CN107602523B

CN107602523B - Genipin analogue, preparation method and application thereof

Info

Publication number: CN107602523B
Application number: CN201710809991.1A
Authority: CN
Inventors: 李家明; 何广卫; 黄伟军; 马晓东; 王杰; 王玉骏; 张艳春; 储昭兴; 许勤龙; 莫佳佳
Original assignee: Hefei Industrial Pharmaceutical Institute Co ltd; Anhui University of Traditional Chinese Medicine AHUTCM
Current assignee: Hefei Industrial Pharmaceutical Institute Co ltd; Anhui University of Traditional Chinese Medicine AHUTCM
Priority date: 2017-09-11
Filing date: 2017-09-11
Publication date: 2020-08-18
Anticipated expiration: 2037-09-11
Also published as: CN107602523A

Abstract

The invention relates to the field of medicinal chemistry, in particular to a genipin analogue (I), a medicinal salt thereof, a preparation method and a medicinal composition containing the genipin analogue (I).

Description

Genipin analogue, preparation method and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to genipin analogues, medicinal salts thereof, a preparation method and a medicinal composition containing the genipin analogues and the medicinal salts thereof, which are used for preventing and treating neurodegenerative diseases such as senile dementia and the like.

Background

Alzheimer's Disease (AD), also known as senile dementia, is a progressive neurodegenerative disease accompanied by cognitive, behavioral and functional disorders, which is the most common cerebral degenerative disease in the elderly. The drugs currently used clinically for the treatment of AD are mainly of two types: one is acetylcholinesterase (AchE) inhibitors such as donepezil, rivastigmine and galantamine (see Pepeu G, giovannin M. cholinesterase inhibitors and [ J ]. curr. Alzheimer. res.2009,6(2):86-96) and the other is N-methyl-D-aspartate receptor (NMDAR) antagonists such as memantine (see Hellweg R, Wirth Y, Janetzky W, et al. efficacy of memantine in delayinating working in Alzheimer's Disease (AD): counterproneranalysis of amino acids with ligands to channel AD [ J. Because the causes of the Alzheimer's disease are complex and the mechanism is not completely clear, the current clinically used drugs can only partially improve symptoms, but can not delay or stop the progress of neurodegeneration. Therefore, further and finding effective therapeutic drugs remains a challenge to researchers.

The natural product has the characteristics of rich structure and various biological activities, and is an important source of lead compounds. Cape jasmine has long been used as a traditional Chinese medicine for promoting intelligence, inducing resuscitation, relieving senile dementia and the like (see the pharmacodynamics research review of Lihuan, Panlinmei, Zhuhuaxu and Coptis detoxification decoction on senile dementia [ J ]. modern Chinese medicine research and practice, 2010,24(4): 86-89). Genipin is the main effective component of gardenia, and belongs to iridoid compounds. Modern pharmacological studies have shown that Genipin and its glycosides have anti-inflammatory, anti-platelet aggregation, anti-cancer, hypoglycemic, learning-enhancing, and other effects (see Ryota A, Yosuker H, Takeshi Y. Genhose attributes lipid-induced change in vitro and neural activation in the transdermal amino complex nucleus and the central amino complex nucleus [ J ]. Eur J Pharmacol,2014,741(15): 1-7; Q.S. Wang, J.Tiana, Y.L.Cui, et al. genisis active biological permeability transition of monoclonal antibody and molecular modification [ 11J ] (2014J.) (373J.),373, 373, J.S. Wang, J.S.Tiana, Y.L.Cui., et al. Thin-derivative of monoclonal antibody and molecular derivative of biological enzyme, 275, 3J. (NF 5, 2014, 373, 1-7). However, genipin has low blood concentration and unstable structure, and is easily combined with glycine to generate gardenia blue, which can cause hepatotoxicity and renal toxicity, thereby affecting the practical application (see Hou Y C, Tsai S Y, Lai P Y, et al, metabolism and pharmacology of geneticin and geneticin in. J. food. chem. Toxicol.,2008,46(8): 2764. quadrature. 2769; Kawata Y, Hattori M, Akao T, et al, Formation of nitro-binding microorganisms from geneticin and gardenosideb human intestinal bacteria [ J ]. plant. Med. 1991,57(6): 536. quadrature. 542.). The stability of the compound is improved by structural modification at position 1, such as 1-isopropoxygenipin.

Disclosure of Invention

The invention takes genipin as a lead compound, substitutes 10-site alcoholic hydroxyl with aryl methylene piperazinyl, designs and synthesizes a series of genipin derivatives. The activity screening finds that the compound has obvious acetylcholinesterase inhibition effect, is superior to positive control drugs of donepezil, genipin and 1-isopropoxy genipin, and has certain medicinal prospect.

The structural formula of the compound of the invention is as follows:

wherein X represents CH or N;

y represents CH or N;

R₁represents CH₃Or i-Pr;

R₂is optionally substituted H, C₁～C₆Alkyl, halogen, methoxy, trifluoromethyl or nitro.

Preferred compounds of the present invention are of any of the following structures:

the invention also discloses a preparation method of the compound, taking the compound YH15 as an example, the preparation method comprises the following steps:

other compounds can be prepared by selecting corresponding raw materials and adopting a similar method.

The pharmaceutically acceptable salts of the compounds of the present invention have the same pharmacodynamic activity as the compounds.

The invention also discloses a pharmaceutical composition which contains the compound or the medicinal salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be common tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, oral liquid, injection and other preparation forms which are conventional in pharmaceutics.

Typically, the compounds of the invention are administered to humans in a dosage range of 1mg to 1000mg per day. Dosages outside this range may also be used depending on the dosage form and the severity of the disease.

