CN113956182B - HDAC/MAO-B dual inhibitor and preparation and application thereof - Google Patents

HDAC/MAO-B dual inhibitor and preparation and application thereof Download PDF

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CN113956182B
CN113956182B CN202111180441.0A CN202111180441A CN113956182B CN 113956182 B CN113956182 B CN 113956182B CN 202111180441 A CN202111180441 A CN 202111180441A CN 113956182 B CN113956182 B CN 113956182B
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白仁仁
谢恬
叶向阳
姚传胜
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Abstract

The application discloses an HDAC/MAO-B dual inhibitor, a preparation method thereof and application thereof in preparing medicaments and neuroprotective antioxidants for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase. The HDAC/MAO-B dual inhibitor has the following general formula (I) or (II): in the formulas (I) and (II): r is each independently an aromatic group or a substituted aromatic group. The HDAC/MAO-B dual inhibitor has both an HDAC inhibiting effect and a MAO-B inhibiting effect, and is a multi-target hydroxamic acid/anthranilamide propynylamine derivative which realizes neuroprotection and antioxidation by the cooperation of a propynylamine group and a hydroxamic acid or anthranilamide group.

Description

HDAC/MAO-B dual inhibitor and preparation and application thereof
Technical Field
The application relates to the field of pharmaceutical chemistry, in particular to an HDAC/MAO-B dual inhibitor and preparation and application thereof.
Background
Alzheimer's Disease (AD) is a progressive neurodegenerative Disease characterized by abnormal deposition of amyloid beta peptide and microtubule-associated protein tau, the most common form of dementia in elderly, accounting for about 60% -70% of the population suffering from dementia. The pathogenesis of AD is quite complex and is not yet fully elucidated. Among them, cholinergic hypothesis, beta-amyloid theory, tau protein abnormal phosphorylation theory, metal ion hypothesis, oxidative stress, and inflammatory hypothesis are the main pathogenesis hypothesis.
Monoamine oxidase (monoamine oxidase, MAO) is A metabolic enzyme containing flavin adenine dinucleotide, present in the outer mitochondrial membrane, and comprises two subtypes, MAO-A and MAO-B, respectively. The biological activity of MAO-B in cerebral cortex and hippocampus of AD patient is obviously enhanced, while high level of MAO-B generates H through oxidative deamination 2 O 2 Can react with iron to generate hydroxyl free radicals through Fenton reaction, so as to stimulate the generation of Reactive Oxygen Species (ROS), and finally lead to neuron injury and inflammatory reaction. Studies have shown that redox damage is a significant feature of AD and evidence of ROS-mediated neuronal damage is observed in the brains of AD patients. Therefore, MAO-B has been considered as a valuable potential target for the treatment of AD in recent years, and has received extensive attention and research.
With the development of genomics and bioinformatics, there is increasing evidence that inflammation and immune response in the brain are key factors in the onset and progression of AD. During AD progression, chronic inflammation mediated by aβ deposition leads to microglial and astrocyte dysfunction, which in turn leads to deregulation and damage of neurons, ultimately leading to worsening of cognitive function.
Prior studies have demonstrated that histone deacetylases (histone deacetylase, HDACs) play a key role in innate immunity and IFN signaling pathways, as well as lymphocyte development and function, and HDACs can regulate TLR and IFN signaling pathways affecting the innate immune process of the body. In addition, HDACs can also regulate antigen presentation processes, as well as lymphocyte growth and differentiation, thereby affecting the adaptive immune process of the body. These effects are quite complex and diverse, with multiple effects of promotion/inhibition. Of the 18 HDAC subtypes, HDAC1 activity plays an important role in neuroinflammatory regulation, and inhibition of HDAC1 activity has a potential anti-inflammatory effect. Therefore, HDAC1 is also a valuable potential target for the treatment of AD.
In summary, the development of multi-target small molecule compounds with dual inhibitory effects on MAO-B and HDAC, neuroprotection and antioxidant by using multi-target design strategies is a potentially effective method for treating AD.
Disclosure of Invention
Aiming at the technical problems, the application provides an HDAC/MAO-B dual inhibitor which has both an HDAC inhibiting effect and an MAO-B inhibiting effect, and is a multi-target hydroxamic acid/anthranilamide propynylamine derivative which realizes neuroprotection and antioxidation by the cooperation of a propynylamine group and a hydroxamic acid or anthranilamide group.
Based on reasonable drug design principle, the application designs and synthesizes novel small molecular compounds with multi-target points of HDAC and MAO-B inhibiting activity and potential AD resisting activity.
HDAC/MAO-B dual inhibitors are compounds having the following general formula (I) or (II) and/or pharmaceutically acceptable salts thereof:
in the formulas (I) and (II):
r is each independently an aromatic group or a substituted aromatic group.
Further, R is each independently phenyl, benzyl, aromatic heterocycle, or substituted phenyl, benzyl, aromatic heterocycle.
In a preferred embodiment, in formulae (I), (II):
r is independently selected from the following structures:
R 1 the following groups, which are H, mono-or di-substituted on the ring: -F, -Cl, -NH 2 、-NHCOCH 3 、-OH、-Ph、-OPh、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-OCF 3 、-SCF 3 。
Further preferably, in the formulae (I), (II):
r is independently selected from the following structures:
R 1 the following groups, which are H, mono-or di-substituted on the ring: -F, -Cl, -CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-SCF 3 、-NH 2 。
In a preferred embodiment, the dual HDAC/MAO-B inhibitor is a compound having the following formula (I-1) or (II-1) and/or a pharmaceutically acceptable salt thereof:
in the formula (I-1), (II-1):
R 1 the following groups, each independently H, mono-or di-substituted on the ring: -F, -Cl, -NH 2 、-NHCOCH 3 、-OH、-Ph、-OPh、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-CF 3 、-OCF 3 、-SCF 3 。
In a preferred embodiment, the dual HDAC/MAO-B inhibitor is compound I having the structure 1 ～I 16 、II 1 ～II 16 And/or pharmaceutically acceptable salts thereof:
the application also provides a preparation method of the HDAC/MAO-B dual inhibitor.
1. The HDAC/MAO-B dual inhibitors are compounds having the general formula (I):
the method specifically comprises the following steps:
nucleophilic substitution reaction is carried out on bromopropyne 1 and aromatic group or substituted aromatic group amine compound to generate intermediate 2, nucleophilic substitution reaction is carried out on bromopropyne 1 and methyl bromobenzoate to obtain intermediate 3, and then intermediate 3 is hydrolyzed and subjected to NH 2 The OTHP amide is condensed and deprotected to obtain the hydroxamate propynylamine derivative shown in the formula (I).
2. The HDAC/MAO-B dual inhibitors are compounds having the general formula (II):
the method specifically comprises the following steps:
one of the amino groups of the o-phenylenediamine 4 is protected by di-tert-butyl dicarbonate mono Boc to obtain an intermediate 5, then the intermediate 5 is reacted with 4-chloromethyl benzoyl chloride to generate an intermediate 6, nucleophilic substitution reaction is carried out on the intermediate 6 and a bromopropyne 1 and an aromatic group or substituted aromatic group amine compound to generate an intermediate 2, nucleophilic substitution reaction is carried out on the intermediate 2 to obtain an intermediate 7, and finally deprotection is carried out to obtain the o-aminobenzamide propynylamine derivative of the formula (II).
In the two synthetic routes, R 1 The preferred range of substituents is: -H, -Cl, -F, -CH 3 、-OCH 3 、-3,4-Cl、-2,6-Cl、-3-Cl-4-F。
The application also provides application of the HDAC/MAO-B dual inhibitor in preparing medicaments and neuroprotective antioxidants for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase.
Such diseases include Alzheimer's disease, parkinson's disease, inflammatory diseases, and the like.
Compared with the prior art, the application has the main advantages that: the HDAC/MAO-B dual inhibitor has both an HDAC inhibiting effect and a MAO-B inhibiting effect, and is a multi-target hydroxamic acid/anthranilamide propynylamine derivative which realizes neuroprotection and antioxidation by the synergy of a propynylamine group and hydroxamic acid or anthranilamide group.
Drawings
FIG. 1 shows the results of measuring cell viability and antioxidant activity by CCK-8 method and DCFH-DA method;
FIG. 2 is a schematic diagram of example 6 (I) 6 ) Inhibition of intracellular ROS production;
FIG. 3 is a schematic diagram of example 6 (I) 6 ) Effect on scopolamine-induced cognitive impairment in ICR mice.
Detailed Description
The application will be further elucidated with reference to the drawings and to specific embodiments. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The methods of operation, under which specific conditions are not noted in the examples below, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer.
Example 1: preparation of 4- ((benzyl (propargyl) amine) methyl) -N-hydroxybenzoamide (Compound I) 1 ) Is prepared from
To a 50mL round bottom flask equipped with a magnetic stirrer was added benzylamine (964 mg,9 mmol), potassium carbonate (622 mg,4.5 mmol) and N in sequenceN-dimethylformamide DMF (10 mL) was stirred at room temperature. A solution of bromopropyne (1, 534 mg,4.5 mmol) in N, N-dimethylformamide (10 mL) was then slowly added dropwise using a constant pressure dropping funnel, and the reaction was continued at room temperature after completion of the dropwise addition. TLC monitored the progress of the reaction, with n-hexane as developing reagent: ethyl acetate (3:2 by volume). After completion of the reaction, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20 mL. Times.3), and then the organic phase was washed with water (20 mL. Times.2) and saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the column was purified on silica gel with n-hexane as eluent: ethyl acetate (5:1 by volume) eventually gave a pale yellow liquid, intermediate 2 (434 mg, 67%). 1 H-NMR(400MHz,DMSO-d 6 )δ7.36-7.30(m,2H),7.15-7.09(m,2H),3.71(s,2H),3.25(d,J＝2.5Hz,2H),3.08(t,J＝2.4Hz,1H). 13 C-NMR(100MHz,DMSO-d 6 )δ140.1,128.1,128.0,126.6,82.8,73.8,51.2,36.6.
To a 50mL round bottom flask equipped with a magnetic stirrer were added, in order, intermediate 2 (390 mg,2.7 mmol), bromomethylbenzoate (806 mg,3.5 mmol), triethylamine (273 mg,2.7 mmol) and acetonitrile (15 mL), and the mixture was heated to 60℃to react. TLC monitored the progress of the reaction, with n-hexane as developing reagent: ethyl acetate (volume ratio 5:1 to 20:1). After the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent, methylene chloride (15 mL) and water (15 mL) were added to shake the mixture to dissolve and separate the liquid, the aqueous layer was extracted with methylene chloride (15 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the column was purified on silica gel with n-hexane as eluent: ethyl acetate (volume ratio 5:1) eventually gave a pale yellow liquid, intermediate 3 (459, 58%). 1 H-NMR(400MHz,DMSO-d 6 )δ7.95(d,J＝8.3Hz,2H),7.52(d,J＝8.3Hz,2H),7.39-7.25(m,5H),3.85(s,3H),3.71(s,2H),3.64(s,2H),3.26(t,J＝2.3Hz,1H),3.20(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ166.6,144.8,138.7,129.7,129.2,129.1,129.0,128.8,127.7,78.6,77.0,57.2,56.8,52.5,41.3.
Intermediate 3 (660 mg,3 mmol) was dissolved in 15mL of methanol and 10% aqueous sodium hydroxide (4.5 mL,11.25 mmol) was added and the reaction was refluxed for 40min. After the reaction is completed, in trueThe solvent was evaporated under air, the residue was dissolved in water (10 mL), then acidified with concentrated hydrochloric acid or acetic acid under ice bath conditions, filtered and washed with water to give a white solid, the resulting white solid (2 mmol) solution was stirred in 15mL dichloromethane DCM at 0 ℃ for 15min, 1-hydroxybenzotriazole HOBt (324 mg,2.4 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI (230 mg,2.4 mmol) were then added and stirring continued in ice bath for 15min. Subsequently, O- (2H-tetrahydropyran-2-yl) hydroxylamine (234 mg,2 mmol) was added and the mixture was reacted at room temperature overnight. After complete conversion of the starting material, 15mL of water was added and extracted three times with dichloromethane (15 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product (n-hexane: ethyl acetate volume ratio 5:1) was purified by a silica gel column to give a pale yellow liquid. To 10mL of a dichloromethane solution of the resulting pale yellow liquid was slowly added dropwise a 10mL dichloromethane solution of trifluoroacetic acid TFA (2719 mg,23.85 mmol), and the resulting mixture was stirred at room temperature for 10h. After the reaction was completed, saturated sodium bicarbonate was added until bubbles disappeared, and extracted three times with dichloromethane (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the crude product was purified on silica gel column (dichloromethane: methanol volume ratio 60:1 to 20:1) and recrystallized from n-hexane/dichloromethane to give compound I 1 (37%) of a tan solid with a melting point of 117.1-118.4 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),9.00(s,1H),7.73(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.36-7.32(m,4H),7.29-7.24(m,1H),3.66(s,2H),3.62(s,2H),3.25(t,J＝2.3Hz,1H),3.18(d,J＝1.6Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,141.9,138.4,131.7,128.6,128.5,128.4,127.2,127.0,78.2,76.5,56.7,56.3,40.8.HRMS(ESI)calcd for C 18 H 19 N 2 O 2 295.1441[M+H] + ,found 295.1441.
Example 2: n-hydroxy-4- (((2-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound I) 2 ) Is prepared from
Substitution of benzylamine with 2-methylbenzylamine Compound I was obtained by the synthetic method of reference example 1 2 (29%) of a white solid having a melting point of 112.1-112.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),9.00(s,1H),7.71(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.31-7.29(m,1H),7.17-7.13(m,3H),3.67(s,2H),3.62(s,2H),3.27(t,J＝2.2Hz,1H),3.12(d,J＝2.0Hz,2H),2.31(s,3H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.2,141.8,137.2,136.1,131.7,130.2,129.6,128.6,127.3,126.9,125.6,78.2,76.5,56.5,55.1,40.5,18.8.HRMS(ESI)calcd for C 19 H 21 N 2 O 2 309.1598[M+H] + ,found 309.1583.
Example 3:4- (((4-Fluorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoic acid amide (Compound I) 3 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 4-fluorobenzylamine to give compound I 3 (42%) light brown solid with a melting point of 135.9-137.0 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.19(s,1H),9.02(s,1H),7.72(d,J＝8Hz,2H),7.43-7.37(m,4H),7.19-7.14(m,2H),3.65(s,2H),3.60(s,2H),3.26(d,J＝2.0Hz,1H),3.17(d,J＝2.0Hz,2H).13C NMR(100MHz,DMSO-d 6 )δ164.2,161.4(d, 1 J＝241.2Hz),141.9,134.5(d, 4 J＝2.9Hz),131.7,130.5(d, 3 J＝8.0Hz),128.5,127.0,115.1(d, 2 J＝21Hz),78.2,76.6,56.3,55.9,40.8.HRMS(ESI)calcd for C 18 H 18 FN 2 O 2 313.1347[M+H]+,found 313.1340.
Example 4: n-hydroxy-4- (((4-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound I) 4 ) Is prepared from
Substitution of benzylamine with 4-methylbenzylamine, reference is made to the examplesThe synthetic procedure of example 1 gives compound I 4 (49%) off-white solid with a melting point of 138.9-140.2 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.99(s,1H),7.72(d,J＝7.8Hz,2H),7.41(d,J＝7.8Hz,2H),7.23(d,J＝7.6Hz,2H),7.15(d,J＝7.7Hz,2H),3.64(s,2H),3.57(s,2H),3.22(t,J＝2.3Hz,1H),3.16(d,J＝2.3Hz,2H),2.28(s,3H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,141.9,136.2,135.2,131.7,128.9,128.6,128.4,126.9,78.3,76.3,56.4,56.2,40.7,20.7.HRMS(ESI)calcd for C 19 H 21 N 2 O 2 309.1598[M+H] + ,found 309.1598.
Example 5:4- (((2-chlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoamide (compound I) 5 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 2-chlorobenzylamine to give compound I 5 (36%) off-white solid with a melting point of 127.6-130.0 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.19(s,1H),9.03(s,1H),7.71(d,J＝7.7Hz,2H),7.56(d,J＝7.4Hz,1H),7.43(t,J＝8.4Hz,3H),7.33(dt,J＝22.8,7.5Hz,2H),3.76(s,2H),3.72(s,2H),3.30(s,1H),3.22(s,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.5,142.1,136.2,133.9,132.3,131.2,129.9,129.4,129.1,127.7,127.4,78.6,77.2,56.9,54.4,41.5.HRMS(ESI)calcd for C 18 H 18 ClN 2 O 2 329.1051[M+H] + ,found329.1047.
Example 6:4- (((2-Fluorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoic acid amide (Compound I) 6 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 2-fluorobenzylamine to give compound I 6 (49%) light brown solid with a melting point of 115.4-116.8 DEG C. 1 H-NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.99(s,1H),7.71(d,J＝8.1Hz,2H),7.48(td,J＝7.5,1.8Hz,1H),7.41(d,J＝8.0Hz,2H),7.36-7.30(m,1H),7.22-7.14(m,2H),3.69(s,4H),3.26(t,J＝2.3Hz,2H),3.21(d,J＝2.3Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.6,161.3(d, 1 J＝243.8Hz),142.2,132.2,131.5(d, 4 J＝4.4Hz),129.7(d, 3 J＝8.2Hz),128.9,127.4,125.4(d, 2 J＝14Hz),124.8(d, 4 J＝3.3Hz),115.8(d, 2 J＝21.5Hz),78.66,76.93,56.90,50.19,41.53.HRMS(ESI)calcd for C 18 H 18 FN 2 O 2 313.1347[M+H]+,found 313.1341.
Example 7:4- (((3-chlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoamide (compound I) 7 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 3-chlorobenzylamine to give compound I 7 (52%) off-white solid with a melting point of 123.1-125.2 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.20(s,1H),9.03(s,1H),7.74(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.42-7.37(m,1H),7.35-7.33(m,3H),3.68(s,2H),3.65(s,2H),3.35(s,1H),3.20(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,141.7,141.1,133.1,131.8,130.3,128.5,128.3,127.2,127.2,127.0,78.1,76.7,56.4,56.1,40.9.HRMS(ESI)calcd for C 18 H 18 ClN 2 O 2 329.1051[M+H] + ,found329.1052.
Example 8: n-hydroxy-4- (((2-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound I) 8 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 2-methoxybenzylamine to give compound I 8 (49%) off-white solid with a melting point of 127.8-130.5 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.98(s,1H),7.72(d,J＝7.8Hz,2H),7.42(d,J＝7.9Hz,2H),7.39(dd,J＝7.5,1.7Hz,1H),7.26-7.22(m,1H),6.98-6.92(m,2H),3.77(s,3H),3.68(s,2H),3.62(s,2H),3.32(s,1H),3.24(d,J＝2.3Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.2,157.4,142.1,131.6,129.3,128.4,128.2,126.9,126.0,120.2,110.87,78.8,76.1,56.6,55.3,50.5,41.4.HRMS(ESI)calcd for C 19 H 21 N 2 O 3 325.1547[M+H]+,found 325.1537.
Example 9: n-hydroxy-4- (((4-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound I) 9 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 4-methoxybenzylamine to give compound I 9 (48%) off-white solid with a melting point of 123.5-124.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),9.00(s,1H),7.72(d,J＝8.2Hz,2H),7.41(d,J＝8.0Hz,2H),7.26(d,J＝8.6Hz,2H),6.90(d,J＝8.6Hz,2H),3.73(s,3H),3.64(s,2H),3.55(s,2H),3.23(t,1H),3.16(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.2,158.4,142.0,131.7,130.1,129.8,128.4,126.9,113.7,78.3,76.3,56.2,56.1,55.0,40.6.HRMS(ESI)calcd for C 19 H 21 N 2 O 3 325.1547[M+H]+,found 325.1533.
Example 10: n-hydroxy-4- (((3-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound I) 10 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 3-methylbenzylamine to give compound I 10 (49%) off-white solid with a melting point of 109.8-111.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.99(s,1H),7.72(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.25-7.21(m,1H),7.15-7.14(m,2H),7.07(d,J＝7.6Hz,1H),3.66(s,2H),3.58(s,2H),3.24(t,J＝2.4Hz,1H),3.17(d,J＝2.4Hz,2H),2.30(s,3H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,141.9,138.2,137.4,131.7,129.2,128.4,128.2,127.8,126.9,125.7,78.2,76.3,56.7,56.4,40.8,21.0.HRMS(ESI)calcd for C 19 H 21 N 2 O 2 309.1598[M+H] + ,found 309.1589.
Example 11:4- (((2, 6-dichlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoamide (Compound I) 11 ) Is prepared from
Substitution of benzylamine with 2, 6-dichlorobenzylamine, compound I was obtained by the synthetic method of reference example 1 11 (34%) of a reddish brown solid having a melting point of 103.5-105.1 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),9.01(s,1H),7.67(d,J＝7.7Hz,2H),7.47(d,J＝7.5Hz,2H),7.35(d,J＝7.6Hz,1H),7.30(d,J＝7.9Hz,2H),3.96(s,2H),3.71(s,2H),3.29(s,1H),3.14(s,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ161.1,141.5,136.2,133.8,131.7,130.1,128.7,128.4,126.8,78.3,76.5,55.5,52.6,40.8.HRMS(ESI)calcd for C 18 H 17 Cl 2 N 2 O 2 363.0662[M+H]+,found 363.0660.
Example 12:4- (((3, 4-dichlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoamide (Compound I) 12 ) Is prepared from
Substitution of benzylamine with 3, 4-dichlorobenzylamine, compound I was obtained by the synthetic method of reference example 1 12 (46%) off-white solid with a melting point of 152.6-154.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.19(s,1H),9.03(s,1H),7.73(d,J＝7.8Hz,2H),7.62-7.58(m,2H),7.41(d,J＝7.9Hz,2H),7.36(dd,J＝8.2,1.9Hz,1H),3.66(s,2H),3.63(s,2H),3.29(t,J＝2.3Hz,1H),3.19(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.0,141.5,139.8,131.7,130.9,130.5,130.3,129.6,128.7,128.4,126.9,78.0,76.5,56.3,55.5,40.9.HRMS(ESI)calcd for C 18 H 17 Cl 2 N 2 O 2 363.0662[M+H]+,found 363.0656.
Example 13:4- (((3-Fluorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoic acid amide (Compound I) 13 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 3-fluorobenzylamine to give compound I 13 (41%) off-white solid with a melting point of 114.9-116.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),9.00(s,1H),7.73(d,J＝8.4Hz,2H),7.43(d,J＝8.2Hz,2H),7.38(dd,J＝8.0,6.1Hz,1H),7.21-7.07(m,3H),3.67(s,2H),3.65(s,2H),3.27(t,J＝2.4Hz,1H),3.20(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,162.3(d, 1 J＝242.0Hz),141.7,141.6(d, 3 J＝7.1Hz),131.8,130.3(d, 3 J＝8.3Hz),128.5,127.0,124.5(d, 4 J＝2.4Hz),115.0(d, 2 J＝21.0Hz),114.0(d, 2 J＝20.8Hz),78.1,76.6,56.3,56.1,40.9.HRMS(ESI)calcd for C 18 H 18 FN 2 O 2 313.1347[M+H]+,found 313.1332.
Example 14:4- (((4-chlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzoamide (compound I) 14 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 4-chlorobenzylamine to give compound I 14 (48%) off-white solid with a melting point of 146.8-147.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.20(s,1H),9.03(s,1H),7.73(d,J＝8.0Hz,2H),7.44-7.37(m,6H),3.66(s,2H),3.62(s,2H),3.36(s,1H),3.19(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,141.8,137.5,131.8,131.7,130.4,128.5,128.4,127.0,78.1,76.6,56.3,55.9,40.8.HRMS(ESI)calcd for C 18 H 18 ClN 2 O 2 329.1051[M+H] + ,found 329.1042.
Example 15:4- (((3-chloro-4-fluoro) (propargyl) amine) methyl) -N-hydroxybenzoic acid amide (compound I) 15 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 3-chloro-4-fluorobenzylamine to give compound I 15 (49%) off-white solid with a melting point of 140.1-141.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.19(s,1H),9.03(s,1H),7.72(d,J＝8.0Hz,2H),7.54-7.51(m,1H),7.41(d,J＝8.0Hz,2H),7.39-7.37(m,2H),3.66(s,2H),3.62(s,2H),3.28(t,J＝2.3Hz,1H),3.19(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,156.3(d, 1 J＝244.2Hz),141.6,136.4(d, 4 J＝3.6Hz),131.7,130.3,129.0(d, 3 J＝7.3Hz),128.4,127.0,119.2(d, 2 J＝17.5Hz),116.7(d, 2 J＝20.6Hz),78.1,76.5,56.3,55.5,40.8.HRMS(ESI)calcd for C 18 H 17 ClFN 2 O 2 347.0957[M+H]+,found 347.0952.
Example 16: n-hydroxy-4- (((3-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound I) 16 ) Is prepared from
The synthesis of example 1 was followed by substituting benzylamine with 3-methoxybenzylamine to give compound I 16 (48%) off-white solid with a melting point of 114.5-115.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ11.16(s,1H),8.99(s,1H),7.73(d,J＝8.3Hz,2H),7.42(d,J＝8.1Hz,2H),7.26(t,J＝7.8Hz,1H),6.92(ddd,J＝7.8,5.1,1.5Hz,2H),6.85-6.82(m,1H),3.75(s,3H),3.66(s,2H),3.60(s,2H),3.24(t,J＝2.2Hz,1H),3.20(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.1,159.3,141.8,140.0,131.7,129.4,128.4,127.0,120.7,114.1,112.5,78.3,76.3,56.7,56.2,54.92,40.9.HRMS(ESI)calcd for C 19 H 21 N 2 O 3 325.1547[M+H]+,found 325.1543.
Example 17: n- (2-aminophenyl) -4- (((2-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound II) 1 ) Is prepared from
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To a 100mL round bottom flask equipped with a magnetic stirrer were added o-phenylenediamine (4, 1.0g,9 mmol) and chloroform (30 mL) and the reaction mixture was cooled to 0deg.C. Sodium bicarbonate (0.78 g,5.4 mmol) and sodium chloride (0.54 g,5.4 mmol) were added sequentially to the reaction system and stirred at 0deg.C for 30min. A solution of di-tert-butyl dicarbonate (2.02 g,9.2 mmol) in chloroform (20 mL) was then slowly added dropwise using a constant pressure dropping funnel, and after completion of the addition, the reaction mixture was stirred at 0deg.C for 10min and then warmed to reflux for reaction. TLC monitored the progress of the reaction, with n-hexane as developing reagent: ethyl acetate (3:1 by volume). After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, extracted with dichloromethane (30 ml×3) and water (20 mL), and then the organic layer was washed with saturated sodium bicarbonate (50 mL) and saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, purified on silica gel, and the eluent was n-hexane: ethyl acetate (3:1 to 2:1 by volume) eventually gave an off-white solid, intermediate 5 (1.14 g, 61%). 1 H-NMR(400MHz,DMSO-d 6 )δ8.28(s,1H),7.18(d,J＝8.0Hz,1H),6.84(td,J＝7.6,1.6Hz,1H),6.68(dd,J＝8.0,1.5Hz,1H),6.53(td,J＝7.5,1.5Hz,1H),4.82(s,2H),1.46(s,9H). 13 C-NMR(100MHz,DMSO-d 6 )δ153.6,141.2,124.9,124.5,123.7,116.3,115.7,78.6,28.2.
To a 100mL round bottom flask equipped with a magnetic stirrer were added intermediate 5 (1.14 g,5.5 mmol), triethylamine (557 g,5.5 mmol) and dichloromethane (30 mL) and the reaction mixture was cooled to 0deg.C. A solution of chloromethylbenzoyl chloride (1.56 g,8.25 mmol) in dichloromethane (20 mL) was slowly added dropwise using a constant pressure dropping funnel, and after the addition was completed, the reaction mixture continued to react at 0 ℃. TLC monitored the progress of the reaction and the developing solvent was dichloromethane. After the reaction was completed, the organic layer was washed with water (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the reaction solvent, and purified on silica gel with n-hexane as eluent: ethyl acetate (3:1 by volume) eventually gave a white solid, intermediate 6 (1.51 g, 76%). 1 H-NMR(400MHz,DMSO-d 6 )δ9.87(s,1H),8.70(s,1H),7.98(d,J＝8.2Hz,2H),7.61(d,J＝8.1Hz,2H),7.56(ddd,J＝7.9,3.3,1.7Hz,2H),7.19(dtd,J＝22.0,7.5,1.6Hz,2H),4.86(s,2H),1.46(s,9H). 13 C-NMR(100MHz,DMSO-d 6 )δ164.9,153.5,141.4,134.2,131.8,129.6,128.9,128.0,126.1,125.7,124.1,123.8,79.6,45.4,28.0.
To a 25mL round bottom flask equipped with a magnetic stirrer were added in order intermediate 6 (433 mg,1.20 mmol), intermediate 2 (188 mg,1.18 mmol), potassium carbonate (163 mg,1.18 mmol), potassium iodide (20 mg,0.12 mmol) and acetonitrile (15 mL), and the reaction mixture was heated to 60℃for reaction. TLC monitored the progress of the reaction, with n-hexane as developing reagent: ethyl acetate (volume ratio 5:1 to 20:1). After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent, the mixture was dissolved by shaking with the addition of water (15 mL) and methylene chloride (15 mL), separated, the aqueous layer was extracted with methylene chloride (15 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on column silica gel with n-hexane as eluent: ethyl acetate (volume ratio 5:1) eventually gave a pale yellow liquid, intermediate 7 (399 mg, 91%).
To a 25mL round bottom flask equipped with a magnetic stirrer were added intermediate 7 (1 mmol) and dichloromethane (6 mL) and the reaction mixture was stirred at room temperature. A solution of trifluoroacetic acid (228 g,2 mmol) in dichloromethane (6 mL) was slowly added dropwise using a constant pressure dropping funnel, and the reaction mixture continued to be reversed at room temperature after completion of the additionShould be. TLC monitored the progress of the reaction, with n-hexane as developing reagent: ethyl acetate (3:2 by volume). After the completion of the reaction, a saturated sodium hydrogencarbonate solution was added to the reaction mixture to remove excess trifluoroacetic acid, and extracted with water (15 mL) and methylene chloride (6X 3 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent to give a crude product, which was then recrystallized from n-hexane and ethyl acetate to give compound II 1 (76%) white solid with a melting point of 137.5-139.1 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.61(s,1H),7.95(d,J＝7.9Hz,2H),7.44(d,J＝8.0Hz,2H),7.34-7.31(m,1H),7.19-7.16(m,4H),6.97(td,J＝7.6,1.6Hz,1H),6.78(dd,J＝8.0,1.5Hz,1H),6.60(td,J＝7.5,1.5Hz,1H),4.88(s,2H),3.72(s,2H),3.65(s,2H),3.27(t,J＝2.3Hz,1H),3.15(d,J＝2.4Hz,2H),2.34(s,3H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.0,142.1,137.2,136.1,133.5,130.2,129.6,128.5,127.8,127.2,126.6,126.4,125.5,123.4,116.2,116.1,78.2,76.5,56.5,55.0,40.5,18.8.HRMS(ESI)calcd for C25H26N3O384.2070[M+H]+,found 384.2071.
Example 18: n- (2-aminophenyl) -4- ((benzyl (propargyl) amine) methyl) benzamide (Compound II) 2 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N-benzylpropynylamine, and Compound II was obtained by the method of example 17 2 (78%) white solid with a melting point of 143.6-145.0 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.62(s,1H),7.97(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.39-7.34(m,4H),7.27(ddd,J＝8.6,5.2,2.2Hz,1H),7.17(dd,J＝7.9,1.5Hz,1H),6.97(td,J＝7.6,1.5Hz,1H),6.78(dd,J＝8.0,1.4Hz,1H),6.60(td,J＝7.5,1.5Hz,1H),4.88(s,2H),3.71(s,2H),3.65(s,2H),3.25(t,J＝2.2Hz,1H),3.22(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.0,142.1,138.3,133.5,128.6,128.3,128.3,127.8,127.1,126.6,126.4,123.4,116.2,116.1,78.2,76.3,56.6,56.4,40.8.HRMS(ESI)calcd for C 24 H 24 N 3 O 370.1914[M+H]+,found 370.1909.
Example 19: n- (2-aminophenyl) -4- (((2-chlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 3 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (2-chlorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 3 (68%) of a white solid with a melting point of 124.1-126.7 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.62(s,1H),7.91(d,J＝7.8Hz,2H),7.50(d,J＝8.0Hz,2H),7.38-7.33(m,3H),7.15(d,J＝7.8Hz,1H),6.96(td,J＝7.6,1.6Hz,1H),6.77(dd,J＝8.1,1.4Hz,1H),6.58(td,J＝7.5,1.4Hz,1H),4.89(s,2H),3.99(s,2H),3.75(s,2H),3.31(t,J＝2.3Hz,1H),3.16(d,J＝2.3Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.1,141.9,135.7,133.6,133.4,130.6,129.5,128.9,128.5,127.9,127.2,126.7,126.5,123.3,116.3,116.1,78.2,76.7,56.5,53.9,41.0.HRMS(ESI)calcd for C 24 H 23 ClN 3 O 404.1524[M+H]+,found 404.1523.
Example 20: n- (2-aminophenyl) -4- (((3-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound II) 4 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (3-methylbenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 4 (76%) white solid with a melting point of 137.2-139.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.63(s,1H),7.97(d,J＝7.9Hz,2H),7.49(d,J＝8.0Hz,2H),7.26-7.22(m,1H),7.16(d,J＝7.8Hz,3H),7.08(d,J＝7.5Hz,1H),6.97(td,J＝7.6,1.5Hz,1H),6.78(dd,J＝8.0,1.4Hz,1H),6.59(td,J＝7.5,1.4Hz,1H),4.89(s,2H),3.70(s,2H),3.60(s,2H),3.25(t,1H),3.21(d,J＝2.4Hz,2H),2.31(s,3H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.0,142.1,138.2,137.4,133.5,129.2,128.4,128.2,127.8(127.83),127.8(127.79),126.6,126.4,125.7,123.4,116.2,116.1,78.3,76.3,56.6,56.4,40.8,21.0.HRMS(ESI)calcd for C25H26N3O 384.2070[M+H]+,found 384.2069.
Example 21: n- (2-aminophenyl) -4- (((4-fluorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 5 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (4-fluorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 5 (80%) white solid with a melting point of 135.7-138.1 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.63(s,1H),7.96(d,J＝7.9Hz,2H),7.48(d,J＝8.0Hz,2H),7.42-7.38(m,2H),7.17(td,J＝8.7,2.1Hz,3H),6.99-6.95(m,1H),6.78(dd,J＝8.1,1.4Hz,1H),6.59(td,J＝7.5,1.5Hz,1H),4.88(s,2H),3.70(s,2H),3.63(s,2H),3.26(t,J＝2.3Hz,1H),3.20(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,161.4(d, 1 J＝241.1Hz),143.1,142.1,134.5(d, 4 J＝2.9Hz),133.6,130.5(d, 3 J＝8.1Hz),128.4,127.9,126.7,126.5,123.4,116.3,116.1,115.1(d, 2 J＝21.1Hz),78.2,76.5,56.3,55.80,40.7.HRMS(ESI)calcd for C 24 H 23 FN 3 O 388.1820[M+H]+,found 388.1814.
Example 22: n- (2-aminophenyl) -4- (((3-fluorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 6 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (3-fluorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 6 (53%) of a white solid having a melting point of 137.9-139.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.63(s,1H),7.97(d,J＝7.9Hz,2H),7.49(d,J＝7.9Hz,2H),7.40(td,J＝7.9,6.1Hz,1H),7.24-7.15(m,3H),7.13-7.08(m,1H),6.97(ddd,J＝8.8,7.4,1.6Hz,1H),6.78(dd,J＝8.0,1.4Hz,1H),6.59(td,J＝7.5,1.5Hz,1H),4.89(s,2H),3.72(s,2H),3.67(s,2H),3.28(t,J＝2.3Hz,1H),3.23(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,162.3(d, 1 J＝242.1Hz),143.1,142.0,141.5(d, 3 J＝7.0Hz),133.6,130.3(d, 3 J＝8.2Hz),128.4,127.9,126.6,126.4,124.5(d, 4 J＝2.4Hz),123.4,116.3,116.1,115.0(d, 2 J＝21.1Hz),114.0(d, 2 J＝20.8Hz),78.2,76.5,56.4,56.1,40.9.HRMS(ESI)calcd for C 24 H 23 FN 3 O 388.1820[M+H]+,found 388.1819.
Example 23: n- (2-aminophenyl) -4- (((3-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound II) 7 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (3-methoxybenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 7 (76%) white solid with a melting point of 140.6-143.0 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.65(s,1H),7.96(d,J＝7.9Hz,2H),7.49(d,J＝7.5Hz,2H),7.29-7.24(m,1H),7.15(d,J＝7.8Hz,1H),6.99-6.93(m,3H),6.84(dd,J＝8.2,3.0Hz,1H),6.78-6.75(m,1H),6.59(dd,J＝9.1,5.9Hz,1H),4.90(s,2H),3.75(s,3H),3.69(s,2H),3.62(s,2H),3.28(t,J＝2.4Hz,1H),3.23(d,J＝2.7Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,159.3,143.0,142.1,140.0,133.5,129.3,128.3,127.8,126.6,126.4,123.4,120.7,116.2,116.1,114.1,112.5,78.3,76.3,56.6,56.3,54.9,40.9.HRMS(ESI)calcd for C 25 H 26 N 3 O 2 400.2020[M+H]+,found 400.2016.
Example 24: n- (2-aminophenyl) -4- (((3, 4-dichlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 8 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (3, 4-dichlorobenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 8 (68%) white solid with a melting point of 139.1-140.3 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.66(s,1H),7.97(d,J＝7.8Hz,2H),7.63-7.60(m,2H),7.48(d,J＝8.0Hz,2H),7.38(dd,J＝8.3,2.0Hz,1H),7.15(d,J＝7.8Hz,1H),6.97(td,J＝7.6,1.6Hz,1H),6.77(dd,J＝8.1,1.4Hz,1H),6.59(td,J＝7.6,1.4Hz,1H),4.91(s,2H),3.71(s,2H),3.65(s,2H),3.31(t,J＝2.2Hz,1H),3.22(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.0,143.0,141.8,139.8,133.6,131.0,130.5,130.3,129.6,128.8,128.4,127.9,126.6,126.4,123.3,116.2,116.1,78.1,76.5,56.4,55.4,40.9.HRMS(ESI)calcd for C 24 H 22 Cl 2 N 3 O 438.1134[M+H]+,found 438.1136.
Example 25: n- (2-aminophenyl) -4- (((4-chlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 9 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (4-chlorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 9 (74%) of a white solid having a melting point of 126.2-127.7 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.62(s,1H),7.97(d,J＝7.9Hz,2H),7.48(d,J＝7.9Hz,2H),7.43-7.38(m,4H),7.17(dd,J＝7.9,1.5Hz,1H),6.97(td,J＝7.6,1.5Hz,1H),6.78(dd,J＝8.1,1.4Hz,1H),6.60(td,J＝7.5,1.5Hz,1H),4.88(s,2H),3.71(s,2H),3.64(s,2H),3.26(t,J＝2.3Hz,1H),3.21(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.0,142.0,137.4,133.6,131.7,130.4,128.4,128.3,127.9,126.6,126.4,123.4,116.2,116.1,78.1,76.4,56.4,55.8,40.8.HRMS(ESI)calcd for C 24 H 23 ClN 3 O 404.1524[M+H]+,found 404.1527.
Example 26: n- (2-aminophenyl) -4- (((2, 6-dichlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 10 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (2, 6-dichlorobenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 10 (19%) white solid with a melting point of 174.5-176.3 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.60(s,1H),7.91(d,J＝7.9Hz,2H),7.49(d,J＝8.0Hz,2H),7.38-7.33(m,3H),7.15(d,J＝7.8Hz,1H),6.96(td,J＝7.6,1.6Hz,1H),6.77(dd,J＝8.0,1.4Hz,1H),6.59(td,J＝7.5,1.5Hz,1H),4.88(s,2H),3.99(s,2H),3.75(s,2H),3.29(t,J＝2.3Hz,1H),3.17(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.0,143.0,141.7,136.2,133.8,133.5,130.0,128.6,128.3,127.7,126.5,126.4,123.3,116.2,116.1,78.3,76.3,55.5,52.6,40.7.HRMS(ESI)calcd for C 24 H 22 Cl 2 N 3 O 438.1134[M+H]+,found 438.1113.
Example 27: n- (2-aminophenyl) -4- (((4-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound II) 11 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (4-methoxybenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 11 (75%) of a white solid with a melting point of 126.7-128.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.65(s,1H),7.96(d,J＝7.9Hz,2H),7.48(d,J＝7.9Hz,2H),7.28(d,J＝8.7Hz,2H),7.16(dd,J＝7.9,1.5Hz,1H),6.99-6.90(m,3H),6.78(dd,J＝8.0,1.5Hz,1H),6.59(td,J＝7.5,1.5Hz,1H),4.91(s,2H),3.74(s,3H),3.68(s,2H),3.56(s,2H),3.27(t,J＝2.3Hz,1H),3.18(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,158.4,143.0,142.2,133.5,130.1,129.8,128.3,127.8,126.6,126.4,123.4,116.2,116.1,113.7,78.3,76.2,56.2,56.0,55.0,40.6.HRMS(ESI)calcd for C 25 H 26 N 3 O 2 400.2020[M+H]+,found 400.2013.
Example 28: n- (2-aminophenyl) -4- (((2-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound II) 12 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (2-methoxybenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 12 (77%) white solid with a melting point of 139.8-142.2 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.61(s,1H),7.95(d,J＝7.9Hz,2H),7.49(d,J＝7.9Hz,2H),7.42(dd,J＝7.5,1.8Hz,1H),7.25(ddd,J＝8.7,7.4,1.8Hz,1H),7.17(dd,J＝7.9,1.6Hz,1H),7.00-6.94(m,3H),6.78(dd,J＝8.0,1.5Hz,1H),6.60(td,J＝7.5,1.5Hz,1H),4.88(s,2H),3.79(s,3H),3.73(s,2H),3.65(s,2H),3.27(d,J＝2.4Hz,2H),3.23(t,J＝2.3Hz,1H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,157.4,143.1,142.4,133.4,129.3,128.3,128.2,127.7,126.6,126.4,126.1,123.4,120.2,116.2,116.1,110.9,78.8,76.1,56.6,55.3,50.4,41.4.HRMS(ESI)calcd for C 25 H 26 N 3 O 2 400.2020[M+H]+,found 400.2022.
Example 29: n- (2-aminophenyl) -4- (((3-chloro-4-fluorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 13 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (3-chloro-4-fluorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 13 (73%) of a white solid having a melting point of 133.4-134.8 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.66(s,1H),7.97(d,J＝7.8Hz,2H),7.55-7.54(m,1H),7.48(d,J＝7.9Hz,2H),7.41-7.38(m,2H),7.15(d,J＝7.8Hz,1H),6.97(td,J＝7.6,1.6Hz,1H),6.77(dd,J＝8.0,1.5Hz,1H),6.61-6.57(m,1H),4.91(s,2H),3.70(s,2H),3.64(s,2H),3.31(t,J＝2.3Hz,1H),3.22(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,156.3(d, 1 J＝244.2Hz),143.0,141.8,136.4(d, 4 J＝3.6Hz),133.6,130.3,129.0(d, 3 J＝7.3Hz)128.4,127.9,126.6,126.4,123.3,119.3(d, 2 J＝17.5Hz),116.7(d, 2 J＝20.7Hz),116.2,116.1,78.1,76.5,56.3,55.4,40.8.HRMS(ESI)calcd for C24H22ClFN3O 422.1430[M+H]+,found 422.1433.
Example 30: n- (2-aminophenyl) -4- (((2-fluorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 14 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (2-fluorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 13 (43%) of a white solid having a melting point of 123.6-125.0 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.62(s,1H),7.96(d,J＝7.9Hz,2H),7.49(td,J＝7.8,5.7Hz,3H),7.34(tdd,J＝7.5,5.3,1.9Hz,1H),7.24-7.16(m,3H),6.97(td,J＝7.6,1.6Hz,1H),6.78(d,J＝7.9Hz,1H),6.60(td,J＝7.6,1.4Hz,1H),4.88(s,2H),3.74(s,2H),3.72(s,2H),3.26(t,J＝2.1Hz,1H),3.24(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,160.8(d, 1 J＝243.7Hz),143.0,141.9,133.5,130.5(d, 4 J＝4.3Hz),129.2(d, 3 J＝8.2Hz),128.3,127.8,126.6,126.4,125.0,124.8,124.3(d, 4 J＝3.2Hz),123.4,116.2(d, 2 J＝13.5Hz),115.3(d, 2 J＝21.5Hz),78.1,76.4,56.4,49.6,41.0.HRMS(ESI)calcd for C 24 H 23 FN 3 O 388.1820[M+H]+,found 388.1818.
Example 31: n- (2-aminophenyl) -4- (((3-chlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II) 15 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (3-chlorobenzyl) propynylamine, and Compound II was obtained by the method of example 17 15 (75%) white solid with a melting point of 135.2-136.9 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.63(s,1H),7.97(d,J＝7.9Hz,2H),7.49(d,J＝8.0Hz,2H),7.41-7.33(m,4H),7.16(d,J＝7.8Hz,1H),6.97(td,J＝7.6,1.5Hz,1H),6.78(dd,J＝8.1,1.5Hz,1H),6.59(td,J＝7.5,1.4Hz,1H),4.89(s,2H),3.71(s,2H),3.66(s,2H),3.28(t,J＝2.4Hz,1H),3.22(d,J＝2.4Hz,2H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.0,141.9,141.1,133.6,133.0,130.2,128.4,128.2,127.9,127.2,127.1,126.6,126.4,123.4,116.2,116.1,78.1,76.5,56.4,56.0,40.9.HRMS(ESI)calcd for C 24 H 23 ClN 3 O 404.1524[M+H]+,found 404.1525.
Example 32: n- (2-aminophenyl) -4- (((4-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound II) 16 ) Is prepared from
N- (2-methylbenzyl) propynylamine was replaced with N- (4-methylbenzyl) propynylamine, and Compound II was obtained by the method of Synthesis example 17 16 (68%) of a white solid with a melting point of 133.8-135.6 ℃. 1 H-NMR(400MHz,DMSO-d 6 )δ9.62(s,1H),7.96(d,J＝7.9Hz,2H),7.48(d,J＝8.0Hz,2H),7.25(d,J＝7.8Hz,2H),7.16(d,J＝8.0Hz,3H),6.97(td,J＝7.6,1.5Hz,1H),6.78(dd,J＝8.0,1.4Hz,1H),6.59(td,J＝7.5,1.4Hz,1H),4.88(s,2H),3.69(s,2H),3.59(s,2H),3.25(t,1H),3.19(d,J＝2.4Hz,2H),2.29(s,3H). 13 C-NMR(100MHz,DMSO-d 6 )δ165.1,143.0,142.2,136.2,135.2,133.5,128.9,128.6,128.3,127.8,126.6,126.4,123.4,116.2,116.1,78.3,76.3,56.3(56.32),56.3(56.31),40.7,20.7.HRMS(ESI)calcd for C 25 H 26 N 3 O 384.2070[M+H]+,found 384.2073.
Pharmacological experimental data
1. Determination of MAO-B inhibitory Activity of Compounds
The experimental method comprises the following steps: monoamine oxidase B inhibitor screening kit (fluorescence) from Sigma-Aldrich was placed at-80 ℃ and stored for use. Test enzyme solutions, test substrate solutions, compound working solutions (100 nM) were prepared as per the specification. Firstly, 10 mu L of working solution is added into a black 96-well plate by using a pipette, then 50 mu L of test enzyme solution is added, the solution is placed into a microplate reader which is preheated to 37 ℃ after the addition is finished, the incubation is carried out for 10min, the test substrate solution is added after the incubation is finished, the solution is placed into the microplate reader, the fluorescence value of the solution is measured at 37 ℃ for 30min, and the solution is scanned every 1min for 30 times. The experiment is mainly divided into 2 groups, namely a sample group (S) and a blank control group (EC), wherein the sample group comprises a positive control group and a compound test group, and each group is tested twice in parallel. After the test was completed, the slope of each compound (including positive control and blank) was obtained by fitting, and the inhibition was calculated according to the formula inhibition (%) = (blank slope-sample slope)/blank slope×100%. The inhibition ratios calculated under different concentrations are calculated according to the Graphpad Prism software to obtain corresponding IC 50 Values.
TABLE 1 inhibition of MAO-B by examples 1-32
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TABLE 2 preferred embodiment IC for MAO-B inhibitory Activity 50 Value of
By IC 50 As can be seen from the measurement of the values, the implementationExample 6 (I) 6 ，IC 50 =99.0±1.3 nM) was most excellent in the 32 compounds in this case.
2. Assay of MAO-A inhibitory Activity of preferred Compounds
The experimental method comprises the following steps: monoamine oxidase A inhibitor screening kit (fluorescence) from Sigma-Aldrich was placed at-80℃and stored for use. Test enzyme solutions, test substrate solutions, compound working solutions (10, 100, 500, 800, 1000, 4000, 6000, 8000, 10000 nM) were prepared as required by the specification. Except that the incubation temperature was adjusted to 25 ℃, other procedures were referenced to MAO-B inhibition activity test experiments.
TABLE 3 inhibition activity and selectivity of preferred embodiments for MAO-B/MAO-A
As is clear from the results in Table 3, example 6 (I 6 ) Shows potent MAO-B inhibitory activity and selectivity (SI=100.2). Example 6 (I) 6 ) Is identified as a potent and selective MAO-B inhibitor.
3. Determination of the Compounds for the inhibition of HDAC1 Activity
The experimental method comprises the following steps: HDAC1 inhibition activity was screened using HDAC1 kit based on fluorescence method (λex=360 nm/λem=465 nm). The test procedure was divided into two steps and performed on the same microplate. First, incubating an acetylated lysine substrate with HDAC 1; the second step was performed using HDAC developer treatment to release fluorescent products, at an excitation wavelength of 360nm and an emission wavelength of 465 nm. Finally, the inhibition of the compound was calculated by the formula inhibition (%) = (initial activity-sample activity)/initial activity x 100%, and IC was calculated by plotting the inhibition versus concentration according to the results of the different inhibition 50 Values.
As a result of Table 4, the derivative of the formula (II) series (II 7 、II 12 ) Has significantly weaker HDAC1 inhibitory activity than the derivatives of the general formula (I) 2 、I 6 、I 11 、I 15 ). In these preferred embodiments I 6 The strongest inhibitory activity against HDAC1 (IC 50 =21.4 nM), comparable to the positive control SAHA (IC 50 ＝13.3nM)。
TABLE 4 preferred examples IC for HDAC1 inhibitory Activity 50 Value of
4. Example 6 (I) 6 ) Determination of neuroprotective Effect and antioxidant Activity
4.1 neuroprotective Effect test
The experimental method comprises the following steps: digesting and counting cells to prepare a cell suspension of 1.0X10 5 Mu.l of cell suspension was added per well to each of a 96-well cell culture plate at a volume of one mL; 96-well cell culture plates were placed at 37 ℃,5%, CO 2 Culturing in an incubator for 24 hours; diluting the medicine with culture medium to required working solution concentration (50 μm), adding 100 μl of corresponding medicine-containing culture medium into each well, reacting for 2 hr, adding Aβ1-42 (40 μm) into each well, and setting up negative control group; 96-well cell culture plates were placed at 37 ℃,5%, CO 2 Culturing in an incubator for 24 hours; CCK-8 staining was performed on 96-well plates, λ=450 nm, and OD values were determined; adding 10 μl of CCK-8 into each well, and culturing in an incubator for 2-3h; gently mixing the mixture for 10min on a shaking table, and removing bubbles in a 96-well plate; the OD value of each well was read by an enzyme-labeled instrument at λ=450 nm, and the inhibition ratio was calculated. Inhibition (%) = (negative control OD value-experimental OD value)/negative control OD value x 100%.
4.2 antioxidant test (streaming)
The experimental method comprises the following steps: the cells were washed once with PBS (centrifugation 1000rpm,5 min), collected and adjusted to a cell concentration of 1X 10 6 /mL; the DCFH-DA was diluted 1:1000 with serum-free medium to a final concentration of 10. Mu.M, and the cells were collected and suspended in the diluted DCFH-DA for 20min in a 37℃cell incubator. Each 3-5min is reversed and mixed uniformly to make the probe and the cell fully contacted; washing the cells 3 times with serum-free cell culture medium to sufficiently remove DCFH-DA that did not enter the cells; intracellular active oxygen was detected by flow cytometry (ex=488nm; em=530 nm)And (3) the situation.
4.3 antioxidant testing (imaging)
The experimental method comprises the following steps: the cells in the logarithmic growth phase are digested and inoculated into a 24-well plate, after the cells are attached to the wall, the corresponding medicine-containing culture medium is added according to the group setting, and a negative control group is established at the same time; after the compound is acted for 2 hours, Aβ1-42 is added for 24 hours; washing the cells twice with PBS; diluting DCFH-DA with serum-free culture solution according to a ratio of 1:1000 to obtain a final concentration of 10. Mu.M, and adding the final concentration into a 24-well plate; washing the cells 3 times with serum-free cell culture medium to sufficiently remove DCFH-DA that did not enter the cells; the intracellular active oxygen was observed under a microscope.
The results of the above experiment are shown in FIGS. 1 and 2.
Compared to the blank, aβ1-42 treated cell viability was significantly reduced to 52.31% (47.69% reduction), while the example 6 compound treated cell viability was increased to 73.62%, indicating that the example 6 compound had a reverse nerve damage effect. As shown in FIG. 2, compound I 6 Significantly reduced intracellular ROS production, consistent with significantly reduced green fluorescence intensity (I 6 +Abeta 1-42vs Abeta 1-42:21.76%vs 44.58%). In conclusion, compound I 6 Has neuroprotective and ROS production inhibiting activities, which are related to their antioxidant effects.
5. Example 6 (I) 6 ) In vivo behavioural testing
The experimental method comprises the following steps: after purchase, mice were kept seven days prior to animal center feeding, eliminating the environmental stress effects. IP administration (positive drug, test drug) (15 mg/kg,3 mg/ml) or blank solvent, and scopolamine (15 mg/kg,3 mg/ml) was intraperitoneally injected respectively after 30min for 15 days. The behavioral studies of each mouse included 11-14 days of learning memory training (no movement trajectories recorded for the first two days) and 15 days of exploratory trials (five days total). The water maze device is placed in a dark room, an escape platform with the diameter of 10cm is placed in the center of the fourth quadrant, during the experiment, a mouse is trained to search the escape platform once in each of the four quadrants of the pool, the time for the mouse to find the escape platform (successful escape) is recorded every time for 120 seconds. Whether or not the mice successfully reached the platform within 120s, they were kept on the platform for 10s. On the last day (day 5) the platform was evacuated, the mice received a 120s exploration experiment from the second quadrant, and then the time to the missing platform and the number of times the platform was crossed were recorded. The escape latency, the running track, the number of platform position intersections and other data are recorded by Panlab SMART 3.0, and are processed by Graphpad Prism 8 software.
As shown in fig. 3, the control group showed normal spatial learning and memory ability, while the model group was treated with scopoletin significantly prolonged the time to find the hidden platform (fig. 3A and 3B, first pass platform distance: 7.7±1.2vs2.4±0.5; first pass platform time: 41.4±5.9vs 12.5±2.7), the number of times to enter the hidden platform was significantly reduced (fig. 3C, number of passes platform: 2.0±0.5vs 5.8±0.9), showing severe impairment of spatial learning and memory ability of mice, which was in an unordered trace with the model group (D-2). Compared with the model group, the time for finding the hidden platform of the mice treated by the eupronin is obviously shortened (the distance of the first crossing platform is 2.9+/-0.7vs 7.7+/-1.2, the time of the first crossing platform is 14.0+/-2.9vs 41.4+/-5.9), the frequency of entering the hidden platform is obviously increased (the frequency of crossing the platform is 3.9+/-0.5vs 2.0+/-0.5 in FIG. 3C), and the eupronin has a good effect of improving the cognitive function. In addition, example 6 (I) 6 ) The distance and time for the treated mice to first traverse the platform was significantly reduced (fig. 3A and 3B, first traverse the platform distance: 3.4+ -0.4vs 7.7+ -1.2; first pass through platform time: 18.4.+ -. 2.5vs 41.4.+ -. 5.9) showing example 6 (I 6 ) Has good cognitive enhancing effect. And example 6 (I) 6 ) In contrast, the younger group exhibited greater cognitive and memory improvement capabilities (fig. 3A and 3B, first crossing platform distance: 2.9+ -0.7vs 3.4+ -0.4; first pass through platform time: 14.0.+ -. 2.9vs. 18.4.+ -. 2.5). Interestingly, example 6 (I 6 ) More times than you Jiang Ning entered the hidden platform at the same time (FIG. 3C, number of passes through the platform: 4.5.+ -. 0.4vs 3.9.+ -. 0.5).
Based on the above results, compound I 6 Significantly improves the learning and memory ability of ICR mice, and shows potential therapeutic effect.
Further, it is to be understood that various changes and modifications of the present application may be made by those skilled in the art after reading the above description of the application, and that such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (5)

  1. An HDAC/MAO-B dual inhibitor, characterized by being a compound I having the following structure 6 And/or pharmaceutically acceptable salts thereof:
  2. 2. the method of preparing a dual HDAC/MAO-B inhibitor according to claim 1, wherein the dual HDAC/MAO-B inhibitor is compound I 6 The synthetic route is as follows:
    the preparation method specifically comprises the following steps:
    bromopropyne 1 and 2-fluorobenzylamine R-NH 2 Nucleophilic substitution reaction is carried out to generate intermediate 2, then nucleophilic substitution reaction is carried out with bromomethyl benzoate to obtain intermediate 3, and then intermediate 3 is hydrolyzed and NH is carried out 2 Condensation and deprotection of OTHP amide to obtain compound I 6 I.e. compound I in the synthetic route.
  3. 3. Use of a dual HDAC/MAO-B inhibitor according to claim 1 for the manufacture of a medicament for the prevention and treatment of a related disease by inhibiting monoamine oxidase MAO-B and histone deacetylase.
  4. 4. The use according to claim 3, wherein the disease comprises alzheimer's disease, parkinson's disease, inflammation.
  5. 5. Use of a dual HDAC/MAO-B inhibitor according to claim 1 for the preparation of a neuroprotective antioxidant.
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