CN107098832A - A kind of honokiol derivative and preparation method and application - Google Patents
A kind of honokiol derivative and preparation method and application Download PDFInfo
- Publication number
- CN107098832A CN107098832A CN201710100322.7A CN201710100322A CN107098832A CN 107098832 A CN107098832 A CN 107098832A CN 201710100322 A CN201710100322 A CN 201710100322A CN 107098832 A CN107098832 A CN 107098832A
- Authority
- CN
- China
- Prior art keywords
- compound
- salt
- pharmaceutically
- honokiol
- alkali metal
- 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.)
- Granted
Links
- FVYXIJYOAGAUQK-UHFFFAOYSA-N honokiol Chemical class C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims description 16
- VVOAZFWZEDHOOU-UHFFFAOYSA-N honokiol Natural products OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 claims abstract description 73
- BYTORXDZJWWIKR-UHFFFAOYSA-N Hinokiol Natural products CC(C)c1cc2CCC3C(C)(CO)C(O)CCC3(C)c2cc1O BYTORXDZJWWIKR-UHFFFAOYSA-N 0.000 claims abstract description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 150000002148 esters Chemical class 0.000 claims abstract description 38
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 11
- 239000010452 phosphate Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000007924 injection Substances 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 239000011734 sodium Substances 0.000 claims description 18
- 229910052783 alkali metal Inorganic materials 0.000 claims description 17
- 150000001340 alkali metals Chemical class 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 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 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 7
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 7
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 6
- 201000005917 gastric ulcer Diseases 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 241000417413 Gentiana cephalantha Species 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 229910019213 POCl3 Inorganic materials 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 241000194019 Streptococcus mutans Species 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 230000000295 complement effect Effects 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- -1 glidant Substances 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 230000019635 sulfation Effects 0.000 claims description 4
- 238000005670 sulfation reaction Methods 0.000 claims description 4
- 241000590002 Helicobacter pylori Species 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 229940037467 helicobacter pylori Drugs 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- YYHPEVZFVMVUNJ-UHFFFAOYSA-N n,n-diethylethanamine;sulfur trioxide Chemical compound O=S(=O)=O.CCN(CC)CC YYHPEVZFVMVUNJ-UHFFFAOYSA-N 0.000 claims description 3
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 238000004040 coloring Methods 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 208000002925 dental caries Diseases 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 17
- 241001465754 Metazoa Species 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 4
- 238000009472 formulation Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 159000000000 sodium salts Chemical class 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000002504 physiological saline solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 150000003222 pyridines Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 235000018977 lysine Nutrition 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 241000206575 Chondrus crispus Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical class [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002669 lysines Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 235000002710 Ilex cornuta Nutrition 0.000 description 1
- 241001310146 Ilex cornuta Species 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000675 anti-caries Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000008108 microcrystalline cellulose Chemical class 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C305/00—Esters of sulfuric acids
- C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
- C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the compound as shown in formula I：In formula, R1、R2Selected from H, sulfuric ester or its can pharmaceutically receive salt, phosphate or its can pharmaceutically receive salt, and R1、R2It is asynchronously H.The noval chemical compound that the present invention is provided, has more preferable dissolubility relative to honokiol in water, is more beneficial for preparing the various formulations such as piece agent, injection, is easily absorbed and is utilized by human body or animal body, so as to play more preferable drug effect.
Description
Technical field
The invention belongs to chemical medicine field, and in particular to a kind of honokiol derivative and preparation method and application.
Background technology
Honokiol is a kind of active component contained in Magnoliacea plant or Cortex Magnoliae Officinalis, is used in traditional medicine
History is very long, pungent, warm-natured, has effects that promoting the circulation of qi dampness elimination, warm in pain, relieving asthma.However, honokiol is extremely difficult
It is dissolved in water, it is not easy to absorbed and utilized by organism, has a strong impact on it and play drug effect.
The content of the invention
It is an object of the invention to provide a kind of honokiol derivative and preparation method and application.
The compound as shown in formula I that the present invention is provided：
In formula,
R1、R2Selected from H, sulfuric ester or its can pharmaceutically receive salt, phosphate or its can pharmaceutically receive salt, and R1、
R2It is asynchronously H.
Further, R1、R2Selected from H, sulfuric ester or its can pharmaceutically receive salt, and R1、R2It is asynchronously H；
Described sulfuric ester or its can pharmaceutically to receive salt as follows：
Wherein, R3For H, alkali metal or organic amine.
Further, R1、R2Simultaneously for sulfuric ester or its can pharmaceutically receive salt when, the described compound such as a institutes of formula I
Show：
In formula, R1a、R2aSeparately or concurrently it is selected from H, alkali metal or organic amine.
Further, R1a、R2aIt is simultaneously H.
Further, R1a、R2aSeparately or concurrently it is selected from H or alkali metal, and R1a、R2aIt is asynchronously H；Described alkali metal
For lithium, sodium or potassium.
Further, described compound is single sodium or double sodium salt.
