CN108558986A - Enoxolone analog derivative containing piperazine structure and preparation method thereof and purposes - Google Patents
Enoxolone analog derivative containing piperazine structure and preparation method thereof and purposes Download PDFInfo
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- CN108558986A CN108558986A CN201810526145.3A CN201810526145A CN108558986A CN 108558986 A CN108558986 A CN 108558986A CN 201810526145 A CN201810526145 A CN 201810526145A CN 108558986 A CN108558986 A CN 108558986A
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- China
- Prior art keywords
- piperazine
- enoxolone
- benzene
- product
- preparation
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- 150000002342 glycyrrhetinic acids Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 125000004193 piperazinyl group Chemical group 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 36
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims description 11
- 229960003720 enoxolone Drugs 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims description 10
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 9
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 3
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 2
- PXFJLKKZSWWVRX-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)piperazine Chemical class C1=C(Cl)C(Cl)=CC=C1N1CCNCC1 PXFJLKKZSWWVRX-UHFFFAOYSA-N 0.000 claims description 2
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical class ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- FPWNLURCHDRMHC-UHFFFAOYSA-N 4-chlorobiphenyl Chemical group C1=CC(Cl)=CC=C1C1=CC=CC=C1 FPWNLURCHDRMHC-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- REARIAGUFTUEKI-UHFFFAOYSA-N 1-phenyl-4-(trifluoromethyl)piperazine Chemical compound C1CN(C(F)(F)F)CCN1C1=CC=CC=C1 REARIAGUFTUEKI-UHFFFAOYSA-N 0.000 claims 1
- 235000009508 confectionery Nutrition 0.000 claims 1
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical class CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 201000011510 cancer Diseases 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 102000000536 PPAR gamma Human genes 0.000 description 10
- 108010016731 PPAR gamma Proteins 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003809 water extraction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 0 CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@@]3(*)C[C@@]2(C)O)C3=C2)[C@](C)(CC3)C1C2=O)[C@]3OC(C*(CC1)CC*1N)=O Chemical compound CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@@]3(*)C[C@@]2(C)O)C3=C2)[C@](C)(CC3)C1C2=O)[C@]3OC(C*(CC1)CC*1N)=O 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 235000002710 Ilex cornuta Nutrition 0.000 description 2
- 241001310146 Ilex cornuta Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 239000012888 bovine serum Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical group C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RUIMBVCRNZHCRQ-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)piperazine Chemical compound CC1=CC(C)=CC=C1N1CCNCC1 RUIMBVCRNZHCRQ-UHFFFAOYSA-N 0.000 description 1
- WSOZOSOIGLKJTH-UHFFFAOYSA-N 1-benzhydryl-2-chloropiperazine Chemical class ClC1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 WSOZOSOIGLKJTH-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 206010016825 Flushing Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 125000002168 glycyrrhetinic acid group Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- -1 p-trifluoromethyl phenyl piperazine Piperazine Chemical compound 0.000 description 1
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical group C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Enoxolone analog derivative that the invention discloses a kind of containing piperazine structure and preparation method thereof and purposes.Shown in the structure of enoxolone analog derivative such as formula (I).The present invention discloses the preparation method of the Enoxolone derivative and purposes.Enoxolone derivative of the present invention significantly inhibits cancer cell, and raw materials used cheap, simple and easy to get, reaction step is few, and yield is high, is suitble to industrialized production, is a kind of lead drug with preferable foreground.
Description
Technical field
The present invention relates to the derivatives of enoxolone, and in particular to a kind of Enoxolone derivative containing piperazine structure and its
Preparation method and the purposes as anticancer drug.
Background technology
Enoxolone (Glycyrrhetinic Acid, write a Chinese character in simplified form GA) is a kind of from the extraction of the rhizome of Chinese traditional herbs Radix Glycyrrhizae
Pentacyclic triterpenoid out, mainly based on 18- β-enoxolone.By constantly study find enoxolone and its
Derivative has anti-inflammatory, antiulcer, antiviral and antitumor, antiallergy, reducing blood lipid, promotes various works such as absorption of insulin
With.But enoxolone itself is very faint to the inhibiting effect of tumour, therefore, how to be improved enhancing activity to its structure
It is to be worth solving the problems, such as.
Invention content
The object of the present invention is to provide a kind of Enoxolone derivatives containing piperazine structure, have to cancer cell apparent
Inhibiting effect；Invention also provides the preparation methods of the Enoxolone derivative containing piperazine structure, and the method provided
Scientific and reasonable, simple and practicable, reaction step is few, and yield is high, is suitble to industrialized production.
Technical scheme is as follows：
Enoxolone derivative of the present invention containing piperazine structure, shown in structure such as formula (I)：
In formula (I), R is：
Wherein, R1Selected from unsubstituted C1-C3 alkyl, the C1-C3 alkyl replaced by 1~2 benzene or halogeno-benzene, benzene,
The benzene that ortho position or contraposition are replaced by the following group substituent group：C1-C3 alkyl, halogen, nitro, trifluoromethyl；
R2Selected from unsubstituted C1-C3 alkyl.
Further, R1Selected from unsubstituted C1-C2 alkyl, the C1-C2 alkyl replaced by 2 benzene or halogeno-benzene, right
The benzene that position is replaced by the following group substituent group：C1-C2 alkyl, halogen, nitro, trifluoromethyl；R2Selected from unsubstituted C1-C2 alkane
Base.
Further, halogen is chlorine, fluorine or bromine；Halogen in halogeno-benzene is chlorine, fluorine or bromine.
Specifically, the R in Enoxolone derivative structure is selected from following substituent group：
The present invention also provides the preparation methods of the Enoxolone derivative containing piperazine structure, including：
(1) enoxolone is scattered in methanol, the concentrated sulfuric acid is added and is reacted, product a is made；
(2) product a is scattered in dichloromethane, bromoacetyl bromide is added and is reacted, product b is made；
(3) in the presence of alkali, the piperazine of product b and different substituents, which is scattered in organic solvent, to be reacted, and is made described
Enoxolone derivative.
In step (1), the time of the reaction is 8~16h, is further 12h, and reaction temperature is 65~90 DEG C, into one
Step is 75 DEG C.
In step (2), the time of the reaction is 1~5h, is further 1~2h, and reaction carries out under condition of ice bath；Production
The molar ratio of object a methyl glycyrrhetates and bromoacetyl bromide is 1:1~2, it is further 1:1.2.
In step (3), alkali is potassium carbonate or triethylamine；The time of the reaction is 6~10h, and reaction temperature is 80~90
℃；Organic solvent is selected from acetonitrile, ethyl alcohol, and the molar ratio of the piperazine of product b and different substituents is 1:1~1.5.
The piperazine of the different substituents is selected from N methyl piperazine, phenylpiperazine, 4- aminomethyl phenyls piperazine, 2,4- dimethyl
Phenylpiperazine, 2- methoxyphenylpiperazderivatives, 4- methoxyphenylpiperazderivatives, 3- methoxyphenylpiperazderivatives, p-trifluoromethyl phenyl piperazine
Piperazine, 2- fluorophenyls piperazine, 3- chlorophenylpiperazines, 3,4- dichlorophenylpiperazines, 4- nitrobenzophenones piperazine, diphenylmethyl piperazine or
4- chlorodiphenyl vlmethylpiperazins.
The Enoxolone derivative containing piperazine structure of the present invention significantly inhibits cancer cell, therefore this
The Enoxolone derivative containing piperazine structure of invention can be used for preparing anticancer (such as liver cancer, breast cancer) drug.
The present invention also provides a kind of drugs, contain the Enoxolone derivative.Drug, which also contains, can pharmaceutically add
Adaptable dosage form is made in the auxiliary material added.
The antitumor Enoxolone derivative of the present invention is the agonist of PPAR γ, and piperazine ring is introduced to the C3 of enoxolone
Position, can enhance the different kind organism activity of enoxolone, and the phenylpiperazine substituent group of Enoxolone derivative of the present invention can have
The active pocket constraint chamber of the H12 spiralizations of effect ground and PPAR γ combines, and the effect of " ship anchor " is functioned similarly to, molecule anchor
It is scheduled on PPAR γ；The main body framework of enoxolone is then located near the opening of constraint chamber, can form strong hydrogen bond
The stability that enhancing small molecule is combined with PPAR γ；30 carboxyls of enoxolone can extend to PPAR γ's after being replaced by methyl esters
H12 spirals constrain the rear side of chamber, further enhance the compatibility with PPAR γ, play good antitumor action.The present invention chooses
It selects the optimal compound of antitumor activity (embodiment 1) and has done western-blot experiments of the PPAR γ in MCF-7 cells,
We arrange western-blot experimental datas (Fig. 1), make block diagram (Fig. 2), we can be apparent from from figure
Find out, drug effect concentration is bigger, and the expression quantity of PPAR γ is higher, illustrates that embodiment 1 can enhance the table of PPAR γ albumen
Up to amount, to play good antitumor activity.
Advantageous effect：
The Enoxolone derivative containing piperazine structure of the present invention significantly inhibits cancer cell, original used
Material is cheap, and simple and easy to get, reaction step is few, and yield is high, is suitble to industrialized production, is a kind of drug with great potential.
Description of the drawings
Fig. 1 is that the western-blot of compound 1 is tested；
Fig. 2, which is compound 1, influences the expression quantity of PPAR γ.
Specific implementation mode
With reference to embodiment, the present invention will be further described, but the scope of the present invention is not appointed by these embodiments
What is limited.
Embodiment 1：The preparation of compound 1
(1) 1g enoxolones are dissolved in 50mL methanol, then add the 0.5mL concentrated sulfuric acids, back flow reaction (reaction in 12 hours
Temperature is 75 DEG C) after by reaction solution evaporated under reduced pressure, using ethyl acetate and water extraction, (the two volume ratio is 1:3) it, collects organic
Layer, anhydrous sodium sulfate drying, solvent under reduced pressure are evaporated, obtain crude product and obtain pure product a with ethyl alcohol recrystallization.
(2) product a (addition 1mmol) is dissolved in dichloromethane (addition 20ml), acetyl bromide is then added
Bromine (addition 1.2mmol), ice bath react 1-2 hour, by reaction solution evaporated under reduced pressure after the completion of reaction, with ethyl acetate and
NaHCO3(the two volume ratio is 1 to saturated aqueous solution:3) it extracting, collected organic layer, anhydrous sodium sulfate drying, solvent under reduced pressure is evaporated,
It obtains crude product and obtains pure product b with acetone recrystallization.
Wherein,
Product a
Product is white powder, yield 65%.M.p.210.5-214.1℃；1H NMR(400MHz,CDCl3)δ5.67
(s, 1H), 3.70 (s, 3H), 3.23 (m, 1H), 2.80 (dt, J=13.6,4.5Hz, 1H), 2.37 (s, 1H), 1.37 (s, 3H),
1.15(s,3H),1.14(s,3H),1.13(s,3H),1.01(s,3H),0.81(s,6H).
Product b
Product is white powder, yield 75%.M.p.165-167℃；1H NMR(400MHz,CDCl3)δ5.67(s,
1H), 4.58 (d, J=10.9Hz, 1H), 3.83 (q, J=12.2Hz, 2H), 3.69 (s, 5H), 2.35 (d, J=8.3Hz, 1H),
2.29-2.20 (m, 1H), 1.80 (d, J=13.0Hz, 4H), 1.70-1.53 (m, 8H), 1.35 (d, J=8.4Hz, 5H), 1.25
(s,2H),1.17–1.10(m,9H),0.92(s,5H),0.81(s,5H).
(3) N methyl piperazine of 1mmol products b and 1mmol are dissolved in acetonitrile, the potassium carbonate of 3mmol is then added, returned
Stream reacts 6-10 hour (reaction temperature is 82 DEG C), by reaction solution evaporated under reduced pressure after the completion of reaction, is extracted with ethyl acetate and water
Take (the two volume ratio be 1:3), organic layer is dried with anhydrous sodium sulfate, and solvent under reduced pressure is evaporated, obtained crude product acetone weight
Crystallization obtains the compound 1 of above structure.
Product is white powder, yield 70%.M.p.219-222℃；1H NMR(400MHz,CDCl3)δ5.66(s,
1H), 4.58 (dt, J=17.6,7.0Hz, 1H), 3.69 (s, 3H), 3.28-3.16 (m, 2H), 3.21 (d, J=2.6Hz, 2H),
2.80 (dt, J=13.4,3.3Hz, 1H), 2.58 (d, J=43.9Hz, 8H), 2.36 (s, 1H), 2.31 (s, 3H), 2.11-
1.56 (m, 13H), 1.43 (s, 1H), 1.36 (s, 3H), 1.34-1.29 (m, 2H), 1.15 (d, J=3.6Hz, 6H), 1.12 (s,
3H),0.88(s,7H),0.80(s,3H).
Embodiment 2：The preparation of compound 2
(1) 1g enoxolones are dissolved in 50mL methanol, then add the 0.5mL concentrated sulfuric acids, 75 DEG C of back flow reactions 12 hours
Afterwards by reaction solution evaporated under reduced pressure, using ethyl acetate and water extraction, (the two volume ratio is 1:3), collected organic layer, anhydrous slufuric acid
Sodium is dried, and solvent under reduced pressure is evaporated, obtains crude product and obtain pure product a with ethyl alcohol recrystallization.
(2) product 1mmol a are dissolved in 20mL dichloromethane, 1.2mmol bromoacetyl bromides is then added, ice bath reacts 1-
2 hours, by reaction solution evaporated under reduced pressure after the completion of reaction, with ethyl acetate and NaHCO3Saturated aqueous solution extracts (the two volume
Than being 1:3), collected organic layer, anhydrous sodium sulfate drying, solvent under reduced pressure is evaporated, obtain crude product obtained with acetone recrystallization it is pure
Product b.
(3) diphenylmethyl piperazine of 1mmol products b and 1mmol are dissolved in acetonitrile, the carbonic acid of 3mmol is then added
Potassium, 6-10 hour of back flow reaction (reaction temperature is 90 DEG C), by reaction solution evaporated under reduced pressure after the completion of reaction, with ethyl acetate with
(the two volume ratio is 1 for water extraction:3), organic layer is dried with anhydrous sodium sulfate, and solvent under reduced pressure is evaporated, and obtained crude product is with third
Ketone is recrystallized to give the compound 2 of above structure.
Product is white powder, yield 73%.M.p.133-135℃；1H NMR(400MHz,CDCl3)δ5.66(s,
1H), 4.58 (dt, J=17.6,7.0Hz, 1H), 3.69 (s, 3H), 3.28-3.16 (m, 2H), 3.21 (d, J=2.6Hz, 2H),
2.80 (dt, J=13.4,3.3Hz, 1H), 2.58 (d, J=43.9Hz, 8H), 2.36 (s, 1H), 2.31 (s, 3H), 2.11-
1.56 (m, 13H), 1.43 (s, 1H), 1.36 (s, 3H), 1.34-1.29 (m, 2H), 1.15 (d, J=3.6Hz, 6H), 1.12 (s,
3H),0.88(s,7H),0.80(s,3H).
Embodiment 3：The preparation of compound 3
(1) 1g enoxolones are dissolved in 50mL methanol, then add the 0.5mL concentrated sulfuric acids, 75 DEG C of back flow reactions 12 hours
Afterwards by reaction solution evaporated under reduced pressure, using ethyl acetate and water extraction, (the two volume ratio is 1:3), collected organic layer, anhydrous slufuric acid
Sodium is dried, and solvent under reduced pressure is evaporated, obtains crude product and obtain pure product a with ethyl alcohol recrystallization.
(2) 1mmol products a is dissolved in 20mL dichloromethane, 1.2mmol bromoacetyl bromides is then added, ice bath reacts 1-2
A hour, by reaction solution evaporated under reduced pressure after the completion of reaction, with ethyl acetate and NaHCO3Saturated aqueous solution extracts (the two volume ratio
It is 1:3), collected organic layer, anhydrous sodium sulfate drying, solvent under reduced pressure is evaporated, obtain crude product obtained with acetone recrystallization it is pure
Product b.
(3) the 4- aminomethyl phenyls piperazine (No. CAS is 39593-08-3) of 1mmol products b and 1mmol are dissolved in acetonitrile,
Then the potassium carbonate of 3mmol is added, 6-10 hour (reaction temperature is 90 DEG C) of back flow reaction subtracts reaction solution after the completion of reaction
Pressure is evaporated, and is extracted with ethyl acetate and water, and organic layer is dried with anhydrous sodium sulfate, and solvent under reduced pressure is evaporated, and obtained crude product is used
Acetone recrystallization obtains the compound 3 of above structure.
Product is white powder, yield 72%.M.p.172-174℃；1H NMR (400MHz, CDCl3) δ 7.32 (d, J=
5.9Hz, 4H), 5.66 (s, 1H), 4.61-4.52 (m, 1H), 3.68 (d, J=3.2Hz, 4H), 3.54 (s, 2H), 3.21 (d, J
=2.3Hz, 2H), 2.80 (dd, J=10.2,3.6Hz, 1H), 2.62 (dt, J=53.5,12.1Hz, 11H), 2.35 (d, J=
8.7Hz,1H),2.11–1.91(m,3H),1.68–1.54(m,7H),1.38–1.32(m,5H),1.30(s,1H),1.22(d,J
=2.4Hz, 3H), 1.16 (t, J=4.5Hz, 5H), 1.13 (d, J=3.2Hz, 3H), 0.88-0.85 (m, 7H), 0.80 (d, J
=4.0Hz, 3H)
Embodiment 4：The preparation of compound 4
The preparation method is the same as that of Example 1.N methyl piperazine is replaced with 1-4- nitrobenzophenone piperazines, obtains target compound 4.
Product is yellow powder, yield 79%.M.p.250-251℃；1H NMR(400MHz,CDCl3)δ8.16–8.08
(m, 2H), 6.86-6.79 (m, 2H), 5.67 (s, 1H), 4.61 (dt, J=11.7,4.1Hz, 1H), 3.69 (d, J=3.3Hz,
4H), 3.50 (s, 5H), 3.32 (s, 2H), 2.80 (d, J=3.8Hz, 6H), 2.36 (s, 1H), 2.12-1.88 (m, 4H),
1.81-1.53 (m, 8H), 1.39-1.29 (m, 6H), 1.16 (d, J=5.0Hz, 6H), 1.13 (d, J=3.2Hz, 3H), 0.88
(d, J=1.8Hz, 7H), 0.81 (s, 3H)
Embodiment 5：The preparation of compound 5
The preparation method is the same as that of Example 1.N methyl piperazine is replaced with the chloro- diphenylmethyl piperazines of 1-4-, obtains target compound
5。
Product is white powder, yield 75%.M.p.144-145℃；1H NMR (400MHz, CDCl3) δ 7.35 (d, J=
7.5Hz, 5H), 7.26 (s, 2H), 7.22 (s, 1H), 7.18 (t, J=7.0Hz, 1H), 5.66 (s, 1H), 4.58 (d, J=
10.1Hz, 1H), 4.21 (s, 1H), 3.73-3.65 (m, 5H), 3.21 (s, 2H), 2.80 (d, J=14.3Hz, 1H), 2.62 (s,
4H), 2.44 (s, 4H), 2.35 (s, 1H), 2.12-1.87 (m, 4H), 1.76-1.52 (m, 8H), 1.34 (dd, J=22.9,
13.1Hz, 7H), 1.14 (d, J=11.3Hz, 9H), 0.86 (d, J=6.0Hz, 7H), 0.80 (s, 3H)
Embodiment 6：The preparation of compound 6
The preparation method is the same as that of Example 1.N methyl piperazine is replaced with 1-4- chlorophenylpiperazines, obtains target compound 6.
Product is white powder, yield 69%.M.p.249-250℃；1H NMR (400MHz, CDCl3) δ 7.20 (d, J=
9.0Hz, 2H), 6.84 (d, J=9.0Hz, 2H), 5.67 (s, 1H), 4.61 (dt, J=11.7,4.1Hz, 1H), 3.69 (d, J=
3.3Hz, 4H), 3.29 (d, J=3.1Hz, 2H), 3.22 (t, J=4.8Hz, 5H), 2.85-2.69 (m, 6H), 2.37 (s, 1H),
2.13-1.90 (m, 4H), 1.77-1.54 (m, 8H), 1.33 (dd, J=16.5,9.2Hz, 6H), 1.16 (d, J=5.8Hz,
6H), 1.13 (d, J=3.2Hz, 3H), 0.89 (s, 7H), 0.81 (s, 3H)
Embodiment 7：The preparation of compound 7
The preparation method is the same as that of Example 1.N methyl piperazine is replaced with 1-3- trifluoromethylphenypiperazine piperazines, obtains target compound 7.
Product is white powder, yield 73%.M.p.261-263℃；1H NMR (400MHz, CDCl3) δ 7.48 (d, J=
8.7Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 5.67 (s, 1H), 4.61 (dt, J=11.7,4.1Hz, 1H), 3.69 (d, J=
3.3Hz, 4H), 3.34 (d, J=18.1Hz, 7H), 2.89-2.66 (m, 6H), 2.37 (s, 1H), 2.12-1.89 (m, 4H),
1.81-1.54 (m, 8H), 1.34 (dd, J=16.7,9.2Hz, 6H), 1.16 (d, J=5.7Hz, 6H), 1.13 (d, J=
3.2Hz,3H),0.88(s,7H),0.81(s,3H).
Embodiment 8：The preparation of compound 8
The preparation method is the same as that of Example 1.N methyl piperazine is replaced with -4 methyl piperazine of 1- amino, obtains target compound 8.
Product is white powder, yield 67%.M.p.261-263℃；1H NMR(400MHz,CDCl3)δ6.44(s,
1H), 5.67 (s, 1H), 5.58-5.43 (m, 1H), 4.86 (d, J=15.3Hz, 1H), 4.67 (s, 1H), 4.24 (d, J=
55.6Hz, 2H), 3.69 (s, 6H), 3.06 (d, J=8.5Hz, 2H), 2.91-2.63 (m, 3H), 2.38 (s, 4H), 2.16-
1.73 (m, 7H), 1.72-1.54 (m, 5H), 1.34 (d, J=25.6Hz, 6H), 1.19 (dd, J=38.4,12.0Hz, 11H),
0.92 (d, J=11.9Hz, 7H), 0.81 (s, 3H)
Embodiment 9：The preparation of compound 9
Preparation method is the same as embodiment 9.N methyl piperazine is replaced with Pyridylpiperazine (No. CAS by 34803-66-2), obtains mesh
Mark compound 9.
Product is white powder, yield 78%.M.p.248-250℃；1H NMR(400MHz,CDCl3)δ8.19(dd,J
=5.0,1.3Hz, 1H), 7.49 (t, J=7.2Hz, 1H), 6.69-6.59 (m, 2H), 5.67 (s, 1H), 4.68-4.55 (m,
1H), 3.69 (d, J=3.3Hz, 4H), 3.62 (s, 5H), 3.28 (d, J=4.0Hz, 2H), 2.87-2.64 (m, 6H), 2.36
(s, 1H), 2.11-1.93 (m, 4H), 1.81-1.53 (m, 8H), 1.38-1.30 (m, 6H), 1.16 (d, J=4.5Hz, 6H),
1.13 (d, J=3.1Hz, 3H), 0.88 (d, J=1.9Hz, 7H), 0.81 (s, 3H)
Here is the detection research of the Enoxolone derivative active anticancer containing piperazine ring of embodiment 1-9.
Experiment material
1.1 cell strain
HepG2 cell lines；MCF-7 cell strainHJ2mm.
1.2 reagent
DMEM culture mediums (GIBCO), newborn bovine serum (Hangzhou Chinese holly biological engineering material), trypsase (Sigma),
Dual anti-(the Gibco USA) of 10000 units, PBS buffer solution (the Shanghai biotech inc Yuan Pei).Other commonization
It is that domestic analysis is pure to learn reagent.
Experimental method
The preparation of 2.1 culture mediums
90mL DMEM culture mediums (Gibcio USA) culture medium adds inactivation newborn bovine serum (Hangzhou Chinese holly bioengineering
Material) dual anti-(the Gibco USA) of 10mL and 1mL10000 units be complete culture solution, is marked, it is standby in 4 DEG C of preservations
With.Trypsase is made into 0.25% solution with PBS buffer solution, is saved backup for 4 DEG C after filtration sterilization.
The preparation of 2.2 liquids
Accurately weigh sample 1.0mg.It is added in the 1.5mL centrifuge tubes of sterilizing, DMSO 1mL is added, are made into 1mg/mL
Stoste, -40 DEG C of freezen protectives.After melting before use respective concentration application is diluted to appropriate PBS fliud flushings.
2.3 cell culture and passage
Cell bacterium adhere-wall culture is in the Tissue Culture Flask of complete culture solution containing 10mL, in 37 DEG C, 5%CO2, under saturated humidity
Culture.Cell is washed twice after covering with bottom of bottle with the PBS buffer solution of sterilizing, 0.25% trypsin digestion and cell 1min is added,
Fall trypsase, after jog cell can be completely fallen off, after adding full nutrient solution 30mL, dispels cell with pipette, be sub-packed in 3
In a new Tissue Culture Flask, continue to cultivate.
2.4 active anticancers are tested
One bottle of cell for just growing up to intact monolayer is taken, cell is collected after trypsin digestion, is blown and beaten uniformly with pipette,
Two drop cell suspension trypan blues (Trypan Blue) are taken to dye, with living cell counting number under microscope to 1 × 104A cell/
ML. 90 μ L cell suspensions are added per hole into 96 well culture plates, culture plate is placed in CO2It is cultivated in incubator for 24 hours, takes out culture
In the solution of 10 μ L samples containing various concentration of every Kong Zhongjia after plate so that drug final concentration is respectively 50,25,12.5,
6.25,3.125 μM, each concentration sets 3 parallel holes, separately sets 6 hole cells and makees normal control hole and Positive control wells.After adding medicine
Culture plate is placed in CO in vibrating mixing in micropore plate oscillator2Continue culture in incubator for 24 hours.Culture plate is taken out, is added per hole
The MTT liquid of 10 μ L5mg/mL vibrates mixing, continues to cultivate 4h.15min is shaken after being added per 150 μ LDMSO of hole.Microplate reader measures
Each hole light absorption (OD values) measures wavelength 570nm.Two kinds of cell Proliferations of drug pair are calculated by SPSS softwares according to each hole OD values
Inhibiting rate, i.e. IC50 values, experimental result be shown in Table 1.
Table 1
Table 1 shows that the inhibition of two kinds of cell Proliferations of Enoxolone derivative pair provided by the invention has remarkable effect, tool
There is wide anti-cancer applications foreground.
Claims (10)
1. a kind of Enoxolone derivative containing piperazine structure, which is characterized in that shown in its structure such as formula (I)：
In formula (I), R is：
Wherein, R1Selected from unsubstituted C1-C3 alkyl, the C1-C3 alkyl replaced by 1~2 benzene or halogeno-benzene, benzene, ortho position or
Align the benzene replaced by the following group substituent group：C1-C3 alkyl, halogen, nitro, trifluoromethyl；
R2Selected from unsubstituted C1-C3 alkyl.
2. the Enoxolone derivative according to claim 1 containing piperazine structure, which is characterized in that R1Selected from unsubstituted
C1-C2 alkyl, the benzene that is replaced by the following group substituent group by C1-C2 alkyl that 2 benzene or halogeno-benzene replace, contraposition：C1-C2 alkane
Base, halogen, nitro, trifluoromethyl；
R2Selected from unsubstituted C1-C2 alkyl.
3. the Enoxolone derivative according to claim 1 containing piperazine structure, which is characterized in that halogen be chlorine, fluorine or
Bromine；Halogen in halogeno-benzene is chlorine, fluorine or bromine.
4. the Enoxolone derivative according to claim 1 containing piperazine structure, which is characterized in that R is selected from following substitution
Base：
5. the preparation method of the Enoxolone derivative according to claim 1 containing piperazine structure, which is characterized in that packet
It includes：
(1) enoxolone is scattered in methanol, the concentrated sulfuric acid is added and is reacted, product a is made；
(2) product a is scattered in dichloromethane, bromoacetyl bromide is added and is reacted, product b is made；
(3) in the presence of alkali, the piperazine of product b and different substituents, which is scattered in organic solvent, to be reacted, and is made described sweet
Careless acid derivative.
6. the preparation method of the Enoxolone derivative according to claim 5 containing piperazine structure, which is characterized in that step
(1) in, the time of the reaction is 8~16h, and reaction temperature is 65~90 DEG C；In step (2), time of the reaction is 1~
5h, reaction carry out under condition of ice bath；The molar ratio of product a methyl glycyrrhetates and bromoacetyl bromide is 1:1~2.
7. the preparation method of the Enoxolone derivative according to claim 5 containing piperazine structure, which is characterized in that step
(3) in, alkali is potassium carbonate or triethylamine；The time of the reaction is 6~10h, and reaction temperature is 80~90 DEG C；Organic solvent selects
From acetonitrile, ethyl alcohol, the molar ratio of the piperazine of product b and different substituents is 1:1~1.5.
8. the preparation method of the Enoxolone derivative according to claim 5 containing piperazine structure, which is characterized in that step
(3) in, the piperazine of the different substituents is selected from N methyl piperazine, phenylpiperazine, 4- aminomethyl phenyls piperazine, 2,4- dimethyl benzenes
Base piperazine, 2- methoxyphenylpiperazderivatives, 4- methoxyphenylpiperazderivatives, 3- methoxyphenylpiperazderivatives, p-trifluoromethyl phenyl piperazine,
2- fluorophenyls piperazine, 3- chlorophenylpiperazines, 3,4- dichlorophenylpiperazines, 4- nitrobenzophenones piperazine, diphenylmethyl piperazine or 4-
Chlorodiphenyl vlmethylpiperazin.
9. according to Enoxolone derivative of the Claims 1 to 4 any one of them containing piperazine structure in preparing anticancer drug
Application.
10. a kind of drug contains Claims 1 to 4 any one of them Enoxolone derivative.
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