The following are some of the compounds of the invention in pharmacodynamic testing and results:

experiment one in vitro AChE inhibition experiment:

using Ellman spectrophotometry in vitro to examine the inhibition of genipin analogue on acetylcholine enzyme in rat striatum, and simultaneously using blank group, genipin and donepezil as positive control group to perform experiment, configuring 0.05mol/L phosphate buffer solution with pH of 7.2, substrate thioacetyl choline concentration of 5mmol/L, developer 5, 5-dithio-dinitrobenzoic acid (DTNB) concentration of 1mmol/L, dissolving genipin analogue with PBS solvent, and performing a series of double dilution (concentration of 2.00 × 10 respectively) at 1:2^-5,1.00×10^-5,5.00×10^-6,2.50×10^-6,1.25×10^-6,6.25×10^-7,3.13×10^-7,1.56×10^-7,7.81×10^-8, 3.91×10^-8,1.95×10^-8,9.77×10^-9mol/L) for screening the activity. If active, IC can be determined by inhibition of activity at a range of concentrations₅₀The value is obtained. Respectively adding 100 mu L of a compound to be detected and 20 mu L of enzyme into a 96-well plate by using a pipette, slightly shaking and uniformly mixing, incubating for 10 minutes in a constant-temperature oven at 37 ℃, taking out, then respectively adding 40 mu L of thioacetyl choline substrate, then continuously incubating for 20 minutes in the constant-temperature oven at 37 ℃, then adding 40 mu L of color development agent DTNB, slightly shaking and uniformly mixing; the absorbance was measured at 412nm using a microplate reader. Then, the inhibition rate I (I ═ 1- (A) is used_Measuring-A_{Air conditioner})/(A_{Sign board}-A_{Air conditioner})]× 100%) was plotted against inhibitor concentration C, and IC was determined by linear fitting of sigmoidal curves₅₀The value is obtained. The inhibitory activity of the compounds of the present invention against acetylcholinesterase is shown in Table 1.

TABLE 1 inhibition of acetylcholinesterase by genipin analogs

In-vitro AChE inhibitory activity experiments show that the compounds of the invention have certain in-vitro inhibitory activity on acetylcholinesterase, which is superior to genipin and 1-isopropoxygenipin, and the activity of the compound YH12 is stronger than that of a positive control drug donepezil.

Experimental couple A β_1-42Protective effects of induced PC12 cell injury

Inoculating 10000 (medium differentiation type) cells of PC12 (low-medium differentiation type) in logarithmic growth phase into a 96-well culture plate, culturing for 24h, removing original culture solution, replacing low-serum culture solution, adding nerve growth factor (NGF, the final concentration is 50 mu g/L), continuously incubating for about 96h for later use, adding Amyloid β -protein (1-42) into the 96-well plate to cause PC12 cell damage, the Amyloid β -protein is 25 mu g/ml, adding to-be-tested drugs with different concentrations after about 30min, the final concentrations are 0 and 3.2 × 10^-7， 1.0×10^-6，3.2×10^-6，1.0×10^-5，3.2×10^-5，1.0×10^-4And 3.2 × 10^-4mol/L, adding CO₂The incubator continues to culture for 72h, and each group is provided with 4 multiple holes. And (3) detecting by adopting an MTT colorimetric method. A detection step: 1. after incubation for 72 hours by each drug to be tested, discarding the culture solution, adding a culture solution containing MTT (MTT final concentration is 0.5mg/mL), and continuing incubation for 4 hours; 2. after incubating in the incubator for 4h, terminating the culture and sucking out the culture solution in the holes; 3. adding 200 mu L of dimethyl sulfoxide into each hole, and oscillating to fully dissolve crystals; 4. the absorbance of each well at 570nm was measured on a full-automatic enzyme scale. 5. Cell damage inhibition (%) according to the formula [ ("A")_Measuring-A_Aβ1-42)/(A_control-A_Aβ1-42)]× 100 (%). Compound Pair A β of the present invention_1-42The inhibitory activity of induced PC12 cell damage is shown in table 2.

Cell morphology study: after the amoloid beta-protein is damaged, adding rhodamine 123 (the final concentration is 20 mu mol/L) into a 24-well plate, incubating for 30min, carefully removing the culture solution in the culture solution 24-well plate, adding PBS (phosphate buffer solution) for rinsing for 1-2 times, adding polyformaldehyde for fixing for 15min, determining whether to perform multiple rinsing according to the background fluorescence intensity of the to-be-detected well and the cell intensity, and photographing and recording under a fluorescence microscope.

TABLE 2 genipin analog pair A β_1-42Effects of induced PC12 cell injury: (

n＝4)

△P<0.001vs blank; p<0.05,**P<0.01vs Aβ_1-42Group of

Compound YH5 significantly increased the inhibition rate of cell injury (P < 0.01) at concentrations of 3.2. mu.M, 10. mu.M and 32. mu.M, 11.67%, 16.31% and 19.51%, respectively; in the concentration range of 1-32 μ M, the cell survival rate is dose-dependent with the increase of the concentration, and the effect is the lowest at 3.2 μ M and the maximum at 32 μ M, which shows that the compound YH5 can obviously improve the A beta-induced PC12 cell injury effect and has a certain protection effect on PC12 cells.

Detailed Description

Example 1

Synthesis of methyl 7-isopropoxy- ((4- (4-methylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH15)

Step 1 Synthesis of isopropyl genipin

Sequentially adding genipin (2.0g,8.8mmol), p-toluenesulfonic acid monohydrate (2.0g,10.5 mmol) and isopropanol (20 mL) into a 100mL single-neck bottle, reacting at 80 ℃ for 1h, detecting by TLC (petroleum ether-ethyl acetate 1:1) to ensure that the reaction is almost complete, and adding saturated NaHCO₃Quenching the aqueous solution, filtering, and using CH for filtrate₂Cl₂(3 × 50mL) and combined CH₂Cl₂Layer, dried over anhydrous sodium sulfate, and CH recovered under reduced pressure₂Cl₂This gave a yellow oil which was purified by silica gel column chromatography (petroleum ether-ethyl acetate 4:1) to give 2.0g of a pale yellow oil in 84.3% yield.

Step 2 Synthesis of methylsulfonyl isopropyl genipin

In a 100mL single-necked flask were added sequentially isopropyl genipin (2.0g,7.5mmol) and CH₂Cl₂30mL、Et₃N (1.6mL, 11.6mmol), methanesulfonyl chloride (0.9g,7.9mmol) is slowly dropped under ice bath conditions, after dropping, the ice bath is continued to stir for 2h, TLC (petroleum ether-ethyl acetate 1:1) detects that the reaction is almost complete, 10% diluted hydrochloric acid is washed (3 × 20mL), organic phases are combined, anhydrous sodium sulfate is dried, and the oily matter is obtained by concentration, wherein the yield is 58.1%.

Step 31- (4-methylbenzyl) piperazine synthesis

Piperazine (6.5g,75.6mmol), CH were added sequentially to a 250mL single-necked flask₂Cl₂80mL of p-methylbenzyl chloride (3.0g,21.4mmol) in CH was slowly added dropwise at 0 deg.C₂Cl₂After the solution is dripped, the solution is stirred for 6 hours in an ice bath, the TLC (petroleum ether-ethyl acetate 1:1) detects that the reaction is almost complete, the solution is washed by water (4 × 50mL), and a saturated NaCl solution (2 × 30mL) is washed, dried by anhydrous sodium sulfate, and concentrated to obtain 1.8g of oily matter with the yield of 44.3 percent.

