2Hz,1H),6.88–6.80(m,2H),4.04(s,3H),3.84(s,2H),3.74(s,3H),3.67(s,2H),3.8(t,J＝2.4Hz,1H),3.29(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ160.21,159.75,146.29,144.65,139.16,133.94,129.96,121.62,114.89,114.73,113.44,78.01,77.94,57.56,55.49,53.86,43.51,41.96.
Example 14
Preparation method of 1-methyl-2- ((2-fluorobenzyl (propargyl) amino) methyl) -5-hydroxypyridin-4 (1H) -one (a 14)
4-fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.55g, 4mmol) and N, N-dimethylformamide (10 mL) were added to a 50mL single-neck flask, and a solution of 3-bromopropyne (0.12g, 1mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel, followed by stirring at 30 ℃ for 12 hours, after completion of the reaction, ethyl acetate (15 mL) was added, extraction was performed with 20mL × 3 saturated brine, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (N-hexane: ethyl acetate 5:1), and the eluate containing the target compound (obtained by TLC spot plate) was collected and concentrated under reduced pressure to give a bright yellow transparent liquid (0.11 g) with a yield of 67.5%.
The bright yellow transparent liquid (0.10g, 0.61mmol) was taken out, and 1-methyl-2- (chloromethyl) -5-hydroxypyridin-4-one (0.26g, 1mmol) and triethylamine (0.15g, 1.5mmol) obtained by the reaction in example 1 were added to a 50mL single-neck flask, and reacted at 60 ℃ for 36 hours, and after the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 30.
The oily liquid (0.15g, 0.38mmol) and anhydrous dichloromethane (15 mL) were charged into a 100mL single-neck flask, and 1.0mol/L boron trichloride (1.11 mL, available from Sahn chemical Co., ltd., batch No.: GK130009, solvent: dichloromethane) was diluted with anhydrous dichloromethane (10 mL) and placed in a constant pressure dropping funnel under N 2 Slowly adding the diluted boron trichloride solution dropwise at-30 ℃ under protection, continuously keeping the temperature and stirring for 2h after dripping, adding 10mL of methanol at low temperature for quenching, transferring to room temperature and continuously stirring for reacting for 12h, finally concentrating the reaction solution, and recrystallizing by using a methanol/ether (v: v = 1:5) mixed solvent to obtain a white solid a14 (0.10 g) with the yield of 87.7%.
m.p.176-178℃；ESI-HRMS:m/z calcd for C 17 H 17 FN 2 O 2 [M+H]+:301.1347；found:301.1346； 1 H NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),8.29(s,1H),7.45–7.30(m,3H),7.21–7.12(m,2H),4.02(s,3H),3.88(s,2H),3.73(s,2H),3.40(t,J＝2.4Hz,1H),3.29(d,J＝2.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ161.29(d, 1 J C-F ＝244.1Hz),160.24,146.21,144.70,133.98,131.96(d, 3 J C-F ＝4.1Hz),130.21(d, 3 J C-F ＝8.2Hz),124.91(d, 4 J C-F ＝3.2Hz),124.51(d, 2 J C-F ＝14Hz),115.86(d, 2 J C-F ＝21.4Hz),114.83,77.96,77.89,54.03,50.42,43.33,41.79.
Comparative example 1
The compound of formula 6 was prepared in the same manner as in example 1 except that potassium carbonate (0.114g, 1.04mmol) was used in place of triethylamine (0.11g, 1.04mmol) in the preparation of formula 6 to give the intermediate of formula 6 in a yield of 0.12g and 46.7%
Comparative example 2
The preparation process of the compound a1 is the same as that in example 1, except that in this example, after the dropwise addition of boron trichloride is completed, stirring is continued at room temperature for 12 hours, then 10mL of methanol is added for quenching, stirring is continued for reaction for 2 hours, and the obtained reaction solution is subjected to post-treatment to finally fail to obtain the compound a 1.
The reason why the b1 compound cannot be obtained is that the reaction occurs in the system in the process of continuously stirring at room temperature for 12 hours after the boron trichloride is dripped, and because the excessive boron trichloride in the reaction system is not quenched, the reaction phenomenon can be verified: the system changes from a solid suspension into a clear solution with a large amount of oily substances adhered to the bottom of the bottle, which indicates that the originally generated a1 compound can be subjected to other reactions and further converted into other compounds or mixtures.
