CN103588854A - Limonin oxime ether derivatives as well as preparation methods and medical applications thereof - Google Patents

Limonin oxime ether derivatives as well as preparation methods and medical applications thereof Download PDF

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CN103588854A
CN103588854A CN201310567630.2A CN201310567630A CN103588854A CN 103588854 A CN103588854 A CN 103588854A CN 201310567630 A CN201310567630 A CN 201310567630A CN 103588854 A CN103588854 A CN 103588854A
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CN103588854B (en
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徐云根
杨芸
朱启华
王欣慧
龚国清
杨俐嫣
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/008—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by two hetero atoms
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Abstract

The invention relates to the field of medicinal chemistry, in particular to limonin oxime ether derivatives (I) and (II) as well as preparation methods and medical applications thereof. Pharmacology experiments prove that the limonin oxime ether derivatives have analgesia and anti-inflammatory effects and can be used for relieving pain and inflammatory diseases clinically.

Description

Obacalactone oxime ether derivatives, its method for making and medicinal use
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the water-soluble obacalactone of a class and deoxidation obacalactone oxime ether derivatives, the effect of their preparation method and analgesia, anti-inflammatory.
Background technology
Data demonstration, whole world people's every days approximately 5,500,000 stands the torment of pain caused by cancer, and China has more than 100,000,000 pain patients at least.Pain, the most original misery of this mankind, has become global pharmaceutical industries questions of common interest, and various analgesics release one after another, and people's health in the side effect causing due to anodyne abuse on the other hand also serious harm.
Limonoids is highly oxidized tetracyclic triterpenoid Rutaceae and Meliaceae plant family, is extensively present in citrus.Separation obtains about more than 300 kinds of limonoidss so far, and obacalactone is the representative in this compounds.Obacalactone is soluble in fat-soluble organic solvent, and in methyl alcohol, ethanol, solubleness is larger, but it is water-soluble hardly, and oral administration biaavailability is extremely low, has limited its clinical application.
Figure BDA0000413957100000011
Early stage research is mainly the chemical substance that causes citrus fruit and fruit juice bitter taste in order to seek.People mainly concentrate in bioactive research in recent years.At present, limonoid has been proved to be and has had biological activity widely.Matsuda etc. (Planta Medica, 1998,64:339-342) obacalactone of Cong Shu Mao Wuzhuying India and China separation has obvious analgesia and anti-inflammatory action.Shi Ying etc. (Food science, 2007,28:515-518) studies confirm that in tangerine seed, limonin substances has significant topical pain relief antiinflammation.
Summary of the invention
The invention discloses the compound of a class I, II general formula, through pharmacological evaluation, show, compound of the present invention has good analgesia, anti-inflammatory activity.Therefore, formula I of the present invention, the clinical effect that can be used for alleviating pain and there is anti-inflammatory of II compound.
Figure BDA0000413957100000021
R representative:
Figure BDA0000413957100000022
R 1, R 2representative: CH 3, C 2h 5, C 3h 7, CH (CH 3) 2or C 4h 9
M=1 or 2;
N=1 or 2.
General formula compound I of the present invention can be prepared by following method:
Figure BDA0000413957100000023
Wherein:
By compound III, through oximate, prepared the process of compound IV, reactant is oxammonium hydrochloride; Catalyzer is pyridine, triethylamine or salt of wormwood; Solvent is ethanol or Virahol.
By compound IV, through etherificate, prepared the process of Compound I, reactant is RX, R representative:
Figure BDA0000413957100000024
Wherein: R 1, R 2representative: CH 3, C 2h 5, C 3h 7, CH (CH 3) 2or C 4h 9; M=1 or 2; N=1 or 2
The process of being prepared Compound I by compound IV, alkali used is sodium hydride, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium hydroxide or potassium hydroxide; Catalyzer is Tetrabutyl amonium bromide (TBAB) or benzyltriethylammoinium chloride (TEBA); Activator is sodium iodide or potassiumiodide; Solvent is DMF, tetrahydrofuran (THF) or both mixed solvents.
By Compound I, through salify, prepared the process of Compound I HCl, the diethyl ether solution that reactant is saturated hydrogenchloride, the ethanolic soln of saturated hydrogenchloride, the methanol solution of saturated hydrogenchloride or the ethyl acetate solution of saturated hydrogenchloride; Solvent is methyl alcohol, ethanol, methylene dichloride or ethyl acetate.