Step 47 Synthesis of methyl Isopropoxyphyllate- ((4- (4-methylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH15)

In a 250mL single-necked flask were added methanesulfonylisopropyl genipin (1.5g,4.3mmol), 1- (4-methylbenzyl) piperazine (1.6g,8.4mmol), and K in that order₂CO₃(1.2g,8.7mmol) and DMF 20mL, reacting at room temperature for 4h, detecting by TLC (petroleum ether-ethyl acetate 1:1) that the reaction is almost complete, adding water 10mL, CH₂Cl₂(2 × 30mL), the organic phases were combined, washed with saturated NaCl solution (3 × 30mL), dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (5: 1 petroleum ether-ethyl acetate) to give an oil, which was dissolved in 5mL of methanol, adjusted to pH 2 with concentrated HCl, frozen, precipitated, filtered and the filter cake was dried to give 1.0g of a white solid with a yield of 48.8%, mp 223.1-224.4 ℃.¹H NMR(300MHz,D₂O)7.42(s,1H,3-H),7.28(d, J＝8.0Hz,2H,ArH),7.21(d,J＝8.0Hz,2H,ArH),6.28(s,1H,7-H),4.67(d,J＝8.4Hz,1H, 1-H),4.33(s,2H,CH₂),4.00(d,J＝14.1Hz,1H,10-Ha),3.93(d,J＝14.1Hz,1H,10-Hb),3.79(s, 3H,COOCH₃),3.63–3.39(m,8H,piperazine-H),3.14(m,1H,CH),2.77(ddd,J＝11.1,8.1,2.7Hz,1H,5-H),2.52(t,J＝8.1Hz,1H,9-H),2.22(s,3H,CH₃),2.20–2.16(m,1H,6-Ha),2.04(brdd,J＝17.7,9.4Hz,1H,6-Hb),1.13(d,J＝6.3Hz,3H,CH₃),1.02(d,J＝6.3Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.0,153.4,143.3,141.3,131.2,130.0,124.2,110.3,100.1,95.6,73.8, 60.2,55.6,51.8,47.9,47.0,46.2,38.8,35.4,23.7,22.4,20.9,20.4；IR(KBr,cm^-1)υ:2972.9, 2945.6,2873.2,1712.3,1630.8,1436.1,1384.2,1284.7,1157.0,1103.4,941.9,849.0；ESI-Mass for C₂₆H₃₆N₂O₄:m/z 441.26(M⁺+H).

Example 2.

Synthesis of methyl 7-methoxy- ((4- (4-methoxybenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH1)

YH1 was obtained as a white solid m.p.226.8-227.9 ℃ by starting from 1- (4-methoxybenzyl) piperazine according to 1.1, 1.2, 1.3, 1.4 of example 1.¹H NMR(300MHz,D₂O)7.39(s,1H,3-H),7.32(d,J＝8.1Hz, 2H,ArH),6.94(d,J＝8.5Hz,2H,ArH),6.18(brs,1H,7-H),5.11(d,J＝2.7Hz,1H,1-H),4.31 (brs,1H,ArCH₂-Ha),4.29(s,3H,ArOCH₃),4.02–3.82(m,1H,ArCH₂-Hb),3.71(s,6H,COOCH₃, OCH₃),3.65–3.47(m,8H,piperazine-H),3.46(s,2H,10-H),3.41(brs,1H,9-H),3.30(brs,1H, 5-H),3.18–2.98(m,1H,6-Ha),2.71(dd,J＝17.6,7.9Hz,1H,6-Hb).¹³CNMR(75MHz,D₂O): 169.9,160.5,151.8,143.1,132.9,128.6,119.7,114.7,111.3,99.1,59.9,56.5,55.4,51.8,47.8,47.7, 45.8,38.7,33.0；IR(KBr,cm^-1)υ:2975.1,2904.6,2834.2,1708.9,1613.3,1517.1,1465.2,1439.6, 1381.9,1253.2,1182.5,1074.4,1032.0,848.9；ESI-Mass for C₂₄H₃₂N₂O₅:m/z 429.25(M⁺+H).

Example 3

Synthesis of methyl 7-methoxy- ((4- (3-methoxybenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH2)

YH2 was obtained as a white solid m.p.226.3-227.4 ℃ by starting from 1- (3-methoxybenzyl) piperazine as described in example 1 under 1.1, 1.2, 1.3, 1.4.¹H NMR(300MHz,D₂O)7.47(s,1H,3-H),7.34(t,J＝7.8Hz, 1H,ArH),7.02(s,1H,ArH),6.99(d,J＝5.7Hz,2H,ArH),6.22(brs,1H,7-H),4.54(d,J＝8.4Hz, 1H,1-H),4.34(s,3H,ArOCH₃),4.05–3.87(m,2H,ArCH₂),3.73(s,3H,COOCH₃),3.60(s,3H, OCH₃),3.59–3.47(m,8H,piperazine-H),3.46(s,1H,10-Ha),3.31(s,1H,10-Hb),3.15–3.05(m, 1H,6-Ha),2.79(dd,J＝15.0,8.6Hz,1H,6-Hb),2.57(dd,J＝16.4,7.7Hz,1H,9-H),2.17–1.95 (m,1H,5-H).¹³C NMR(75MHz,D₂O):170.0,159.4,153.1,142.7,130.8,129.8,128.8,123.7, 116.7,116.1,110.4,102.6,60.2,57.3,55.4,51.8,48.0,45.9,40.6,38.7,35.1,33.0.IR(KBr,cm^-1)υ: 3430.4,2976.8,2945.4,2838.6,2621.8,2514.3,1707.5,1630.5,1585.7,1492.8,1438.3,1369.3, 1269.5,1178.3,1162.5,1080.1,956.8,892.5,785.6,698.5.ESI-Mass for C₂₄H₃₂N₂O₅:m/z 429.29 (M⁺+H).