Example 15
The following are the pharmacological test data for some of the compounds of the invention:
1. determination of the inhibitory Activity of Compounds on MAO-B
The experimental method comprises the following steps:
MAO-B kit was purchased from BioVision and stored at-20 ℃ until use, and enzyme and substrate solutions were prepared in advance by the kit procedure. mu.L of different concentrations of test compound (100nM, 250nM,500nM, 1. Mu.M, 2. Mu.M, 4. Mu.M, 20. Mu.M) and 25. Mu.L of enzyme solution were mixed and added to a Corning bottom-read 96-well microplate and incubated at 37 ℃ for 10 minutes with shaking, followed by 20. Mu.L of substrate solution, and the results were quantified based on the generated fluorescence (excitation, 535nm; emission, 587 nm) in a multi-assay microplate fluorescence reader.
The results show that the compounds prepared in examples 1 to 16 of the invention have better inhibition effect on MAO-B, the highest concentration of the compound can reach 46.69 +/-0.71 percent when the concentration of the drug is 100nM, the compound is close to 49.91 +/-2.73 percent of the positive control drug Pargyline, and the IC of the most effective compound is 50 The value reaches 105.2 +/-3.4 nM and is close to the IC of a positive control drug Pargyline 50 The value was 97.0. + -. 4.2nM. Is a potential lead compound.
TABLE 1 MAO-B inhibition ratio of examples 1 to 14
TABLE 2 IC for inhibitory Activity of some examples 50 Value of
Through IC 50 Value measurement As can be seen, example a1 (IC) 50 =105.2 ± 3.4), example a8 (IC) 50 =119.1 ± 4.8) performed the most excellent among the 14 compounds of the present case.
2. Determination of iron ion chelating ability of Compounds b1 to 14
According to the principle of spectrophotometry, a set of Automatic Titration system (Automatic Titration system) is adopted to pair pK a And (4) carrying out measurement. The system comprises: automatic titrator (Metrohm Dosimat 765 litter mL syringe), pH meter [ Mettler Toledo MP230 with Metrohm pH electrode (6.0133.100) and a reference electrode (6.0733.100)]An ultraviolet-visible spectrophotometer (HP 8453) and a computer programmed with VB.
pK a Titration: a cuvette with a 50mm light path was charged with 45mL (0.1M) of potassium chloride solution, the baseline was corrected, and 40. Mu.L of saturated Na was added 2 EDTA solution, addingAdd 1.5M hydrochloric acid and acidify to pH about 2. 20. Mu.L of a 50mM DMSO solution of the test compound was added with constant stirring. And starting automatic titration after the absorption spectrum is stable. Namely, 0.1M KOH solution is dripped into the automatic burette, the dripping amount is controlled to just increase the pH of the solution by 0.1 unit, after the addition is finished, the system automatically collects a full-wavelength spectrum after 30 seconds after the pH of the system is balanced. (the pH balance of the solution to be measured is determined by the criterion that the change of the pH value is not more than 0.001 within 3 seconds, and the reading is considered to be stable). The system automatically repeats the auto-titration operation until the pH reaches a specified end-point pH value. All data measured in the whole process are recorded and backed up by an internal Visual Basic program. The collected spectral results were analyzed using the hyppec 2014 program and pK was done a And (4) calculating.
Determination of Log β 1: to a quartz cuvette with a light path of 50mm, 45mL of a 0.1M potassium chloride solution was added, the baseline was corrected, and the cuvette was acidified to a pH of about 2.1 with 1.5M hydrochloric acid. 60 μ L of 50mM working solution was added and stabilized for 2min. FeCl was added as ligand/iron =1.1/1 3 The acidic solution of (3) is stirred at a constant speed.
After the OD stabilized, the autoburette added an amount of (4M) HCl solution such that the pH of the solution dropped by 0.1 units. And monitoring the spectrum after the pH value is stable, and collecting and storing all the spectrum signals once if the maximum value of the spectrum absorption curve is stable. (the determination standard of pH stability is that the change of pH value is not more than 0.001 within 3 seconds, and the spectral absorption stability standard is that the change rate is not more than 1% within 2 min). The cycle is repeated until the specified pH value is reached. All data measured in the whole process are recorded and backed up through an internal Visual Basic program.