General formula compound II of the present invention can be prepared by following method:
Figure BDA0000413957100000031
Wherein:
By compound III, through deoxidation Cheng Shuanjian, prepared the process of compound VI, reaction reagent is hydroiodic acid HI; Reaction solvent is acetic acid.
By compound VI, through oximate, prepared the process of compound VI I, reactant is oxammonium hydrochloride; Catalyzer is pyridine, triethylamine or salt of wormwood; Solvent is ethanol, acetonitrile or both mixed solvents.
By compound VI I, through etherificate, prepared the process of Compound I I, reactant is RX, R representative:
Figure BDA0000413957100000032
Wherein: R 1, R 2representative: CH 3, C 2h 5, C 3h 7, CH (CH 3) 2or C 4h 9; M=1 or 2; N=1 or 2
The process of being prepared Compound I I by compound VI I, alkali used is sodium hydride, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium hydroxide or potassium hydroxide; Catalyzer is Tetrabutyl amonium bromide or benzyltriethylammoinium chloride; Activator is sodium iodide or potassiumiodide; Solvent is DMF, tetrahydrofuran (THF) or both mixed solvents.
By Compound I I, through salify, prepared the process of Compound I IHCl, the diethyl ether solution that reactant is saturated hydrogenchloride, the ethanolic soln of saturated hydrogenchloride, the methanol solution of saturated hydrogenchloride or the ethyl acetate solution of saturated hydrogenchloride; Solvent is methyl alcohol, ethanol, methylene dichloride or ethyl acetate.
Below pharmacological testing and the result of part of compounds of the present invention.Wherein compound code name I series (as I-1) represents the derivative of compound of Formula I, and II series (as II-1) represents the derivative of general formula I I compound, and pharmacological evaluation is all the hydrochloride that adopts these compounds.
The acetic acid twisting testing method of the mouse of part of compounds of the present invention is as follows:
Test method:
ICR mouse, male and female half and half, 18～22g, is divided into control group, acetylsalicylic acid group, obacalactone group, the compounds of this invention group at random, 8 every group.Each is organized after gastric infusion 1h, to mouse peritoneal, injects 0.7% acetic acid 0.1ml/10g, observes immediately and record the writhing number of times of each treated animal in 15min, then according to following formula, calculates the inhibiting rate of mouse writhing, the results are shown in Table 1.
Inhibiting rate=(the average writhing number of times of the average writhing number of times-experimental group of negative control group) the average writhing of ÷ negative control group number of times * 100
The impact of table 1 obacalactone Derivatives In Mice acetic acid twisting number of times
Figure BDA0000413957100000041
Figure BDA0000413957100000042
Figure BDA0000413957100000043
Figure BDA0000413957100000051
Note: *p<0.05, *p<0.01, compares with control group.
Mouse acetic acid twisting experimental result shows, can cause the abdominal cavity pain of mouse after abdominal injection 0.7% acetic acid 0.1ml/10g, occurs writhing response, and to mouse writhing, reaction all has obvious restraining effect to compound of the present invention.
The mouse contracting tail experiment test method of part of compounds of the present invention is as follows:
Experimental technique:
ICR male mice, 18～22g, is divided into control group, acetylsalicylic acid group, obacalactone group, the compounds of this invention group at random, 8 every group.The most advanced and sophisticated 3cm of mouse tail is immersed in 48 ℃ of thermostat water baths, and by the thermostat water bath of 48 ℃ of the most advanced and sophisticated 3cm immersions of mouse tail, twice of administration before measurement (5 minutes, interval), gets its mean value.Each administration group is respectively after gavage, measures and respectively organizes after gavage 30 minutes, and 60 minutes, 90 minutes, the preclinical variation of contracting tail of 120 minutes mouse, surpassed 25 seconds nonresponders, and the threshold of pain was by 25 seconds.Then according to following formula, calculate MPE (%).The results are shown in Figure 1 and Fig. 2.
MPE (per-cent of maximum possible effect)=100 × ∣ (threshold of pain-Basic Pain Threshold after administration)/(force stand-by time-Basic Pain Threshold) ∣.Cut-off time is herein defined as 25 seconds, protects mouse tail skin injury-free.
Mouse contracting tail experimental result shows that compound of the present invention all can significantly promote the threshold of pain in mouse contracting end reaction, shows stronger analgesic activities.
The mice ear experiment test method of part of compounds of the present invention is as follows:
Experimental technique:
ICR male mice, 18～22g, is divided into control group, Ibuprofen BP/EP group, obacalactone group, the compounds of this invention group at random, 8 every group.Each organized gastric infusion after 90 minutes, was divided at random model group and was respectively subject to reagent group, 8 every group.Each is organized gastric infusion and at mouse right ear painting dimethylbenzene 25ul, causes inflammation after 90 minutes, and within 30 minutes, post-tensioning neck is put to death, and with 8mm punch tool, ears is punched, and gets ear and weighs, and calculates swelling rate (%) and inhibitory rate of intumesce (%).The results are shown in Table 2.
The effect of table 2 obacalactone Derivatives In Mice ear swelling
Figure BDA0000413957100000061
Figure BDA0000413957100000062
Note: *p<0.05, *p<0.01, * *p<0.005 compares with control group; #p<0.05, ##p<0.01, ###p<0.005 compares with obacalactone group.
Mouse writhing experimental result shows that compound of the present invention has obvious restraining effect to little ear swelling.Wherein Compound I-3 show the strongest active.
Compound of the present invention is changed into water soluble by the water-fast character of obacalactone.
Accompanying drawing explanation
Fig. 1 is the effect of obacalactone derivative I-1～5 hydrochloride to mouse contracting tail
Fig. 2 is the effect of obacalactone derivative I I-1～5 hydrochloride to mouse contracting tail
Embodiment
Embodiment 1
The preparation of compound IV
In 100ml eggplant-shape bottle, add obacalactone (III) 1.0g (0.002mol), oxammonium hydrochloride 1.1g (0.016mol), dehydrated alcohol 45ml, pyridine 15ml, reflux 2.5h.Thin-layer chromatography (TLC) detects, after reacting completely by question response liquid cooling to room temperature, be poured in the 5% dilute hydrochloric acid 125ml that configured in advance is good, adjust its pH for acid, frozen water is cooling.Water layer 50ml dichloromethane extraction three times, combining extraction liquid, saturated common salt washing three times, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure.Crude product methylene dichloride: methyl alcohol (125:1) column chromatography, obtains white solid 0.98g, yield 95%.mp>250℃; 1HNMR(CDCl 3,500MHz),δ(ppm):7.70(1H,brs),7.39(2H,d,J=1.7Hz),6.34(1H,s),5.46(1H,s),4.68(1H,d,J=13.0Hz),4.36(1H,d,J=13.0Hz),3.99(1H,brs),3.81(1H,s),3.57(1H,d,J=11.8Hz),2.96(1H,dd,J 1=3.8Hz,J 2=16.7Hz),2.69(1H,dd,J 1=1.5Hz,J 2=16.7Hz),2.42(1H,d,J=10.2Hz),1.92-2.02(2H,m),1.74–1.88(3H,m),1.49–1.51(1H,m),1.32(3H,s),1.23(3H,s),1.19(3H,s),0.97(3H,s).
Embodiment 2
The preparation of Compound I-1
In the eggplant-shape bottle of 50ml, 0.50g (0.001mol) IV is dissolved in 25ml anhydrous tetrahydro furan completely.Now add 60% sodium hydride 0.2g (0.005mol), the TBAB that adds 1-(2-chloroethyl) piperidine hydrochlorate 0.55g (0.003mol), potassiumiodide 0.17 (0.001mol) and catalytic amount after stirring at room 30min, continue after stirring at room 1h, be warming up to 80 ℃ of reaction 12h.TLC detects to reacting completely, cooling, removes solvent under reduced pressure.Residue adds 100ml water, with 5% dilute hydrochloric acid, adjusts pH to acid, water layer 70ml dichloromethane extraction three times, combining extraction liquid, saturated common salt washing three times, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure.Crude product methylene dichloride: methyl alcohol (75:1) column chromatography, obtains I-1 white solid 0.32g, yield 54%.mp195～198℃;IR(KBr,υcm -1):2932,1746,1561,1414,1021,810; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.40(2H,d,J=1.6Hz),6.36(1H,s),5.47(1H,s),4.67(1H,d,J=13.0Hz),4.33(1H,d,J=13.0Hz),4.24(2H,brs),3.96(1H,s),3.79(1H,s),3.47(1H,dd,J 1=2.6Hz,J 2=13.1Hz),2.95(1H,dd,J 1=3.8Hz,J 2=16.8Hz),2.66(1H,d,J=16.6Hz),2.52(4H,brs),2.39(1H,d,J=11.3Hz),1.72-2.02(6H,m),1.47-1.57(8H,m),1.30(3H,s),1.25(3H,s),1.17(3H,s),0.95(3H,s); 13CNMR(CDCl 3,300MHz),δ(ppm):205.83,169.38,166.87,158.21,143.18,141.01,120.23,109.74,80.39,79.29,78.28,72.33,65.81,64.78,60.68,57.67,54.99,54.29,49.97,46.18,46.03,37.99,35.86,33.14,30.28,25.92,24.15,21.60,21.36,19.78,19.61,18.01;HR-ESIMS?m/z597.3172[M+H] +(calcd?for?C 33H 45N 2O 8,597.3170).
In the eggplant-shape bottle of 25ml, 0.2g I-1 is dissolved in 4ml methylene dichloride completely, under stirring at room, slowly splash into the diethyl ether solution 10ml that HCl is saturated, adularescent solid is separated out, stir after 5min, filter, with diethyl ether solution washing, be dried to obtain I-1HCl white solid 0.13g, 65%, 110 ℃ of yield (decomposition).
Embodiment 3
The preparation of Compound I-2
Compound IV and 1-(2-chloroethyl) morpholine hydrochloride of take is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (75:1) column chromatography, obtains I-2 white solid 0.29g, yield 48%.mp138～141℃;IR(KBr,υcm -1):2963,1750,1025,807; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.41(2H,d,J=4.6Hz),6.36(1H,s),5.49(1H,s),4.66(1H,d,J=13.0Hz),4.33(1H,d,J=13.0Hz),3.96(1H,brs),3.86(4H,brs),3.80(1H,s),3.45(1H,dd,J 1=2.9Hz,J 2=14.0Hz),2.95(1H,dd,J 1=3.8Hz,J 2=16.8Hz),2.67–2.93(4H,brs),2.66(1H,dd,J 1=1.9Hz,J 2=16.7Hz),2.39(1H,d,J=11.6Hz),1.73-2.06(9H,m),1.49-1.53(2H,m),1.30(3H,s),1.25(3H,s),1.17(3H,s),0.97(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.37,166.96,158.44,143.20,140.98,120.14,109.69,80.35,79.27,78.28,71.86,66.88,65.76,64.73,60.65,57.38,54.27,54.04,49.95,46.14,46.03,37.99,35.84,33.09,30.27,21.59,21.34,19.78,19.57,17.99;HR-ESIMS?m/z599.2958[M+H] +(calcd?for?C 32H 43N 2O 9,599.2963).
Take Compound I-2 as starting raw material, and operation, with the preparation method of I-1HCl, obtains I-2HCl white solid 0.15g, 71%, 200 ℃ of yield (decomposition).
Embodiment 4
The preparation of Compound I-3
With compound IV and N, N-diethyl chloroethylamine hydrochloride is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (60:1) column chromatography, obtains I-3 white solid 0.25g, yield 43%.mp134～136℃;IR(KBr,υcm -1):2979,2623,1744,1036,809; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.40(2H,d,J=1.6Hz),6.36(1H,s),5.47(1H,s),4.67(1H,d,J=13.0Hz),4.33(1H,d,J=13.0Hz),4.18(2H,m),3.96(1H,brs),3.80(1H,s),3.48(1H,dd,J 1=2.3Hz,J 2=13.8Hz),2.95(1H,dd,J 1=3.8Hz,J 2=16.7Hz),2.79(2H,brs),2.68(4H,s),2.65(1H,s),2.39(1H,d,J=11.6Hz),1.72-2.50(4H,m),1.49-1.53(2H,m),1.30(3H,s),1.25(3H,s),1.17(3H,s),1.08(6H,brs),0.95(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.43,143.29,140.98,119.99,109.64,80.43,79.18,78.55,65.85,64.71,60.52,54.34,50.12,49.81,47.22,46.28,46.15,45.84,38.13,35.84,32.99,30.30,29.71,21.57,21.46,20.35,19.62,17.87,8.96,8.67;HR-ESIMS?m/z585.3165[M+H] +(calcd?for?C 32H 45N 2O 8,585.3170).
Take Compound I-3 as starting raw material, and operation, with the preparation method of I-1HCl, obtains I-3HCl white solid 0.11g, 52%, 78 ℃ of yield (contraction), 210 ℃ (decomposition).
Embodiment 5
The preparation of Compound I-4
With compound IV and N, N-dimethyl-3-chloro propyl amine hydrochloric acid salt is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (50:1) column chromatography, obtains I-4 white solid 0.20g, yield 34%.mp178～180℃;IR(KBr,υcm -1):2961,1743,1025,810; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.41(1H,s),7.40(1H,s),6.36(1H,s),5.47(1H,s),4.68(1H,d,J=13.1Hz),4.34(1H,d,J=13.1Hz),4.08–4.11(2H,m),3.99(1H,brs),3.79(1H,s),3.40–3.48(2H,m),3.37–3.41(7H,m),2.93(1H,dd,J 1=3.6Hz,J 2=16.9Hz),2.67(1H,d,J=16.9Hz),2.64–2.66(2H,m),2.42(1H,d,J=11.3Hz),1.98-2.04(2H,m),1.79–1.90(2H,m),1.63–1.74(1H,m),1.43–1.55(1H,m),1.32(3H,s),1.26(6H,s),1.18(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.54,167.71,159.98,143.27,140.98,120.00,109.68,80.29,79.08,78.57,70.49,65.88,64.80,60.18,54.94,54.31,49.59,46.23,46.13,42.88,38.08,35.83,32.93,30.21,24.66,21.61,21.42,19.89,19.58,17.84,13.70;HR-ESIMS?m/z571.3012[M+H] +(calcd?for?C 31H 43N 2O 8,571.3014).
Take Compound I-4 as starting raw material, and operation, with the preparation method of I-1HCl, obtains I-4HCl white solid 0.16g, 75%, 218 ℃ of yield (decomposition).
Embodiment 6
The preparation of Compound I-5
Take compound IV and 2-chloroethyl dimethylamine hydrochloride is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (40:1) column chromatography, obtains I-5 white solid 0.18g, yield 31%.mp137～140℃;IR(KBr,υcm -1):2962,1748,1030,810; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.42(1H,s),7.40(1H,t,J=2.8Hz),6.36(1H,d,J=1.5Hz),5.47(1H,s),4.67(1H,d,J=21.7Hz),4.33(1H,d,J=21.8Hz),4.17(2H,t,J=9.5Hz),3.96(1H,brs),3.80(1H,s),3.44-3.51(1H,m),2.95(1H,dd,J 1=6.3Hz,J 2=27.9Hz),2.73–2.60(3H,m),2.40(1H,d,J 1=18.4Hz),2.32(6H,s),2.15–2.02(2H,m),1.97–1.82(1H,m),1.80–1.69(2H,m),1.42–1.56(1H,m),1.29(3H,s),1.25(6H,s),1.17(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.62,168.21,162.21,143.30,141.02,119.98,109.66,80.47,79.18,78.68,67.06,65.96,64.79,60.42,55.46,54.34,49.76,46.37,46.11,44.29,42.83,38.17,35.87,32.91,30.29,24.46,21.59,21.47,20.67,19.57,17.83,13.92;HR-ESIMS?m/z557.2845[M+H] +(calcd?for?C 30H 41N 2O 8,557.2857).
Take Compound I-5 as starting raw material, and operation, with the preparation method of I-1HCl, obtains I-5HCl white solid 0.18g, 84%, 98 ℃ of yield (contraction).
Embodiment 7
The preparation of compound VI
In the eggplant-shape bottle of 250ml, will add successively obacalactone 4g (0.009mol), 70ml hydroiodic acid HI and 70ml acetic acid, 60 ℃ of reactions.TLC tracks to and reacts completely, and slowly pours in 400ml saturated sodium bisulfite solution after question response liquid cooling but, uses 150ml dichloromethane extraction three times, and combining extraction liquid, uses respectively saturated sodium bicarbonate solution, and saturated aqueous common salt is respectively washed secondary, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure.Acetonitrile and water recrystallization for crude product, obtain white or light yellow crystal 2.7g, yield 70%.mp>250℃; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.50(1H,s),7.45(1H,s),6.85(1H,s),6.42(1H,d,J=0.95Hz),5.01(1H,s),4.63(2H,dd,J 1=13.1Hz,J 2=56.0Hz),4.11(1H,brs),2.98(1H,dd,J 1=3.6Hz,J 2=16.9Hz),2.82(1H,t,J=16.0Hz),2.65(1H,dd,J 1=1.95Hz,J 2=16.9Hz),2.61(1H,dd,J 1=3.8Hz,J 2=16.1Hz),2.54(1H,q,J=7.4Hz),2.31(1H,dd,J 1=3.7Hz,J 2=15.8Hz),2.03-2.13(1H,m),1.81-1.91(1H,m),1.54–1.65(1H,m),1.42(3H,s),1.31(3H,s),1.26(3H,s),1.20(3H,s);MS(ESI(-)70V,m/z):455.2([M+H] +)
Embodiment 8
The preparation of compound VI I
In 100ml eggplant-shape bottle, add compound VI 1.0g (0.002mol), oxammonium hydrochloride 1.1g (0.016mol), dehydrated alcohol 20ml, acetonitrile 20ml, pyridine 15ml, reflux 24h.TLC tracks to and reacts completely, and question response liquid cooling, to room temperature, is poured in the 5% dilute hydrochloric acid 125ml that configured in advance is good, and it is acid adjusting pH, and frozen water is cooling.Water layer 50ml dichloromethane extraction three times, combining extraction liquid, and with saturated common salt, wash three times anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure.Crude product methylene dichloride: methyl alcohol (125:1) column chromatography, obtains white solid 0.60g, yield 58%.248 ℃ (carbonization). 1H?NMR(CDCl 3,500MHz),δ(ppm):7.75(1H,brs),7.50(1H,s),7.43(1H,s),6.72(1H,s),6.41(1H,d,J=1.05Hz),5.10(1H,s),4.47(2H,dd,J 1=13.0Hz,J 2=46.3Hz),4.06(1H,brs),3.33(1H,dd,J 1=4.8Hz,J 2=22.0Hz),2.93(1H,dd,J 1=3.6Hz,J 2=10.5Hz),2.63(1H,dd,J 1=2.3Hz,J 2=16.8Hz),2.41(1H,q,J=5.7Hz),2.31(1H,dd,J 1=14.9Hz,J 2=17.1Hz),1.96-2.13(1H,m),1.78-1.86(1H,m),1.51–1.68(1H,m),1.47(3H,s),1.33(3H,s),1.28(3H,s),1.20(3H,s);MS(ESI(-)70V,m/z):470.2([M+H] +)
Embodiment 9
The preparation of Compound I I-1
Compound VI I and 1-(2-chloroethyl) piperidine hydrochlorate of take is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (100:1) column chromatography, obtains II-1 white solid 0.38g, yield 62%.230 ℃ (carbonization).IR(KBr,υcm -1):2937,1754,1721,1039,874; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.51(1H,s),7.44(1H,d,J=1.5Hz),6.77(1H,s),6.42(1H,s),5.02(1H,s),4.45(2H,dd,J 1=12.9Hz,J 2=41.2Hz),4.33(2H,t,J=5.9Hz),4.07(1H,s),3.20(1H,dd,J 1=5.0Hz,J 2=17.6Hz),2.93(1H,dd,J 1=3.5Hz,J 2=16.8),2.72(2H,brs),2.63(1H,dd,J 1=2.3Hz,J 2=16.8Hz),2.52(4H,brs),2.43(1H,dd,J 1=6.5Hz,J 2=13.1Hz),2.35(1H,dd,J 1=14.9Hz,J 2=17.5Hz),1.94–2.10(2H,m),1.82(1H,m),1.57–1.73(5H,m),1.43-1.56(3H,m),1.49(3H,s),1.31(3H,s),1.30(3H,s),1.20(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.68,168.92,165.21,158.74,143.14,141.47,119.98,116.89,109.98,93.97,82.31,81.17,78.17,72.32,64.73,57.84,57.67,55.06,46.14,45.81,45.56,38.79,35.68,30.73,29.02,26.57,25.86,24.12,22.13,21.99,21.85,21.53,19.01,18.19;HR-ESIMS?m/z581.3210[M+H] +(calcd?for?C 33H 45N 2O 7,581.3221).
Take Compound I I-1 as starting raw material, and operation, with the method for I-1HCl, obtains II-1HCl white solid 0.19g, 90%, 108 ℃ of yield (decomposition).
Embodiment 10
The preparation of Compound I I-2
Compound VI I and 1-(2-chloroethyl) morpholine hydrochloride of take is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (70:1) column chromatography, obtains II-2 white solid 0.28g, yield 45%.210 ℃ (carbonization).IR(KBr,υcm -1):2961,1751,1719,1036,871; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.52(1H,s),7.45(1H,t,J=1.6Hz),6.75(1H,s),6.43(1H,d,J=1.0Hz),5.03(1H,s),4.46(2H,dd,J 1=12.9Hz,J 2=42.2Hz),4.34(2H,brs),4.07(1H,t,J=2.7Hz),3.77(4H,brs),3.22(1H,dd,J 1=4.4Hz,J 2=17.3Hz),2.94(1H,dd,J 1=3.5Hz,J 2=16.9Hz),2.76(2H,brs),2.63(2H,dd,J 1=2.4Hz,J 2=16.9Hz),2.59(2H,brs),2.44(1H,dd,J 1=6.6Hz,J 2=13.0Hz),2.34(1H,dd,J 1=14.9Hz,J 2=17.4Hz),1.95–2.10(2H,m),1.77–1.88(1H,m),1.63–1.74(2H,m),1.51–1.61(1H,m),1.50(3H,s),1.31(3H,s),1.3(3H,s),1.20(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.56,168.75,165.16,143.12,141.43,119.90,117.02,109.93,82.29,81.07,78.17,71.75,66.74,65.85,64.70,57.70,57.55,53.96,46.09,45.81,45.62,38.75,35.62,30.69,28.89,26.55,22.07,21.86,21.40,18.15,15.28;HR-ESIMS?m/z583.3001[M+H] +(calcd?for?C 32H 43N 2O 8,583.3014).
Take Compound I I-2 as starting raw material, and operation, with the method for I-1HCl, obtains II-2HCl white solid 0.14g, 66%, 82 ℃ of yield (contraction), 158 ℃ (decomposition).
Embodiment 11
The preparation of Compound I I-3
With compound VI I and N, N-diethyl chloroethylamine hydrochloride is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (50:1) column chromatography, obtains II-3 white solid 0.32g, yield 53%.mp176～178℃;IR(KBr,υcm -1):2969,1758,1721,1041,877; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.51(1H,s),7.44(1H,s),6.80(1H,s),6.42(1H,s),5.03(1H,s),4.44(2H,dd,J 1=12.9Hz,J 2=39.2Hz),4.26(2H,t,J=6.0Hz),4.07(1H,s),3.21(1H,dd,J 1=4.9Hz,J 2=17.7Hz),2.93(1H,dd,J 1=3.3Hz,J 2=16.8Hz),2.75–2.86(2H,m),2.57–2.71(5H,m),2.44(1H,dd,J 1=6.5Hz,J 2=13.0Hz),2.30–2.40(1H,m),1.94–2.08(2H,m),1.75–1.87(2H,m),1.65–1.72(1H,m),1.49(3H,s),1.30(3H,s),1.30(3H,s),1.19(3H,s),1.08(6H,t,J=7.1Hz); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.61,168.92,165.14,158.48,143.05,141.39,119.90,116.72,109.90,82.22,81.11,78.09,73.06,64.62,57.50,51.45,47.91,46.06,45.68,45.41,38.72,35.60,30.65,29.05,26.46,22.06,21.94,21.49,18.11,11.85;HR-ESIMS?m/z569.3217[M+H] +(calcd?for?C 32H 45N 2O 7,569.3221).
Take Compound I I-3 as starting raw material, and operation, with the method for I-1HCl, obtains II-3HCl white solid 0.15g, 71%, 182 ℃ of yield (decomposition).
Embodiment 12
The preparation of Compound I I-4
With compound VI I and N, N-dimethyl-3-chloro propyl amine hydrochloric acid salt is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol 40:1 column chromatography, obtains II-4 white solid 0.25g, yield 42%.220 ℃ (carbonization).IR(KBr,υcm -1):2927,1751,1718,1040,874; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.50(1H,s),7.43(1H,s),6.79(1H,s),6.41(1H,s),5.01(1H,s),4.44(2H,dd,J 1=12.8Hz,J 2=39.1Hz),4.29–4.14(2H,m),4.06(1H,brs),3.18(1H,dd,J 1=5.0Hz,J 2=17.7Hz),2.92(1H,dd,J 1=3.4Hz,J 2=16.8Hz),2.62(1H,dd,J 1=2.0Hz,J 2=16.8Hz),2.30–2.52(4H,m),2.27(6H,s),1.99-2.02(2H,m),1.85–1.93(2H,m),1.75–1.84(1H,m),1.63–1.73(2H,m),1.48(3H,s),1.30(3H,s),1.28(3H,s),1.19(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.65,169.07,165.23,158.37,143.10,141.43,119.94,116.68,109.94,82.29,81.15,78.14,72.79,64.65,59.11,57.55,56.28,46.11,45.72,45.42,45.30,38.77,35.65,30.71,29.14,27.42,26.47,24.19,22.11,21.84,21.52,19.80,18.14,15.28,13.69;HR-ESIMS?m/z555.3056[M+H] +(calcd?for?C 31H 43N 2O 7,555.3065).
Take Compound I I-4 as starting raw material, and operation, with the method for I-1HCl, obtains II-4HCl white solid 0.12g, 56%, 200 ℃ of yield (decomposition).
Embodiment 13
The preparation of compound VI II-5
Take compound VI I and 2-chloroethyl dimethylamine hydrochloride is raw material, and operation is with the method for I-1, crude product methylene dichloride: methyl alcohol (25:1) column chromatography, obtains II-5 white solid 0.15g, yield 26%.210 ℃ (carbonization).IR(KBr,υcm -1):2966.1758,1720,1039,871; 1H?NMR(CDCl 3,500MHz),δ(ppm):7.52(1H,s),7.44(1H,t,J=1.6Hz),6.80(1H,s),6.42(1H,s),5.03(1H,s),4.45(2H,dd,J 1=12.9Hz,J 2=41.8Hz),4.29(2H,t,J=5.7Hz),4.07(1H,s),3.23(1H,dd,J 1=5.0Hz,J 2=17.7Hz),2.93(1H,dd,J 1=3.5Hz,J 2=16.8Hz),2.70(2H,t,J=5.3Hz),2.63(1H,dd,J 1=2.4Hz,J 2=16.8Hz),2.40–2.47(1H,m),2.37(1H,m),2.36(6H,s),1.95–2.07(2H,m),1.77–1.87(1H,m),1.70(2H,m),1.50(3H,s),1.30(3H,s),1.30(3H,s),1.19(3H,s); 13C?NMR(CDCl 3,300MHz),δ(ppm):169.64,168.95,165.17,158.73,143.06,141.39,119.91,116.74,109.91,82.24,81.13,78.08,72.29,64.65,59.26,58.33,57.51,46.06,45.85,45.69,45.47,38.72,35.62,30.65,29.02,26.47,24.30,22.10,21.99,21.48,19.78,18.11,13.69;HR-ESIMS?m/z541.2897[M+H] +(calcd?for?C 30H 41N 2O 7,541.2908).
Take Compound I I-5 as starting raw material, and operation, with the method for I-1HCl, obtains II-5HCl white solid 0.14g, 66%, 152 ℃ of yield (contraction), 201 ℃ (decomposition).
Embodiment 14
Tablet
Get gained compound 0.5g in embodiment 2, starch 2g, dextrin 1g mixes, and with appropriate 30% ethanol, makes wetting agent, granulate, compressing tablet.

Claims (7)

1. general formula (I) or compound (II) or its pharmacy acceptable salt:
Figure FDA0000413957090000011
Wherein: R representative:
Figure FDA0000413957090000012
or
Figure FDA0000413957090000013
R 1, R 2representative: CH 3, C 2h 5, C 3h 7, CH (CH 3) 2or C 4h 9;
M=1 or 2;
N=1 or 2.
2. the preparation method of claim 1 formula of (I) compound, comprising:
Figure FDA0000413957090000014
Wherein the definition of R is with claim 1.
Claim 1 formula of (II) compound preparation method, comprising:
Figure FDA0000413957090000015
Figure FDA0000413957090000021
Wherein the definition of R is with claim 1.
4. the compound of claim 1 or its pharmacy acceptable salt, the acid salt that the general formula (I) that wherein pharmacy acceptable salt is claim 1 or (II) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
5. a pharmaceutical composition, wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
6. the compound of claim 1 or the purposes of its pharmacy acceptable salt in preparing analgesic.
7. the compound of claim 1 or the purposes of its pharmacy acceptable salt in preparing anti-inflammatory drug.
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CN104744558A (en) * 2015-03-23 2015-07-01 中国药科大学 Limonin-7-amino derivatives and preparation method and medicine application thereof
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CN106928311B (en) * 2017-03-24 2019-06-04 中国药科大学 Limonin derivative, preparation method and medical usage
CN111518111A (en) * 2020-05-26 2020-08-11 中国药科大学 Deoxylimonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application
CN111574533A (en) * 2020-05-26 2020-08-25 中国药科大学 Limonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application
CN111518111B (en) * 2020-05-26 2021-06-01 中国药科大学 Deoxylimonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application
CN111574533B (en) * 2020-05-26 2021-06-01 中国药科大学 Limonin A ring-opening aminated derivative or pharmaceutically acceptable salt thereof, preparation method and application
CN113234089A (en) * 2021-05-08 2021-08-10 南京医科大学 Limonin compound, preparation method and application thereof as medicine for treating echinococcosis

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