Example 4

Synthesis of methyl 7-methoxy- ((4- (4-methylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH3)

YH3 was obtained as a white solid m.p.231.3-232.4 ℃ by starting from 1- (4-methylbenzyl) piperazine by the method 1.1, 1.2, 1.3, 1.4 in example 1.¹H NMR(300MHz,D₂O):7.40(s,1H,3-H),7.29(d,J＝8.1Hz,2H,ArH),7.23(d,J＝8.1Hz,2H,ArH),6.18(brs,1H,7-H),5.12(d,J＝3.0Hz,1H,1-H),4.33(s, 2H,CH₂),3.97(d,J＝13.8Hz,1H,10-Ha),3.88(d,J＝13.8Hz,1H,10-Hb),3.60(s,3H,COOCH₃),3.58–3.35(m,8H,piperazine-H),3.30(s,3H,OCH₃),3.09(t,J＝8.1Hz,2H,6-H),2.76–2.68(m,1H,9-H),2.24(s,3H,CH₃),2.12-2.05(m,1H,5-H).¹³C NMR(75MHz,D₂O):169.8,151.7,143.2,141.3,131.1,130.0,128.5,124.3,111.3,99.1,60.2,56.4,55.1,51.8,48.3,47.8, 45.8,38.7,33.0,20.3；IR(KBr,cm^-1)υ:2981.3,2950.6,1712.5,1637.4,1433.6,1368.0,1315.7, 1288.9,1271.8,1197.4,1167.2,1074.0,1024.6,954.1,890.0；ESI-Mass for C₂₄H₃₂N₂O₄:m/z 413.30(M⁺+H).

Example 5

Synthesis of methyl 7-methoxy- ((4- (3-methylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate (YH4)

Following the procedures of 1.1, 1.2, 1.3, 1.4 in example 1, starting from 1- (3-methylbenzyl) piperazine, YH4 was obtained as a white solid, m.p.230.5-231.6 ℃.¹H NMR(300MHz,D₂O):7.48(s,1H,3-H),7.36–7.18(m,4H,ArH),6.28(brs,1H,7-H),4.56(d,J＝8.2Hz,1H,1-H),4.36(s,2H,CH₂),4.08–3.90(m,2H,10-CH₂),3.63(s,3H,COOCH₃),3.61–3.50(m,8H,piperazine-H),3.48(s,3H,OCH₃),3.12(dd,J ＝15.9,7.5Hz,1H,9-H),2.81(brdd,J＝17.0,8.5Hz,1H,6-Ha),2.64–2.49(m,1H,6-Hb),2.27 (s,3H,CH₃),2.06(dd,J＝16.5,8.7Hz,1H,5-H).¹³C NMR(75MHz,D₂O):170.00,153.10, 142.64,139.77,131.72,131.23,129.86,129.33,128.11,127.31,110.44,102.57,60.43,57.30, 55.65,51.82,48.33,47.94,45.98,38.75,35.06,20.33.IR(KBr,cm^-1)υ:2977.1,2947.6,2629.5, 1708.2,1627.6,1438.2,1369.9,1287.6,1178.7,1107.6,957.8,939.5,890.1,766.6,700.3. ESI-Mass for C₂₄H₃₂N₂O₄:m/z 413.26(M⁺+H).

Example 6

Synthesis of methyl 7-methoxy- ((4-benzylpiperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH5)

YH5 was obtained as a white solid in m.p.240.2-241.6 ℃ by starting from 1-benzylpiperazine according to 1.1, 1.2, 1.3, 1.4 of example 1.¹H NMR(300MHz,D₂O)7.50(s,1H,3-H),7.44–7.40(m,5H,ArH),6.21(brs,1H,7-H),5.15(d,J＝2.9Hz,1H,1-H),4.39(s,3H,COOCH₃),4.04-3.88(m,2H,CH₂),3.63 (s,3H,OCH₃),3.60–3.52(m,8H,piperazine-H),3.34(s,2H,10-CH₂),3.17–3.07(m,2H, 6-CH₂),2.75(dd,J＝17.4,8.0Hz,1H,9-H),2.18–2.04(m,1H,5-H).¹³C NMR(75MHz,D₂O): 169.9,160.5,151.8,143.1,132.9,128.6,119.7,114.7,111.3,99.1,59.9,56.5,55.4,51.8,47.8,47.7, 45.8,38.7,33.0；IR(KBr,cm^-1)υ:2989.5,2948.6,2880.1,2830.8,1708.8,1628.0,1436.1,1287.1, 1270.2,1172.6,1073.4,951.3,753.6,700.7；ESI-Massfor C₂₃H₃₀N₂O₄:m/z 399.29(M⁺+H).

Example 7

Synthesis of methyl 7-methoxy- ((4- (4-chlorobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH6)

YH6 was obtained as a white solid, m.p.230.1-231.2 ℃ in the same manner as in example 1 except that 1- (4-chlorobenzyl) piperazine was used as a starting material.¹H NMR(300MHz,D₂O)7.50(s,1H,3-H),7.42(dd,J＝14.1,8.7Hz,4H,ArH),6.27(brs,1H,7-H),4.58(d,J＝8.3Hz,1H,1-H),4.38(s,2H,CH₂),4.05-3.90 (m,2H,10-CH₂),3.64(s,3H,COOCH₃),3.62–3.50(m,8H,piperazine-H),3.49(s,3H,OCH₃), 3.13(q,J＝8.3Hz,1H,5-H),2.82(ddd,J＝11.1,8.4,2.4Hz,1H,6-Ha),2.61(t,J＝7.5Hz,1H, 9-H),2.08(dd,J＝17.5,9.1Hz,1H,6-Hb).¹³C NMR(75MHz,D₂O):170.06,153.10,142.59, 136.16,132.73,129.91,129.47,126.16,110.46,102.58,59.62,57.29,55.67,51.82,48.39,48.03, 45.97,38.73,35.09；IR(KBr,cm^-1)υ:2985.2,2949.8,2843.8,1701.5,1635.4,1494.3,1437.4, 1374.8,1285.2,1179.0,1046.8,1017.1,938.7,854.4；ESI-Mass for C₂₃H₂₉ClN₂O₄:m/z 433.24 (M⁺+H).