Determination of Log β 2 and Log β 3: to a quartz cuvette with a 50mm light path, 25mL of 0.1M KCl solution, 20mL of DMSO was added. And correcting the baseline after the spectrum is stabilized. Acidification was carried out with 1.5M hydrochloric acid to a pH of about 2.5. The test compound solution with a concentration of 50mM is added and stabilized for 2min. FeCl is added in the ratio of ligand/iron ion =5/1 3 The acidic solution of (2) is stirred at a constant speed. After the OD value had stabilized, a certain amount of 0.1M HCl solution was added to the automatic burette to raise the pH of the solution by 0.1 unit. After the pH value is stabilized for 1min,the acquisition and storage of the full spectrum signal is started. (the criterion for pH stabilization is that the pH reading is considered stable when the pH does not change more than 0.001 within 3 seconds. This cycle is repeated until the specified pH is reached. All data measured throughout the process are recorded and backed up by an internal Visual Basic program.
pK determined according to the above method a1 ，pK a2 The numerical values of Log beta 1, log beta 2 and Log beta 3 are calculated by HYSS software fitting to obtain pFe 3+
The results show that pFe of examples a 1-14 3+ The values are basically all larger than 19, which shows that the series of compounds have excellent iron ion chelating activity. In particular example a11, pFe 3+ The value was 21.03, which is approximately 1000-fold stronger than the control drug CP20 used in this experiment. The series of compounds also have potential for further research.
TABLE 3 pFe of examples 1-14 3+ Value of
a：pK a And Log β 1 measurement system: 0.1M KCl solution; log β 2 and Log β 3 measurement systems: KCl (0.1M) =2:3 (V/V)
b: measurement in 0.1M KCl solution
c: the literature Xie YY, lu ZD, kong XL, zhou T, bansal S, hider R.systematic compliance of the mono-, dimethyl-and trimetyl 3-hydroxy-4 (1H) -pyridones-immobilized optimization of the organic active iron cheminer, preferiprone. Eur J Med Chem 2016;115, 132-140) reported CP20 (deferiprone) reference value (0.1 KCl)
As can be seen from the measurement of the iron ion chelation constant, example a9 (pFe = 21.03) and example a11 (pFe = 21.44) performed the most excellent among the 14 compounds in this case.
3. Calculation of drug property parameters of compounds a 1-14 and prediction of blood brain barrier penetration a
The blood brain barrier is the separation of circulating blood and cerebrospinal fluid in the central nervous system. Blood-brain barrier penetration is an important indicator for the measurement of Central Nervous System (CNS) drugs. We have calculated their class constants for examples a1 to 14 and predicted whether they are able to cross the blood brain barrier. All results are carried out on a SwissaDME website (http:// www.swissadme.ch /), and the prediction results show that implementation a 1-14 all accord with five rules of similar drugs, and the prediction results show that the compounds can permeate blood brain barriers, so that the series of compounds have innovation and huge development potential. Specific results are shown in Table four
TABLE 4 values of drug-like properties of examples 1 to 14 a
MW is the molecular mass of the compound; and (3) iLogP: the calculated logarithm of the octanol-water partition coefficient; and (2) tPSA: topological polar surface area; HBA: a hydrogen bond acceptor; HBD: a hydrogen bond donor; BBB permant: blood-brain barrier permeability: 1; inability to cross the blood brain barrier: 0.
through simulation calculation of a website, the 16 compounds in the scheme have good drug-like property and blood brain barrier penetrability.
Claims (9)
1. A modified pyridone hexa-alkynylamine derivative shown as a formula (I) and pharmaceutically acceptable salts thereof:
in formula (I):
R 1 is C 1 -C 6 A linear or branched alkyl group;
R 2 is H;
R 3 is H;
R 4 is composed of
Y 1 、Z 1 Each independently H, CH 3 、Cl、Br、F、I、CF 3 、CN、NH 2 、NO 2 、OH、OCH 3 、CH(CH 3 ) 2 Or C (CH) 3 ) 3 ；
n 1 Or n 2 Is CH 2 Number of (2), n 1 Or n 2 Taking 1-6.
2. The modified derivatives of pyridone hexa-alkynylamine as claimed in claim 1, wherein: y is 1 、Z 1 Each independently H, CH 3 、Cl、F、CF 3 、OCH 3 ，n 1 Or n 2 Is 1 to 3.
3. The modified pyridone hexa-alkynylamine derivative of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the modified derivatives of the pyridone hexa-alkynylamine are one of the following:
4. a pyridone hexa-alkynylamine modified derivative of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is hydrochloride of the pyridone hexa-alkynylamine modified derivative shown in the formula (I).
5. A method for preparing the modified derivatives of pyridone hexa-alkynylamine as shown in formula (I) and pharmaceutically acceptable salts thereof as claimed in claim 1, which comprises the following steps:
(1) Dissolving a compound shown as a formula 4 in an organic solvent A, adding a compound shown as a formula 5 and an alkaline substance B, reacting for 24-48h at 30-80 ℃, and after the reaction is finished, carrying out aftertreatment on an obtained reaction solution C to obtain a compound shown as a formula 6; the mass ratio of the compound of the formula 4 to the compound of the formula 5 to the basic substance B is 1; the alkaline substance B is one or a mixture of any more of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine;
(2) Dissolving the compound of formula 6 obtained in the step (1) in anhydrous dichloromethane to obtain 0.01-0.04 mmol/mL of anhydrous dichloromethane solution of the compound of formula 6, slowly dropwise adding the anhydrous dichloromethane solution of boron trichloride into the anhydrous dichloromethane solution of the compound of formula 6 at-78-0 ℃ under the protection of nitrogen, after dropwise adding, continuously stirring for 1-3h, adding methanol X for quenching, transferring to room temperature, continuously stirring for reacting for 12-24h, and carrying out aftertreatment B on the obtained reaction liquid D to obtain the compound shown in the formula (I); the mass ratio of the compound shown in the formula 6 to the boron trichloride is 1:1-5; the volume of the methanol X is 15-40 mL/mmol based on the substance of the intermediate of the formula 6;
in the formulae 4 to 6 or the formula (I), n 1 、n 2 Is CH 2 Number of (2), n 1 Or n 2 Each is 1-6;
R 1 is C 1 -C 6 A linear or branched alkyl group;
R 2 is H;
R 3 is H;
R 4 is composed of
Y 1 、Z 1 Each independently H, CH 3 、Cl、Br、F、I、CF 3 、CN、NH 2 、NO 2 、OH、OCH 3 、CH(CH 3 ) 2 Or C (CH) 3 ) 3 。
6. A method for preparing the modified derivatives of pyridone hexa-alkynylamine represented by the formula (I) and pharmaceutically acceptable salts thereof according to claim 5, wherein the method comprises the following steps: the organic solvent A in the step (1) is one or a mixture of any more of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide; the addition amount of the organic solvent A is 10-20 mL/mmol based on the amount of the intermediate substance shown in the formula 4.
7. A method for preparing the pyridone hexa-alkynylamine modified derivative shown in the formula (I) and the pharmaceutically acceptable salt thereof as claimed in claim 5, wherein the method comprises the following steps:
the post-treatment A in the step (1) is as follows: concentrating the reaction solution C under reduced pressure, performing silica gel column chromatography, performing gradient elution by using a mixed solution of dichloromethane and methanol = 30;
the mode of post-processing B in the step (2) is as follows: and distilling the obtained reaction liquid D under reduced pressure to remove the solvent, and recrystallizing with a mixed solvent of methanol and diethyl ether to obtain the compound shown in the formula (I), wherein the volume ratio of methanol to diethyl ether in the mixed solvent of methanol and diethyl ether is 1:5.
8. A method for preparing the pyridone hexa-alkynylamine modified derivative shown in the formula (I) and the pharmaceutically acceptable salt thereof as claimed in claim 5, wherein the method comprises the following steps: in the step (1), the reaction temperature is 50-70 ℃, and the reaction time is 30-40h; in the step (2), the reaction temperature is-20 to-40 ℃.
9. Use of a modified derivative of pyridone hexaalkynylamine of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for the preparation of a medicament for the prevention or treatment of a related disease by inhibiting monoamine oxidase, chelating metallic iron ions, anti- Α β and anti-oxidant activity;
the disease is Alzheimer's disease or Parkinson's disease.
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