CN102321239A - Preparation method of water-soluble toluylene compound prodrugs - Google Patents
Preparation method of water-soluble toluylene compound prodrugs Download PDFInfo
- Publication number
- CN102321239A CN102321239A CN201110142129A CN201110142129A CN102321239A CN 102321239 A CN102321239 A CN 102321239A CN 201110142129 A CN201110142129 A CN 201110142129A CN 201110142129 A CN201110142129 A CN 201110142129A CN 102321239 A CN102321239 A CN 102321239A
- Authority
- CN
- China
- Prior art keywords
- mpeg
- peg
- preparation
- prodrug
- solution
- 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
- 229940002612 prodrug Drugs 0.000 title claims abstract description 82
- 239000000651 prodrug Substances 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 76
- -1 toluylene compound Chemical class 0.000 title claims abstract description 25
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims abstract description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000003607 modifier Substances 0.000 claims abstract description 42
- 229940016667 resveratrol Drugs 0.000 claims abstract description 37
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims abstract description 36
- 235000021283 resveratrol Nutrition 0.000 claims abstract description 36
- PJANXHGTPQOBST-VAWYXSNFSA-N trans-stilbene Chemical group C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims abstract description 34
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 111
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 72
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical group C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 claims description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 37
- 238000001953 recrystallisation Methods 0.000 claims description 35
- 239000000126 substance Substances 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 32
- 235000021286 stilbenes Nutrition 0.000 claims description 32
- 238000005406 washing Methods 0.000 claims description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- 244000050510 Cunninghamia lanceolata Species 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 150000002148 esters Chemical class 0.000 claims description 26
- 229930182817 methionine Natural products 0.000 claims description 26
- 229940024606 amino acid Drugs 0.000 claims description 23
- 150000001413 amino acids Chemical class 0.000 claims description 23
- 238000000605 extraction Methods 0.000 claims description 23
- 230000007935 neutral effect Effects 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000012141 concentrate Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 235000018991 trans-resveratrol Nutrition 0.000 claims description 20
- 240000001606 Adenanthera pavonina Species 0.000 claims description 18
- 235000011470 Adenanthera pavonina Nutrition 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 16
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 16
- 239000004473 Threonine Substances 0.000 claims description 16
- 239000001384 succinic acid Substances 0.000 claims description 15
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 14
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 13
- 235000013905 glycine and its sodium salt Nutrition 0.000 claims description 13
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 claims description 12
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 12
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 12
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 12
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 12
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 10
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 9
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 9
- 239000006035 Tryptophane Substances 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 9
- 229960000310 isoleucine Drugs 0.000 claims description 9
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 9
- 229960004799 tryptophan Drugs 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 238000012546 transfer Methods 0.000 claims description 8
- 229960003136 leucine Drugs 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- 230000006837 decompression Effects 0.000 claims description 5
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- BRBDBBJVCXEZLW-UHFFFAOYSA-N CC(C)COC(C)=O.Br Chemical compound CC(C)COC(C)=O.Br BRBDBBJVCXEZLW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229920001427 mPEG Polymers 0.000 claims 21
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims 2
- 229960004452 methionine Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 10
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 7
- 208000030507 AIDS Diseases 0.000 abstract description 3
- 206010003210 Arteriosclerosis Diseases 0.000 abstract description 3
- 201000004624 Dermatitis Diseases 0.000 abstract description 3
- 241000233866 Fungi Species 0.000 abstract description 3
- 206010019799 Hepatitis viral Diseases 0.000 abstract description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract description 3
- 208000010668 atopic eczema Diseases 0.000 abstract description 3
- 208000029078 coronary artery disease Diseases 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 235000013305 food Nutrition 0.000 abstract description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract 2
- IIXHQGSINFQLRR-UHFFFAOYSA-N Piceatannol Natural products Oc1ccc(C=Cc2c(O)c(O)c3CCCCc3c2O)cc1O IIXHQGSINFQLRR-UHFFFAOYSA-N 0.000 abstract 1
- CDRPUGZCRXZLFL-OWOJBTEDSA-N piceatannol Chemical compound OC1=CC(O)=CC(\C=C\C=2C=C(O)C(O)=CC=2)=C1 CDRPUGZCRXZLFL-OWOJBTEDSA-N 0.000 abstract 1
- VLEUZFDZJKSGMX-ONEGZZNKSA-N pterostilbene Chemical compound COC1=CC(OC)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 VLEUZFDZJKSGMX-ONEGZZNKSA-N 0.000 abstract 1
- VLEUZFDZJKSGMX-UHFFFAOYSA-N pterostilbene Natural products COC1=CC(OC)=CC(C=CC=2C=CC(O)=CC=2)=C1 VLEUZFDZJKSGMX-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 50
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 39
- 239000008118 PEG 6000 Substances 0.000 description 23
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 17
- 241000221035 Santalaceae Species 0.000 description 14
- 235000008632 Santalum album Nutrition 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 235000008521 threonine Nutrition 0.000 description 14
- 239000003937 drug carrier Substances 0.000 description 8
- 229960002885 histidine Drugs 0.000 description 7
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 201000001862 viral hepatitis Diseases 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 0 [*+]Oc(cc1)ccc1O Chemical compound [*+]Oc(cc1)ccc1O 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 229940094952 green tea extract Drugs 0.000 description 1
- 235000020688 green tea extract Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003588 threonines Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation method of water-soluble toluylene compound prodrugs. PEG (Polyethylene Glycol) or mPEG (monomethoxy-Polyethylene Glycol)-carboxybutyryl or acetyl-amino acid is taken as a modifier for modifying toluylene compounds such as (E)-3,5-dihydroxy-4-isopropyltoluylene, resveratrol oxide, pterostilbene, piceatannol, resveratrol and the like to prepare prodrugs thereof. By adopting the modified prodrugs, the water solubility and stability of these compounds are improved, the bioactivity is increased, the aim of releasing under control is fulfilled, and the application ranges of these compounds in the industries of medicines, foods and the like are further expanded. The method is suitable for preparing prodrugs by modifying toluylene compounds with the PEG (Polyethylene Glycol) or mPEG (monomethoxy-Polyethylene Glycol)-carboxybutyryl or acetyl-amino acid. The prepared prodrugs are further used for preventing and treating diseases such as fungi, eczema, arteriosclerosis, coronary heart disease, virus hepatitis, AIDS, cancers and the like.
Description
Technical field
The invention belongs to the preparation field of a compounds prodrug, specifically a kind of preparation method of water miscible diphenylethylene compounds prodrug.
Background technology
Diphenylethylene compounds benzene alkene is moral, trans-resveratrol, red sandalwood Stilbene, oxidized resveratrol, white skin China fir alcohol etc. not; Belong to active non-flavones polyphenols; Extensively be present in natural food or the plant; A large amount of research shows: they have the effect of anti-inflammatory, anti-oxidant, antibiotic, Green Tea Extract and anticoagulant, antithrombotic, lipidemia, can be used for prevention and treatment of diseases such as fungi, eczema, arteriosclerosis, coronary heart disease, viral hepatitis, AIDS, cancer.Because the water-soluble and poor stability of such compound molecule; When it can influence the normal performance of its curative effect during as drug use; The shortcoming of this compounds for a change, adopting water miscible macromolecular material to do that carrier modifies molecule is one of rational means.In macromolecular material commonly used; Polyoxyethylene glycol (PEG) or poly glycol monomethyl ether (mPEG) are the pharmaceutical carriers that receives extensive concern; Have the wetting ability and the non-immunogenicity of height, when it is connected to drug molecule, can the character that it is good give drug molecule; Change their biologies in the aqueous solution and distribute behavior and solvability, increase the water solubility and the stability of medicine.PEG or mPEG can directly link to each other with drug molecule and form prodrug, or through connecting arm PEG or mPEG are linked to each other with drug molecule and to modify.Chinese invention patent application 2009100710372 discloses a kind of " hydrophilic polymer---resveratrol conjugate and preparation method "; Utilize mono methoxy polyethylene glycol (mPEG), mono methoxy W 166 successively through carboxylation reaction, acyl chloride reaction exactly; Again with trans-resveratrol prepared in reaction wetting ability resveratrol conjugate; Just water-soluble, stability increase that this product is compared with original trans-resveratrol, biological activity improves.
The applicant's application number is 201010199655.8 Chinese invention patent application; A kind of " PEG, mPEG chemical modifier and prepare the method for trans-resveratrol prodrug " disclosed; It is that carboxylic acid derivative with PEG, mPEG is connected preparation PEG, mPEG chemical modifier with amino acid, is connected with trans-resveratrol to obtain prodrug again, and it is the prodrug of trans-resveratrol that a kind of in the diphenylethylene compounds only studied in this patented claim; The amino acid that relates in the modifier has only 8 kinds; And structure is simple relatively, the necessary amino acid of human body is not all comprised, and is therefore not comprehensive.
Summary of the invention
The technical problem that the present invention will solve; Aim to provide a kind of preparation method of water-soluble diphenylethylene compounds prodrug; It is to be on the basis of 201010199655.8 Chinese invention patent application at application number; The amino acid that is connected on the PEG/mPEG chemical modifier is increased to 12 kinds; 8 seed amino acids comprising needed by human; The modification that also 4 seed amino acids that do not relate in the above-mentioned patented claim is applied to trans-resveratrol obtains new trans-resveratrol prodrug, simultaneously will whole 12 kinds of modifiers be used for other diphenylethylene compounds such as red sandalwood Stilbene, white skin China fir alcohol, oxidized resveratrol and benzene alkene not moral (promptly 3,5-dihydroxyl-4-isopropyl toluylene) prepare prodrug separately respectively.The prodrug of diphenylethylene compounds involved in the present invention is the new compound molecule.The preparation method of the PEG/mPEG modifier that the present invention adopted is simple; After being used for modifying (comprising drug molecule); Improved the water-soluble and stable of drug molecule (compound molecule); And make its amino acid kind that when decomposing, discharges expand to 12 kinds, 8 seed amino acids comprising needed by human are of value to HUMAN HEALTH.
The present invention will solve the problems of the technologies described above, and the technical scheme that is adopted is:
A kind of diphenyl ethene compounds prodrug that obtains by the modification of PEG/mPEG chemical modifier, general formula of molecular structure is following:
In the formula:
Work as R
3During for trans-resveratrol, R
2A kind of in Histidine, methionine(Met), Methionin or the Threonine;
Work as R
3Be benzene alkene not when moral, oxidized resveratrol, red sandalwood Stilbene, white skin China fir alcohol, R
2A kind of in glycocoll, L-Ala, proline(Pro), Xie Ansuan, methionine(Met), phenylalanine(Phe), Isoleucine, leucine, tryptophane, Histidine, Methionin or the Threonine.
The preparation method of aforementioned prodrugs is to be carrier with water miscible PEG or mPEG, is connecting arm with butyryl radicals or ethanoyl, obtains PEG or mPEG carboxylic acid derivative, is connected with amino acid to be prepared from again.
The preparation method of said PEG or mPEG carboxylic acid derivative is divided into two types, wherein:
One, being carrier by water miscible PEG or mPEG, is connecting arm with the succinyl, that is: PEG or mPEG with the Succinic anhydried reaction, obtain the PEG/mPEG-Succinic Acid.Its preparation method carries out according to the following steps order:
1. PEG or mPEG, Succinic anhydried, chloroform and pyridine reflux;
2. remove chloroform under reduced pressure, saturated NaHCO
3Solution is transferred pH7, ethyl acetate extraction, and Hydrogen chloride is transferred pH2～3;
3. dichloromethane extraction merges organic phase, and drying is filtered, and filtrate decompression concentrates, and enriched material is used the anhydrous diethyl ether recrystallization, gets PEG-Succinic Acid or mPEG-Succinic Acid.
Two, being carrier by water miscible PEG or mPEG, is that connecting arm makes with the ethanoyl, that is: PEG or mPEG, and a kind of reaction with in METHYL BROMOACETATE, bromide isobutyl acetate or the bromo-acetic acid tert-butyl obtains PEG/mPEG-acetate.Its preparation method carries out according to the following steps order:
1. room temperature is dissolved in PEG or mPEG in the dry toluene, adds the t-butanol solution of potassium tert.-butoxide;
2. add a kind of in METHYL BROMOACETATE, bromide isobutyl acetate or the bromo-acetic acid tert-butyl, reflux;
3. after the reaction end, filter, filtrate decompression is steamed and is removed the intact raw material of the trimethyl carbinol, toluene and unreacted, and resistates dissolves with methylene dichloride, and the anhydrous diethyl ether recrystallization gets the PEG/mPEG carboxylicesters;
4. above-mentioned carboxylicesters is dissolved in the zero(ppm) water, transfers pH10, stir 30min with NaOH solution;
5. under the frozen water cooling, transfer system pH2～3, stirring at room 20 min, dichloromethane extraction with oxalic acid; Merge organic phase, the saturated common salt water washing is to neutrality, anhydrous sodium sulfate drying; Remove methylene dichloride under reduced pressure, residue is used the anhydrous diethyl ether recrystallization, gets PEG-acetate or mPEG-acetate.
The reaction that is connected between said PEG/mPEG carboxylic acid derivative and amino acid is carried out according to the following steps order:
1. prepare corresponding PEG active ester or mPEG active ester
PEG-Succinic Acid or mPEG-Succinic Acid, PEG-acetate or mPEG-acetate are dissolved in the methylene dichloride, and 0～5 ℃ of DMF solution that adds the NHS of DCC and precooling rises to room temperature naturally, and reaction finishes; The NSC 30023 that generates is reacted in filtering, in filtrating, adds 10% HAc solution then, to remove unreacted DCC; Tell organic phase, the saturated common salt water washing is to neutrality, anhydrous sodium sulfate drying; Filter, concentrate, the anhydrous diethyl ether recrystallization gets PEG or mPEG active ester;
2. the preparation of PEG/mPEG chemical modifier
The PEG/mPEG active ester is dissolved among the DMF, and 0～5 ℃ drips amino acid whose NaHCO
3Solution rises to room temperature naturally, and reaction finishes, and uses diluted hydrochloric acid dissolution, dichloromethane extraction, and the merging organic phase, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters, and concentrates, and the anhydrous diethyl ether recrystallization gets the PEG/mPEG chemical modifier.
The present invention also provides a kind of purposes of above-mentioned PEG/mPEG chemical modifier; Promptly prepare water-soluble diphenylethylene compounds prodrug; Wherein diphenylethylene compounds can be trans-resveratrol, benzene alkene a kind of in moral, oxidized resveratrol, red sandalwood Stilbene, the white skin China fir alcohol not, and their structural formula is respectively suc as formula (I)～formula V:
The preparation method of these several kinds of compound prodrugs carries out according to the following steps order:
1. the PEG/mPEG chemical modifier is dissolved in the methylene dichloride;
2. 0～5 ℃ of DMF solution that adds DCC, DMAP and diphenylethylene compounds rises to room temperature reaction;
3. reaction finishes, and the HAc solution solution of adding 10% is with the DCC of decomposing excessive;
4. organic phase is told in Hydrogen chloride washing, and the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters, and concentrates, and the Virahol recrystallization gets the diphenyl ethene compounds prodrug.
The molecular weight of used water-soluble carrier PEG or mPEG is 2000-75000 among the present invention.
Compared with prior art; The technical progress that the present invention obtained is: on the basis of original 201010199655.8 patented claims; The amino acid that is connected on the PEG/mPEG chemical modifier 4 kinds have been increased; Expand to 12 kinds,, then 4 seed amino acids that do not relate in the Chinese patent 201010199655.8 are applied to the new trans-resveratrol prodrug of modification acquisition of trans-resveratrol comprising 8 seed amino acids of needed by human; With whole 12 kinds of modifiers be used for other diphenylethylene compounds such as red sandalwood Stilbene, white skin China fir alcohol, oxidized resveratrol and benzene alkene not moral (3,5-dihydroxyl-4-isopropyl toluylene) prepare prodrug separately respectively.The prodrug of diphenylethylene compounds involved in the present invention is the new compound molecule, is respectively:
(1) prodrug of trans-resveratrol: PEG (mPEG)-connecting arm-Histidine-trans-resveratrol, PEG (mPEG)-connecting arm-methionine(Met)-trans-resveratrol, PEG (mPEG)-connecting arm-Methionin-trans-resveratrol, PEG (mPEG)-connecting arm-Threonine-trans-resveratrol;
(2) prodrug of red sandalwood Stilbene: PEG (mPEG)-connecting arm-glycocoll-red sandalwood Stilbene; PEG (mPEG)-connecting arm-methionine(Met)-red sandalwood Stilbene; PEG (mPEG)-connecting arm-L-Ala-red sandalwood Stilbene; PEG (mPEG)-connecting arm-proline(Pro)-red sandalwood Stilbene; PEG (mPEG)-connecting arm-Xie Ansuan-red sandalwood Stilbene; PEG (mPEG)-connecting arm-phenylalanine(Phe)-red sandalwood Stilbene; PEG (mPEG)-connecting arm-Isoleucine-red sandalwood Stilbene; PEG (mPEG)-connecting arm-Histidine-red sandalwood Stilbene; PEG (mPEG)-connecting arm-Methionin-red sandalwood Stilbene; PEG (mPEG)-connecting arm-tryptophane-red sandalwood Stilbene; PEG (mPEG)-connecting arm-Threonine-red sandalwood Stilbene;
(3) prodrug of oxidized resveratrol: PEG (mPEG)-connecting arm-glycocoll-oxidized resveratrol; PEG (mPEG)-connecting arm-L-Ala-oxidized resveratrol; PEG (mPEG)-connecting arm-proline(Pro)-oxidized resveratrol; PEG (mPEG)-connecting arm-Xie Ansuan-oxidized resveratrol; PEG (mPEG)-connecting arm-methionine(Met)-oxidized resveratrol; PEG (mPEG)-connecting arm-phenylalanine(Phe)-oxidized resveratrol; PEG (mPEG)-connect arm-Isoleucine-oxidized resveratrol; PEG (mPEG)-connecting arm-Histidine-oxidized resveratrol; PEG (mPEG)-connecting arm-Methionin-oxidized resveratrol; PEG (mPEG)-connecting arm-tryptophane-oxidized resveratrol; PEG (mPEG)-connecting arm-Threonine-oxidized resveratrol;
(4) prodrug of white skin China fir alcohol: PEG (mPEG)-connecting arm-glycocoll-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-L-Ala-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-proline(Pro)-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-Xie Ansuan-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-methionine(Met)-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-phenylalanine(Phe)-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-Isoleucine-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-Histidine-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-Methionin-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-tryptophane-Bai Pi China fir alcohol; PEG (mPEG)-connecting arm-Threonine-Bai Pi China fir alcohol;
(5) the benzene alkene prodrug of moral: PEG (mPEG)-connecting arm-glycocoll-benzene alkene moral not; PEG (mPEG)-connecting arm-L-Ala-benzene alkene is moral not; PEG (mPEG)-connecting arm-proline(Pro)-benzene alkene is moral not; PEG (mPEG)-connecting arm-Xie Ansuan-benzene alkene is moral not; PEG (mPEG)-connecting arm-methionine(Met)-benzene alkene is moral not; PEG (mPEG)-connecting arm-phenylalanine(Phe)-benzene alkene is moral not; PEG (mPEG)-connecting arm-Isoleucine-benzene alkene is moral not; PEG (mPEG)-connecting arm-Histidine-benzene alkene is moral not; PEG (mPEG)-connecting arm-Methionin-benzene alkene is moral not; PEG (mPEG)-connecting arm-tryptophane-benzene alkene is moral not; PEG (mPEG)-connecting arm-Threonine-benzene alkene is moral not.
The preparation method of PEG involved in the present invention, mPEG modifier is simple; After being used for modifying (comprising drug molecule); Improved the water-soluble and stable of drug molecule (compound molecule); And make it when decomposing, discharge the amino acid of needed by human body, the compound range of application after the modification is more extensive.After prodrug gets in the human body; Can discharge the amino acid that needed by human body is wanted when discharging diphenylethylene compounds in vivo; Replenish when adding human body when diphenylethylene compounds uses as medicine or healthcare products, discharge the amino acid of a great deal of simultaneously, be of value to HUMAN HEALTH.The present invention is applicable to the prodrug of preparation diphenylethylene compounds, and prepared prodrug is used for prevention and treatment of diseases such as fungi, eczema, arteriosclerosis, coronary heart disease, viral hepatitis, AIDS, cancer further.
The present invention below will combine specific embodiment to do further explain.
Embodiment
Below each embodiment be a kind of preparation method of water-soluble diphenylethylene compounds prodrug, they only are used to explain the present invention, are not to qualification of the present invention.
The preparation method of embodiment 1 PEG2000-succinyl-Methionin-trans-resveratrol prodrug
Present embodiment may further comprise the steps:
1. the preparation of PEG2000 carboxylic acid derivative
Reaction formula is following:
Get dry PEG20 g (10 mmol), be dissolved in the 80 mL chloroforms, add Succinic anhydried 2.5 g (25 mmol), stir, add 2 mL pyridines (Py), be heated to backflow, react 36 h, steaming desolventizes, and resistates is with the saturated NaHCO of 60 mL
3The solution dissolving, ethyl acetate extraction (20 mL * 3), water is cooled to 0～5 ℃; Transfer pH2～3 with 1 mol/L hydrochloric acid, stir dichloromethane extraction (20 mL * 4) behind 20 min, merge organic phase; The saturated aqueous common salt water washing is neutral, anhydrous sodium sulfate drying, concentrating under reduced pressure; The anhydrous diethyl ether recrystallization gets white solid PEG2000-Succinic Acid 18.04 g, yield 82.0%;
2. the PEG2000 active ester is synthetic
Reaction formula is following:
Get 3 g (1.36 mmol) PEG2000-Succinic Acid and dissolve, be cooled to 0～5 ℃, add the DMF solution (0.32 gNHS is dissolved among 10 mLDMF) of the NHS of 0.56 g (2.73 mmol) DCC and precooling, room temperature reaction 24 h with 25 mL methylene dichloride; Reaction finishes, and removes by filter the NSC 30023 that reaction generates, and in filtrating, adds the HAc solution of 10 mL10% then, stirring at room 30 min; To remove the intact DCC of unreacted, tell organic phase, the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying filters, and concentrates; The anhydrous diethyl ether recrystallization gets PEG2000 active ester 3.13 g, yield 96.0%;
3. make the PEG2000 chemical modifier
Reaction formula is following:
PEG2000 active ester 2 g (0.835 mmol) are dissolved among 20 mLDMF, are cooled to 0～5 ℃ then, drip the NaHCO of Methionin
3(0.49 g Methionin is dissolved in the NaHCO of 5 mL1 mol/L to solution
3In the solution), room temperature reaction 24 h, reaction finishes, with 1 mol/L dissolving with hydrochloric acid, dichloromethane extraction (10 mL * 3); Merge organic layer, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets PEG2000 chemical modifier 1.23 g, yield 60%;
4. the preparation of PEG2000-succinyl-Methionin-trans-resveratrol prodrug
Reaction formula is following:
Get product 0.5 g (0.20 mmol) of step in 3. and be dissolved in the 15 mL methylene dichloride, reduce to 0～5 ℃, add DMF solution (0.14 g trans-resveratrol is dissolved among 5 mLDMF), DCC0.15 g (0.73 mmol), the DMAP0.09g (0.74 mmol) of trans-resveratrol; Room temperature reaction 24 h remove by filter the NSC 30023 that reaction generates, and add 2% hydrochloric acid accent pH3; The DCC of solution decomposing excessive that adds the HAc of 20 mL10%, methylene dichloride (10 mL * 3) aqueous phase extracted merges organic layer; The saturated common salt water washing is to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure; The Virahol recrystallization gets trans-resveratrol prodrug 0.29 g, yield 50%.
Present embodiment also replaces Methionin to prepare the trans-resveratrol prodrug, their preparation similar process with Histidine, methionine(Met), Threonine respectively.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares the trans-resveratrol prodrug with aforementioned used PEG2000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
The preparation method of embodiment 2 PEG2000-succinyl-L-Ala-oxidized resveratrol prodrug
The concrete operations step is following:
1. identical among the preparation method of PEG2000 carboxylic acid derivative, PEG2000 active ester and the embodiment 1;
2. connect the preparation of the PEG2000 chemical modifier of L-Ala
Reaction equation:
PEG2000 active ester 2 g (0.835 mmol) are dissolved among 20 mLDMF, are cooled to 0～5 ℃ then, drip the NaHCO of L-Ala
3(0.30 g L-Ala is dissolved in the NaHCO of 3 mL1 mol/L to solution
3In the solution), room temperature reaction 24 h, reaction finishes, with 1 mol/L dissolving with hydrochloric acid, dichloromethane extraction (10 mL * 3); Merge organic layer, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets PEG2000 chemical modifier 1.21 g, yield 62%;
3. the preparation of PEG2000-Succinic Acid-L-Ala-oxidized resveratrol prodrug
Reaction equation is following:
Get product 0.5 g (0.21 mmol) of step in 2. and be dissolved in the 15 mL methylene dichloride, stir and make its dissolving, temperature reduce to 0～5 ℃; The DMF solution (0.14 g oxidized resveratrol is dissolved among 5 mLDMF), DCC0.15 g (0.73 mmol), the DMAP0.09g (0.74 mmol) that add oxidized resveratrol, room temperature reaction 24 h remove by filter the NSC 30023 that reaction generates; Add 2% hydrochloric acid accent pH3, dichloromethane extraction (10 mL * 3) merges organic layer; The saturated common salt water washing is to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure; The Virahol recrystallization gets oxidized resveratrol prodrug 0.29 g, yield 50%.
Present embodiment also replaces L-Ala to prepare the oxidized resveratrol prodrug, their preparation similar process with glycocoll, proline(Pro), Xie Ansuan, methionine(Met), phenylalanine(Phe), Isoleucine, leucine, tryptophane, Histidine, Methionin, Threonine respectively.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares the oxidized resveratrol prodrug with aforementioned used PEG2000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
The preparation method of embodiment 3 PEG6000-succinyl-glycocoll-red sandalwood Stilbene prodrug
1. the preparation of PEG6000 carboxylic acid derivative
Get the dry PEG6000 of 30 g (0.005 mol) and be dissolved in the 100 mL chloroforms, add Succinic anhydried 1.5 g (0.015 mol), stir, add 2 mL pyridines (Py), be heated to backflow, react 36 h, steaming desolventizes, and resistates is with the saturated NaHCO of 80 mL
3The solution dissolving, ethyl acetate extraction (20 mL * 3), water is cooled to 0～5 ℃; Transfer pH2～3 with 1 mol/L hydrochloric acid, stir dichloromethane extraction (20 mL * 4) behind 20 min, merge organic phase; The saturated aqueous common salt water washing is to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure; The anhydrous diethyl ether recrystallization gets white solid PEG6000-Succinic Acid 26.04 g, yield 84.0%;
2.Synthesizing of PEG6000 active ester
Get 5 g (0.81 mmol) PEG6000-Succinic Acid and dissolve, be cooled to 0～5 ℃, add the DMF solution (0.18 gNHS is dissolved among 10 mLDMF) of the NHS of 0.33 g (1.6 mmol) DCC and precooling, rise to room temperature reaction 24 h with 45 mL methylene dichloride; Reaction finishes, and removes by filter the NSC 30023 that reaction generates, and in filtrating, adds the HAc solution of 20 mL10% then, stirring at room 30 min; To remove the intact DCC of unreacted, tell organic phase, the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying filters, and concentrates; The anhydrous diethyl ether recrystallization gets PEG6000 active ester 4.92 g, yield 95.0%;
3. be connected with the preparation of the PEG6000 chemical modifier of glycocoll
PEG6000 active ester 3.0 g (0.47 mmol) are dissolved among 25 mLDMF, are cooled to 0～5 ℃, drip the NaHCO of glycocoll
3(0.14 g glycocoll is dissolved in the NaHCO of 5 mL1 mol/L to solution
3In the solution), room temperature reaction 24 h, reaction finishes, with 1 mol/L dissolving with hydrochloric acid, dichloromethane extraction (15 mL * 3); Merge organic layer, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets PEG6000 chemical modifier 1.84 g, yield 62%;
4. be connected with the preparation of the PEG6000-succinyl-glycocoll-red sandalwood Stilbene prodrug of glycocoll
Get step 3. in PEG6000 chemical modifier 0.5 g (0.079 mmol) of gained be dissolved in the 15 mL methylene dichloride, be cooled to 0～5 ℃, add DMF solution (0.06 g is dissolved in the 5 mLDMF solution), DCC 0.06 g (0.29 mmol), DMAP 0.03 g (0.25 mmol) of red sandalwood Stilbene; Room temperature reaction 24 h remove by filter the NSC 30023 that reaction generates, and add 2% hydrochloric acid accent pH3; Dichloromethane extraction (10 mL * 3) merges organic layer, and the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying, concentrating under reduced pressure, Virahol recrystallization; Get red sandalwood Stilbene prodrug 0.28 g, yield 53%.
Present embodiment also replaces glycocoll to prepare red sandalwood Stilbene prodrug, their preparation similar process with L-Ala, proline(Pro), Xie Ansuan, methionine(Met), phenylalanine(Phe), Isoleucine, leucine, tryptophane, Histidine, Methionin, Threonine respectively.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares red sandalwood Stilbene prodrug with aforementioned used PEG6000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
The preparation method of embodiment 4 PEG6000-succinyl-proline(Pro)-Bai Pi China fir alcohol prodrug
1. method is identical in the PEG6000 carboxylic acid derivative, the preparation method of PEG6000 active ester and embodiment 3;
2. be connected with the preparation of the PEG6000 modifier of proline(Pro)
PEG6000 active ester 3 g (0.47 mmol) are dissolved among 25 mLDMF, are cooled to 0～5 ℃, drip the NaHCO of proline(Pro)
3(0.22 g proline(Pro) is dissolved in 5 mL1 mol/L NaHCO to solution
3In the solution), room temperature reaction 24 h, reaction finishes, with 1 mol/L dissolving with hydrochloric acid, dichloromethane extraction (15 mL * 3); Merge organic layer, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets PEG6000 chemical modifier 1.95 g, yield 65%;
3. the preparation of PEG6000-succinyl-proline(Pro)-Bai Pi China fir alcohol prodrug
Get step 2. in PEG6000 chemical modifier 0.5 g (0.078 mmol) of gained be dissolved in the 15 mL methylene dichloride, be cooled to 0～5 ℃, add DMF solution (the white skin China fir of 0.05 g alcohol is dissolved in the 5 mLDMF solution), DCC 0.06 g (0.29 mmol), DMAP 0.03 g (0.25 mmol) of white skin China fir alcohol; Room temperature reaction 24 h remove by filter the NSC 30023 that reaction generates, and add 2% hydrochloric acid accent pH3; Dichloromethane extraction (10 mL * 3) merges organic layer, and the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying, concentrating under reduced pressure, Virahol recrystallization; De Baipi China fir alcohol prodrug 0.27 g, yield 51%.
Present embodiment also replaces proline(Pro) to prepare white skin China fir alcohol prodrug with glycocoll, L-Ala, Xie Ansuan, phenylalanine(Phe), methionine(Met), Isoleucine, leucine, tryptophane, Histidine, Methionin, Threonine respectively, and their preparation method is similar.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares white skin China fir alcohol prodrug with aforementioned used PEG6000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
Embodiment 5 PEG6000-succinyl-leucines-benzene alkene is the preparation method of moral prodrug not
Present embodiment concrete operations step is following:
1. method is identical in the PEG6000 carboxylic acid derivative, the preparation method of PEG6000 active ester and embodiment 3;
2. be connected with the preparation of leucic PEG6000 modifier
PEG6000 active ester 3 g (0.47 mmol) are dissolved among 25 mLDMF, are cooled to 0～5 ℃, drip leucic NaHCO
3(0.25 g leucine is dissolved in 15 mL1 mol/L NaHCO to solution
3In the solution), room temperature reaction 24 h, reaction finishes, with 1 mol/L dissolving with hydrochloric acid, dichloromethane extraction (20 mL * 3); Merge organic layer, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets PEG6000 chemical modifier 1.93 g, yield 64%;
3. the not preparation of moral prodrug of PEG6000-succinyl-leucine-benzene alkene
Get step 2. in PEG6000 chemical modifier 0.5 g (0.078 mmol) of gained be dissolved in the 15 mL methylene dichloride, be cooled to 0～5 ℃, add benzene alkene not the DMF solution of moral (0.06 g benzene alkene not moral is dissolved in the 5 mLDMF solution), DCC 0.06 g (0.29 mmol), DMAP 0.03 g (0.25 mmol); Room temperature reaction 24 h remove by filter the NSC 30023 that reaction generates, and add 2% hydrochloric acid accent pH3; Dichloromethane extraction (10 mL * 3) merges organic layer, and the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying; Concentrating under reduced pressure, Virahol recrystallization De Baipi China fir alcohol prodrug 0.26 g, yield 49%.
Present embodiment also will be respectively being that glycocoll, L-Ala, proline(Pro), methionine(Met), Xie Ansuan, phenylalanine(Phe), Isoleucine, tryptophane, Histidine, Methionin, Threonine replace leucine to prepare not moral prodrug of benzene alkene, their preparation similar process.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares not moral prodrug of benzene alkene with aforementioned used PEG6000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
The preparation method of embodiment 6 PEG2000-ethanoyl-Threonines-red sandalwood Stilbene prodrug
1. the preparation of PEG2000 carboxylic acid derivative
Reaction formula is following:
Get the dry PEG2000 of 30 g (0.015 mol) and be dissolved in the 300 mL toluene, steam to remove 60 mL toluene, reduce to room temperature naturally after; Add the t-butanol solution (5.21 g potassium tert.-butoxides are dissolved in the 30 mL trimethyl carbinols) of potassium tert.-butoxide, stir 1 h, add 27.05 g METHYL BROMOACETATEs; Back flow reaction 24 h after reaction finishes, filter; Filtrate decompression is steamed and is removed the intact raw material of the trimethyl carbinol, toluene and unreacted, and resistates dissolves with methylene dichloride, the anhydrous diethyl ether recrystallization; Get PEG2000-ETHYLE ACETATE 30.46 g, yield 93.5%;
With 50 mL dissolved in distilled water, 0.1 mol/LNaOH solution is transferred pH10 with above-mentioned PEG2000-ETHYLE ACETATE, and under the frozen water cooling, the oxalic acid solution with 1% is transferred system pH2～3; Stirring at room 20 min, dichloromethane extraction (20 mL * 3) merges organic phase; The saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying concentrates; Residue is used the anhydrous diethyl ether recrystallization, gets PEG2000-acetate 26.92 g, yield 90.7%;
2. the PEG2000 active ester is synthetic
Reaction formula is following:
Get 20.76 g (9.81 mmol) PEG2000-acetate and dissolve with 50 mL methylene dichloride, add the DMF solution (2.41 gNHS are dissolved among the 20mLDMF) of the NHS of 4.10 g (19.92 mmol) DCC and precooling under 0～5 ℃ of condition, rise to room temperature reaction 24 h naturally, reaction finishes; Remove by filter the NSC 30023 that reaction generates, in filtrating, add the HAc solution of 100 mL10% then, stirring at room 30 min; To remove the intact DCC of unreacted, tell organic phase, the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying filters, and concentrates; The anhydrous diethyl ether recrystallization gets PEG2000 active ester 16.71 g, yield 73.73%;
3. be connected with PEG2000 chemical modifier synthetic of Threonine
Reaction formula is following:
PEG2000 active ester 6 g (2.6 mmol) are dissolved among 60 mLDMF, and stirring makes its dissolving, temperature reduce to 0～5 ℃, drips the NaHCO of Threonine
3(1.24 g Threonines are dissolved in the NaHCO of 20 mL1 mol/L to solution
3In the solution), rise to room temperature reaction 24 h, reaction finishes, with the dissolving with hydrochloric acid of 1 mol/L; Dichloromethane extraction (20 mL * 3) merges organic layer, and the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying filters, and concentrates; The anhydrous diethyl ether recrystallization gets PEG2000 chemical modifier 3.62 g, yield 60%;
4. be connected with the preparation of the red sandalwood Stilbene prodrug of Threonine
Reaction formula is following:
Get PEG2000 chemical modifier 0.5 g (0.22 mmol) that is connected with Threonine and be dissolved in the 15 mL methylene dichloride, stirring makes its dissolving, temperature reduce to 0～5 ℃, adds the DMF solution (0.11 g red sandalwood Stilbene is dissolved among 5 mLDMF) of red sandalwood Stilbene; DCC0.09 g (0.44 mmol), DMAP0.05 g (0.44mmol) rise to room temperature reaction 24 h, add the DCC of the HAc solution decomposing excessive of 20 mL10%; Add 2% hydrochloric acid accent pH3, dichloromethane extraction (10 mL * 3) merges organic layer; The saturated common salt water washing is to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure; The Virahol recrystallization gets red sandalwood Stilbene prodrug 0.37 g, yield 60%.
Present embodiment also substitutes Threonine with glycocoll, L-Ala, proline(Pro), Xie Ansuan, methionine(Met), phenylalanine(Phe), Isoleucine, leucine, tryptophane, Histidine, Methionin respectively, has prepared red sandalwood Stilbene prodrug, their preparation similar process.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares red sandalwood Stilbene prodrug with aforementioned used PEG2000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
The preparation method of embodiment 7 mPEG2000-succinyl-Xie Ansuans-oxidized resveratrol prodrug
1. the preparation of mPEG2000 carboxylic acid derivative
Reaction formula is following:
Get the dry mPEG2000 of 20 g (10 mmol), be dissolved in the 80 mL chloroforms, add Succinic anhydried 1.5 g (15 mmol), stir, add 1 mL pyridine (Py), be heated to backflow, react 36 h, steaming desolventizes, and resistates is with the saturated NaHCO of 60 mL
3The solution dissolving, ethyl acetate extraction (20 mL * 3), water is cooled to 0～5 ℃; Transfer pH2～3 with 1 mol/L hydrochloric acid, stir dichloromethane extraction (20 mL * 4) behind 20 min, merge organic phase; The saturated aqueous common salt water washing is neutral, anhydrous sodium sulfate drying, concentrating under reduced pressure; The anhydrous diethyl ether recrystallization gets white solid mPEG2000-Succinic Acid 17.22 g, yield 82.0%;
2. the mPEG2000 active ester is synthetic
Reaction formula is following:
Get 3 g (1.43 mmol) mPEG2000-Succinic Acid and dissolve, be cooled to 0～5 ℃, add the DMF solution (0.32 gNHS is dissolved among 10 mLDMF) of the NHS of 0.56 g (2.72 mmol) DCC and precooling, reaction 24 h under the room temperature with 25 mL methylene dichloride; Reaction finishes, and removes by filter the NSC 30023 that reaction generates, and in filtrating, adds the HAc solution of 50 mL10% then; Stirring at room 30 min to remove the intact DCC of unreacted, tell organic phase; The saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets mPEG active ester 2.95 g, yield 94.0%;
3. make the mPEG2000 chemical modifier by Xie Ansuan
MPEG2000 active ester 2 g (0.91 mmol) are dissolved among 20 mLDMF, are cooled to 0～5 ℃ then, drip the NaHCO of Xie Ansuan
3(0.21 g Xie Ansuan is dissolved in the NaHCO of 10 mL1 mol/L to solution
3In the solution), room temperature reaction 24 h, reaction finishes, with 1 mol/L dissolving with hydrochloric acid, dichloromethane extraction (10 mL * 3); Merge organic layer, the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets mPEG chemical modifier 1.22 g, yield 61%;
4. the preparation of mPEG2000-succinyl-Xie Ansuan-oxidized resveratrol prodrug
Reaction formula is following:
Get product 0.5 g (0.23 mmol) of step in 3. and be dissolved in the 15 mL methylene dichloride, stir and make its dissolving, temperature reduce to 0～5 ℃; The DMF solution (0.14 g oxidized resveratrol is dissolved among 5 mLDMF), DCC0.15 g (0.73 mmol), the DMAP0.09g (0.74 mmol) that add oxidized resveratrol, room temperature reaction 24 h remove by filter the NSC 30023 that reaction generates; Add 2% hydrochloric acid and transfer pH3, add the DCC of solution decomposing excessive of the HAc of 20 mL10%, dichloromethane extraction (10 mL * 3); Merge organic layer, the saturated common salt water washing is to neutrality, anhydrous sodium sulfate drying; Concentrating under reduced pressure; The Virahol recrystallization gets oxidized resveratrol prodrug 0.27 g, yield 49%.
Present embodiment also replaces Xie Ansuan to prepare the oxidized resveratrol prodrug, their preparation similar process with glycocoll, L-Ala, proline(Pro), methionine(Met), phenylalanine(Phe), Isoleucine, leucine, tryptophane, Histidine, Methionin, Threonine respectively.
In addition; Since PEG/mPEG during as pharmaceutical carrier the most frequently used molecular weight be 2000-75000; Present embodiment is that the PEG/mPEG of 2000-75000 scopes substitutes and prepares the oxidized resveratrol prodrug with aforementioned used mPEG2000 with molecular weight also; This change does not have influence to preparation method and process, need change its charging capacity when just the molecular weight of carrier changes, and has realized goal of the invention equally.
Claims (8)
1. the preparation method of a water-soluble diphenylethylene compounds prodrug promptly modifies the method that diphenylethylene compounds prepares prodrug with PEG, mPEG chemical modifier,
It is characterized in that:The general formula of molecular structure of said prodrug is following:
R
3 Be trans-resveratrol, benzene alkene a kind of in moral, oxidized resveratrol, red sandalwood Stilbene or the white skin China fir alcohol not;
R
2 A kind of in methionine(Met), Histidine, Methionin, Threonine, glycocoll, L-Ala, proline(Pro), Xie Ansuan, phenylalanine(Phe), Isoleucine, leucine or the tryptophane;
Particularly:
Work as R
3 During for trans-resveratrol, R
2 A kind of in Histidine, methionine(Met), Methionin or the Threonine;
Work as R
3 Be benzene alkene not during a kind of in moral, oxidized resveratrol, red sandalwood Stilbene or the white skin China fir alcohol, R
2 A kind of in glycocoll, L-Ala, proline(Pro), Xie Ansuan, phenylalanine(Phe), Isoleucine, leucine, tryptophane, methionine(Met), Histidine, Methionin or the Threonine.
2. the preparation method of water-soluble diphenylethylene compounds prodrug according to claim 1,
It is characterized in that:Said chemical modifier is to be carrier with water miscible PEG or mPEG; With the succinyl is connecting arm; With make after amino acid is connected; The carboxylic acid derivative that specifically obtains PEG or mPEG with PEG or mPEG and Succinic anhydried reaction is PEG-Succinic Acid or mPEG-Succinic Acid, is connected with amino acid to make again.
3. the preparation method of water miscible diphenylethylene compounds prodrug according to claim 2,
It is characterized in that:The preparation method of PEG-Succinic Acid or mPEG-Succinic Acid carries out according to the following steps order:
1. PEG or mPEG, Succinic anhydried, chloroform and pyridine reflux;
2. remove chloroform under reduced pressure, saturated NaHCO
3Solution is transferred pH7, ethyl acetate extraction, and Hydrogen chloride is transferred pH2～3;
3. dichloromethane extraction merges organic phase, and drying is filtered, and filtrate decompression concentrates, and enriched material gets PEG-Succinic Acid or mPEG-Succinic Acid with the anhydrous diethyl ether recrystallization.
4. the preparation method of water-soluble diphenylethylene compounds prodrug according to claim 1,
It is characterized in that:Said chemical modifier is to be carrier with water miscible PEG or mPEG; With the ethanoyl is connecting arm; With make after amino acid is connected; The carboxylic acid derivative that specifically obtains PEG or mPEG with a kind of reaction in PEG or mPEG and METHYL BROMOACETATE, bromide isobutyl acetate or the bromo-acetic acid tert-butyl is PEG-acetate or mPEG-acetate, is connected with amino acid to make again.
5. the preparation method of water-soluble diphenylethylene compounds prodrug according to claim 4,
It is characterized in that:The preparation method of said PEG-acetate or mPEG-acetate carries out according to the following steps order:
1. room temperature is dissolved in PEG or mPEG in the dry toluene, adds the t-butanol solution of potassium tert.-butoxide;
2. add a kind of in METHYL BROMOACETATE, bromide isobutyl acetate or the bromo-acetic acid tert-butyl, reflux;
3. after reaction finishes, filter, filtrate decompression is steamed and is removed the intact raw material of the trimethyl carbinol, toluene and unreacted, and resistates dissolves with methylene dichloride, and the anhydrous diethyl ether recrystallization gets PEG or mPEG carboxylicesters;
4. above-mentioned carboxylicesters is dissolved in the zero(ppm) water, transfers pH10, stir 30min with NaOH solution;
5. under the frozen water cooling, transfer system pH2～3, stirring at room 20 min with oxalic acid solution; Dichloromethane extraction merges organic phase, and the saturated common salt water washing is to neutral; Anhydrous sodium sulfate drying removes methylene dichloride under reduced pressure, and residue gets PEG-acetate or mPEG-acetate with the anhydrous diethyl ether recrystallization.
6. according to the preparation method of each described water-soluble diphenylethylene compounds prodrug among the claim 2-5,
It is characterized in that:Being connected the method for preparing said chemical modifier with amino acid by the carboxylic acid derivative of PEG or mPEG carries out according to following steps:
1. PEG active ester or mPEG active ester is synthetic
The carboxylic acid derivative of PEG or mPEG is dissolved in the methylene dichloride 0～5 ℃ of N that adds the N-hydroxy-succinamide (NHS) of DCC (NSC 57182) and precooling, dinethylformamide (DMF) solution; Naturally rise to room temperature, reaction finishes, the NSC 30023 that the filtering reaction generates; The HAc solution of adding 10% in filtrating to remove unreacted DCC, is told organic phase then; The saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters; Concentrate, the anhydrous diethyl ether recrystallization gets PEG or mPEG active ester;
2. the preparation of PEG, mPEG chemical modifier
PEG or mPEG active ester are dissolved among the DMF, and 0～5 ℃ drips amino acid whose NaHCO
3Solution rises to room temperature naturally, and reaction finishes, and uses diluted hydrochloric acid dissolution, and dichloromethane extraction merges organic phase, and the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters, and concentrates, and the anhydrous diethyl ether recrystallization gets title product PEG or mPEG chemical modifier.
7. according to the preparation method of each described water miscible diphenylethylene compounds prodrug among the claim 2-6,
It is characterized in that:The preparation method of water-soluble diphenylethylene compounds prodrug links to each other with diphenyl ethene compounds PEG, mPEG chemical modifier through ester bond, prepare water-soluble diphenylethylene compounds prodrug, carries out according to the following steps order:
1. PEG, mPEG chemical modifier are dissolved in the methylene dichloride;
0～5 ℃ of DMF solution that adds DCC, DMAP and diphenyl ethene compounds rises to room temperature reaction;
3. reaction finishes, and the HAc solution solution of adding 10% is with the DCC of decomposing excessive;
4. organic phase is told in Hydrogen chloride washing, and the saturated common salt water washing is to neutral, and anhydrous sodium sulfate drying filters, and concentrates, and the Virahol recrystallization gets the diphenyl ethene compounds prodrug.
8. the preparation method of water-soluble diphenyl ethene compounds prodrug according to claim 7,
It is characterized in that:In said PEG, the mPEG chemical modifier, the molecular weight of PEG, mPEG is 2000～75000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101421292A CN102321239B (en) | 2011-05-30 | 2011-05-30 | Preparation method of water-soluble toluylene compound prodrugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101421292A CN102321239B (en) | 2011-05-30 | 2011-05-30 | Preparation method of water-soluble toluylene compound prodrugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102321239A true CN102321239A (en) | 2012-01-18 |
| CN102321239B CN102321239B (en) | 2013-12-11 |
Family
ID=45449086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101421292A Expired - Fee Related CN102321239B (en) | 2011-05-30 | 2011-05-30 | Preparation method of water-soluble toluylene compound prodrugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102321239B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408748A (en) * | 2013-08-13 | 2013-11-27 | 张家港威胜生物医药有限公司 | Synthetic method of water-soluble pterostilbene derivative |
| CN107184990A (en) * | 2017-06-05 | 2017-09-22 | 北京林业大学 | A kind of preparation method of antibody coupling medicine-carried nano particles |
| CN108164419A (en) * | 2017-12-25 | 2018-06-15 | 武汉大学 | The preparation and application of the propofol prodrugs of monodisperse poly glycol monomethyl ether modification |
| WO2019091384A1 (en) * | 2017-11-08 | 2019-05-16 | Yafei Shanghai Biolog Medicine Science & Technology Co., Ltd. | Conjugates of biomolecule and use thereof |
| CN112194788A (en) * | 2020-09-15 | 2021-01-08 | 石家庄学院 | Water-soluble florfenicol and preparation method thereof |
| US11225551B2 (en) | 2018-02-13 | 2022-01-18 | Selection Bioscience Llc | Amphiphilic block copolymer, preparation method thereof and nanomicelle drug-loading system |
| CN115232036A (en) * | 2022-07-21 | 2022-10-25 | 南通大学 | Stilbene polyphenol taurate, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870769A (en) * | 2010-06-13 | 2010-10-27 | 河北科技大学 | PEG (Polyethylene Glycol), mPEG (Methoxy Polyethylene Glycol) chemical modifier and method thereof for preparing water-soluble resveratrol prodrug |
-
2011
- 2011-05-30 CN CN2011101421292A patent/CN102321239B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870769A (en) * | 2010-06-13 | 2010-10-27 | 河北科技大学 | PEG (Polyethylene Glycol), mPEG (Methoxy Polyethylene Glycol) chemical modifier and method thereof for preparing water-soluble resveratrol prodrug |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408748A (en) * | 2013-08-13 | 2013-11-27 | 张家港威胜生物医药有限公司 | Synthetic method of water-soluble pterostilbene derivative |
| CN103408748B (en) * | 2013-08-13 | 2016-06-29 | 张家港威胜生物医药有限公司 | A kind of synthetic method of water-soluble pterostilbene derivative |
| CN107184990A (en) * | 2017-06-05 | 2017-09-22 | 北京林业大学 | A kind of preparation method of antibody coupling medicine-carried nano particles |
| WO2019091384A1 (en) * | 2017-11-08 | 2019-05-16 | Yafei Shanghai Biolog Medicine Science & Technology Co., Ltd. | Conjugates of biomolecule and use thereof |
| CN108164419A (en) * | 2017-12-25 | 2018-06-15 | 武汉大学 | The preparation and application of the propofol prodrugs of monodisperse poly glycol monomethyl ether modification |
| US11225551B2 (en) | 2018-02-13 | 2022-01-18 | Selection Bioscience Llc | Amphiphilic block copolymer, preparation method thereof and nanomicelle drug-loading system |
| CN112194788A (en) * | 2020-09-15 | 2021-01-08 | 石家庄学院 | Water-soluble florfenicol and preparation method thereof |
| CN112194788B (en) * | 2020-09-15 | 2022-08-02 | 石家庄学院 | Water-soluble florfenicol and preparation method thereof |
| CN115232036A (en) * | 2022-07-21 | 2022-10-25 | 南通大学 | Stilbene polyphenol taurate, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102321239B (en) | 2013-12-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102321239A (en) | Preparation method of water-soluble toluylene compound prodrugs | |
| CA2764043C (en) | Improved method for synthesizing pirfenidone | |
| CN102459198A (en) | Crystals | |
| HUE029261T2 (en) | Prodrugs of vitamine k | |
| GB2603382A (en) | Pyridine sulfonamide phosphate compound, preparation method therefor and application thereof | |
| CN103702973A (en) | Amino-propylene-glycol derivatives, preparation method and pharmaceutical composition and use thereof | |
| CN102225913B (en) | Rheinic acid derivatives and treatment application thereof | |
| CA2962725A1 (en) | Polyprenylated phloroglucinol compounds as potent p-glycoprotein inducers | |
| FI104892B (en) | Preparation process of diacetylrhein | |
| CN106750250B (en) | Polyethylene glycol oleanolic acid derivate using amino acid as linking arm and its preparation method and application | |
| CN109721579B (en) | 7, 8-dehydrograpevine derivatives, preparation method, pharmaceutical composition and use thereof | |
| CN104341450A (en) | Synthesis and pharmaceutical application of sulfamide derivative | |
| JP4467888B2 (en) | Aloe-emodin derivatives and their use in the treatment of neoplastic pathology | |
| KR20130135226A (en) | Composition comprising retinol, a precursor or a reaction product of it and a plant extract from at least one chamomilla plant for the treatment of cancer | |
| CN1934086B (en) | Amine salt of carbostyril derivative | |
| CN101524546B (en) | Conjugate conjugated from polyethylene glycol and curcumin derivative | |
| CN102391323A (en) | Tetrahydro-beta-carboline derivative, preparation method thereof and use thereof | |
| RU2566065C2 (en) | Garcinol and cyclodextrin complex and method of its application | |
| CN102225896B (en) | Ether derivatives of rhein and their therapeutic use | |
| CN102250342B (en) | PEG/mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, preparation method and application thereof in modification of toluylene compound | |
| CN108349872A (en) | The synthesis of terphenyl compounds | |
| CN1447799A (en) | Giphenyl derivatives and use thereof as integrin inhibitors | |
| CN105198849A (en) | Scutellarein amine derivative and preparation method and application thereof | |
| US5137921A (en) | Inhibitory agent of an increase in blood sugar level | |
| CN112920239B (en) | Preparation and application of alpha-glucosidase induced release NO donor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhang Yue Inventor after: Yu Yifeng Inventor after: Shi Xianxian Inventor after: Huang Daowei Inventor after: Du Hongxia Inventor after: Zhao Hua Inventor before: Zhang Yue Inventor before: Huang Daowei Inventor before: Du Hongxia Inventor before: Zhao Hua Inventor before: Geng Weijing |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: ZHANG YUE HUANG DAOWEI DU HONGXIA ZHAO HUA GENG WEIJING TO: ZHANG YUE YU YIFENG SHI XIANXIAN HUANG DAOWEI DU HONGXIA ZHAO HUA |
|
| C53 | Correction of patent of invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Yu Yifeng Inventor after: Xu Shixia Inventor after: Zhang Yue Inventor after: Song Haiwen Inventor after: Huang Daowei Inventor after: Du Hongxia Inventor after: Zhao Hua Inventor before: Zhang Yue Inventor before: Yu Yifeng Inventor before: Shi Xianxian Inventor before: Huang Daowei Inventor before: Du Hongxia Inventor before: Zhao Hua |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: ZHANG YUE YU YIFENG SHI XIANXIAN HUANG DAOWEI DU HONGXIA ZHAO HUA TO: YU YIFENG XU SHIXIA ZHANG YUE SONG HAIWEN HUANG DAOWEI DU HONGXIA ZHAO HUA |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20131211 Termination date: 20180530 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |