CN113214339A - Panaxadiol derivatives, preparation method and medical application thereof - Google Patents

Panaxadiol derivatives, preparation method and medical application thereof Download PDF

Info

Publication number
CN113214339A
CN113214339A CN202110298895.1A CN202110298895A CN113214339A CN 113214339 A CN113214339 A CN 113214339A CN 202110298895 A CN202110298895 A CN 202110298895A CN 113214339 A CN113214339 A CN 113214339A
Authority
CN
China
Prior art keywords
trimethyltetrahydro
hexadecahydro
pentamethyl
pyran
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110298895.1A
Other languages
Chinese (zh)
Inventor
尹秀梅
全哲山
庞磊
王思宏
全殷晟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yanbian University
Original Assignee
Yanbian University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yanbian University filed Critical Yanbian University
Priority to CN202110298895.1A priority Critical patent/CN113214339A/en
Publication of CN113214339A publication Critical patent/CN113214339A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention provides a panaxadiol derivative which is a novel compound. The invention also provides a preparation method of the panaxadiol compound, and the method has the advantages of rich raw material sources, simple reaction process operation, and cheap and easily obtained reagents. The compound of the invention is tested by a nerve protection effect experiment of in vitro anti-Abeta 25-35 induced PC12 cell injury, and the result shows that the panaxadiol derivatives of the invention have obvious nerve cell protection effect and can be used for preparing medicines for preventing or treating nerve cell injury diseases.