Example 8

Synthesis of methyl 7-methoxy- ((4- (4-fluorobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH7)

The procedure is as in example 1, 1.1, 1.2, 1.3, 1.4, starting from 1- (4-fluorobenzyl) piperazineThe material was prepared as a white solid YH7 m.p.237.4-238.6 ℃.¹H NMR(300MHz,D₂O)7.51(s,1H,3-H),7.45(dd,J＝8.4,5.4Hz,2H,ArH),7.16(t,J＝8.7Hz,2H,ArH),6.24(brs,1H,7-H),4.59(d,J＝8.4Hz,1H,1-H),4.38 (s,2H,CH₂),4.02(1H,d,J＝13.5Hz,10-Ha),3.94(1H,d,J＝13.5Hz,10-Hb),3.64(s,3H, COOCH₃),3.62–3.51(m,8H,piperazine-H),3.49(s,3H,OCH₃),3.13(q,J＝8.4Hz,1H,5-H), 2.82(ddd,J＝11.4,8.7,2.7Hz,1H,9-H),2.67–2.51(m,1H,6-Ha),2.09(dd,J＝16.5,8.4Hz,1H, 6-Hb).¹³C NMR(75MHz,D₂O):170.1,162.1,153.1,142.5,133.5,133.4,130.0,123.6,116.5, 116.2,110.5,102.6,59.6,57.3,55.7,51.8,48.4,47.9,46.0,38.7,35.1；IR(KBr,cm^-1)υ:2971.9, 2939.9,2840.6,1712.8,1627.6,1601.1,1513.6,1438.0,1364.1,1286.9,1227.9,1187.3,1111.6, 1084.5,947.7,864.4；ESI-Mass for C₂₃H₂₉FN₂O₄:m/z417.30(M⁺+H).

Example 9

Synthesis of methyl 7-methoxy- ((4- (3-fluorobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH8)

YH8 was obtained as a white solid m.p.236.0-237.4 ℃ by starting from 1- (3-fluorobenzyl) piperazine according to 1.1, 1.2, 1.3, 1.4 of example 1.¹H NMR(300MHz,D₂O):7.48(s,1H,3-H),7.45–7.36(m,1H,ArH),7.22(d,J＝8.7Hz,2H,ArH),7.17(s,1H,ArH),6.25(brs,1H,7-H),4.56(d,J＝8.3Hz,1H, 1-H),4.37(s,2H,CH₂),4.05–3.87(m,2H,10-CH₂),3.61(s,3H,COOCH₃),3.60–3.48(m,8H, piperazine-H),3.46(s,3H,OCH₃),3.10(q,J＝8.4Hz,1H,5-H),2.79(ddd,J＝11.1,8.7,2.7Hz, 1H,6-Ha),2.58(t,J＝7.9Hz,1H,9-H),2.06(dd,J＝17.1,9.1Hz,1H,6-Hb).¹³CNMR(75MHz, D₂O):170.1,164.2,160.9,153.1,142.6,131.4,129.9,127.1,118.1,117.6,110.4,102.6,59.7, 57.3,55.7,51.8,48.4,48.1,45.9,38.7,35.1.IR(KBr,cm^-1)υ:2940.7,2627.1,1698.1,1628.1, 1590.6,1437.5,1287.5,1255.4,1178.8,1110.4,965.9,936.9,892.9,789.9.ESI-Mass for C₂₃H₂₉FN₂O₄:m/z 417.27(M⁺+H).

Example 10

Synthesis of methyl 7-methoxy- ((4- (4-trifluoromethylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH9)

YH9 was obtained as a white solid m.p.171.0-172.4 ℃ by starting from 1- (4-trifluoromethylbenzyl) piperazine according to the procedure of 1.1, 1.2, 1.3, 1.4 in example 1.¹H NMR(300MHz,D₂O)7.74(brs,2H,ArH),7.64(s,1H,3-H),7.60–7.46(m,2H,ArH),6.25(brs,1H,7-H),4.56(d,J＝8.1Hz,1H,1-H),4.39(s,2H,CH₂),4.09–3.78(m,2H,10-CH₂),3.61(s,3H,COOCH₃),3.58–3.50(m,8H,piperazine-H),3.47 (s,3H,OCH₃),3.14(q,J＝8.3Hz,1H,5-H),2.80(ddd,J＝11.1,8.4,2.4Hz,1H,6-Ha),2.59(t,J ＝7.5Hz,1H,9-H),2.06(dd,J＝17.5,9.1Hz,1H,6-Hb).¹³C NMR(75MHz,D₂O):170.1,153.1, 142.6,134.9,131.0,130.1,129.9,128.7,127.9,127.2,121.9,110.5,102.6,59.7,57.3,51.8,50.9, 48.2,46.0,42.6,35.3,34.5.IR(KBr,cm^-1)υ:2983.6,2952.7,2883.1,2847.2,1708.9,1628.2, 1458.6,1440.9,1329.8,1265.5,1157.5,1121.7,1077.7,944.3,819.6,780.5,700.9.ESI-Mass for C₂₄H₂₉F₃N₂O₄:m/z 467.29(M⁺+H).

Example 11

Synthesis of methyl 7-methoxy- ((4- (4-nitrobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH10)

YH10 was obtained as a white solid m.p.234.3-235.6 ℃ by starting from 1- (4-nitrobenzyl) piperazine by the method 1.1, 1.2, 1.3, 1.4 in example 1.¹H NMR(600MHz,D₂O):8.28(d,J＝8.2Hz,2H,ArH),7.94(brs,2H,ArH),7.40(s,1H,3-H),6.33(s,1H,7-H),5.73(s,1H,1-H),3.81(brs,1H,ArCH₂-Ha), 3.61(s,3H,COOCH₃),3.58–3.42(m,8H,piperazine-H),3.24(s,3H,OCH₃),3.08(q,J＝7.8Hz, 1H,5-H),2.97–2.88(m,1H,ArCH₂-Hb),2.73(dd,J＝16.3,8.1Hz,1H,10-Ha),2.48(brs,1H, 9-H),2.10(dd,J＝16.6,7.3Hz,1H,10-Hb),1.88(s,2H,6-H).¹³C NMR(75MHz,D₂O):169.96, 153.09,148.74,142.70,134.87,132.53,129.86,124.40,110.44,102.59,59.19,57.33,55.67,51.83, 48.41,46.02,38.78,35.07,20.41.IR(KBr,cm^-1)υ:2979.1,2950.9,2625.7,2539.5,1711.6,1624.9, 1528.7,1466.1,1433.3,1386.0,1350.3,1286.9,1223.8,1088.7,959.9,860.1.ESI-Mass for C₂₃H₂₉N₃O₆:m/z 444.27(M⁺+H).

Example 12

Synthesis of methyl 7-methoxy- ((4- (3-methylpyridine) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate (YH11)

YH11 was obtained as a white solid m.p.197.1-198.3 ℃ by starting from 1- (pyridin-3-ylmethyl) piperazine as described in example 1, 1.1, 1.2, 1.3, 1.4.¹H NMR(300MHz,D₂O)8.98(s,1H,Pyridine-H),8.84(d,J＝ 5.7Hz,1H,Pyridine-H),8.74(d,J＝8.2Hz,1H,Pyridine-H),8.11(t,J＝7.8Hz,1H,Pyridine-H), 7.45(s,1H,3-H),6.23(d,J＝18.1Hz,1H,7-H),4.55(d,J＝8.3Hz,1H,1-H),3.97(brs,2H,CH₂), 3.83-3.61(m,8H,piperazine-H),3.59(s,3H,COOCH₃),3.46(s,2H,10-CH₂),3.30(s,3H,OCH₃), 3.09(t,J＝8.1Hz,1H,9-H),2.79(ddd,J＝11.1,8.7,2.7Hz,1H,5-H),2.70–2.56(m,1H,6-Ha), 2.04(dd,J＝17.1,9.4Hz,1H,6-Hb).¹³C NMR(75MHz,D₂O):169.8,153.1,151.7,149.7,143.4, 129.8,129.1,128.2,110.4,102.5,99.1,57.3,56.48,56.0,55.6,55.1,51.8,48.6,46.0,38.7,35.0, 32.9.IR(KBr,cm^-1)υ:2978.7,2956.3,2824.1,1701.8,1633.2,1532.7,1436.2,1460.2,1379.3, 1289.1,1179.3,1083.5,946.7,891.0,686.1；ESI-Mass for C₂₂H₂₉N₃O₄:m/z 400.22(M⁺+H).

Example 13

Synthesis of methyl 7-methoxy- ((4- ((3,5, 6-trimethylpyrazin-2-yl) methyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH12)

YH12 was obtained as a white solid in m.p.182.5-183.9 ℃ by starting from 2,3, 5-trimethyl-6- (piperazin-1-ylmethyl) pyrazine as described in example 1, 1.2, 1.3, 1.4.¹H NMR(300MHz,D₂O)7.50(s,1H,3-H),6.28 (d,J＝17.9Hz,1H,7-H),4.74(s,2H,CH₂),4.59(d,J＝8.3Hz,1H,1-H),4.13–3.95(m,2H, 10-CH₂),3.86–3.65(m,8H,piperazine-H),3.62(s,3H,COOCH₃),3.50(s,3H,OCH₃),3.34(s, 1H,9-H),3.13(q,J＝8.1Hz,1H,5-H),2.80(ddd,J＝11.4,8.4,2.4Hz,1H,6-Ha),2.62(s,3H, CH₃),2.60(s,3H,CH₃),2.57(s,3H,CH₃),2.12(dd,J＝17.1,9.6Hz,1H,6-Hb).¹³C NMR(75 MHz,D₂O):170.1,155.6,153.1,147.8,144.3,143.4,129.8,128.4,110.5,102.6,57.3,56.0,51.8, 49.4,48.4,46.0,38.8,35.1,33.0,20.6,17.4,15.9.IR(KBr,cm^-1)υ:2997.5,2951.2,2873.4,2843.1, 1701.7,1631.0,1436.7,1392.6,1290.9,1179.7,1078.7,950.6,891.0,768.7,722.6；ESI-Mass for C₂₄H₃₄N₄O₄:m/z 443.34(M⁺+H).

Example 14

Synthesis of methyl 7-isopropoxy- ((4- (4-methoxybenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH13)

YH13 was obtained as a white solid m.p.225.3-226.5 ℃ by starting from 1- (4-methoxybenzyl) piperazine as described in example 1 under 1.1, 1.2, 1.3, 1.4.¹H NMR(300MHz,D₂O)7.45(s,1H,3-H),7.38(d,J＝8.7Hz, 2H,ArH),6.97(d,J＝8.7Hz,2H,ArH),6.32(s,1H,7-H),4.68(d,J＝8.4Hz,1H,1-H),4.35(s, 2H,CH₂),4.02(dd,J＝12.7,6.3Hz,2H,10-CH₂),3.94–3.85(m,1H,CH),3.75(s,3H,COOCH₃), 3.62(s,3H,OCH₃),3.61–3.45(m,8H,piperazine-H),3.12(q,J＝8.4Hz,1H,6-Ha),2.82(ddd,J ＝11.4,8.7,2.7Hz,1H,5-H),2.55(t,J＝8.0Hz,1H,9-H),2.07(brdd,J＝17.4,9.4Hz,1H,6-Hb), 1.17(d,J＝6.0Hz,3H,CH₃),1.07(d,J＝6.0Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.0, 160.5,153.4,143.1,132.9,130.0,119.7,114.8,110.3,100.1,73.8,72.9,60.0,55.6,55.4,51.8,48.3, 47.8,46.2,38.8,35.4,33.8,22.4,20.9；IR(KBr,cm^-1)υ:2972.1,2830.7,1712.0,1631.0,1518.0, 1437.8,1382.9,1251.4,1157.9,1104.3,945.2,857.9；ESI-Mass for C₂₆H₃₆N₂O₅:m/z 457.21 (M⁺+H).

Example 15

Synthesis of methyl 7-isopropoxy- ((4- (3-methoxybenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate (YH14)

YH14 was obtained as a white solid m.p.208.0-209.2 ℃ by starting from 1- (3-methoxybenzyl) piperazine according to 1.1, 1.2, 1.3, 1.4 of example 1.¹H NMR(300MHz,D₂O)7.44(s,1H,3-H),7.36(t,J＝8.3Hz, 1H,ArH),7.07–6.97(m,3H,ArH),6.26(s,1H,7-H),4.67(d,J＝8.4Hz,1H,1-H),4.38(s,2H, CH₂),4.03(dd,J＝13.5,7.8Hz,2H,10-CH₂),3.96–3.85(m,1H,CH),3.74(s,3H,COOCH₃), 3.66(s,3H,OCH₃),3.61–3.47(m,8H,piperazine-H),3.11(q,J＝8.4Hz,1H,6-Ha),2.81(ddd,J ＝11.4,8.4,2.7Hz,1H,5-H),2.55(t,J＝7.5Hz,1H,9-H),2.06(brdd,J＝17.6,9.5Hz,1H,6-Hb), 1.16(d,J＝6.0Hz,3H,CH₃),1.06(d,J＝6.0Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.0, 159.4,153.4,143.3,130.8,129.9,128.8,123.8,116.6,116.2,110.3,100.1,73.8,60.3,55.6,55.5, 51.8,48.3,48.1,46.2,38.8,35.4,23.7,22.4,20.9；IR(KBr,cm^-1)υ:2973.2,2947.8,2883.6,2831.9, 1706.6,1629.8,1371.3,1437.1,1270.1,1160.3,1101.6,940.3,888.5,787.1,697.6；ESI-Mass for C₂₆H₃₆N₂O₅:m/z 457.16(M⁺+H).

Example 16

Synthesis of methyl 7-isopropoxy- ((4- (3-methylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH16)

YH16 was obtained as a white solid m.p.204.1-205.4 ℃ by starting from 1- (3-methylbenzyl) piperazine by the method 1.1, 1.2, 1.3, 1.4 in example 1.¹H NMR(300MHz,D₂O)7.46(s,1H,3-H),7.37–7.17(m,4H,ArH),6.32(s,1H,7-H),4.68(d,J＝8.4Hz,1H,1-H),4.36(s,2H,CH₂),4.03(dd,J＝12.3,5.7Hz, 2H,10-CH₂),3.98–3.85(m,1H,CH),3.62(s,3H,COOCH₃),3.61–3.40(m,8H,piperazine-H), 3.12(q,J＝8.4Hz,1H,5-H),2.82(ddd,J＝11.1,8.4,2.4Hz,1H,6-Ha),2.56(t,J＝7.9Hz,1H, 9-H),2.27(s,3H,CH₃),2.08(brdd,J＝17.5,9.3Hz,1H,6-Hb),1.17(d,J＝6.0Hz,3H,CH₃),1.07 (d,J＝6.0Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.0,153.4,143.1,139.8,131.7,131.2, 130.0,129.4,128.1,127.3,110.3,100.1,73.8,60.5,55.6,51.8,48.3,48.0,46.2,38.8,35.4,22.4, 21.0,20.4；IR(KBr,cm^-1)υ:2972.9,2879.6,2847.2,1709.2,1624.7,1438.9,1383.6,1288.3, 1161.8,1102.4,942.5,893.8,767.1,703.8；ESI-Mass for C₂₆H₃₆N₂O₄:m/z 441.26(M⁺+H).

Example 17

Synthesis of methyl 7-isopropoxy- ((4-benzylpiperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH17)

YH17 was obtained as a white solid in m.p.214.3-215.7 ℃ by starting from 1-benzylpiperazine according to 1.1, 1.2, 1.3, 1.4 of example 1.¹H NMR(300MHz,D₂O)7.47(s,1H,3-H),7.42–7.40(m,5H,ArH),6.32 (s,1H,7-H),4.73(d,J＝6.0Hz,1H,1-H),4.41(s,2H,CH₂),4.02(dd,J＝11.7,6.3Hz,2H, 10-CH₂),3.99–3.94(m,1H,CH),3.63(s,3H,COOCH₃),3.61–3.46(m,8H,piperazine-H),3.13 (q,J＝8.5Hz,1H,6-Ha),2.82(ddd,J＝11.4,8.7,2.7Hz,1H,5-H),2.56(t,J＝7.7Hz,1H,9-H), 2.09(brdd,J＝17.4,9.3Hz,1H,6-Hb),1.17(d,J＝6.2Hz,3H,CH₃),1.07(d,J＝6.2Hz,3H, CH₃).¹³C NMR(75MHz,D₂O)170.0,153.4,143.1,131.3,130.7,130.0,129.5,127.4,110.3, 100.1,73.8,60.5,55.6,51.9,48.3,48.0,46.2,38.8,35.4,22.4,21.0；IR(KBr,cm^-1)υ:2976.4, 2923.7,2830.1,1716.0,1633.0,1457.8,1440.1,1380.9,1294.7,1156.4,1107.0,952.0,937.2, 891.3,751.2,701.1；ESI-Mass for C₂₅H₃₄N₂O₄:m/z 427.15(M⁺+H).

Example 18

Synthesis of methyl 7-isopropoxy- ((4- (4-chlorobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH18)

The procedure is as described in example 1, 1.1, 1.2, 1.3, 1.4 method operation, using 1- (4-chlorobenzyl) piperazine as raw material to prepare YH18 white solid, m.p.238.1-239.3 ℃.¹H NMR(300MHz,D₂O)7.48(s,1H,3-H),7.41(q,J＝8.5Hz,4H,ArH),6.30(brs,1H,7-H),5.28(s,1H,1-H),4.37(s,2H,CH₂),4.06–4.00(m,1H,CH),3.98–3.86(m,2H,10-CH₂),3.63(s,3H,COOCH₃),3.60–3.37(m,8H,piperazine-H),3.12(q,J＝8.4Hz,1H,5-H),2.82(dd,J＝15.1,8.7Hz,1H,6-Ha),2.54(t,J＝7.6Hz,1H,9-H),2.09(dd,J＝17.3, 9.0Hz,1H,6-Hb),1.16(d,J＝6.2Hz,3H,CH₃),1.06(d,J＝6.0Hz,3H,CH₃).¹³C NMR(75MHz, D₂O)170.1,153.4,143.1,136.1,132.7,130.1,129.5,126.2,110.3,100.1,73.8,59.6,55.6,51.8, 48.4,48.1,46.2,38.8,35.5,22.3,20.9；IR(KBr,cm^-1)υ:2972.6,2880.2,2863.3,1710.2,1630.2, 1438.1,1385.0,1288.6,1162.4,1088.7,935.6,853.0；ESI-Mass for C₂₅H₃₃ClN₂O₄:m/z 461.26 (M⁺+H).

Example 19

Synthesis of methyl 7-isopropoxy- ((4- (4-fluorobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH19)

YH19 was obtained as a white solid m.p.239.5-240.8 ℃ by starting from 1- (4-fluorobenzyl) piperazine by the method 1.1, 1.2, 1.3, 1.4 in example 1.¹H NMR(300MHz,D₂O)7.49(s,1H,3-H),7.44(dd,J＝9.0,5.4Hz,2H,ArH),7.16(t,J＝8.8Hz,2H,ArH),6.27(brs,1H,7-H),5.30(brs,1H,1-H),4.40(s,2H, CH₂),4.07–4.00(m,2H,10-CH₂),3.98–3.87(m,1H,CH),3.63(s,3H,COOCH₃),3.62–3.42(m,8H,piperazine-H),3.13(q,J＝8.8Hz,1H,5-H),2.83(dd,J＝16.1,7.2Hz,1H,6-Ha),2.56(t, J＝8.0Hz,1H,9-H),2.10(dd,J＝17.8,9.6Hz,1H,6-Hb),1.17(d,J＝6.2Hz,3H,CH₃),1.07(dd, J＝6.2Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.1,165.4,162.1,153.4,143.2,133.6,133.5, 130.0,116.5,116.2,110.3,100.1,73.8,59.6,55.6,51.8,48.0,46.2,38.8,35.4,33.8,22.4,20.9；IR (KBr,cm^-1)υ:2975.9,2931.8,2884.5,2826.1,1710.4,1631.8,1514.7,1437.3,1385.9,1289.3, 1226.9,1166.9,1105.2,936.0,888.7,859.7；ESI-Mass for C₂₅H₃₃FN₂O₄:m/z 445.27(M⁺+H).

Example 20

Synthesis of methyl 7-isopropoxy- ((4- (4-trifluoromethylbenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH20)

Following the procedure of 1.1, 1.2, 1.3, 1.4 in example 1, 1- (4-trifluoromethylbenzyl) piperazine produced YH20 as a white solid, m.p.226.2-227.5 ℃.¹H NMR(300MHz,D₂O)7.75(d,J＝8.1Hz,2H,ArH),7.61(d, J＝8.0Hz,2H,ArH),7.49(s,1H,3-H),6.32(s,1H,7-H),4.75(d,J＝6.0Hz,1H,1-H),4.47(s, 2H,CH₂),4.02(dd,J＝14.7,6.3Hz,2H,10-CH₂),3.98–3.85(m,1H,CH),3.63(s,3H,COOCH₃), 3.61–3.46(m,8H,piperazine-H),3.14(q,J＝8.7Hz,1H,5-H),2.83(ddd,J＝11.1,8.1,2.4Hz, 1H,6-Ha),2.56(t,J＝7.7Hz,1H,9-H),2.10(dd,J＝17.5,9.4Hz,1H,6-Hb),1.17(d,J＝6.2Hz, 3H,CH₃),1.07(d,J＝6.2Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.1,153.4,143.2,131.8, 130.0,126.4,126.3,125.6,122.0,110.3,100.1,73.8,64.2,59.7,55.6,51.8,48.3,46.2,38.8,35.5, 23.7,22.3,20.9；IR(KBr,cm^-1)υ:2975.3,2907.8,1705.6,1635.1,1439.0,1386.7,1327.4,1290.4, 1271.5,1166.7,1068.7,938.1,861.0；ESI-Mass for C₂₆H₃₃F₃N₂O₄:m/z 495.16(M⁺+H).

Example 21

Synthesis of methyl 7-isopropoxy- ((4- (4-nitrobenzyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH21)

YH21 was obtained as a white solid m.p.240.6-241.8 ℃ by starting from 1- (4-nitrobenzyl) piperazine by the method of 1.1, 1.2, 1.3, 1.4 in example 1.¹H NMR(300MHz,D₂O)8.25(d,J＝8.8Hz,2H,ArH),7.70(d,J＝8.8Hz,2H,ArH),7.48(s,1H,3-H),6.28(brs,1H,7-H),5.30(d,J＝2.1Hz,1H,1-H),4.53(s, 2H,CH₂),4.07–4.00(m,2H,10-CH₂),3.98–3.90(m,1H,CH),3.63(s,3H,COOCH₃),3.62–3.46(m,8H,piperazine-H),3.14(q,J＝8.5Hz,1H,5-H),2.83(dd,J＝16.1,10.0Hz,1H,6-Ha), 2.57(t,J＝8.1Hz,1H,9-H),2.10(dd,J＝17.5,9.4Hz,1H,6-Hb),1.17(d,J＝6.3Hz,3H,CH₃), 1.07(dd,J＝6.3Hz,3H,CH₃).¹³C NMR(75MHz,D₂O)170.1,153.4,148.8,143.2,135.0,132.5, 130.0,124.4,110.3,100.1,73.9,59.2,55.6,51.8,48.5,46.2,38.8,35.5,33.9,22.4,20.9；IR(KBr, cm^-1)υ:2968.7,2956.4,2887.9,2821.8,1700.2,1635.1,1522.3,1439.7,1385.5,1347.6,1297.1, 1269.4,1160.8,1111.6,938.7,858.9；ESI-Massfor C₂₅H₃₃N₃O₆:m/z 472.24(M⁺+H).

Example 22

Synthesis of methyl 7-isopropoxy-7- ((4- ((3,5, 6-trimethylpyrazin-2-yl) methyl) piperazin-1-yl) methyl) -1,4a,5,7 a-tetrahydro [ c ] pyran-4-carboxylate hydrochloride (YH22)

YH22 was obtained as a white solid in m.p.185.3-186.7 ℃ by starting from 2,3, 5-trimethyl-6- (piperazin-1-ylmethyl) pyrazine as described in example 1, 1.1, 1.2, 1.3, 1.4.¹H NMR(300MHz,D₂O)7.49(s,1H,3-H),6.35(s,1H,7-H),5.32(brs,1H,1-H),4.78–4.73(m,1H,CH),4.17–4.03(m,2H,CH₂),4.02–3.87(m,2H,10-CH₂),3.84–3.64(m,8H,piperazine-H),3.62(s,3H,COOCH₃),3.2–3.0(m,2H,CH₂),2.84(ddd,J＝11.4,8.4,2.4Hz,1H,5-H),2.61(s,3H,CH₃),2.60(s,3H,CH₃),2.56(s,3H, CH₃),2.11(dd,J＝17.5,9.2Hz,1H,9-H),1.17(d,J＝6.2Hz,3H,CH₃),1.07(dd,J＝6.2Hz,3H, CH₃).¹³C NMR(75MHz,D₂O)170.1,155.3,153.5,148.0,144.2,143.7,143.3,129.9,110.3, 100.2,73.9,56.1,55.7,51.8,49.4,48.4,46.2,38.9,35.5,22.4,21.0,20.6,17.6,16.1.IR(KBr,cm^-1) υ:2975.4,2898.8,1705.9,1630.2,1533.8,1436.6,1386.4,1285.7,1264.9,1163.4,1103.5,1003.7, 949.1,888.5,761.9；ESI-Mass forC₂₆H₃₈N₄O₄:m/z 471.28(M⁺+H).

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein X represents CH or N;

y represents CH or N;

R₁represents CH₃Or i-Pr;

R₂is H, C₁～C₆Alkyl, halogen, methoxy, trifluoromethyl or nitro.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of any one of the structures:

3. a compound of the structure:

4. a compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is the hydrochloride, sulfate, phosphate, hydrobromide, maleic, fumaric, citric, methanesulfonic, p-toluenesulfonic, tartaric, or acetate salt of the compound of formula (I).

5. A pharmaceutical composition comprising a compound of claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound of claim 1, 2 or 3 for the preparation of an acetylcholinesterase inhibitor.

7. Use of a compound of claim 1, 2 or 3 for the preparation of a medicament for the treatment or prevention of a neurodegenerative disease.

8. The use of claim 7, wherein the neurodegenerative disease is senile dementia.