CN102250187B - Glycyrrhetinic acid derivate and preparation method thereof - Google Patents
Glycyrrhetinic acid derivate and preparation method thereof Download PDFInfo
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- CN102250187B CN102250187B CN 201110103482 CN201110103482A CN102250187B CN 102250187 B CN102250187 B CN 102250187B CN 201110103482 CN201110103482 CN 201110103482 CN 201110103482 A CN201110103482 A CN 201110103482A CN 102250187 B CN102250187 B CN 102250187B
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- glycyrrhetinic acid
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- enoxolone derivative
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title claims abstract description 72
- 229960003720 enoxolone Drugs 0.000 title claims abstract description 45
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims abstract description 10
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 41
- 150000002342 glycyrrhetinic acids Chemical class 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 11
- -1 palmitinic acid phosphatidylethanolamines Chemical class 0.000 claims description 11
- 229940067605 phosphatidylethanolamines Drugs 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000005466 alkylenyl group Chemical group 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical group CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 5
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 241000219198 Brassica Species 0.000 claims description 4
- 235000003351 Brassica cretica Nutrition 0.000 claims description 4
- 235000003343 Brassica rupestris Nutrition 0.000 claims description 4
- 235000010460 mustard Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 208000006454 hepatitis Diseases 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 229940079593 drug Drugs 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003699 antiulcer agent Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical group C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- ZLGYVWRJIZPQMM-HHHXNRCGSA-N 2-azaniumylethyl [(2r)-2,3-di(dodecanoyloxy)propyl] phosphate Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCC ZLGYVWRJIZPQMM-HHHXNRCGSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101710142246 External core antigen Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- SPPIIOPGDLITJE-VLQRKCJKSA-N diazanium;(2s,3s,4s,5r,6s)-6-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-5-[(2r,3r,4s,5s,6s)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]oxy-3,4-dihy Chemical compound N.N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O SPPIIOPGDLITJE-VLQRKCJKSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002047 solid lipid nanoparticle Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229930182493 triterpene saponin Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a glycyrrhetinic acid derivate shown in formula (I). In formula (I), R1 and R2 are C9-21 alkyl or alkenyl, and R1 and R2 can be the same or different. The preparation method comprises the following step: reacting glycyrrhetinic acid and phosphatidyl ethanolamine at 0-100 DEG C for 1-10 hours in an organic solvent in the presence of dicyclohexylcarbodiimide and p-dimethylaminopyridine. Compared with glycyrrhetinic acid, the prepared glycyrrhetinic acid derivate (the compound shown in formula (I)) has obviously-enhanced anti-hepatitis activity. Formula (I) is shown in the specification.
Description
Technical field
The present invention relates to derivative of a kind of glycyrrhetinic acid and preparation method thereof.
Background technology
Glycyrrhetinic acid (Glycyrrhetinic acid) has another name called glycyrrhetinic acid, is the product that the saccharic acid chain is sloughed in the hydrolysis of triterpene saponin Potenlini in the Radix Glycyrrhizae.Glycyrrhetinic acid is that Potenlini is (such as monoammonium glycyrrhizinate, diammonium glycyrrhizinate) activeconstituents behind the internal metabolism, glycyrrhetinic acid has antiulcer agent, antibiotic, antitumor, anti-hepatitis, the effect such as reducing blood-fat and the HIV (human immunodeficiency virus)-resistant activity [honor of passing away, Zhao Jie, Liu Lin etc. the Study prospects of glycyrrhetinic acid. the journal .2005 of University Of Dalian, 26 (4): 85-88].Glycyrrhetinic acid has been obtained breakthrough research in the applied research for the treatment of hepatic disease, by improving hepatocellular adsorptive power is reached the effect that protects the liver, and has the effect that suppresses liver cancer.
The glycyrrhetinic acid structural formula is as follows:
Glycyrrhetinic acid is water-soluble hardly, mainly reduces its toxic side effect and increases its solubleness in water by glycyrrhetinic acid being carried out structural modification in the prior art.To the modification of glycyrrhetinic acid mainly for 3 hydroxyl or 30 s' carboxyl or simultaneously both are modified.
Modification to 30 carboxyls mainly concentrates on introducing metal ion salify, becomes ester, becomes acid amides with various amine or amino acid, becomes sugar ester with sugared aglucon with various alcohol, to obtain active higher compound.As S.Rozen etc. with 3-0-acetyl-Radix Glycyrrhizae time acyl chlorides, triethylamine in methylene dichloride with the glycine ethyl ester hydrochloride normal-temperature reaction; obtain N-(3-0-acetyl-Radix Glycyrrhizae time acyl group)-glycine ethyl ester [S Rozen; I Shahak; E D Bergmann.Some derivatives ofglycyrrhe-tic acid.IsraelJournal of Chemi stry; 1971,9:185-189.] the gained compound is as anti ulcer agent.Above-mentioned technology is more to the reactions steps of the structure of modification of glycyrrhetinic acid, need to protect first 3 hydroxyls, and then deprotection.Although and the gained derivative improved activity, whether increased new toxic side effect, awaits further research.At N, react in pyridine with succinyl oxide again by the lower condensation of N '-dicyclohexylcarbodiimide (DCC) with stearyl alcohol and glycyrrhetinic acid for Mao Shengjun etc., obtains the stearic alcohol ester of 3-O-succinyl-glycyrrhetinic acid, used as the guide molecule of liver target liposomes.It mainly utilizes glycyrrhetinic acid to the targeting of liver, with other drug target liver [Jin Hui is etc. the preparation of liver cell targeting glycyrrhetinic acid finishing liposome for Mao Shengjun, Hou Shixiang. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2003,28 (4): 328-331.].
Summary of the invention
Technical problem to be solved by this invention provides a kind of Enoxolone derivative and preparation method thereof.
In order to address the above problem, the invention provides following technical proposals:
The structure of Enoxolone derivative of the present invention (following represent with GA-PE) is shown in figure below (I):
Formula (I)
Wherein
R
1And R
2Be C
9-21Alkyl or alkenyl, be preferably C
9, C
11, C
13, C
15, C
17, C
21Alkyl or alkenyl, C more preferably
13, C
15, C
17Alkyl or alkenyl, most preferably be C
17Alkyl.R
1And R
2Can be identical or different.
In addition, the invention still further relates to the preparation method of formula (I) compound (GA-PE), can carry out according to the method that following reaction formula is summarized:
Below, according to reaction formula preparation method of the present invention is described.Under 0～100 ℃ of temperature of reaction, make glycyrrhetinic acid and phosphatidylethanolamine in organic solvent (Solvent), reaction is 1～10 hour in the presence of dicyclohexylcarbodiimide (DCC) and p dimethylamino pyridine (DMAP), obtains formula (I) compound.
Described phosphatidylethanolamine is selected from DSPE (DSPE), two palmitinic acid phosphatidylethanolamines (DPPE), DMPEA (DMPE), DOPE (DOPE), two mustard acyl phosphatidylethanolamines (DEPE), two lauroyl phosphatidylethanolamines (DLPE), two caprinoyl phosphatidylethanolamines (DDPE), preferred DSPE or DOPE.
Described organic solvent is selected from methylene dichloride, trichloromethane, acetone, ethyl acetate, ether, tetrahydrofuran (THF), toluene, preferred ether.
Described temperature of reaction is preferably room temperature, namely 25～35 ℃.
The described reaction times is preferably 1.5～4 hours, more preferably 2～3 hours.
The mol ratio of glycyrrhetinic acid, phosphatidylethanolamine, dicyclohexylcarbodiimide, p dimethylamino pyridine is 1.1～1.3: 1: 1～1.5: 0.01～0.05.
Gained formula (I) compound ether recrystallization.
Compare with glycyrrhetinic acid, the antihepatitic activity of gained Enoxolone derivative of the present invention (being formula (I) compound) has remarkable increase; And reactions steps of the present invention is simple, easily control; Gained derivative lipotropy increases, and can easierly be prepared into Nano medication transfer system (emulsion, solid lipid nanoparticle, liposome etc.).
Embodiment
Illustrate in greater detail the present invention below in conjunction with embodiment, but the present invention is not subjected to any restriction of these records.
Embodiment 1
N-(distearyl phosphatide acyloxy ethyl)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
17Alkyl)
Get the 1g glycyrrhetinic acid, the 1.32g DSPE, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.9g white solid.
Embodiment 2
N-(two palmityl phosphatide acyloxy ethyls)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
15Alkyl)
Get the 1g glycyrrhetinic acid, the 1.22g DPPE, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.82g white solid.
Embodiment 3
N-(two mnyristoyl phosphatide acyloxy ethyls)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
13Alkyl)
Get the lg glycyrrhetinic acid, the 1.12g DMPEA, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.73g white solid.
Embodiment 4
N-(two lauroyl phosphatide acyloxy ethyls)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
11Alkyl)
Get the 1g glycyrrhetinic acid, 1.02g two lauroyl phosphatidylethanolamines, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.64g white solid.
Embodiment 5
N-(oleoyl phosphatide acyloxy ethyl)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
17Thiazolinyl)
Get the 1g glycyrrhetinic acid, the 1.31g DOPE, the 0.36g dicyclohexylcarbodiimide, the 0.0lg p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.9g white solid.
Embodiment 6
N-(two mustard acyl phosphatide acyloxy ethyls)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
21Thiazolinyl)
Get the 1g glycyrrhetinic acid, 1.51g two mustard acyl phosphatidylethanolamines, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 2.1g white solid.
Embodiment 7
N-(two caprinoyl phosphatidyl oxygen base ethyls)-glycyrrhetinic acid acid amides (compound (I), wherein R
1And R
2Be C
9Alkyl)
Get the 1g glycyrrhetinic acid, 0.92g two caprinoyl phosphatidylethanolamines, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.6g white solid.
Embodiment 8
N-(palmityl oleoyl phosphatide acyloxy ethyl)-glycyrrhetinic acid acid amides (compound (I), wherein R
1Be C
15Alkyl, R
2Be C
17Thiazolinyl)
Get the 1g glycyrrhetinic acid, 1.27g palmityl oleoyl phosphatidylethanolamine, the 0.36g dicyclohexylcarbodiimide, the 0.01g p dimethylamino pyridine adds the 20ml ether, stirs 2 hours under room temperature.Filter, filtrate is concentrated, and resistates ether recrystallization obtains the 1.9g white solid.
Embodiment 1～8 compound is all through carbon spectrum hydrogen spectrum conclusive evidence.
Embodiment 9 In vitro cell experiments
The HepG2-2.2.15 cell places 37 ℃, saturated humidity 5%CO with the DMEM liquid that contains 20% calf serum, 0.03%L-glutamine, 100U/ml penicillin, 100U/ml Streptomycin sulphate, 380 μ g/ml G418
2Cultivate in the incubator.Culturing cell becomes individual cells to be inoculated in culture plate (1 * 10 with tryptic digestion
5Cells/well), add nutrient solution 4ml, in 37 ℃, saturated humidity 5%CO
2Cultivate the pastille nutrient solution that changes to different concns behind the 48h in the incubator, establish simultaneously and do not contain the medicine control group, positive drug control group (glycyrrhetinic acid); Every 24h renews the pastille nutrient solution, and totally 3 times, the cell conditioned medium liquid-20 that swaps out ℃ preservation is to be checked, and collecting cell extracts core HBV DNA.
Adopt the drug-induced cytotoxic effect of morphological observation, and use the MTT colorimetric analysis, judge survivaling cell proliferation and metabolism situation and cell-cytotoxic reaction in each hole.Guarantee the restraining effect of HBsAg, HbeAg and HBV DNA during detection of drugs is to cell culture supernatant under non-toxic concn.
Adopt the ELISA determination techniques to detect HbsAg and HbeAg in the supernatant liquor.After 3 parallel holes are averaged, calculate inhibiting rate (OD=450nm).
Inhibiting rate=(the average OD value of the control group-average OD value of medicine group) the average OD value of ÷ control group * 100%
Adopt fluorescence quantitative PCR method to detect the level of the cell culture fluid HBV DNA that collects.
Inhibiting rate=(control group on average copy value-medicine group on average copy value) ÷ control group is copy value * 100% on average
The results are shown in than table 1
Table 1 medicine is to the restraining effect (N=3) of 2.2.15 cell HbsAg, HbeAg and HBV DNA
The result shows, embodiment 1～8 compound and glycyrrhetinic acid ratio all have remarkable increase to the restraining effect of HBsAg, HBeAg and HBV DNA.
Claims (10)
1. the Enoxolone derivative of a formula (I) expression,
Wherein, the R in the formula (I)
1And R
2Be C
9-21Alkyl or alkenyl, and R
1And R
2Can be identical or different.
2. Enoxolone derivative according to claim 1 is characterized in that, the R in the formula (I)
1And R
2Be C
9, C
11, C
13, C
15, C
17, C
21Alkyl or alkenyl, and R
1And R
2Can be identical or different.
3. Enoxolone derivative according to claim 2 is characterized in that, the R in the formula (I)
1And R
2Be C
13, C
15, C
17Alkyl or alkenyl, and R
1And R
2Can be identical or different.
4. Enoxolone derivative according to claim 3 is characterized in that, the R in the formula (I)
1And R
2Be C
17Alkyl or alkenyl, and R
1And R
2Can be identical or different.
5. the preparation method of the arbitrary described Enoxolone derivative of claim 1 to 4, it is characterized in that, under 0～100 ℃ of temperature of reaction, make glycyrrhetinic acid and phosphatidylethanolamine in organic solvent, in the presence of dicyclohexylcarbodiimide and p dimethylamino pyridine, reacted 1～10 hour, obtain formula (I) compound.
6. the preparation method of Enoxolone derivative according to claim 5, described phosphatidylethanolamine is selected from DSPE, two palmitinic acid phosphatidylethanolamines, DMPEA, DOPE, two mustard acyl phosphatidylethanolamines, two lauroyl phosphatidylethanolamines, a kind of in the two caprinoyl phosphatidylethanolamines.
7. the preparation method of Enoxolone derivative according to claim 6 is characterized in that, the mol ratio of glycyrrhetinic acid, phosphatidylethanolamine, dicyclohexylcarbodiimide, p dimethylamino pyridine is 1.1～1.3: 1: 1～1.5: 0.01～0.05.
8. the preparation method of Enoxolone derivative according to claim 7 is characterized in that, described organic solvent is selected from methylene dichloride, trichloromethane, acetone, ethyl acetate, ether, tetrahydrofuran (THF), a kind of or combination of toluene.
9. the preparation method of Enoxolone derivative according to claim 8 is characterized in that, selected organic solvent is ether.
10. the preparation method of Enoxolone derivative according to claim 9 is characterized in that, temperature of reaction is 25～35 ℃, and the reaction times is 1.5～4 hours.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147859A (en) * | 1987-02-26 | 1992-09-15 | Indena S.P.A. | Complexes of glycerrhetinic acid with phospholipids and pharmaceutical and cosmetic compositions containing them |
| CN1827634A (en) * | 2005-03-04 | 2006-09-06 | 北京美倍他药物研究有限公司 | Nitrate derivatives of glycyrrhetic acid and glycyrrhetinic acid and pharmaceutical use thereof |
| CN1948332A (en) * | 2005-10-14 | 2007-04-18 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN101775059A (en) * | 2010-02-04 | 2010-07-14 | 中国药科大学 | Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof |
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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147859A (en) * | 1987-02-26 | 1992-09-15 | Indena S.P.A. | Complexes of glycerrhetinic acid with phospholipids and pharmaceutical and cosmetic compositions containing them |
| CN1827634A (en) * | 2005-03-04 | 2006-09-06 | 北京美倍他药物研究有限公司 | Nitrate derivatives of glycyrrhetic acid and glycyrrhetinic acid and pharmaceutical use thereof |
| CN1948332A (en) * | 2005-10-14 | 2007-04-18 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN101775059A (en) * | 2010-02-04 | 2010-07-14 | 中国药科大学 | Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof |
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