Description

Panaxadiol derivatives, preparation method and medical application thereof
Technical Field
The invention discloses a kind of panaxadiol derivative, and also provides a preparation method of the panaxadiol derivative; the invention further provides medical application of the panaxadiol derivative, belonging to the field of chemical medicine.
Background
Panaxane ginsenoside is a tetracyclic triterpene compound obtained by hydrolyzing dammarane ginsenoside separated from Ginseng radix (Panax ginseng C.A.Mey) of Panax of Araliaceae of Umbelliferae. Panaxadiol (Panaxadiol, structure formula shown in figure)I shown as the formula I, which is called PD hereinafter) and has the chemical name of (3S, 8R, 10R, 12R, 14R) -4,4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopentyl [ a]Phenanthrene-3, 12-diol, formula: c30H52O3Molecular weight 460.74.
Figure RE-GDA0003122943590000011
Disclosure of Invention
The invention aims to provide a novel panaxadiol derivative and a preparation method thereof.
The invention also aims to provide application of the compounds in preventing or treating nerve cell injury diseases.
The invention relates to a panaxadiol derivative which has a structure shown in a formula II:
Figure RE-GDA0003122943590000012
wherein, when X is oxygen, R is the following group:
(A) aromatic hydrocarbons: phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 3-fluorophenyl, benzyl;
(B) alkane: ethyl, propyl, isopropyl, heptyl, hexyl, cyclohexyl, allyl:
when X is sulfur, R is phenyl:
the compounds having the above general formula II are:
IIa: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylbenzylcarbamate;
IIb: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylphenylcarbamate;
IIc: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (4-chlorophenyl) carbamate;
IId: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (4-methoxyphenyl) carbamate;
IIe: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracen-3-yl (4-fluorophenyl) carbamate;
IIf: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl p-tolylcarbamate;
IIj: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (3-fluorophenyl) carbamate;
IIh: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylcarbamic acid ethyl ester;
IIi: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylheptylcarbamate;
IIg: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylisopropylcarbamate;
IIk: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylhexylcarbamate;
IIl: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopentyl [ a ] phenanthryl-3-cyclohexylcarbamate;
IIm: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylallylcarbamate;
IIn: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylpropylcarbamate;
IIo: o- ((3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R-2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl) phenylthiocarbamate;
the invention also provides a synthetic route of the compound of the general formula II as follows:
Figure RE-GDA0003122943590000031
weighing panaxadiol and dissolving in a solvent, adding isocyanate or isothiocyanate under low-temperature stirring, wherein the molar number of the isocyanate or isothiocyanate is at least 2 times that of the panaxadiol, adding a catalyst, stirring and reacting under the protection of nitrogen, detecting by TLC, evaporating the solvent in a solvent system after the reaction, and performing chromatographic separation on the residual solid silica gel column (chloroform: methanol is 100: 1) or preparing by a thin layer to obtain the compound of the general formula II;
in the method for preparing the panaxadiol derivative, the catalyst is any one of sodium hydrogen, triethylamine and N, N-diisopropylethylamine. The solvent is one of tetrahydrofuran, toluene and chloroform, and the mole ratio of the panaxadiol to the solvent is 0.05-0.2;
in the method for preparing the panaxadiol derivative, the ratio of the mole number of the panaxadiol to the mole number of the isocyanate or the isothiocyanate is 1-10: 1, the molar ratio of the panaxadiol to the catalyst is 1-10, and the reaction temperature is 80-120 ℃.
The derivative disclosed by the invention adopts an MTT method to determine A beta25-35Induce neuroprotective effects of PC12 cell injury, the structure indicates the tested chemotherapyThe compound shows better nerve cell protection effect.
The invention also provides application of the panaxadiol derivative in preparing a medicament for treating nerve cell protection.
The invention also provides application of the panaxadiol derivative in preparation of an anti-Alzheimer disease drug or a health-care product.
The method for preparing the panaxadiol derivative is simple, high in purity, low in cost and suitable for industrial production.
The invention has the positive effects that:
a panaxadiol derivative is disclosed, which is a new kind of compound. Simultaneously, the method for preparing the panaxadiol compound has the advantages of rich raw material sources, simple reaction process operation and cheap and easily obtained reagents. The compounds of the invention are directed against Abeta in vitro25-35The result of the experiment test of the nerve protection effect of inducing the PC12 cell damage shows that the panaxadiol derivatives have obvious nerve cell protection effect and can be used for preparing the medicines for preventing or treating the nerve cell damage diseases.
The specific implementation mode is as follows:
the following examples illustrate the invention in detail, but the practice of the invention is not limited thereto; the reagents and raw materials used in the invention are commercially available, and are analytically pure without special labels.
Example 1
IIa (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylbenzylcarbamate;
Figure RE-GDA0003122943590000041
placing panaxadiol (55.00mg) in 10mL anhydrous toluene, slowly adding benzyl isocyanate or isothiocyanate (32mg), TEA or DIEA (33 μ L) dropwise under ice bath, removing ice bath, stirring at 100 deg.C under nitrogen protection for 12-15 ℃And (4) hours. TCL detection reaction until the material disappeared, toluene (3X 10mL) extraction three times, saturated NaCl (2X 10mL) solution after washing, anhydrous Na2SO4Drying, filtering under reduced pressure, and spin-drying to obtain crude product. Purification by silica gel chromatography using methanol/dichloromethane (100: 1) as eluent gave compound IIa. The yield was 63%.1H NMR(300MHz,CDCl3)δ7.38–7.27(m,5H),6.70(s,1H),4.92(s,1H), 4.49–4.28(m,3H),3.56(td,J＝10.0,4.9Hz,1H),2.33(s,1H),1.99–1.85(m,2H),1.83– 1.67(m,4H),1.66–1.35(m,11H),1.34–1.22(m,10H),1.19(s,3H),1.11–1.02(m,2H), 0.98(s,3H),0.89(s,9H),0.80(s,3H).13C NMR(125MHz,CDCl3)δ156.79,138.78, 128.65,127.54,127.42,81.46,76.66,73.10,69.89,56.02,54.73,51.21,49.84,49.19,45.05, 39.82,38.60,38.10,37.04,36.46,35.75,34.84,33.03,31.14,30.57,27.99,27.15,25.17, 24.17,19.43,18.20,17.07,16.52,16.29,16.18,15.64。
Example 2
IIb: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylphenylcarbamate;
Figure RE-GDA0003122943590000051
the preparation method is the same as that of example 1; the yield was 57%.1H NMR(300MHz,CDCl3)δ7.32(d,J＝7.6Hz, 2H),7.24(d,J＝7.4Hz,2H),6.97(t,J＝7.2Hz,1H),6.49(s,1H),6.19(s,1H),4.41(dd,J＝11.4,4.7Hz,1H),3.48(td,J＝10.1,4.8Hz,1H),1.93–1.78(m,2H),1.78–1.60(m,5H), 1.59–1.35(m,11H),1.32–1.22(m,2H),1.20(s,4H),1.15(s,4H),1.12(s,3H),1.08–0.96 (m,2H),0.92(s,3H),0.86(s,3H),0.85(s,3H),0.82(s,3H),0.80(s,3H).13C NMR(125 MHz,CDCl3)δ153.62,138.17,129.02,123.19,118.55,81.93,76.66,73.10,69.88,56.05, 54.74,51.22,49.85,49.20,39.84,38.61,38.10,37.07,36.46,35.76,34.83,33.03,31.14, 30.59,28.05,27.16,25.18,24.11,19.44,18.22,17.08,16.62,16.29,16.20,15.66。
Example 3
IIc: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (4-chlorophenyl) carbamate;
Figure RE-GDA0003122943590000052
the preparation method is the same as that of example 1; the yield was 64%.1H NMR(300MHz,CDCl3)δ7.35(d,J＝8.5Hz,2H), 7.28–7.22(m,2H),6.60(s,1H),6.27(s,1H),4.47(dd,J＝11.4,4.3Hz,1H),3.54(td,J＝10.1,4.9Hz,1H),2.01–1.85(m,2H),1.85–1.67(m,5H),1.67–1.39(m,11H),1.38–1.30 (m,2H),1.27(s,4H),1.22(s,4H),1.18(s,3H),1.14–1.03(m,2H),0.99(s,3H),0.92(s, 3H),0.91(s,3H),0.89(s,3H),0.86(s,3H).13C NMR(125MHz,CDCl3)δ153.46,136.80, 129.00,128.17,119.76,82.23,76.66,73.11,69.87,56.04,54.74,51.22,49.85,49.20,39.84, 38.59,38.09,37.06,36.46,35.76,34.82,33.03,31.14,30.59,28.05,27.17,25.18,24.09, 19.44,18.21,17.08,16.61,16.29,16.19,15.66。
Example 4
IId: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (4-methoxyphenyl) carbamate;
Figure RE-GDA0003122943590000061
the preparation method is the same as that of example 1; the yield was 54%.1H NMR(300MHz,CDCl3)δ8.35(s,1H),7.65(d,J ＝9.0Hz,2H),7.04(d,J＝9.0Hz,2H),6.27(s,1H),4.92–4.76(m,1H),3.88(s,3H),3.56 (td,J＝10.8,5.4Hz,1H),2.02–1.89(m,2H),1.87–1.74(m,5H),1.71–1.39(m,11H), 1.39–1.31(m,2H),1.27(s,4H),1.23(s,4H),1.19(s,3H),1.17–1.13(m,1H),1.10–1.06 (m,1H),1.05–1.02(m,3H),1.00(s,3H),0.96(s,3H),0.95(s,3H),0.90(s,3H).13C NMR (125MHz,CDCl3)δ155.83,153.94,131.28,120.39,114.23,81.76,76.66,73.10,69.88, 56.05,55.52,54.74,51.22,49.85,49.20,39.84,38.61,38.10,37.06,36.47,35.76,34.84, 33.03,31.14,30.59,28.05,27.16,25.18,24.13,19.44,18.22,17.08,16.61,16.29,16.19, 15.66。
Example 5
IIe: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracen-3-yl (4-fluorophenyl) carbamate;
Figure RE-GDA0003122943590000071
the preparation method is the same as that of example 1; the yield was 59%.1H NMR(300MHz,CDCl3)δ7.34(s,2H),6.99(t,J ＝8.6Hz,2H),6.53(s,1H),6.26(s,1H),4.46(dd,J＝11.5,4.4Hz,1H),3.54(td,J＝10.2, 5.0Hz,1H),2.00–1.84(m,2H),1.83–1.66(m,5H),1.65–1.41(m,11H),1.39–1.29(m, 2H),1.26(s,4H),1.22(s,4H),1.18(s,3H),1.14–1.02(m,2H),0.98(s,3H),0.92(s,3H), 0.91(s,3H),0.89(s,3H),0.86(s,3H).13C NMR(125MHz,CDCl3)δ158.87(d,JCF＝242.2 Hz),153.76,134.17,120.25,115.69,82.09,76.66,73.11,69.87,56.03,54.73,51.21,49.85, 49.20,39.83,38.59,38.09,37.06,36.46,35.76,34.82,33.03,31.14,30.59,28.05,27.16, 25.17,24.11,19.44,18.21,17.07,16.60,16.29,16.19,15.66。
Example 6
IIf: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl p-tolylcarbamate;
Figure RE-GDA0003122943590000072
the preparation method is the same as that of example 1; the yield was 69%.1H NMR(300MHz,CDCl3)δ7.27(d,J＝5.4Hz, 2H),7.10(d,J＝8.3Hz,2H),6.48(s,1H),6.26(s,1H),4.46(dd,J＝11.5,4.2Hz,1H),3.54 (td,J＝10.1,5.1Hz,1H),2.30(s,3H),2.00–1.85(m,2H),1.83–1.69(m,4H),1.68–1.40 (m,12H),1.39–1.30(m,2H),1.26(s,4H),1.22(s,4H),1.18(s,3H),1.14–1.02(m,2H), 0.98(s,3H),0.93(s,3H),0.91(s,3H),0.89(s,3H),0.86(s,3H).13C NMR(125MHz, CDCl3)δ153.72,135.57,132.71,129.49,118.64,81.77,76.66,73.10,69.88,56.05,54.73, 51.21,49.85,49.20,39.83,38.61,38.09,37.06,36.46,35.76,34.83,33.03,31.14,30.58, 28.05,27.16,25.18,24.12,20.73,19.44,18.21,17.08,16.62,16.29,16.19,15.66。
Example 7
IIj: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (3-fluorophenyl) carbamate;
Figure RE-GDA0003122943590000081
the preparation method is the same as that of example 1; the yield was 53%.1H NMR(300MHz,DMSO-d6)δ9.72(s,1H),7.40 (d,J＝11.4Hz,1H),7.28(dt,J＝17.3,8.6Hz,2H),6.79(t,J＝7.8Hz,1H),5.60(s,1H), 4.47–4.27(m,1H),3.43–3.35(m,1H),1.90–1.61(m,8H),1.60–1.36(m,10H),1.34– 1.22(m,3H),1.19(s,4H),1.11(s,6H),1.06–0.97(m,2H),0.92(s,3H),0.87(s,9H),0.84 (s,3H).13C NMR(125MHz,DMSO-d6)δ162.38(d,JCF＝240.8Hz),153.53,141.27, 130.33,114.01,108.71,108.54,80.73,76.23,72.51,69.16,55.27,54.14,50.74,49.01,48.94, 40.19,38.10,37.82,36.55,35.94,35.18,34.38,32.79,30.66,30.36,27.77,27.12,24.60, 23.79,19.28,17.79,16.89,16.60,16.00,15.80,15.45。
Example 8
IIh: preparation of ethyl (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylcarbamate;
Figure RE-GDA0003122943590000082
the preparation method is the same as that of example 1; the yield was 54%.1H NMR(300MHz,CDCl3)δ6.25(s,1H),4.56(s, 1H),4.35(dd,J＝11.3,4.6Hz,1H),3.53(td,J＝10.3,5.1Hz,1H),3.30–3.12(m,2H),1.99 –1.84(m,2H),1.83–1.66(m,4H),1.64–1.39(m,12H),1.38–1.28(m,2H),1.26(s,4H), 1.22(s,4H),1.18(s,3H),1.16–1.10(m,3H),1.09–1.01(m,2H),0.96(s,3H),0.93–0.85 (m,9H),0.81(s,3H).13C NMR(125MHz,CDCl3)δ156.67,80.96,76.66,73.09,69.89, 56.02,54.73,51.22,49.84,49.19,45.42,39.82,38.61,38.09,37.04,36.46,35.76,34.84, 33.03,31.14,30.58,27.99,27.16,25.18,24.18,19.43,18.21,17.07,16.52,16.29,16.18, 15.65,15.31。
Example 9
IIi: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylheptyl carbamate;
Figure RE-GDA0003122943590000091
the preparation method is the same as that of example 1; the yield was 57%.1H NMR(300MHz,CDCl3)δ6.24(s,1H),4.59(s, 1H),4.36(dd,J＝10.3,3.6Hz,1H),3.53(td,J＝10.3,5.1Hz,1H),3.16(s,2H),2.01–1.84 (m,2H),1.83–1.37(m,18H),1.27(s,15H),1.22(s,3H),1.18(s,3H),1.09–1.01(m,2H), 0.98(s,3H),0.88(s,12H),0.81(s,3H).13C NMR(125MHz,CDCl3)δ156.79,80.94,76.65, 73.08,69.89,56.02,54.73,51.21,49.84,49.20,40.99,39.82,38.61,38.10,37.04,36.46, 35.76,34.84,33.03,31.75,31.14,30.58,30.07,28.96,27.98,27.16,26.73,25.17,24.18, 22.59,19.43,18.21,17.07,16.53,16.29,16.18,15.65,14.07。
Example 10
IIg: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylisopropylcarbamate;
Figure RE-GDA0003122943590000101
the preparation method is the same as that of example 1; the yield was 63%.1H NMR(300MHz,CDCl3)δ6.25(s,1H),4.51– 4.28(m,2H),3.80(s,1H),3.53(td,J＝10.2,5.0Hz,1H),2.01–1.84(m,2H),1.82–1.66 (m,5H),1.65–1.28(m,13H),1.26(s,4H),1.22(s,4H),1.18(s,3H),1.16(s,3H),1.14(s, 3H),1.11–1.01(m,2H),0.98(s,3H),0.88(s,9H),0.82(s,3H).13C NMR(125MHz,CDCl3) δ155.97,80.80,76.65,73.08,69.89,56.03,54.73,51.21,49.84,49.19,42.89,42.10,39.82, 38.61,38.10,37.04,36.46,35.75,34.84,33.03,31.13,30.58,27.99,27.16,25.17,24.17, 23.15,19.43,18.21,17.07,16.55,16.29,16.18,15.64。
Example 11
IIk: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylhexylcarbamate;
Figure RE-GDA0003122943590000102
the preparation method is the same as that of example 1; the yield was 54%.1H NMR(300MHz,CDCl3)δ6.25(s,1H),4.59(s, 1H),4.41–4.27(m,1H),3.53(td,J＝10.1,5.1Hz,1H),3.16(s,2H),2.01–1.84(m,2H), 1.83–1.35(m,19H),1.29(s,7H),1.27(s,4H),1.22(s,4H),1.18(s,3H),1.11–1.01(m, 2H),0.98(s,3H),0.88(s,12H),0.81(s,3H).13C NMR(125MHz,CDCl3)δ156.79,80.93, 76.65,73.08,69.89,56.02,54.73,51.21,49.84,49.20,40.99,39.82,38.61,38.10,37.04, 36.46,35.75,34.84,33.03,31.49,31.13,30.58,30.03,27.98,27.16,26.44,25.17,24.18, 22.56,19.43,18.21,17.07,16.52,16.29,16.18,15.64,14.01。
Example 12
IIl: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopentyl [ a ] phenanthryl-3-cyclohexylcarbamate;
Figure RE-GDA0003122943590000111
the preparation was carried out as in example 1, giving a yield of 65%.1H NMR(300MHz,CDCl3)δ6.24(s,1H),4.48(s, 1H),4.35(dd,J＝11.3,4.4Hz,1H),3.53(td,J＝10.3,5.1Hz,2H),2.00–1.83(m,4H),1.82 –1.66(m,7H),1.65–1.29(m,15H),1.26(s,4H),1.22(s,4H),1.18(s,4H),1.16–1.00(m, 5H),0.98(s,3H),0.88(s,9H),0.82(s,3H).13C NMR(125MHz,CDCl3)δ155.98,80.76, 76.65,73.08,69.89,56.02,54.73,51.22,49.83,49.70,49.20,39.82,38.61,38.11,37.04, 36.46,35.75,34.84,33.54,33.03,31.13,30.58,28.00,27.16,25.56,25.17,24.86,24.17, 19.43,18.21,17.07,16.54,16.29,16.18,15.64。
Example 13
IIm: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylallylcarbamate;
Figure RE-GDA0003122943590000112
the preparation method is the same as that of example 1; the yield was 59%.1H NMR(300MHz,CDCl3)δ6.25(s,1H),5.96– 5.76(m,1H),5.19(dd,J＝17.2,1.3Hz,1H),5.12(dd,J＝10.2,1.0Hz,1H),4.69(s,1H), 4.37(dd,J＝11.3,4.8Hz,1H),3.81(s,2H),3.53(td,J＝10.3,5.1Hz,1H),2.00–1.84(m, 2H),1.83–1.66(m,5H),1.64–1.35(m,11H),1.34–1.28(m,2H),1.26(s,4H),1.22(s, 4H),1.18(s,3H),1.11–1.01(m,2H),0.98(s,3H),0.92–0.85(m,9H),0.82(s,3H).13C NMR(125MHz,CDCl3)δ156.61,134.83,115.82,81.29,76.66,73.09,69.88,56.02,54.73, 51.21,49.84,49.20,43.42,39.83,38.60,38.10,37.04,36.46,35.76,34.84,33.02,31.13, 30.58,27.98,27.16,25.17,24.15,19.43,18.21,17.07,16.52,16.29,16.17,15.65。
Example 14
IIn: preparation of (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylpropylcarbamate;
Figure RE-GDA0003122943590000121
the preparation method is the same as that of example 1; the yield was 61%.1H NMR(300MHz,CDCl3)δ6.27(s,1H),4.62(s, 1H),4.37(dd,J＝11.8,4.4Hz,1H),3.55(td,J＝10.3,5.1Hz,1H),3.15(s,2H),2.03–1.85 (m,2H),1.84–1.72(m,3H),1.70–1.41(m,15H),1.40–1.31(m,2H),1.28(s,4H),1.24(s, 4H),1.20(s,3H),1.13–1.03(m,2H),0.99(s,3H),0.97–0.86(m,12H),0.83(s,3H).13C NMR(125MHz,CDCl3)δ156.82,80.94,76.66,73.08,69.89,56.02,54.73,51.21,49.84, 49.20,42.66,39.82,38.61,38.10,37.04,36.46,35.75,34.84,33.02,31.13,30.58,27.98, 27.16,25.17,24.17,23.29,19.43,18.21,17.07,16.52,16.29,16.18,15.64,11.23。
Example 15
IIo preparation of O- ((3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R-2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl) phenylthiocarbamate;
Figure RE-GDA0003122943590000122
the preparation method is the same as that of example 1; the yield was 61%.1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.33(t,J ＝7.2Hz,3H),7.18(d,J＝7.5Hz,2H),6.27(s,1H),5.20(dd,J＝11.7,4.2Hz,1H),3.54(td, J＝10.1,5.1Hz,1H),2.04–1.87(m,3H),1.84–1.70(m,4H),1.68–1.39(m,11H),1.27(s, 7H),1.22(s,3H),1.18(s,3H),1.15–1.09(m,1H),1.07–1.02(m,1H),0.98(s,3H),0.92(s, 6H),0.89(s,3H),0.85(s,3H).13C NMR(125MHz,CDCl3)δ188.89,136.93,128.98, 125.47,122.06,91.00,76.66,73.11,69.86,55.87,54.73,51.21,49.75,49.17,39.83,38.49, 37.08,36.46,35.76,34.78,33.04,31.13,30.58,29.70,27.92,27.15,25.19,23.29,19.43, 18.14,17.39,17.02,16.29,16.18,15.64。
Test example 1
In vitro anti-Abeta25-35Experimental test for neuroprotective effect of inducing PC12 cell injury
The influence of the target compound on the survival rate of PC12 cells was evaluated by using 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay. PC12 cells were cultured at 1X 105cells/mL were seeded at a density in complete medium in 96-well plates and incubated for 24 hours (100 μ L/well). Then, the administration group was added with the target compound at different concentrations (50. mu.L/well), and the remaining group was administered with 50. mu.L of the medium and cultured for another 4 hours. Subsequently, the administration group and the model group were administered with a β25-35(20. mu.M) and incubated for 24 hours. mu.L of MTT (5g/L, PBS buffer) was added to each well and the cells were further incubated for 4 hours. After removal of the supernatant, DMSO (150. mu.L/well) was added and shaken for 15 min. The optical density was measured at a wavelength of 570nm using a microplate reader (Thermo SCIENTIFIC, MA, USA).
TABLE 1 shows the inhibition of Abeta by panaxadiol derivatives25-35Protective effect of inducing PC12 cell damage:
Figure RE-GDA0003122943590000131
note: results are expressed as mean ± standard deviation (n ═ 5).#P<0.05、##P<0.01 and###P<0.001 compared to blank;*P<0.05、**P<0.01 and***P<0.001 compared to the Α β -induced group.

Claims (8)

1. A kind of panaxadiol derivative is characterized in that the derivative has a structure shown in a formula II:
Figure 350567DEST_PATH_IMAGE001
when X is oxygen, R is the following group;
(A) aromatic hydrocarbons: phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 3-fluorophenyl, benzyl;
(B) alkane: ethyl, propyl, isopropyl, heptyl, hexyl, cyclohexyl, allyl;
when X is sulfur, R is phenyl.
2. The panaxadiol derivative according to claim 1, wherein the panaxadiol derivative is:
IIa: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylbenzylcarbamate;
IIb: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylphenylcarbamate;
IIc: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (4-chlorophenyl) carbamate;
IId: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (4-methoxyphenyl) carbamate;
IIe: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracen-3-yl (4-fluorophenyl) carbamate;
IIf: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl p-tolylcarbamate;
IIj: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl (3-fluorophenyl) carbamate;
IIh: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylcarbamic acid ethyl ester;
IIi: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylheptylcarbamate;
IIg: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylisopropylcarbamate;
IIk: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylhexylcarbamate;
IIl: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopentyl [ a ] phenanthryl-3-cyclohexylcarbamate;
IIm: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylallylcarbamate;
IIn: (3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R) -2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-ylpropylcarbamate;
IIo O- ((3S, 8R, 10R, 12R, 14R) -12-hydroxy-4, 4,8,10, 14-pentamethyl-17- ((R-2,6, 6-trimethyltetrahydro-2H-pyran-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthryl-3-yl) phenylthiocarbamate.
3. Use of the panaxadiol derivative as described in claims 1-2 in the preparation of anti-alzheimer drugs or health products.
4. Use of a class of panaxadiol derivatives as defined in claims 1-2 for the manufacture of a medicament for the treatment of neuronal protection.
5. A process for preparing the panaxadiol derivatives according to claims 1-2, wherein:
weighing panaxadiol, dissolving in a solvent, adding isocyanate or isothiocyanate under low-temperature stirring, wherein the molar number of the isocyanate or isothiocyanate is at least 2 times that of the panaxadiol, adding a catalyst, stirring and reacting under the protection of nitrogen, detecting by TLC, evaporating the solvent in a solvent system after the reaction, and performing chromatographic separation on the residual solid silica gel column (chloroform: methanol = 100: 1) or preparing by a thin layer to obtain the compound of the general formula II.
6. The method for preparing panaxadiol derivative according to claim 5, wherein the catalyst is any one of triethylamine, N-diisopropylethylamine, and sodium hydrogen; the solvent is one of tetrahydrofuran, toluene and chloroform.
7. The method of claim 5, wherein the ratio of the number of moles of the panaxadiol to the number of moles of the cyanate ester or isothiocyanate is 1 to 10: 1, the molar ratio of the panaxadiol to the catalyst is 1-10, and the reaction temperature is 80-120 ℃.
8. The panaxadiol derivative prepared according to claim 5 is used for preparing a medicament for preventing or treating nerve cell injury diseases.
CN202110298895.1A 2021-03-20 2021-03-20 Panaxadiol derivatives, preparation method and medical application thereof Pending CN113214339A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110298895.1A CN113214339A (en) 2021-03-20 2021-03-20 Panaxadiol derivatives, preparation method and medical application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110298895.1A CN113214339A (en) 2021-03-20 2021-03-20 Panaxadiol derivatives, preparation method and medical application thereof

Publications (1)

Publication Number Publication Date
CN113214339A true CN113214339A (en) 2021-08-06

Family

ID=77084006

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110298895.1A Pending CN113214339A (en) 2021-03-20 2021-03-20 Panaxadiol derivatives, preparation method and medical application thereof

Country Status (1)

Country Link
CN (1) CN113214339A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114853839A (en) * 2022-06-13 2022-08-05 延边大学 Panaxadiol compound, preparation method and medical application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108992453A (en) * 2018-09-12 2018-12-14 烟台大学 The new application of the tumor drug resistance reversal of a kind of ocotillol type sapogenin derivative
CN111362998A (en) * 2020-04-23 2020-07-03 烟台大学 Aza 20(R) -panaxadiol derivative and anti-tumor application thereof
CN111647036A (en) * 2020-04-30 2020-09-11 烟台大学 Ocotillol esterified derivatives, preparation method thereof and application thereof in preparing anti-inflammatory drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108992453A (en) * 2018-09-12 2018-12-14 烟台大学 The new application of the tumor drug resistance reversal of a kind of ocotillol type sapogenin derivative
CN111362998A (en) * 2020-04-23 2020-07-03 烟台大学 Aza 20(R) -panaxadiol derivative and anti-tumor application thereof
CN111647036A (en) * 2020-04-30 2020-09-11 烟台大学 Ocotillol esterified derivatives, preparation method thereof and application thereof in preparing anti-inflammatory drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
庞磊: "高乌甲素和人参二醇衍生物的设计合成及其生物活性研究", 《中国学位论文全文数据库》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114853839A (en) * 2022-06-13 2022-08-05 延边大学 Panaxadiol compound, preparation method and medical application thereof
CN114853839B (en) * 2022-06-13 2023-07-21 延边大学 Panaxadiol compound, and preparation method and medical application thereof

Similar Documents

Publication Publication Date Title
Barakat et al. Synthesis, in vitro biological activities and in silico study of dihydropyrimidines derivatives
CN112979733B (en) Anti-hepatitis B virus compound and preparation method and application thereof
CN113735709B (en) Cannabidiol-2-butyrate and application thereof
CN113214339A (en) Panaxadiol derivatives, preparation method and medical application thereof
CN111875612B (en) Chromanone spliced pyrrole spiro-oxoindole skeleton and trifluoromethyl compound and preparation method and application thereof
CN113666824A (en) Cannabidiol-2-propionate and application thereof
CN109776556B (en) Pyrazolone xanthone skeleton spliced oxindole or benzofuranone compound and preparation method and application thereof
CN108947949B (en) Anxiolytic deuterated compounds and medical application thereof
CN113480559B (en) Artemether derivative and preparation method and application thereof
CN108164463A (en) A kind of 1,8- Naphthalamide derivatives and its synthetic method and application with non-small cell lung cancer selective inhibitory
Listunov et al. Ethynylogation approach in pharmacophore design: from alkynyl-to butadiynyl-carbinols vs antitumoral cytotoxicity
WO2015138039A1 (en) Methods and reagents for radiolabeling
CN114539292B (en) Novel podophyllotoxin spliced antitumor active molecular compound and preparation method and application thereof
CN114874172A (en) Oridonin derivative, preparation method and medical application thereof
CN111808113B (en) Hexahydroxanthone spliced spiro-oxoindole skeleton and ketoester group compound and preparation method and application thereof
CN110028519B (en) Xanthone skeleton spliced double-helix epoxidized indole compound and preparation method and application thereof
CN108250207B (en) Coumarin compound and preparation method and application thereof
Paradas et al. Clarifying the structure of granadaene: total synthesis of related analogue [2]-granadaene and confirmation of its absolute stereochemistry
CN108276267B (en) Fluorine-containing 1, 1-stilbene derivative, preparation method and application thereof
CN108276420B (en) 8, 13-dihydrobenzo [5,6] chromene [2,3-b ] indole compound and synthetic method thereof
CN112300118A (en) Novel benzothiopyranone compound and preparation method and application thereof
CN107501380B (en) 23-hydroxy betulinic acid 23-position modified derivative, preparation method and application thereof
CN107793416A (en) Thio matrine derivative and preparation method and application
CN109180775A (en) C-28 imines substituted white birch lipidol isomers derivative and its preparation method and application
CN115417857B (en) Piperidine alkaloid in Chinese medicinal Alangium chinense and extraction purification and semisynthesis method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20210806

WD01 Invention patent application deemed withdrawn after publication