Further, described compound is single or double triethanolamine salt, single or double lysine salt.
Further, R1、R2Selected from H, phosphate or its can pharmaceutically receive salt, and R1、R2It is asynchronously H；
Described phosphate or its can pharmaceutically to receive salt as follows：
Wherein, R4、R5Separately or concurrently it is selected from H, alkali metal or organic amine.
Further, R1、R2Simultaneously for phosphate or its can pharmaceutically receive salt when, the described compound such as b institutes of formula I
Show：
In formula, R1b、R2b、R3b、R4bSeparately or concurrently it is selected from H, alkali metal or organic amine.
Further, R1b、R2b、R3b、R4bIt is simultaneously H.
Further, R1b、R2b、R3b、R4bSeparately or concurrently it is selected from H or alkali metal, and R1b、R2b、R3b、R4bIt is asynchronously
H；Described alkali metal is lithium, sodium or potassium.
Further, described compound is single sodium or tetrasodium salt.
Further, described compound is single triethanolamine salt, mono-lysine salts.
Present invention also offers the preparation method of above-claimed cpd, it is characterised in that：It comprises the following steps：
1., honokiol and phosphorus esterification reagent or Sulfation reagent, react, obtain reaction product in the basic conditions；
2., by step 1. gained reaction product post processing or/and into salt, produce the compound shown in formula I.
Further, described phosphorus esterification reagent is selected from POCl3 or tribromo oxygen phosphorus；Described Sulfation reagent choosing
From pyridine. sulfur trioxide complex compound, triethylamine sulfur trioxide complex.
Prevention and/or treatment tumour are being prepared present invention also offers above-mentioned compound or its pharmaceutically acceptable salt
Medicine in application.
Further, described tumour is cancer of pancreas or G. cephalantha.
Prepared present invention also offers above-mentioned compound or its pharmaceutically acceptable salt with bacteriostatic activity
Medicine in application.
Further, described bacterium is Gram-negative bacteria, streptococcus mutans or helicobacter pylori.
Prevention and/or treatment carious tooth are being prepared present invention also offers above-mentioned compound or its pharmaceutically acceptable salt
Medicine in application.
Further, described carious tooth is the carious tooth as caused by streptococcus mutans.
Burst present invention also offers above-mentioned compound or its pharmaceutically acceptable salt in preparation prevention and/or treatment stomach
Application in the medicine of ulcer.
Further, described gastric ulcer is by the microbial gastric ulcer of H. pylori.
Prevention and/or treatment inflammation are being prepared present invention also offers above-mentioned compound or its pharmaceutically acceptable salt
Medicine in application.
Present invention also offers a kind of pharmaceutical composition, it be using above-mentioned compound or its pharmaceutically acceptable salt as
Active component, adds the preparation that pharmaceutically conventional auxiliary material or complementary composition is prepared.
Further, described auxiliary material or complementary composition are selected from diluent, filler, colouring agent, glidant, lubrication
In agent, adhesive, stabilizer, suspending agent, buffer any one or it is two or more.
Further, described preparation include tablet, capsule, oral liquid, injection, transdermal agent, aerosol solid pharmaceutical preparation,
Liposome and/or sustained-release preparation.
The noval chemical compound that the present invention is provided, has more preferable dissolubility relative to honokiol in water, is more beneficial for system
The various formulations such as standby piece agent, injection, are easily absorbed and are utilized by human body or animal body, so as to play more preferable drug effect.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, replaces or changes.
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, replaces or changes.
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
Embodiment 1 prepares honokiol sulfuric ester and its salt
Honokiol (cas35354-74-6, molecular weight 266) 10g, pyridine. sulfur trioxide complexing are added in 50ml pyridines
17 grams of thing (cas26412-87-3, molecular weight 159) (3 equivalent), is stirred overnight at room temperature, is concentrated under reduced pressure, and adds 50ml diluted acid water,
100ml ethyl acetate is extracted in three times, and ethyl acetate layer is concentrated to dryness after drying, and obtains the double sulfuric esters of white solid honokiol
10.5 grams；
Honokiol (cas35354-74-6, molecular weight 266) 10g, triethylamine sulfur trioxide network are added in 50ml pyridines
19.4 grams of compound (cas761-01-3, molecular weight 181.25) (3 equivalent), is stirred overnight at room temperature, is concentrated under reduced pressure, and adds 50ml dilute
Sour water, 100ml ethyl acetate is extracted in three times, and ethyl acetate layer is concentrated to dryness after drying, and obtains white solid honokiol double
10.2 grams of sulfuric ester；
The double sulfuric esters of honokiol：1HNMR(300MHz,D2O):δ(ppm)7.36-7.38(m,4H),7.21(brs,2H),
5.97(brs,2H),5.00-5.06(m,4H),3.33-3.43(m,4H)；
ESI-MS m/z:426。
The structural formula of the double sulfuric esters of honokiol is as follows：
Honokiol (cas35354-74-6, molecular weight 266) 10g, pyridine. sulfur trioxide complexing are added in 50ml pyridines
5.7 grams of thing (cas26412-87-3, molecular weight 159) (1 equivalent), is stirred overnight at room temperature, is concentrated under reduced pressure, and adds 50ml diluted acid water,
100ml ethyl acetate is extracted in three times, and ethyl acetate layer is concentrated to dryness after drying, obtained by preparative high performance liquid chromatography and
2.5 grams of magnolol Monosulfate；
Take the double sulfuric esters of 5 grams of honokiols to be dispersed in 10ml water, add 2 equivalent dilute sodium hydroxides and 50ml acetone,
White solid is obtained, double 4.7 grams of the sulfuric ester double sodium salts of honokiol are filtrated to get；
The double sulfuric ester double sodium salts of honokiol：1HNMR(300MHz,D2O):δ(ppm)7.36-7.39(m,4H),7.21
(brs,2H),5.97(brs,2H),5.00-5.06(m,4H),3.33-3.43(m,4H)；
ESI-MS m/z:470；
Elementary analysis (Elemental Analysis)：C45.90；H,3.49；Na,9.80；O,27.21；S,13.61.
The structural formula of the double sulfuric ester double sodium salts of honokiol is as follows：
Take the double sulfuric esters of 5 grams of honokiols to be dispersed in 10ml water, add 1 equivalent dilute sodium hydroxide and 50ml acetone,
White solid is obtained, double 4.7 grams of the sulfuric ester mono-sodium salts of honokiol are filtrated to get；
The double sulfuric ester mono-sodium salts of honokiol：1HNMR(300MHz,D2O):δ(ppm)7.36-7.39(m,4H),7.22
(brs,2H),5.96(brs,2H),5.00-5.06(m,4H),3.33-3.43(m,4H)；
ESI-MS m/z:447；
Elementary analysis (Elemental Analysis)：C,48.15；H,3.88；Na,5.11；O,28.54；S,14.4.
Take the double sulfuric esters of 5 grams of honokiols to be dissolved in 50ml acetone, add 1 or 2 equivalent lysines, respectively obtain its list
Lysine or double lysine salts；1 or 2 equivalent triethanolamines are added, its single triethanolamine or double triethanolamine salts is respectively obtained；
The double triethanolamine salts of the double sulfuric esters of honokiol：1HNMR(300MHz,D2O):δ(ppm)7.36-7.39(m,4H),
7.22(brs,2H),5.96(brs,2H),5.00-5.06(m,4H),3.97(m,12H),3.48(m,12H),3.33-3.43
(m,4H)。
Embodiment 2 prepares honokiol phosphate and its salt
Honokiol (cas35354-74-6, molecular weight 266) 10g, POCl3 is added in 50ml pyridines
23 grams of (cas10025-87-3, molecular weight 153.33) (4 equivalent), is stirred overnight at room temperature, is concentrated under reduced pressure, and adds 50ml frozen water and stirs
Mix, be concentrated under reduced pressure, add 50ml acetone, separate out white solid, be filtrated to get 10.1 grams of honokiol biphosphonate；
Honokiol biphosphonate：1HNMR(300MHz,D2O):δ(ppm)7.21-7.43(m,6H)6.01(brs,2H),
4.96-5.07(m,4H),3.33-3.66(m,4H)；
ESI-MS m/z:425.2[M-H]-。
The structural formula of honokiol biphosphonate is as follows：
Honokiol (cas35354-74-6, molecular weight 266) 10g, POCl3 is added in 50ml pyridines
5.8 grams of (cas10025-87-3, molecular weight 153.33) (1 equivalent), is stirred overnight at room temperature, is concentrated under reduced pressure, and adds 50ml frozen water and stirs
Mix, be concentrated under reduced pressure, 1.2 grams of honokiol phosplate is obtained by preparative high performance liquid chromatography；
Take 5 grams of honokiol biphosphonates to be dispersed in 10ml water, add 1 equivalent dilute sodium hydroxide and 50ml acetone,
White solid is obtained, 4.2 grams of honokiol biphosphonate mono-sodium salt is obtained；
Honokiol biphosphonate mono-sodium salt：1HNMR(300MHz,D2O):δ (ppm) 7.3-7.45 (m, 6H), 6.00
(brs,2H),5.00-5.06(m,4H),3.38-3.68(m,4H)；
ESI-MS m/z:446.9[M-H]-。
Elementary analysis (Elemental Analysis)：C,48.28；H,4.22；Na,5.12；O,28.59；P,13.81.
The structural formula of honokiol biphosphonate mono-sodium salt is as follows：
Take 5 grams of honokiol biphosphonates to be dispersed in 10ml water, add 4 equivalent dilute sodium hydroxides and 50ml acetone,
White solid is obtained, 4.4 grams of honokiol biphosphonate tetrasodium salt is obtained；
Honokiol biphosphonate tetrasodium salt：1HNMR(300MHz,D2O):δ (ppm) 7.3-7.45 (m, 6H), 6.00
(brs,2H),5.01-5.06(m,4H),3.37-3.68(m,4H)；
Elementary analysis (Elemental Analysis)：C,42.00；H,3.11；Na,17.92；O,24.84；P,12.10.
The structural formula of honokiol biphosphonate tetrasodium salt is as follows：
Take 5 grams of honokiol bis phosphoric acid acid esters to be dissolved in 50ml acetone, add 1 equivalent lysine, obtain its singly bad ammonia
Acid.
The water-soluble testing experiment of the honokiol sulfuric ester of embodiment 3, phosphate and its salt
Detection method：The test sample for being ground into fine powder is weighed, as in the distilled water of 25 DEG C of ± 2 DEG C of certain capacities, every
Dissolving situation in 5min strengths shaking 30s, observation 30min, when such as without visually visible particles of solute or drop, that is, is considered as
It is completely dissolved.
Easily dissolving means that solute 1g (ml) can dissolve in solvent is less than 1ml；
It is readily soluble to mean that solute 1g (ml) dissolve in solvent 1~less than 10ml；
Dissolving means that solute 1g (ml) can dissolve in solvent 10~less than 30ml；
It is slightly molten to mean that solute 1g (ml) dissolve in solvent 30~less than 100ml；
Slightly soluble means that solute lg (ml) can dissolve in solvent 100~less than 1000ml；
Soluble,very slightly means that solute 1g (ml) can dissolve in solvent 1000~less than 10 000ml；
It is almost insoluble or insoluble mean that solute 1g (ml) can not be completely dissolved in solvent 10000ml.
Result of the test is shown in Table 1.
Table 1, soluble test result
| Test sample title | It is water-soluble |
| Honokiol | Soluble,very slightly |
| The double sulfuric esters of honokiol | Dissolving |
| The double sulfuric ester mono-sodium salts of honokiol | It is readily soluble |
| The double sulfuric ester double sodium salts of honokiol | Easily dissolve |
| The double lysine salts of the double sulfuric esters of honokiol | It is readily soluble |
| Honokiol biphosphonate | Dissolving |
| Honokiol biphosphonate mono-sodium salt | It is readily soluble |
| Honokiol biphosphonate tetrasodium salt | Easily dissolve |
| Honokiol biphosphonate mono-lysine salts | It is readily soluble |
As a result show, the compounds of this invention has more preferable dissolubility relative to honokiol in water, be more beneficial for system
The various formulations such as standby piece agent, injection, are easily absorbed and are utilized by human body or animal body, so as to play more preferable drug effect.
Application of the compounds of this invention of embodiment 4 in antineoplastic is prepared
About 1,000,000 tumour cells (cancer of pancreas) of mouse bare subcutaneous injection, are inoculated with 3 weeks or so, once tumour naked eyes are visible, choosing
Select no bleeding, necrosis, infection, diameter of tumor be 0.3-0.4cm nude mices tested.Tumor bearing nude mice is randomly divided into physiological saline
Control group, DMSO control groups, administration group be divided into 40mg/Kg honokiols group (DMSO dissolve, referred to as administration 1 group), 40mg/Kg and
The double sulfuric ester double sodium salt groups of magnolol (physiological saline solution, referred to as 2 groups of administration), 40mg/Kg honokiol biphosphonate list sodium
Salt group (physiological saline solution, referred to as 3 groups of administration), 40mg/Kg honokiol biphosphonate tetrasodium salts group (physiological saline solution,
Referred to as 4 groups of administration), every group of 8 nude mices.Medicine group is by every intraperitoneal injection every time；Measured and counted once every 6 days, and survey
Determine growth curve, after treatment in 30 days, put to death nude mice stripping knurl body and weigh, calculate each group tumour inhibiting rate；It the results are shown in Table 2 and table 3.
Table 2, different compounds are in different time points nude mice lotus knurl volume (unit cm3, average ± standard deviation)
| 0 day | 6 days | 12 days | 18 days | 24 days | 30 days | |
| Physiological saline group | 0.251±0.055 | 0.413±0.105 | 0.980±0.289 | 2.078±1.247 | 3.154±1.134 | 4.467±1.97 |
| DMSO groups | 0.229±0.048 | 0.458±0.970 | 1.232±0.550 | 2.166±1.113 | 3.301±1.275 | 4.772±1.68 |
| It is administered 1 group | 0.266±0.076 | 0.450±0.123 | 0.909±0.357 | 1.378±0.685 | 1.883±0.821 | 2.690±0.992 |
| It is administered 2 groups | 0.240±0.057 | 0.441±0.221 | 0.885±0.476 | 1.345±0.576 | 1.612±0.714 | 2.207±0.981 |
| It is administered 3 groups | 0.256±0.077 | 0.438±0.352 | 0.900±0.475 | 1.361±0.622 | 1.745±0.846 | 2.375±0.765 |
| It is administered 4 groups | 0.261±0.084 | 0.461±0.475 | 0.901±0.284 | 1.359±0.701 | 1.801±0.795 | 2.402±0.893 |
Table 3, different compounds transplant tumor weight and tumour inhibiting rate (unit g, average ± standard deviation) after 30 days
| Transplant tumor weight | Tumour inhibiting rate | |
| Physiological saline group | 2.536±0.754 | - |
| DMSO groups | 2.210±543 | - |
| It is administered 1 group | 1.424±0.407 | 35.6% |
| It is administered 2 groups | 1.102±0.726 | 56.6 |
| It is administered 3 groups | 1.211±0.492 | 52.2% |
| It is administered 4 groups | 1.223±0.693 | 51.8% |
There is significant difference (p compared with the volume of control group<0.05).
As a result show, compared with honokiol, the compounds of this invention has higher tumour inhibiting rate.
Application of the compounds of this invention of embodiment 5 in antibacterials and/or anti-caries tooth medicine is prepared
Carried out using disk diffusion method, experimental result is shown in Table 4.
The minimal inhibitory concentration (MIC, μ g/mL) of table 4, different compounds
As a result show, honokiol is active for Gram-negative bacteria E.coli and P.aeruginosa unrestraint, and
The compounds of this invention (the double sulfuric ester double sodium salts of honokiol, honokiol bis phosphoric acid mono-sodium salt, the sodium of honokiol biphosphonate four
Salt) antibacterial activity is shown, it can apply to prepare the medicine with bacteriostatic activity.
Meanwhile, streptococcus mutans is the Main Pathogenic Bacteria for causing carious tooth reason, and helicobacter pylori is causing a disease for gastric ulcer
Bacterium, the compounds of this invention (the double sulfuric ester double sodium salts of honokiol, honokiol bis phosphoric acid mono-sodium salt, honokiol biphosphonate
Tetrasodium salt), the medicine for preparing prevention and/or treatment carious tooth is can apply to, or, prevent and/or treatment stomach applied to preparing
The medicine of ulcer.
Application of the compounds of this invention of embodiment 6 in anti-inflammatory drug is prepared
Rat carragheen pedal swelling is tested：1% carragheen 0.2mL/ is injected under the right metapedes plantar aponeurosis of SD male rats only
Inflammation is caused, the disposable intraperitoneal injection 0.3mL's of administration group, it is divided into：1 group of 40mg/Kg honokiols DMSO solution, administration 2 is administered
The double sulfuric ester double sodium salt aqueous solution of group 40mg/Kg honokiols, the double lysines of the double sulfuric esters of 3 groups of 40mg/Kg honokiols of administration
Saline solution, is administered 4 groups of 40mg/Kg honokiol biphosphonate tetrasodium salt aqueous solution, and control group injects normal saline, and
Determine administration before, 0.5,1,2,3 and 4h right metapedes diameter.Each rat causes the difference of scorching front and rear sufficient diameter to be swelling, experiment
It the results are shown in Table 5.
The antiphlogistic effects of table 5, different compounds
As a result show, the compounds of this invention is made for the inflammation as caused by carragheen with good anti-inflammatory and/or anti-inflammatory
With, can apply to prepare prevention and/or treatment inflammation medicine.
A kind of medicinal tablets composition of the double sulfuric ester double sodium salts of the honokiol of embodiment 7
The invention discloses double sulfuric ester double sodium salt medicinal tablets compositions of a kind of honokiol and preparation method thereof.And thickness
The double sulfuric ester double sodium salt medicinal tablets compositions of plain phenol, containing the double sulfuric ester double sodium salts of 0.5g or 1g honokiols, 93.5g or
93g microcrystalline celluloses, 4g sodium carboxymethyl starches, 2g magnesium stearates.The preparation method of tablet composition of the present invention, including with
Lower step：A, the double sulfuric ester double sodium salts of honokiol and microcrystalline cellulose are mixed using conventional method；B, mixture a is pelletized；
C, sodium carboxymethyl starch, magnesium stearate are mixed with making pellet, and suppress 1000.
A kind of medicinal liquid injection composition of the honokiol biphosphonate mono-sodium salt of embodiment 8
The invention discloses a kind of honokiol biphosphonate mono-sodium salt medicinal liquid injection composition and preparation method thereof.With
Magnolol biphosphonate mono-sodium salt medicinal liquid injection composition, contains 0.2g honokiol biphosphonate mono-sodium salts, the anhydrous Chinese hollys of 20g
Rafter acid sodium, 10g sodium sulfites, enough water for injection.The preparation method of injecta composition of the present invention, including following step
Suddenly：A, dissolves honokiol biphosphonate mono-sodium salt, sodium citrate and sodium sulfite, and be formulated into 2000mL with water for injection；
B, a step resulting solution are filtered, and in embedding under inert gas shielding in the 2mL ampoules of dry sterilization, totally 1000 bottles；C, ampoule
Pressure sterilizing, leak detection.
The multidrug resistance of the anti-G. cephalantha of the double sulfuric ester double sodium salts of the honokiol of embodiment 9
The G. cephalantha cell YCU-N861 that mouse bare subcutaneous injection is handled through cross resistance, once tumour naked eyes can
See, use vernier caliper measurement tumour, and using formula volume=(wide square * length) * 0.52, wherein width is most path, is calculated
Gross tumor volume V0.Handled immediately with the double sulfuric ester double sodium salt aqueous solution of daily 40mg/Kg honokiols, daily by 0.3ml
The daily intraperitoneal injection of the solution, at the same using inject equivalent adriamycin, cis-platinum, methotrexate (MTX), vincristine and physiological saline as
Control, uses vernier caliper measurement tumour after 14 days, and using formula volume=(wide square * length) * 0.52, wherein width is minimum
Footpath, calculates gross tumor volume Vt。
Utilize formula relative tumour volume (RTV)=final gross tumor volume (Vt)/first administration pre-neoplastic volume (V0), meter
Relative tumour volume is calculated, 6 are the results are shown in Table.
The result of the test of table 6, the anti-G. cephalantha of different pharmaceutical group
P<0.01, administration group is compared with each group；P>0.05, physiological saline group with addition to administration group other each groups compared.
As a result show, the compounds of this invention for G. cephalantha Hemapoiesis tumour, with good inhibition,
Compared with other contrast groups, relative tumour volume (RTV) is smaller.
To sum up, the noval chemical compound that the present invention is provided, has more preferable dissolubility, more favorably relative to honokiol in water
In preparing the various formulations such as piece agent, injection, easily absorbed and utilized by human body or animal body, so as to play more preferable medicine
Effect.
Claims (24)
1. the compound as shown in formula I：
In formula,
R1、R2Selected from H, sulfuric ester or its can pharmaceutically receive salt, phosphate or its can pharmaceutically receive salt, and R1、R2No
It is simultaneously H.
2. compound according to claim 1, it is characterised in that：R1、R2Selected from H, sulfuric ester or its can pharmaceutically receive
Salt, and R1、R2It is asynchronously H；
Described sulfuric ester or its can pharmaceutically to receive salt as follows：
Wherein, R3For H, alkali metal or organic amine.
3. compound according to claim 2, it is characterised in that：R1、R2Simultaneously for sulfuric ester or its can pharmaceutically receive
During salt, described compound is as shown in a of formula I：
In formula, R1a、R2aSeparately or concurrently it is selected from H, alkali metal or organic amine.
4. compound according to claim 3, it is characterised in that：R1a、R2aIt is simultaneously H.
5. compound according to claim 3, it is characterised in that：R1a、R2aH or alkali metal are separately or concurrently selected from, and
R1a、R2aIt is asynchronously H；Described alkali metal is lithium, sodium or potassium.
6. compound according to claim 5, it is characterised in that：Described alkali metal is sodium.
7. compound according to claim 3, it is characterised in that：Described organic amine is triethanolamine or lysine.
8. compound according to claim 1, it is characterised in that：R1、R2Selected from H, phosphate or its can pharmaceutically receive
Salt, and R1、R2It is asynchronously H；
Described phosphate or its can pharmaceutically to receive salt as follows：
Wherein, R4、R5Separately or concurrently it is selected from H, alkali metal or organic amine.
9. compound according to claim 8, it is characterised in that：R1、R2Simultaneously for phosphate or its can pharmaceutically receive
During salt, described compound is as shown in the b of formula I：
In formula, R1b、R2b、R3b、R4bSeparately or concurrently it is selected from H, alkali metal or organic amine.
10. compound according to claim 9, it is characterised in that：R1b、R2b、R3b、R4bIt is simultaneously H.
11. compound according to claim 9, it is characterised in that：R1b、R2b、R3b、R4bSeparately or concurrently selected from H or alkali gold
Category, and R1b、R2b、R3b、R4bIt is asynchronously H；Described alkali metal is lithium, sodium or potassium.
12. compound according to claim 11, it is characterised in that：The alkali metal is sodium, and R1b、R2b、R3b、R4bIn,
All of which is selected from sodium or only one is selected from sodium.
13. the preparation method of the compound described in claim 1~12 any one, it is characterised in that：It comprises the following steps：
1., honokiol and phosphorus esterification reagent or Sulfation reagent, react, obtain reaction product in the basic conditions；
2., the reaction product of step 1. gained is post-processed or/and into salt, produces the compound shown in formula I.
14. preparation method according to claim 13, it is characterised in that：Described phosphorus esterification reagent be selected from POCl3 or
Tribromo oxygen phosphorus；Described Sulfation reagent is selected from pyridine. sulfur trioxide complex compound, triethylamine sulfur trioxide complex.
15. the compound or its pharmaceutically acceptable salt described in claim 1~13 any one are preparing prevention and/or controlled
Treat the application in the medicine of tumour.
16. application according to claim 15, it is characterised in that：Described tumour is cancer of pancreas or G. cephalantha.
17. the compound or its pharmaceutically acceptable salt described in claim 1~13 any one are being prepared with bacterium suppression
Make the application in the medicine of activity.
18. application according to claim 17, it is characterised in that：Described bacterium is Gram-negative bacteria, deformation hammer
Bacterium or helicobacter pylori.
19. the compound or its pharmaceutically acceptable salt described in claim 1~13 any one are preparing prevention and/or controlled
Treat the application in carious tooth, gastric ulcer, the medicine of inflammation.
20. application according to claim 19, it is characterised in that：Described carious tooth is the dental caries as caused by streptococcus mutans
Tooth.
21. application according to claim 19, it is characterised in that：Described gastric ulcer is microbial by H. pylori
Gastric ulcer.
22. a kind of pharmaceutical composition, it is characterised in that：It is with the compound described in claim 1~13 any one or its
Pharmaceutically acceptable salt is active component, adds the preparation that pharmaceutically conventional auxiliary material or complementary composition is prepared.
23. pharmaceutical composition according to claim 22, it is characterised in that：Described auxiliary material or complementary composition are selected from dilute
Release any one in agent, filler, colouring agent, glidant, lubricant, adhesive, stabilizer, suspending agent, buffer or two
More than kind.
24. pharmaceutical composition according to claim 22, it is characterised in that：Described preparation includes tablet, capsule, oral
Liquid, injection, transdermal agent, aerosol solid pharmaceutical preparation, liposome and/or sustained-release preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016100989395 | 2016-02-23 | ||
| CN201610098939 | 2016-02-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107098832A true CN107098832A (en) | 2017-08-29 |
| CN107098832B CN107098832B (en) | 2019-08-30 |
Family
ID=59674970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710100322.7A Active CN107098832B (en) | 2016-02-23 | 2017-02-23 | A kind of honokiol derivative and the preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107098832B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109771431A (en) * | 2018-02-10 | 2019-05-21 | 成都贝诺科成生物科技有限公司 | The new application of honokiol derivative |
| CN109966303A (en) * | 2018-03-06 | 2019-07-05 | 成都贝诺科成生物科技有限公司 | The purposes of honokiol derivative in the preparation of antitumor drugs |
| CN110664795A (en) * | 2019-09-20 | 2020-01-10 | 广东省禾基生物科技有限公司 | Water-soluble composition, preparation method and application thereof |
| CN111039847A (en) * | 2019-12-05 | 2020-04-21 | 深圳市老年医学研究所 | Magnolol derivative and preparation method and application thereof |
| WO2021052272A1 (en) * | 2019-09-20 | 2021-03-25 | 广东省禾基生物科技有限公司 | Magnolol derivative, preparation method therefor, and use thereof |
| CN112592367A (en) * | 2019-09-17 | 2021-04-02 | 成都贝诺科成生物科技有限公司 | Magnolol derivative and preparation method and application thereof |
| CN112587533A (en) * | 2019-09-17 | 2021-04-02 | 成都贝诺科成生物科技有限公司 | Application of honokiol derivative in preparation of medicine for preventing and/or treating bovine mastitis |
| WO2021129747A1 (en) * | 2019-12-26 | 2021-07-01 | 深圳市老年医学研究所 | Magnolol and sulforaphane conjugate, and preparation method therefor |
| US11903907B2 (en) * | 2017-10-24 | 2024-02-20 | Taipei Medical University | Soluble honokiol derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008137420A1 (en) * | 2007-05-03 | 2008-11-13 | Emory University | Honokiol analogs and their use in treating cancers |
-
2017
- 2017-02-23 CN CN201710100322.7A patent/CN107098832B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008137420A1 (en) * | 2007-05-03 | 2008-11-13 | Emory University | Honokiol analogs and their use in treating cancers |
Non-Patent Citations (4)
| Title |
|---|
| CHUNYAN WANG等: "Honokiol Metabolites Study in Rat Kidney Employing UHPLC‑Q‑TOF/MS and 13C Stable Isotope Labeling", 《CHROMATOGRAPHIA》 * |
| DONG, YINFENG等: "Characterization of metabolic profile of honokiol in rat feces using liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and 13C stable isotope labeling", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| LAI, HUIJUN等: "Identification of honokiol metabolites in rats by the method of stable isotope cluster technique and ultra-high performance liquid chromatography/quadrupole-time-of-flight mass spectrometry", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| LIU, JUAN等: "Identification of metabolites of honokiol in rat urine using 13C stable isotope labeling and liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry", 《JOURNAL OF CHROMATOGRAPHY A》 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11903907B2 (en) * | 2017-10-24 | 2024-02-20 | Taipei Medical University | Soluble honokiol derivatives |
| CN109771431A (en) * | 2018-02-10 | 2019-05-21 | 成都贝诺科成生物科技有限公司 | The new application of honokiol derivative |
| CN109966303A (en) * | 2018-03-06 | 2019-07-05 | 成都贝诺科成生物科技有限公司 | The purposes of honokiol derivative in the preparation of antitumor drugs |
| CN112592367A (en) * | 2019-09-17 | 2021-04-02 | 成都贝诺科成生物科技有限公司 | Magnolol derivative and preparation method and application thereof |
| CN112587533A (en) * | 2019-09-17 | 2021-04-02 | 成都贝诺科成生物科技有限公司 | Application of honokiol derivative in preparation of medicine for preventing and/or treating bovine mastitis |
| CN110664795A (en) * | 2019-09-20 | 2020-01-10 | 广东省禾基生物科技有限公司 | Water-soluble composition, preparation method and application thereof |
| WO2021052272A1 (en) * | 2019-09-20 | 2021-03-25 | 广东省禾基生物科技有限公司 | Magnolol derivative, preparation method therefor, and use thereof |
| WO2021052269A1 (en) * | 2019-09-20 | 2021-03-25 | 广东省禾基生物科技有限公司 | Water-soluble composition, preparation method and application thereof |
| CN110664795B (en) * | 2019-09-20 | 2022-12-27 | 广东省禾基生物科技有限公司 | Water-soluble composition, preparation method and application thereof |
| CN111039847A (en) * | 2019-12-05 | 2020-04-21 | 深圳市老年医学研究所 | Magnolol derivative and preparation method and application thereof |
| CN111039847B (en) * | 2019-12-05 | 2021-04-16 | 深圳市老年医学研究所 | Magnolol derivative and preparation method and application thereof |
| WO2021129747A1 (en) * | 2019-12-26 | 2021-07-01 | 深圳市老年医学研究所 | Magnolol and sulforaphane conjugate, and preparation method therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107098832B (en) | 2019-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107098832B (en) | A kind of honokiol derivative and the preparation method and application thereof | |
| Wasserman | Studies on vitamin D3 and the intestinal absorption of calcium and other ions in the rachitic chick | |
| CN103096907B (en) | Can be used for reducing inflammation the preparation containing Echinacea angustifolia and the extract of Rhizoma Zingiberis Recens with peripheral pain | |
| WO2006072962A1 (en) | Calcium potassium ferrocyanide, a prophylactic mixture comprising this compound and the use thereof for decorporation of radiocesium in subjects affected by nuclear radiation | |
| CN105294676B (en) | A kind of jamaicin double salt and its production and use | |
| US20220313713A1 (en) | Vaporizable psychoactive alkaloid composition and preparation thereof | |
| DE2543350C2 (en) | Preparations for the manufacture of &uarr; 9 &uarr; &uarr; 9 &uarr; &uarr; m &uarr; Technetium radio diagnostics | |
| TWI500421B (en) | Pharmaceutical composition | |
| EP0136464B1 (en) | Therapeutic compositions for oral use containing stable s-adenosy1-l-methionine salts | |
| CN101317904B (en) | Uses of smoked plum extract in resisting virus, bacteria, mycoplasma or chlamydia of livestock and poultry | |
| AU2013346766A1 (en) | Effervescent tablet | |
| JP2022520665A (en) | Liquid propolis extract, its formulation and its use | |
| CN106188176B (en) | Phillygenol glucuronic acid derivative, preparation method and applications | |
| CN103127015B (en) | Alfacalcidol dropping pill and preparation method thereof | |
| CN103655593A (en) | Composite medicine preparation for prevention and treatment of bacterium and virus polyinfection diseases of livestock as well as preparation method and application thereof | |
| CN112592367A (en) | Magnolol derivative and preparation method and application thereof | |
| EP3097921A1 (en) | Composition comprising active ingredients of vegetable origin | |
| CN114099480A (en) | Atomizing inhalation type polydatin solution and preparation method thereof | |
| CN113940342A (en) | Paraquat composition containing cyclodextrin derivative and application of paraquat composition to attenuation of mammals | |
| CN106880639A (en) | Aspirin and compound enteric-coated of vitamin C and preparation method thereof | |
| CN109847067A (en) | A kind of Diclofenac-glycine-resveratrol conjugate, preparation method and application | |
| CN113940343B (en) | Paraquat composition containing esterified starch and application of paraquat composition to attenuation of mammals | |
| CN103083269B (en) | Dropping pills containing mannose ester and preparation method thereof | |
| CA3161491C (en) | Vaporizable psychoactive alkaloid composition and preparation thereof | |
| CN101161652B (en) | Quinolizine derivatives having antibacterial activity |
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 | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20190415 Address after: 610000 No. 88 South Keyuan Road, Chengdu High-tech Zone, Sichuan Province, 10 buildings, 6 floors, 602 Applicant after: Chengdu Benoko Chengdu Biological Technology Co., Ltd. Address before: 610011 No. 97 Ziwei East Road, Jinjiang District, Chengdu City, Sichuan Province Applicant before: CHENGDU YISHAN BIOTECHNOLOGY CO., LTD. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |