CN111072597B - Piperine derivative and preparation method and application thereof - Google Patents

Abstract

The invention provides a piperine derivative and a preparation method and application thereof. The piperine derivative is a compound shown as a formula (I), or a salt, a stereoisomer or a hydrate thereof. The compound can effectively protect nerve cells and improve the survival rate of the nerve cells, so the compound can effectively treat neurodegenerative diseases and can be used for preparing medicines for treating the neurodegenerative diseases.

Description

A kind of piperine derivative and its preparation method and application

technical field

The invention belongs to the technical field of chemical medicines, and in particular relates to a piperine derivative and its preparation method and application.

Background technique

Neurodegenerative diseases result in progressive loss of brain function and overlapping clinical syndromes. For example, Alzheimer's disease (AD), but also vascular dementia, frontotemporal dementia (FTD), mixed dementia and dementia with Lewy bodies (LBD) can present cognitive deficits. Similarly, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD) and spinocerebellar ataxia (SCA) cause damage to the motor system. Aging is a common risk factor in all of these diseases. According to the 2015 United Nations report on the aging of the world's population, it is expected to more than double in the next 35 years, and the number of people aged 60 and over in the world is nearly 2.1 billion. Despite improvements in life expectancy, Alzheimer's disease (AD) and related neurodegenerative disorders are likely to be the most dreaded diseases of the elderly, and an unchecked epidemic of these devastating diseases will leave patients, families, and societies impose heavy economic burdens.

Although they have distinct clinical manifestations, reflecting the loss of specific neurons and synapses in different brain regions, neurodegenerative diseases share common features and mechanisms. Neurodegenerative diseases are a group of diseases characterized by loss of neuronal structure and/or function. At the molecular level, neurodegenerative diseases share several similarities, such as abnormal deposition of proteins (which are misfolded in many diseases), mitochondrial stress leading to the formation of reactive oxygen species (ROS), microglial activation, and neuroinflammation , dysregulation of protein stability (involving the ubiquitin-proteasome pathway and the autophagosome pathway), programmed cell death (including apoptosis), and receptor dysregulation related to synaptic plasticity, memory, learning, and other functions. Current treatments for these diseases are only symptomatic and will not slow or reverse disease progression.

Contents of the invention

In order to solve the above problems, the present invention provides a piperine derivative and its preparation method and application.

The present invention provides a compound represented by formula (I), or a salt thereof, or a stereoisomer thereof, or a hydrate thereof:

in,

X is O, S or Se;

n is 0 or 1;

R ₁ is selected from

n ₁ is 1;

n ₂ , n ₃ , n ₄ are 0 or 1;

但当n为0时，R₃不为氟；所述烷基的取代基为卤素；所述烷氧基的取代基为卤素；R ₃ is selected from substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkoxy, cyano, halogen, hydroxyl, phenyl,

But when n is 0, R ₃ is not fluorine; the substituent of the alkyl group is halogen; the substituent of the alkoxy group is halogen;

m and x are independently integers from 1 to 8;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₈ alkyl;

R ₇ and R ₈ are independently selected from C ₁ -C ₅ alkyl, C ₃ -C ₈ cycloalkyl;

时，R₂选自

When n is 0 or ₁ , R1 is selected from

, _R2 is selected from

时，R₂选自

When _n is 0, R1 is selected from

, _R2 is selected from

时，R₂选自

When n is ₁ , R1 is selected from

, _R2 is selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , and R _39-42 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl.

Further, the compound is shown in formula (II):

in,

R ₁ is selected from

n ₁ is 1;

n ₂ , n ₃ , n ₄ are 0 or 1;

所述烷基的取代基为卤素；所述烷氧基的取代基为卤素；R ₃ is selected from substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkoxy, cyano, halogen, hydroxyl, phenyl,

The substituent of the alkyl group is halogen; the substituent of the alkoxy group is halogen;

m and x are independently integers from 1 to 8;

R ₉ to R ₁₃ , R ₁₄ to R ₁₇ , R ₁₈ to R ₂₁ , R ₂₂ to R ₂₅ , R ₂₂ ' to R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl, or C ₁ ~C ₈ alkyl group;

R ₇ and R ₈ are independently selected from C ₁ -C ₅ alkyl, C ₃ -C ₈ cycloalkyl;

时，R₂选自

When _R1 is selected from

, _R2 is selected from

时，R₂选自

R ₁ is selected from

, _R2 is selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , and R _39-42 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl.

Further, the compound is shown in formula (III):

in,

R ₁ is selected from

n ₁ is 1;

n ₂ , n ₃ , n ₄ are 0 or 1;

所述烷基的取代基为卤素；所述烷氧基的取代基为卤素；R ₃ is selected from substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkoxy, cyano, chlorine, hydroxyl, phenyl,

The substituent of the alkyl group is halogen; the substituent of the alkoxy group is halogen;

m and x are independently integers from 1 to 8;

R ₉ to R ₁₃ , R ₁₄ to R ₁₇ , R ₁₈ to R ₂₁ , R ₂₂ to R ₂₅ , R ₂₂ ' to R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl, or C ₁ ~C ₈ alkyl group;

R ₇ and R ₈ are independently selected from C ₁ -C ₅ alkyl, C ₃ -C ₈ cycloalkyl;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , and R _39-42 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl.

Further, the compound is shown in formula (II-A):

in,

n ₁ is 1;

R ₃ is selected from C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, cyano, phenyl, halogen, hydroxyl,

m and x are independently 1 or 2;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₅ alkyl group;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , and R _39-42 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl.

Further, the compound is shown in formula (II-B):

in,

n ₂ is 0 or 1;

R ₃ is selected from C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, cyano, phenyl, halogen, hydroxyl,

m and x are independently 1 or 2;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₅ alkyl group;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl;

Or, the compound is shown in formula (II-C):

in,

n ₃ is 0 or 1;

R ₃ is selected from C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, cyano, phenyl, halogen, hydroxyl,

m and x are independently 1 or 2;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₅ alkyl group;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl;

Or, the compound is shown in formula (II-D):

in,

n ₄ is 0 or 1;

R ₃ is selected from C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, cyano, phenyl, halogen, hydroxyl,

m and x are independently 1 or 2;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₅ alkyl group;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl;

Or, the compound is shown in formula (II-E):

in,

R ₇ is selected from C ₁ -C ₅ alkyl, C ₃ -C ₈ cycloalkyl;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl;

Or, the compound is shown in formula (II-F):

in,

R ₈ is selected from C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl;

Or, the compound is shown in formula (II-G):

in,

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl;

Or, the compound is shown in formula (II-H):

in,

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , and R _39-42 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₈ alkyl.

Further, the compound is shown in formula (III-A):

in,

n ₁ is 1;

R ₃ is selected from C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, cyano, phenyl, chlorine, hydroxyl,

m and x are independently 1 or 2;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₅ alkyl group;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl;

Or, the compound is shown in formula (III-B):

in,

n ₂ is 0 or 1;

R ₃ is selected from C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, cyano, phenyl, halogen, hydroxyl,

m and x are independently 1 or 2;

R ₉ ~ R ₁₃ , R ₁₄ ~ R ₁₇ , R ₁₈ ~ R ₂₁ , R ₂₂ ~ R ₂₅ , R ₂₂ ' ~ R ₂₅ ' are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ ~ C ₅ alkyl group;

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , R _39-42 are independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl;

Or, the compound is shown in formula (III-C):

_{R2 is} selected from

R _26-30 , R _31-34 , R _35-36 , R _37-38 , and R _39-42 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl or C ₁ -C ₅ alkyl.

Further, the compound is one of the following compounds:

The present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its hydrate in the preparation of a drug for treating neurodegenerative diseases.

Further, the neurodegenerative disease is Alzheimer's disease, vascular dementia, frontotemporal dementia, mixed dementia, Lewy body dementia, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, spinocerebellar Ataxia.

The present invention also provides a medicine, which is prepared from the aforementioned compound, or its salt, or its stereoisomer, or its hydrate as the active ingredient, plus pharmaceutically acceptable adjuvants or auxiliary ingredients preparations.

In the present invention, the minimum and maximum values of carbon atom content in hydrocarbon groups are represented by prefixes, for example, prefixes C _a ~ C _b alkyl indicate any alkyl group containing "a" to "b" carbon atoms.

中R₃表示苯环上的取代基，n₁表示取代基的个数。In the present invention,

Among them, R ₃ represents the substituent on the benzene ring, and n ₁ represents the number of substituents.

In the present invention, halogen refers to fluorine, chlorine, bromine, and iodine.

In the present invention, room temperature is 25±5°C; overnight is 12±2h.

The compound of the present invention can effectively protect nerve cells and improve the survival rate of nerve cells. Therefore, the compound of the present invention can effectively treat neurodegenerative diseases and can be used for preparing medicines for treating neurodegenerative diseases.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Description of drawings

Figure 1 is a graph of the mean cell viability of the compounds of the invention with respect to PC-12 cytoprotective activity.

detailed description

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products. In order to facilitate the description of the synthetic routes and methods of the examples later, the abbreviations of the main raw materials or reagents used in the examples are now made into the following table 1.

The abbreviation of main raw material or reagent used in the embodiment of table 1

Embodiment 1, the preparation of (E, E)-1-[4-(1-methoxyphen-4-yl)-1-oxo-2,4-pentadienyl]-piperidine

step 1:

A solution of piperidine (0.10 mol) and _Et3N (10.12 g, 0.10 mol) in DCM (50 mL) was stirred at 0 °C, crotonyl chloride (0.10 mol) was added dropwise, then the reaction was slowly warmed to room temperature and stirred for 8 hours , the reaction was monitored by TLC. After the reaction was completed, the dichloromethane layer was washed 3 times with 50 mL of saturated NaHCO ₃ aqueous solution, and then the dichloromethane layer was washed with 50 mL of water. Dry over anhydrous Na ₂ SO ₄ and concentrate under reduced pressure to obtain light yellow viscous liquid 2a. ¹ H NMR (400MHz, CDCl ₃ ) δ6.58(dq, J=13.9,6.8Hz,1H),6.06(d,J=15.0Hz,1H),3.31(d,J=34.4Hz,4H),1.64 (d,J=6.8Hz,3H),1.42(dd,J=10.7,5.7Hz,2H),1.33(d,J=4.8Hz,4H).Exact mass calcd for C9H15NO[M+H] ⁺ :154.1232 ;found 154.1235.

Step 2:

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated NaOH solution was added, stirred for 30 minutes, and then p-methoxybenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 3a. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43 (ddd, J=12.4, 6.3, 1.7Hz, 1H), 7.40-7.37(m, 2H), 6.89-6.85(m, 2H), 6.81-6.77(m ,2H),6.43(d,J=14.6Hz,1H),3.81(s,3H),3.58(s,4H),1.70-1.63(m,2H),1.58(dt,J=11.0,5.5Hz, 4H). ¹³ C NMR (101MHz, CDCl ₃ )δ165.61, 160.12, 142.87, 138.30, 129.38, 128.40, 125.07, 119.72, 114.29, 55.40, 47.04, 43.54, 26.21, 24.76. Exact mass ⁺ C2 :272.1572; found272.1576.

Embodiment 2, the preparation of (E, E)-1-[2-(1-methoxyphen-2-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and o-methoxybenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 3b. ¹ H NMR (400MHz, CDCl ₃ ) δ7.42(dd, J=14.5, 10.3Hz, 1H), 7.28-7.22(m, 1H), 7.04(d, J=7.7Hz, 1H), 6.97(s, 1H),6.94-6.77(m,3H),6.49(d,J＝14.7Hz,1H),3.82(s,3H),3.59(s,4H),1.74-1.64(m,2H),1.63-1.51 (m,4H) ^.13 C NMR(101MHz,CDCl ₃ )δ165.48,159.97,142.33,138.48,137.99,129.80,127.48,121.25,119.77,114.47,112.13,55.38,47.05,43.39,25.86,2act.86,2act masscalcd for C17H21NO2[M+H] ⁺ :272.1572; found 272.1576.

Example 3, Preparation of (E, E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then m-methoxybenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 3c. ¹ H NMR (400MHz, CDCl ₃ ) δ7.48(dd, J=7.6, 1.6Hz, 1H), 7.45(dd, J=14.8, 11.2Hz, 1H), 7.28-7.23(m, 1H), 7.18( d,J=15.7Hz,1H),7.00-6.91(m,2H),6.88(d,J=8.3Hz,1H),6.45(d,J=14.8Hz,1H),3.87(s,3H), 3.58(m,4H),1.71-1.63(m,2H),1.59(dt,J=10.9,5.4Hz,4H). ¹³ C NMR(101MHz,CDCl ₃ )δ165.67,157.45,143.37,133.82,129.74,127.81 ,127.32,125.61,120.79,120.37,111.18,55.61,47.04,43.35,26.84,25.74,24.79. Exact mass calcd for C17H21NO2[M+H] ⁺ :272.1572;

Example 4, Preparation of (E, E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then dimethylaminobenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 3d. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43(dd, J=14.6, 9.9Hz, 1H), 7.34(d, J=8.8Hz, 2H), 6.81-6.72(m, 2H), 6.67(d, J＝8.6Hz, 2H), 6.37(d, J＝14.6Hz, 1H), 3.56(d, J＝22.9Hz, 4H), 2.98(s, 6H), 1.71-1.63(m, 2H), 1.57( dd, J＝13.5, 10.6Hz, 4H). Exact mass calcd for C18H24N2O[M+H] ⁺ :285.1967; found285.1972.

Example 5, Preparation of (E, E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then diethylaminobenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 3e. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44(dd, J=14.6, 10.3Hz, 1H), 7.31(d, J=8.7Hz, 2H), 6.79-6.69(m, 2H), 6.62(d, J＝8.7Hz, 2H), 6.35(d, J＝14.6Hz, 1H), 3.66-3.51(m, 4H), 3.37(q, J＝7.0Hz, 4H), 1.65(m, 2H), 1.62- 1.53(m,4H),1.17(t,J＝7.1Hz,6H).Exact mass calcd for C20H28N2O[M+H] ⁺ :313.2280; found 313.2285.

Example 6, Preparation of (E,E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then p-cyanobenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 3f. ¹ H NMR (400MHz, MeOD) δ 7.90 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.4Hz, 2H), 7.39 (dd, J = 14.6, 10.9Hz, 1H), 7.21 ( dd,J=15.5,11.0Hz,1H),7.00(d,J=15.5Hz,1H),6.80(d,J=14.6Hz,1H),3.71-3.64(m,4H),1.79-1.71(m ,2H),1.67(d,J＝22.8Hz,4H).Exact mass calcd for C17H18N2O[M+H] ⁺ :266.1419; found 266.1423.

Example 7, Preparation of (E,E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then 4-phenylbenzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography gave the product 3g. ¹ H NMR (400MHz, CDCl ₃ ) δ7.63-7.56 (m, 4H), 7.52 (d, J = 8.4Hz, 2H), 7.49-7.40 (m, 3H), 7.36 (dt, J = 9.3, 4.2 Hz,1H),6.95(dd,J=15.5,10.1Hz,1H),6.88(d,J=15.5Hz,1H),6.50(d,J=14.7Hz,1H),3.60(d,J=40.1 Hz,4H),1.73-1.64(m,2H),1.60(m,4H). ¹³ CNMR(101MHz,CDCl ₃ )δ165.37,142.35,141.28,140.46,138.02,135.53,128.85,127.54,127.45,127.09,126. ,120.94,46.98,43.29,26.77,25.64,24.69. Exact mass calcd for C22H23NO[M+Na] ⁺ :340.1677; found 340.1685.

Example 8, Preparation of (E,E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then 4-(1-pyrrolinyl)benzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product 3h. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44 (dd, J = 14.6, 10.5Hz, 1H), 7.33 (d, J = 8.7Hz, 2H), 6.78 (d, J = 15.4Hz, 1H), 6.70 (dd, J=15.4,10.5Hz,1H),6.52(d,J=8.6Hz,2H),6.35(d,J=14.6Hz,1H),3.58(m,4H),3.35-3.28(m, 4H),2.03-1.98(m,4H),1.69-1.63(m,2H),1.61-1.53(m,4H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.01,148.23,143.81,139.70,128.56,122.16 ,117.61,111.88,47.74,46.96,43.30,26.82,25.56,24.85. Exact mass calcd for C20H26N2O[M+Na] ⁺ :333.1947; found333.1947.

Example 9-21

The synthetic method of other piperine derivatives is the same as in Examples 2-8, except that the type of aromatic aldehyde is changed. The aromatic aldehyde raw materials, the structural formula of the obtained compound and the NMR results of the obtained compound are shown in Table 2.

The raw material of table 2 preparation compound, gained compound structural formula and compound NMR result

Example 22, Preparation of (E,E)-1-[3-(1-methoxyphen-3-yl)-1-oxo-2,4-pentadienyl]-piperidine

step 1:

At 0°C, a solution of piperidine (0.10mol) and _Et3N (10.12g, 0.10mol) in dichloromethane (50mL) was stirred, crotonyl chloride (0.10mol) was added dropwise, then the reaction was slowly warmed to room temperature and stirred For 8 hours, the reaction was monitored by TLC. After the reaction was completed, the organic layer was washed three times with 50 mL of saturated NaHCO ₃ aqueous solution, and then with 50 mL of H ₂ O. Dry over anhydrous Na ₂ SO ₄ and concentrate under reduced pressure to obtain light yellow viscous liquid 2a. (with the step 1 of embodiment 1)

Step 2:

Intermediate 2a (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated sodium hydroxide solution was added, stirred for 30 minutes, and then 4-(1-pyrrolinyl)benzaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product p-3i.

Dissolve the obtained compound p-3i in 2 mL of trifluoroacetic acid, stir at room temperature for 1 hour, add saturated sodium bicarbonate solution to quench the reaction after the reaction is completed, extract the aqueous phase with 10 mL of ethyl acetate for 3 times, combine the organic phase, and the organic phase Concentration under reduced pressure afforded 3i as a light yellow powdery solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.37(dd, J=9.3,4.5Hz,1H),7.33(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),6.77 -6.73(m,2H),6.39(d,J＝14.7Hz,1H),3.57(s,4H),3.40(s,4H),3.30(s,4H),1.64(m,2H),1.58( m,4H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.39,150.08,143.77,138.98,129.46,128.51,125.01,119.13,116.71,46.23,45.27,43.88,43.44,26.47,25.87.cdcal for mass. C20H26N2O[M+Na] ⁺ :348.2052; found348.2056.

Example 23, Preparation of (2E, 4E)-N, N-diethyl-5-(4-(piperazin-1-yl)phenyl)penta-2,4-diamine

step 1:

At 0°C, a solution of diethylamine (0.10mol) and Et ₃ N (10.12g, 0.10mol) in dichloromethane (50mL) was stirred, and crotonyl chloride (0.10mol) was added dropwise, then the reaction was slowly warmed to room temperature and Stir for 8 hours and monitor the reaction by TLC. After the reaction was completed, the organic layer was washed three times with 50 mL of saturated NaHCO ₃ aqueous solution, and then with 50 mL of H ₂ O. Dry over anhydrous Na ₂ SO ₄ and concentrate under reduced pressure to obtain light yellow viscous liquid 2b.

Step 2:

Dissolve intermediate 2b (1equiv, 2.4mmol) with 2mL dimethyl sulfoxide, add 1mL saturated sodium hydroxide solution, stir for 30 minutes, then add 1-BOC-4-(4-formylphenyl)piperazine ( 1 equiv, 2.4 mmol). Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with water, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product p-3j.

Dissolve the obtained compound p-3j in 2 mL of TFA, stir at room temperature for 1 hour, add saturated sodium bicarbonate solution to quench the reaction after the reaction is completed, extract the aqueous phase with 10 mL of ethyl acetate for 3 times, combine the organic phase, and depressurize the organic phase Concentration afforded 3j as a pale yellow powdery solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46 (ddd, J＝14.6, 6.1, 3.8Hz, 1H), 7.38 (d, J＝8.6Hz, 2H), 6.87 (d, J＝8.6Hz, 2H) ,6.83-6.75(m,2H),6.34(d,J=14.6Hz,1H),3.43(m,8H),3.23(d,J=4.7Hz,4H),1.21(m,6H),0.91- 0.79(m,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.17,147.66,143.01,138.55,130.53,128.36,125.00,119.83,116.45,47.73,44.41,42.38,41.15. Na] ⁺ :336.2052; found 336.2005.

Example 24, Preparation of (2E, 4E)-N-ethyl-5-(4-(piperazin-1-yl)phenyl)pentane-2,4-diamine

step 1:

At 0°C, a solution of ethylamine (0.10mol) and _Et3N (10.12g, 0.10mol) in dichloromethane (50mL) was stirred, and crotonyl chloride (0.10mol) was added dropwise, then the reaction was slowly warmed to room temperature and stirred For 8 hours, the reaction was monitored by TLC. After the reaction was completed, the organic layer was washed three times with 50 mL of saturated NaHCO ₃ aqueous solution, and then with 50 mL of H ₂ O. Dry over anhydrous Na ₂ SO ₄ and concentrate under reduced pressure to obtain light yellow viscous liquid 2c.

Step 2:

Intermediate 2c (1equiv, 2.4mmol) was dissolved with 2mL dimethyl sulfoxide, added 1mL saturated sodium hydroxide solution, stirred for 30 minutes, and then added 1-BOC-4-(4-formylphenyl)piperazine ( 1 equiv, 2.4 mmol). Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% hydrochloric acid, extracted with dichloromethane, the organic phase was washed with water, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography gave the product p-3k.

Dissolve the obtained compound p-3k in 2 mL of trifluoroacetic acid, stir at room temperature for 1 hour, add saturated sodium bicarbonate solution to quench the reaction after the reaction is completed, extract the aqueous phase with 10 mL of ethyl acetate for 3 times, combine the organic phase, and the organic phase Concentration under reduced pressure afforded 3k as a pale yellow powdery solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46 (ddd, J＝14.6, 6.1, 3.8Hz, 1H), 7.38 (d, J＝8.6Hz, 2H), 6.87 (d, J＝8.6Hz, 2H) ,6.83-6.75(m,2H),6.34(d,J=14.6Hz,1H),3.43(m,8H),3.23(d,J=4.7Hz,4H),1.21(m,6H),0.91- 0.79(m,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.17,147.66,143.01,138.55,130.53,128.36,125.00,119.83,116.45,47.73,44.41,42.38,41.15. Na] ⁺ :336.2052; found 336.2005.

Example 25, (2E,4E)-5-(benzo[d][1,3]dioxazol-5-yl)-N,N-diethylpentamethyl-2,4-dienamide preparation of

Intermediate 2b (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated NaOH solution was added, stirred for 30 minutes, and then piperonal (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with H ₂ O, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product 3m. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44 (ddd, J=14.6, 7.4, 2.6Hz, 1H), 6.99 (d, J=1.5Hz, 1H), 6.89 (dd, J=8.0, 1.5Hz, 1H), 6.77(d, J=8.5Hz, 2H), 6.75(d, J=5.0Hz, 1H), 6.36(d, J=14.6Hz, 1H), 5.97(s, 2H), 3.53-3.34( m,4H),1.23(t,J=7.1Hz,3H),1.17(t,J=6.5Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ165.88,148.21,148.14,142.50,138.44,131.05, 125.36,122.53,120.27,108.50,105.71,101.28,42.22,40.98,15.03,13.26. Exact mass calcd for C16H19NO3[M+Na] ⁺ :296.1263; found 296.1265.

Example 26, Preparation of (2E, 4E)-5-(benzo[d][1,3]dioxazol-5-yl)-N-ethylpenta-2,4-diamine

Intermediate 2c (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated NaOH solution was added, stirred for 30 minutes, and then piperonal (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with H ₂ O, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product 3n. ¹ H NMR (400MHz, DMSO) δ8.03 (t, J = 5.4Hz, 1H), 7.26 (d, J = 1.5Hz, 1H), 7.15 (dd, J = 15.0, 10.2Hz, 1H), 7.00 ( dd,J=8.1,1.5Hz,1H),6.97-6.88(m,2H),6.85(d,J=15.5Hz,1H),6.07(d,J=15.0Hz,1H),6.05(s,2H ),3.21-3.12(m,2H),1.06(t,J＝7.2Hz,3H). ¹³ C NMR(101MHz,DMSO)δ164.89,147.90,147.65,139.05,137.68,130.86,125.27,124.67,122.57,108.40 ,105.60,101.22,33.40,14.75. Exactmass calcd for C14H15NO3[M+Na] ⁺ :268.0950; found 268.0952.

Example 27, Preparation of (2E,4E)-N,N-diethyl-5-(thiophen-2-yl)pentane-2,4-diamide

Intermediate 2b (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated NaOH solution was added, stirred for 30 minutes, and then 2-thiophenecarbaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with H ₂ O, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product 3u. ¹ H NMR (400MHz, DMSO) δ7.57(d, J=5.1Hz, 1H), 7.28(d, J=3.6Hz, 1H), 7.20-7.15(m, 1H), 7.15-7.11(m, 1H ),7.09(dd,J=5.1,3.6Hz,1H),6.73(dd,J=15.4,11.1Hz,1H),6.06(d,J=15.1Hz,1H),3.55-3.34(m,4H) ,1.24(t,J=7.1Hz,3H),1.18(t,J=6.5Hz,3H). ¹³ C NMR(101MHz,DMSO)δ165.06,141.05,138.21,130.47,128.19,127.81,126.68,126.09,125.12 ,42.12,40.89,15.03,13.16. Exact masscalcd for C11H13NOS[M+Na] ⁺ :258.0929; found 258.0928.

Example 28, Preparation of (2E,4E)-N-ethyl-5-(thiophen-2-yl)pentane-2,4-diamide

Intermediate 2c (1 equiv, 2.4 mmol) was dissolved in 2 mL of DMSO, 1 mL of saturated NaOH solution was added, stirred for 30 minutes, and then 2-thiophenecarbaldehyde (1 equiv, 2.4 mmol) was added. Stir at room temperature for 6-8 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was neutralized with 5% HCl, extracted with DCM, the organic phase was washed with H ₂ O, and dried over anhydrous Na ₂ SO ₄ . Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product 3v. ¹ H NMR (400MHz, DMSO) δ8.04(t, J=5.3Hz, 1H), 7.55(d, J=5.1Hz, 1H), 7.26(d, J=3.6Hz, 1H), 7.20-7.15( m,1H),7.15-7.11(m,1H),7.09(dd,J=5.1,3.6Hz,1H),6.73(dd,J=15.4,11.1Hz,1H),6.09(d,J=15.1Hz ,1H),3.17(qd,J=7.2,5.8Hz,2H),1.06(t,J=7.2Hz,3H). ¹³ C NMR(101MHz,DMSO)δ164.76,141.35,138.36,130.66,128.19,127.99, 126.79, 126.18, 125.22, 33.42, 14.74. Exact mass calcd for C11H13NOS[M+Na] ⁺ :230.0616; found 230.0617.

Example 29, Preparation of (2E, 4E)-5-(4-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one

Dissolve compound 3a in anhydrous DCM, pre-cool at -78°C for 30 minutes, add the prepared 1M BBr ₃ DCM solution dropwise, stir at -78°C for two hours, slowly rise to room temperature, and stir at room temperature for 4h until complete reaction. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into water to quench the reaction, neutralized with saturated NaHCO ₃ solution, extracted with ethyl acetate, combined organic phases, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded series compound 4a. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46-7.37(m, 1H), 7.30(d, J=8.4Hz, 2H), 6.86(d, J=8.4Hz, 2H), 6.74(m, 2H) ,6.40(d,J＝14.4Hz,1H),3.60(s,4H),1.72-1.63(m,2H),1.60(s,4H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.12,157.12,143.73 ,139.18,128.76,128.63,124.35,118.75,115.93,100.00,27.10,26.35,24.58. Exact mass calcd for C16H19NO2[M+Na] ⁺ :280.1313; found 280.1314.

Example 30, Preparation of (2E,4E)-5-(2-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one

Dissolve compound 3b in anhydrous DCM, pre-cool at -78°C for 30 minutes, add the prepared 1M BBr ₃ DCM solution dropwise, stir at -78°C for two hours, slowly rise to room temperature, and stir at room temperature for 4h until complete reaction. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into water to quench the reaction, neutralized with saturated NaHCO ₃ solution, extracted with ethyl acetate, combined organic phases, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded series compound 4b. ¹ H NMR (400MHz, DMSO) δ9.88(s, 1H), 7.44(d, J=6.7Hz, 1H), 7.22(ddd, J=14.4, 8.4, 2.1Hz, 1H), 7.17-7.03(m ,3H),6.86(d,J=7.8Hz,1H),6.80(t,J=7.4Hz,1H),6.70(d,J=14.4Hz,1H),3.52(s,4H),1.65-1.55 (m,2H),1.48(s,4H). ¹³ C NMR(101MHz,DMSO)δ164.31,155.49,142.52,133.51,129.53,127.26,127.13,123.04,120.71,119.30,115.94,46.04,42.4083,25.6. ,24.16. Exactmass calcd for C16H19NO2[M+Na] ⁺ :280.1313; found 280.1314.

Example 31, Preparation of (2E,4E)-5-(3-hydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one

Compound 3c was dissolved in anhydrous DCM, pre-cooled at -78°C for 30 minutes, the prepared 1M BBr ₃ DCM solution was added dropwise, stirred at -78°C for two hours, slowly raised to room temperature, and stirred at room temperature for 4h until complete reaction. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into water to quench the reaction, neutralized with saturated NaHCO ₃ solution, extracted with ethyl acetate, combined organic phases, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded series compound 4c. ¹ H NMR (400MHz, MeOD) δ7.33 (dd, J = 14.7, 10.9 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.03-6.91 (m, 3H), 6.83 (d, J =15.6Hz,1H),6.73(dd,J=8.0,2.0Hz,1H),6.66(d,J=14.7Hz,1H),3.67-3.56(m,4H),1.69(dd,J=10.5, 5.5Hz,2H),1.59(s,4H) ^.13C NMR(101MHz,MeOD)δ167.62,158.88,144.26,140.43,139.20,130.77,128.02,121.54,119.77,116.93,114.43,468.14,474.64,2 ,25.53. Exact mass calcd for C16H19NO2[M+Na] ⁺ :280.1313; found 280.1314.

Example 32, Preparation of (2E,4E)-N,N-diethyl-5-(4-hydroxyphenyl)penta-2,4-dienamide

Compound 3d was dissolved in anhydrous DCM, pre-cooled at -78°C for 30 minutes, and the prepared 1M BBr ₃ DCM solution was added dropwise, stirred at -78°C for two hours, slowly raised to room temperature, and stirred at room temperature for 4h until complete reaction. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into water to quench the reaction, neutralized with saturated NaHCO ₃ solution, extracted with ethyl acetate, combined organic phases, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded series of compounds 4d. ¹ H NMR (400MHz, DMSO) δ8.02 (dd, J = 15.9, 11.2Hz, 1H), 7.30 (d, J = 8.5Hz, 2H), 6.80 (d, J = 8.5Hz, 2H), 6.64 ( d, J=15.9Hz, 1H), 6.45(t, J=11.2Hz, 1H), 5.59(d, J=11.2Hz, 1H), 2.75(q, J=7.2Hz, 4H), 1.11(t, J＝7.2Hz,6H). ¹³ C NMR(101MHz,DMSO)δ169.84,158.33,138.98,136.85,128.14,127.55,123.84,123.09,115.77,41.74,12.45.Exact mass calcd for C15H17NO2[M+Na] ⁺ 268.1313; found 268.1316.

Example 33, Preparation of (2E,4E)-N-ethyl-5-(4-hydroxyphenyl)pentane-2,4-diamine

Compound 3e was dissolved in anhydrous DCM, pre-cooled at -78°C for 30 minutes, the prepared 1M BBr ₃ DCM solution was added dropwise, stirred at -78°C for two hours, slowly raised to room temperature, and stirred at room temperature for 4h until complete reaction. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into water to quench the reaction, neutralized with saturated NaHCO ₃ solution, extracted with ethyl acetate, combined organic phases, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded series compound 4e. ¹ H NMR (400MHz, DMSO) δ8.11 (dd, J=15.9, 11.1Hz, 1H), 7.29 (d, J=8.4Hz, 2H), 6.84 (d, J=8.4Hz, 2H), 6.58( d, J=15.9Hz, 1H), 6.35(t, J=11.1Hz, 1H), 5.59(d, J=11.1Hz, 1H), 2.79(q, J=7.2Hz, 2H), 1.13(t, J＝7.2Hz,3H). ¹³ C NMR(101MHz,DMSO)δ170.69,158.54,137.07,135.54,127.90,127.55,126.30,123.50,115.82,34.16,13.63.Exact mass calcd for C13H15NO2[M+Na] ⁺ 240.1000; found 240.1001.

Example 34, Preparation of (E)-1-(piperidin-1-yl)-3-(4-(pyrrolidinyl-1-yl)phenyl)prop-2-en-1-one

step 1:

Dissolve the corresponding aromatic aldehyde (1.3mmol) in 15mL pyridine and 1.5mL piperidine, add malonic acid (0.3g, 2.86mmol), heat to reflux for 8h, and detect the reaction by TLC. After the reaction was completed, add hydrochloric acid under ice bath to adjust the pH to acidic, and a precipitate was formed, which was filtered with suction, and the filter cake was washed with ice water. Recrystallization from ethanol afforded the corresponding acid 6a.

Step 2:

Dissolve 6a (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) followed by piperidine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 7a. ¹ H NMR (400MHz, CDCl ₃ ) δ7.61(d, J=15.2Hz, 1H), 7.41(d, J=8.7Hz, 2H), 6.67(d, J=15.2Hz, 1H), 6.52(d ,J=8.7Hz,2H),3.62(s,4H),3.32(t,J=6.6Hz,4H),2.04-1.97(m,4H),1.71-1.63(m,2H),1.60(d, J＝4.6Hz, 4H). ¹³ C NMR (101MHz, CDCl ₃ ) δ166.30, 148.76, 143.11, 129.37, 122.73, 111.55, 111.49, 47.55, 46.85, 43.37, 26.72, 25.46, 24.78. Exact mass calcd for C2O8 Na] ⁺ :307.1786; found 307.1784.

Example 35, Preparation of (E)-N,N-diethyl-3-(4-(pyrrolidin-1-yl)phenyl)acrylamide

Dissolve 6a (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with diethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 7b. ¹ H NMR (400MHz, CDCl ₃ ) δ7.64(d, J=15.2Hz, 1H), 7.40(d, J=8.7Hz, 2H), 6.58(d, J=15.2Hz, 1H), 6.51(d ,J=8.7Hz,2H), 3.55-3.39(m,4H), 3.30(t,J=6.6Hz,4H), 2.10-1.92(m,4H), ^1.32-1.10 (m,6H). NMR(101MHz, CDCl ₃ )δ166.73, 148.88, ^143.15 , 129.51, 122.77, 111.77, 111.64, 47.63, 42.31, 41.11, 25.54, 15.13, 13.43.

Example 36, (E)-3-(benzo[d][1,3]dioxan-5-yl)-1-(piperidin-1-yl)prop-2-en-1-one preparation

step 1:

Dissolve the corresponding aromatic aldehyde (1.3mmol) in 15mL pyridine and 1.5mL piperidine, add malonic acid (0.3g, 2.86mmol), heat to reflux for 8h, and detect the reaction by TLC. After the reaction was completed, add hydrochloric acid under ice bath to adjust the pH to acidic, and a precipitate was formed, which was filtered with suction, and the filter cake was washed with ice water. Recrystallization from ethanol afforded the corresponding acid 6b.

Step 2:

Dissolve 6b (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) followed by piperidine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 7c. ¹ H NMR (400MHz, CDCl ₃ ) δ7.56 (d, J=15.3Hz, 1H), 7.03 (d, J=1.4Hz, 1H), 6.99 (dd, J=8.0, 1.4Hz, 1H), 6.79 (d,J=8.0Hz,1H),6.73(d,J=15.3Hz,1H),5.98(s,2H),3.61(s,4H),1.71-1.64(m,2H),1.64-1.56( m,4H). ¹³ C NMR(101MHz,CDCl ₃ )δ165.62,148.98,148.34,142.13,130.10,123.74,115.86,108.63,106.50,101.53,26.22,24.81.Exact mass calcd ^{forC15H17Na.1} :2 ;found 282.1105.

Example 37, Preparation of (E)-3-(benzo[d][1,3]dioxan-5-yl)-N,N-diethylacrylamide

Dissolve 6b (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with diethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 7d. ¹ H NMR (400MHz, CDCl ₃ ) δ7.62 (d, J=15.3Hz, 1H), 7.03 (d, J=1.6Hz, 1H), 7.00 (dd, J=8.0, 1.6Hz, 1H), 6.80 (d,J=8.0Hz,1H),6.65(d,J=15.3Hz,1H),5.99(s,2H),3.47(s,4H),1.25(t,J=6.5Hz,3H),1.18 (t, J＝6.5Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ166.01, 149.00, 148.32, 142.18, 130.08, 123.83, 115.97, 108.65, 106.51, 101.53, 42.41, 41.22, 15.22, 13.39 mass calcd for C14H17NO3[M+Na] ⁺ :270.1106; found 270.1107.0

Example 38, Preparation of (E)-3-(benzo[d][1,3]dioxan-5-yl)-N-ethylacrylamide

Dissolve 6b (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with ethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 7e. ¹ H NMR (400MHz, CDCl ₃ ) δ7.52 (d, J = 15.5Hz, 1H), 6.98 (d, J = 1.5Hz, 1H), 6.96 (dd, J = 8.0, 1.5Hz, 1H), 6.78 (d,J=8.0Hz,1H),6.21(d,J=15.5Hz,1H),5.70(s,1H),3.41(qd,J=7.3,5.9Hz,2H),1.20(t,J= 7.3Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ166.08,149.11,148.34,140.65,129.45,123.88,118.99,108.65,106.45,101.54,34.73,15.05.Exact mass calcd for ^C12H13 242.0793; found 242.0787.

Example 39, Preparation of (E)-1-(piperidin-1-yl)-3-(thiophen-2-yl)prop-2-en-1-one

step 1:

Dissolve the corresponding aromatic aldehyde (1.3mmol) in 15mL pyridine and 1.5mL piperidine, add malonic acid (0.3g, 2.86mmol), heat to reflux for 8h, and detect the reaction by TLC. After the reaction was completed, add hydrochloric acid under ice bath to adjust the pH to acidic, and a precipitate was formed, which was filtered with suction, and the filter cake was washed with ice water. Recrystallization from ethanol afforded the corresponding acid 6c.

Step 2:

Dissolve 6c (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) followed by piperidine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded product 7f. ¹ H NMR (400MHz, CDCl ₃ ) δ7.78(d, J=14.9Hz, 1H), 7.30(d, J=5.0Hz, 1H), 7.20(d, J=3.5Hz, 1H), 7.03(dd ,J=5.0,3.5Hz,1H),6.72(d,J=14.9Hz,1H),3.62(s,4H),1.68(d,J=4.2Hz,2H),1.62(s,4H).Exact mass calcd for C12H15NOS[M+Na] ⁺ :244.0772; found 244.0775.

Example 40, Preparation of (E)-N,N-diethyl-3-(thiophen-2-yl)acrylamide

Dissolve 6c (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with diethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography yielded 7 g of the product. ¹ H NMR (400MHz, CDCl ₃ ) δ7.81(d, J=15.1Hz, 1H), 7.29(d, J=5.1Hz, 1H), 7.20(d, J=3.5Hz, 1H), 7.02(dd ,J=5.1,3.5Hz,1H),6.62(d,J=15.1Hz,1H),3.55-3.37(m,4H),1.21(s,6H). ¹³ CNMR(101MHz,CDCl ₃ )δ205.56,165.53 ,140.77,135.17,130.10,128.08,127.02,116.75,42.41,41.23,15.21,13.35.Exact mass calcd for C11H15NOS[M+Na] ⁺ :232.0772;found232.0774.

Example 41, Preparation of (E)-N-ethyl-3-(thiophen-2-yl)acrylamide

Dissolve 6c (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with ethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography afforded the product 7h. ¹ H NMR (400MHz, CDCl ₃ ) δ7.73(d, J=15.3Hz, 1H), 7.29(d, J=5.1Hz, 1H), 7.19(d, J=3.4Hz, 1H), 7.02(dd ,J=5.1,3.7Hz,1H),6.19(d,J=15.3Hz,1H),5.67(s,1H),3.48-3.36(m,2H),1.20(t,J=7.3Hz,3H) ^.13 C NMR(101MHz,CDCl ₃ )δ165.68,140.18,133.67,130.24,128.10,127.23,119.88,34.75,15.02.Exact mass calcd for C9H11NOS[M+Na] ⁺ :204.0459;found204.0453.

Example 42, Preparation of (E)-3-(4-(piperazin-1-yl)phenyl)-1-(piperidin-1-yl)prop-2-en-1-one

step 1:

Dissolve the corresponding aromatic aldehyde (1.3mmol) in 15mL pyridine and 1.5mL piperidine, add malonic acid (0.3g, 2.86mmol), heat to reflux for 8h, and detect the reaction by TLC. After the reaction was completed, add hydrochloric acid under ice bath to adjust the pH to acidic, and a precipitate was formed, which was filtered with suction, and the filter cake was washed with ice water. Recrystallization from ethanol afforded the corresponding acid 6d.

Step 2:

Dissolve 6d (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) followed by piperidine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography yielded the product p-8i.

Step 3:

The obtained compound p-8a was dissolved in 2 mL of trifluoroacetic acid and stirred for 1 hour. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction, and extracted three times with 10 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a light yellow Powdered solid 8a. ¹ H NMR (400MHz, CDCl ₃ ) δ7.56(d, J=15.4Hz, 1H), 7.44(d, J=8.7Hz, 2H), 6.86(d, J=8.7Hz, 2H), 6.77(d ,J=15.4Hz,1H),3.61(d,J=19.9Hz,4H),3.49-3.36(m,4H),3.34-3.16(m,4H),1.72-1.64(m,2H),1.60( d, J＝4.1Hz, 4H). ¹³ C NMR (101MHz, CDCl ₃ ) δ165.71, 150.99, 141.74, 129.11, 127.96, 116.23, 115.19, 47.03, 46.82, 43.77, 43.38, 26.76, 25.64, 24.66. Calcdact mass for C18H25N3O[M+H] ⁺ :300.2076; found 300.2076.

Example 43, Preparation of (E)-N,N-diethyl-3-(4-(piperazin-1-yl)phenyl)acrylamide

Dissolve 6d (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with diethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography gave the product p-8b. The obtained compound p-8b was dissolved in 2 mL of trifluoroacetic acid and stirred for 1 hour. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction, and extracted three times with 10 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a light yellow Powdered solid 8b. ¹ HNMR (400MHz, CDCl ₃ ) δ7.64(d, J=15.3Hz, 1H), 7.44(d, J=8.7Hz, 2H), 6.88(d, J=8.7Hz, 2H), 6.67(d, J＝15.3Hz, 1H), 3.48(d, J＝2.6Hz, 4H), 3.35-3.19(m, 4H), 3.08(dd, J＝6.0, 4.0Hz, 4H), 1.26(s, 6H). ¹³ C NMR(101MHz,CDCl3)δ166.21,152.17,142.17,129.08,126.67,115.38,114.36,48.94,45.56,42.26,41.09,29.70,15.06.Exact mass calcd forC17H25N3O[M+H] ⁺ :288.2076；found 288.2077.

Example 44, Preparation of (E)-N-ethyl-3-(4-(piperazin-1-yl)phenyl)acrylamide

Dissolve 6d (1 mmol) in 2 mL of N,N-dimethylformamide (DMF), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU) (1.5 mmol) was then added with ethylamine (1.2 mmol). The reaction was stirred at room temperature for 4 hours, and the reaction was checked by TLC. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted three times with 2 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. Purification by silica gel column chromatography gave the product p-8c. The obtained compound p-8c was dissolved in 2 mL of trifluoroacetic acid and stirred for 1 hour. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction, and extracted three times with 10 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a light yellow Powdered solid 8c. ¹ H NMR (400MHz, CDCl ₃ ) δ7.54(d, J=15.5Hz, 1H), 7.40(d, J=8.8Hz, 2H), 6.86(d, J=8.8Hz, 2H), 6.21(d ,J=15.5Hz,1H),5.55(s,1H),3.46-3.35(m,2H),3.27-3.16(m,4H),3.07-2.97(m,4H),1.20(t,J=7.3 Hz,3H) ^.13 C NMR(101MHz,CDCl ₃ )δ166.54,152.62,140.82,129.20,125.80,117.32,115.29,49.43,46.05,34.68,15.11.Exact mass calcd for C15H21N3O[M ⁺ Na]+63 found 260.1762.

Prove the beneficial effect of the present invention below by concrete test example

Test example 1, the pharmacological test of compound of the present invention

The present invention also provides a pharmacological activity screening experiment of the above compound, that is, an in vitro biochemical level PC-12 cell protection experiment. PC-12 cells are derived from Rattus norvegicus (Rattus norvegicus) adrenal pheochromocytoma, which is a tumor cell of the sympathetic nervous system. It is a catecholaminergic cell and is often used for phenotype-based in vitro pharmacological activity screening of drugs for neurodegenerative diseases. A large number of scholars have used the cells to make in vitro disease cell models to study the role of different pathogenic factors in the pathogenesis of nervous system diseases, and they have also been used for drug development research against neurodegenerative diseases. The injury of PC-12 cells induced by hydrogen peroxide can simulate the response of nerve cells to oxidative stress; the intervention of small molecule drugs can preliminarily determine the effect of drugs on nerve cells by inhibiting the injury of PC-12 cells induced by hydrogen peroxide. Cell protection.

Materials: H ₂ O ₂ : Kelun Chemical; MTT, Biyuntian Biotechnology Co., Ltd.; Serum, Grassland Green Field Biotechnology Co., Ltd.; Medium, hyclone;

Method: Preparation of H ₂ O ₂ injury model: PC-12 cells (1×10 ⁴ cells/well) were seeded in 96-well plates and cultured for 24 hours, then treated with 12.5 μM compound for 24 hours, and then treated with 650 μM H ₂ O ₂ Fresh medium was replaced, and after 24 hours, fresh medium was replaced, and 20 μL of MTT (5 mg/mL) was added to each well, and the cell viability was determined by MTT assay. Without compound treatment, only H ₂ O ₂ was used for modeling as the model control group; and a blank control group (normally cultured PC-12 cells) was set up.

1. Compound preparation

1) Use 100% DMSO to prepare the test compound into a solution with a concentration of 10 mmol/L.

2) Use RPMI 1640 medium to prepare H ₂ O ₂ into a solution with a concentration of 10 mmol/L.

2. Read and record the raw data of each well, and convert the raw data accordingly.

Cell viability=compound conversion value/blank value*100, where the blank value is the data of the DMSO control group.

Figure 1 and Table 3 are the average cell viability of the compounds of the present invention with respect to the PC-12 cytoprotective activity.

Table 3 The compounds of the present invention affect the survival rate of PC-12 cells

It can be seen from Figure 1 and Table 3 that some compounds (3a, 3g, 3h, 3m-3t, 3w, 3ab, 4e, 7a and 7b, etc.) have greater toxicity, making PC-12 cell damage more serious, and nerve cells No protection. However, the rest of the compounds showed different degrees of protective effects on nerve cells, among which compounds 3b, 3i-3k, 3u, 3v, 3x, 4b-4d, 4f, 4g, 7c-7e, 8a and 8b, at a concentration of 12.5μM, The PC-12 cell survival rate can reach 60-90%, and the effect is good; while the compound 3b has the best protective effect on nerve cells, and the PC-12 cell survival rate can reach 88.82% at a concentration of 12.5 μM.

In summary, the compound of the present invention can effectively protect nerve cells and improve the survival rate of nerve cells. Therefore, the compound of the present invention can effectively treat neurodegenerative diseases, and can be used to prepare drugs for treating neurodegenerative diseases.

Claims (9)

1. A compound, or a salt thereof, characterized in that: the compound is shown as a formula (II-A):

formula (II-A)

Wherein,

n ₁ is 1;

R ₃ is selected from

；

R ₁₄ ~R ₁₇ Selected from hydrogen;

R ₂ is selected from

、

Or

；

R _26~30 、R ₃₅ 、R _39~42 Selected from hydrogen; r is ₃₆ Is selected from C ₁ ~C ₅ An alkyl group.

2. A compound, or a salt thereof, characterized by: the compound is represented by formula (II-E):

formula (II-E)

Wherein,

R ₇ is selected from C ₁ ~C ₅ Alkyl groups of (a);

R ₂ is selected from

；

R _26~30 Selected from hydrogen;

or, the compound is represented by formula (II-F):

formula (II-F)

Wherein,

R ₈ is selected from C ₁ ~C ₃ Alkyl of (C) ₃ ~C ₅ A cycloalkyl group;

R ₂ is selected from

；

R _26~30 Selected from hydrogen.

3. A compound, or a salt thereof, characterized by: the compound is shown as a formula (III-A):

formula (III-A)

Wherein,

n ₁ is 1;

R ₃ is selected from

；

R ₁₄ ~R ₁₇ Selected from hydrogen;

R ₂ is selected from

Or

；

R _26~30 、R _39~42 Selected from hydrogen.

4. A compound, or a salt thereof, characterized in that: the compound is one of the following compounds:

。

5. use of a compound according to any one of claims 1 to 4, or a salt thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease.

6. Use according to claim 5, characterized in that: the neurodegenerative disease is Alzheimer disease, vascular dementia, frontotemporal dementia, mixed dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis, huntington chorea, parkinson disease, and spinocerebellar ataxia.

7. A medicament, characterized by: the compound or the salt thereof as defined in any one of claims 1 to 4 is used as an active ingredient, and a pharmaceutically acceptable adjuvant or auxiliary ingredient is added to prepare the preparation.

8. Use of a compound, or a salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease; the compound is one of the following compounds:

。

9. use according to claim 8, characterized in that: the neurodegenerative disease is Alzheimer disease, vascular dementia, frontotemporal dementia, mixed dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis, huntington chorea, parkinson disease, and spinocerebellar ataxia.

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