CN101525338A - Water soluble oridonin derivative and preparation method thereof - Google Patents
Water soluble oridonin derivative and preparation method thereof Download PDFInfo
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- CN101525338A CN101525338A CN200810065505A CN200810065505A CN101525338A CN 101525338 A CN101525338 A CN 101525338A CN 200810065505 A CN200810065505 A CN 200810065505A CN 200810065505 A CN200810065505 A CN 200810065505A CN 101525338 A CN101525338 A CN 101525338A
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical class C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 title abstract description 17
- -1 sulphosuccinic acid ester Chemical group 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 101100134922 Gallus gallus COR5 gene Proteins 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 125000005340 bisphosphate group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims description 2
- 229910019213 POCl3 Inorganic materials 0.000 claims 2
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 150000003890 succinate salts Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000003814 drug Substances 0.000 description 16
- 239000011734 sodium Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000011347 resin Substances 0.000 description 10
- 229920005989 resin Polymers 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 230000009466 transformation Effects 0.000 description 7
- 239000000284 extract Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 241001646826 Isodon rubescens Species 0.000 description 5
- 230000000274 adsorptive effect Effects 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000011010 flushing procedure Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 241001183967 Isodon Species 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ONVABDHFQKWOSV-UHFFFAOYSA-N 16-Phyllocladene Natural products C1CC(C2)C(=C)CC32CCC2C(C)(C)CCCC2(C)C31 ONVABDHFQKWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 208000005045 Interdigitating dendritic cell sarcoma Diseases 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108050008598 Phosphoesterases Proteins 0.000 description 1
- WHRDRHNMTIXZNY-OSMZMOMSSA-N Ponicidin Chemical compound C1C[C@H]2[C@@]34[C@@H](O)CCC(C)(C)[C@H]4[C@H](O)[C@]4(O)[C@@]52C(=O)C(=C)[C@@H]1[C@@H]5O[C@H]3O4 WHRDRHNMTIXZNY-OSMZMOMSSA-N 0.000 description 1
- WHRDRHNMTIXZNY-GZNFNYIESA-N Ponicidin Natural products CC1(C)CC[C@@H](O)[C@@]23[C@H]4O[C@H]5[C@H]6CC[C@@H]2[C@@]5(C(=O)C6=C)[C@](O)(O4)[C@@H](O)[C@H]13 WHRDRHNMTIXZNY-GZNFNYIESA-N 0.000 description 1
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002622 anti-tumorigenesis Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ONVABDHFQKWOSV-HPUSYDDDSA-N ent-kaur-16-ene Chemical compound C1C[C@H](C2)C(=C)C[C@@]32CC[C@@H]2C(C)(C)CCC[C@@]2(C)[C@@H]31 ONVABDHFQKWOSV-HPUSYDDDSA-N 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- CAQAFLRZJHXSIS-UHFFFAOYSA-N oridonin Natural products CC1(C)C=CC(O)C23COC(O)(C(O)C12)C45C(O)C(CCC34)C(=C)C5=O CAQAFLRZJHXSIS-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a water soluble oridonin derivative shown as a general formula (1) and preparation method thereof. Water soluble groups such as succinate, sulphosuccinic acid ester, sulphonic acid ester, and the like are added through the structure so as to greatly improve the water solubility and the medicinal property of the water soluble oridonin derivative.
Description
Technical field
The present invention relates to rubescensine A, relate in particular to water soluble oridonin derivative and preparation method thereof.
Background technology
Rabdosia rubescens derives from the Labiatae Rabdosia plant fork (Rabdosia rubescens (Hemsl.) Hara) of cracking rice.The seventies, Medical Science Inst., Henan Prov., Henan Medical Univ. and Yunnan Province's plant research are studied chemical ingredients, pharmacological action and the clinical efficacy of Rabdosia rubescens jointly.Found main anticancer active constituent wherein---rubescensine A (Oridonin) and rubescensine B (Ponicidin) etc.Pharmacopoeia of the People's Republic of China version in 1977 is recorded Rabdosia rubescens.Because the no overt toxicity that the antitumor action that this plant and main active ingredient thereof are good and they show in toxicity test, Rabdosia rubescens has caused the domestic and international scholar's of the world of medicine extensive concern.
From the Rabdosia plant, in isolated more than 100 the diterpenes compositions, have more than 30 of certain anti-tumor activity arranged.What wherein have rubescensine A type (kaurene type) has about 17 kinds, and their content in plant with rubescensine A for the highest, its activity research serves as maximum with rubescensine A also.Rubescensine A is the diterpene-kind compound with alpha-methylene cyclopentanone, has definite external and intravital anti-tumor activity, anticancer spectrum is also wider, as human body esophageal squamous cell carcinoma cell, s180, ehrlich carcinoma, people's liver cancer BEL-7402, reticulum cell sarcoma solid-type (ARS), lung cancer SPCA-1 cell etc. are all had tangible lethal effect (Medical Science Inst., Henan Prov.'s pharmacology medicine group, a kind of new antitumorigenic substance-rubescensine A, Science Bulletin, 1978,23 (1): 53-56; Zhang Shouwei, Liu Jiajun, compound ' Donglingcao ' first element be to the influence of the telomerase activation of lung cancer SPCA-cell, clinical lung section magazine, 2003,8 (3): 204-206).
Rubescensine A is colourless prism-shaped crystallization, and taste is extremely bitter, water insoluble, dissolves in organic solvents such as ether, methyl alcohol, ethanol, and the water-soluble of rubescensine A only is 0.75mg/ml, and the character of its poorly water-soluble has limited its application as medicine greatly.
Summary of the invention
For addressing the above problem, the object of the present invention is to provide a kind of highly water-soluble Oridonin derivative, its as rubescensine A before drug compound in blood, can change into rubescensine A very soon.
Another object of the present invention is to provide the preparation method of highly water-soluble Oridonin derivative.
Oridonin derivative of the present invention is represented with following general formula (1):
R1, R2, R3 and R4 represent separately separately: PO
3M
2, SO
3M, CO (CHX) nCO
2M, H or COR5;
Wherein:
M representation metal ion or amine salt ion are preferably Li
+, Na
+, K
+, 1/2Mg
++, 1/2Ca
++Perhaps NR6R7R8R9
+
R5 represents the alkyl of the straight or branched of C1-C6, for example: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.; The substituted alkyl that perhaps contains water soluble group, described water soluble group is preferably: amido, carboxylic acid group, phosphate or sulfonic group;
R6, R7, R8, R9 be representative separately separately: the alkyl of the straight or branched of H, C1-C6 or substituted alkyl, for example: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.;
N＝1-5；
X representative: H, OR10, NR11R12, CO
2M or CO
2NR6R7;
R11 and R12 be representative separately separately: the alkyl of H, C1-C6 or substituted alkyl, R10 are represented the alkyl or the substituted alkyl of the straight or branched of H, C1-C6.
Preferred The compounds of this invention is that wherein R1 represents CO (CHX) nCO
2Na, R2, R3 and R4 represent H, most preferably are R1 and represent CO (CH
2)
2CO
2Na, R2, R3 and R4 represent H.
Preferred The compounds of this invention is that wherein R1 represents PO
3Na
2, R2, R3 and R4 represent H.
Preferred The compounds of this invention is that wherein R1 and R2 represent PO
3Na
2, R3 and R4 represent H.
Preferred The compounds of this invention is that wherein R1 represents SO
3Na, R2 represent H or SO
3Na, R3 and R4 represent H.
Preferred The compounds of this invention is that wherein R1 represents COCHNH
2CH
3, R2, R3 and R4 represent H.
The method of a kind of preparation Oridonin derivative shown in general formula (1) may further comprise the steps:
1) will insult in the winter first element under acidic conditions with reactive ketone, utilize hemiketal hydroxyl of rubescensine A and a hydroxyl to form the ketal protection, form the described compound of general formula (2), chemical equation is as follows:
R13 and R14 are from representing separately: alkyl or cyclic alkyl;
2) compound shown in the general formula (2) and acid-respons are formed soluble ester, can be divided into following several situation:
A) with compound shown in the general formula (2) and the reaction of activatory carboxylic acid derivative, be preferably dicarboxylic anhydride, be formed with the ester of water soluble group, reaction formula is as follows:
N=1-6 wherein;
B) with compound and POCl shown in the general formula (2)
3Reaction is removed protection and salify through hydrolysis, is formed with the phosphate derivative of water soluble group, and reaction formula is as follows:
C) with compound and excessive POCl shown in the general formula (2)
3Reaction is removed protection and salify through hydrolysis, is formed with the bisphosphate derivative of water soluble group, and reaction formula is as follows:
D) with compound and SO shown in the general formula (2)
3-Py or excessive SO
3-Py reaction is removed protection and salify through hydrolysis, forms the sulfonate derivatives of water soluble group, and reaction formula is as follows:
Wherein R2 represents H or SO
3Na;
E) with the amino acid reaction of compound shown in the general formula (2) and amino t-BOC protection, remove protection and salify through hydrolysis, form water-soluble propylhomoserin ester derivative, reaction formula is as follows:
The method of above-mentioned preparation Oridonin derivative shown in general formula (1); wherein ketone is preferably acetone; with rubescensine A under the tosic acid condition with reactive ketone; utilize a hemiketal hydroxyl and a hydroxyl of rubescensine A to form the ketal protection; form the rubescensine A of propylidene protection, chemical equation is as follows:
Wherein R13 and R14 represent CH respectively
3
Improved greatly with water-soluble the comparing all of the method for the invention synthetic rubescensine A prodrug derivant than rubescensine A, water-soluble all greater than the solubleness of 100mg/ml, strengthened their pharmaceutical properties.To utilize phosphoesterase (phosphotases) and esterification enzyme (esterases) to change into rubescensine A transformation period t1/2 in blood be 15 minutes to three hours to institute's synthetic rubescensine A prodrug derivant in addition, is fit to medicinal.
Embodiment
Synthesizing of the rubescensine A of embodiment 1 propylidene protection
Under nitrogen protection, the 10mg tosic acid is added to 0.3g (0.823mmol) rubescensine A, in the mixture of 0.51ml 2,2-Propanal dimethyl acetal (4.12mmol) and acetone, stirs 6 hours under the room temperature.Add the sodium bicarbonate powder neutralization, evaporate to dryness.Resistates neutral alumina purifying, PE: EA=1: 1 wash-out, obtain the rubescensine A (yield=98%) that the 3.27g propylidene is protected, be lily pressed powder.H1?NMR(CDCl3)：6.14(s，1H)，5.73(d，J＝11.2Hz，1H)，5.54(s，1H)，4.78(s，1H)，4.23(d，J＝10Hz，1H)，4.05(d，J＝10.0Hz，1H)，3.91(m，1H)，3.46(m，1H)，3.05(d，J＝8.8Hz，1H)，2.53(m，1H)，1.95(m，1H)，1.81-1.43(m，10H)，1.73(s，3H)，1.33(s，3H)，1.17(s，3H)，1.15(s，3H)。
Embodiment 2
When R1 represents CO (CH
2)
2CO
2Na; when R2, R3 and R4 represented H, the preparation of the Oridonin derivative shown in the general formula 1: under nitrogen protection, 74mg Succinic anhydried (0.74mmol) was added in the mixture of the rubescensine A (0.247mmol) of 100mg propylidene protection and pyridine; be heated to 80 ℃ and stirred evaporate to dryness 24 hours.Macroporous adsorptive resins AB-8 on the resistates earlier is 4 water flushing with pH value, is that 7.0 water washes with pH value then, uses ethanol elution at last, concentrated white solid.This white solid is dissolved in methyl alcohol and strong acidic ion resin and stirred 2 days, filters, and filtrate concentrates, and through the reversed-phase column purifying, the methanol wash-out is among the NaOH and obtain the rubescensine A Soduxin.H1?NMR(D2O)：6.16(s，1H)，5.68(s，1H)，4.96(s，1H)，4.33(d，J＝10.4Hz，1H)，3.70(d，J＝6.0Hz，1H)，3.10(d，J＝10.0，1H)，2.51(m，2H)，2.47(m，3H)，2.53(m，3H)，2.20-1.40(m，10H)，1.33(s，3H)，1.27(s，3H)。Under the room temperature, its solubleness in water is greater than 5g/100ml, with quantity of sample and rat anticoagulate plasma mixing, hatches under 37 ℃, extracts medicine in different time points with acetonitrile and carries out HPLC and analyze, and measuring the transformation period of medicine in blood is 2.2h.
Embodiment 3
When R1 represents PO
3Na
2When R2, R3 and R4 represented H, the preparation of the Oridonin derivative shown in the general formula 1: under nitrogen protection, 13 μ l phosphorus oxychloride added (0.15mmol) in the mixture of the rubescensine A (0.05mmol) of 20mg propylidene protection and pyridine; stirring at room 24 hours, evaporate to dryness.Macroporous adsorptive resins AB-8 on the resistates earlier is 4 water flushing with pH value, is that 7.0 water washes with pH value then, uses ethanol elution at last, concentrated 15mg white solid.This white solid is dissolved in methyl alcohol and strong acidic ion resin and stirred 2 days, filters, and filtrate concentrates, and through the reversed-phase column purifying, the methanol wash-out is among the NaOH and obtain the rubescensine A sodium phosphate.H1?NMR(D2O)：6.24(s，1H)，5.77(s，1H)，5.10(s，1H)，4.36(d，J＝10.4Hz，1H)，4.20(d，J＝10.4Hz，1H)，3.94(m，1H)，3.79(d，J＝6.4Hz)，3.16(d，J＝9.4Hz，1H)，2.61(m，1H)，2.16(m，2H)，2.53(m，3H)，1.80-1.40(m，10H)，1.49(s，3H)，1.07(s，3H)，P13NMR(D2O).：-1.56(s)。Under the room temperature, its solubleness in water is greater than 13g/100ml, with quantity of sample and rat anticoagulate plasma mixing, hatches under 37 ℃, extracts medicine in different time points with acetonitrile and carries out HPLC and analyze, and measuring the transformation period of medicine in blood is 20min.
Embodiment 4
When R1 and R2 represent PO
3Na
2When R3 and R4 represented H, the preparation of the Oridonin derivative shown in the general formula 1: under nitrogen protection, 44 μ l phosphorus oxychloride added (0.5mmol) in the mixture of the rubescensine A (0.05mmol) of 20mg propylidene protection and pyridine; stirring at room 24 hours, evaporate to dryness.Macroporous adsorptive resins AB-8 on the resistates earlier is 4 water flushing with pH value, is that 7.0 water washes with pH value then, uses ethanol elution at last, concentrated white solid.This white solid is dissolved in methyl alcohol and strong acidic ion resin and stirred 2 days, filters, and filtrate concentrates, and through the reversed-phase column purifying, the methanol wash-out is among the NaOH and obtain the rubescensine A diphosphate sodium.H1?NMR(D2O)：6.27(s，1H)，5.80(s，1H)，5.09(s，1H)，4.38(d，J＝10.4Hz，1H)，4.23(d，J＝10.4Hz，1H)，4.04(m，1H)，3.83(d，J＝6.4Hz)，3.22(d，J＝9.4Hz，1H)，2.63(m，1H)，2.20-1.40(m，10H)，1.36(s，3H)，1.10(s，3H)，P13NMR(D2O).：-11.0(s)，-14.7。Under the room temperature, its solubleness in water is greater than 14g/100ml, with quantity of sample and rat anticoagulate plasma mixing, hatches under 37 ℃, extracts medicine in different time points with acetonitrile and carries out HPLC and analyze, and measuring the transformation period of medicine in blood is 35min.
Embodiment 5
When R1 represents SO
3Na, R2 represents H, when R3 and R4 represent H, the preparation of the Oridonin derivative shown in the general formula 1: under nitrogen protection, SO
3-Py (0.15mmol) is added in the mixture of the rubescensine A (0.05mmol) of 20mg propylidene protection and pyridine, stirring at room 24 hours, evaporate to dryness.Macroporous adsorptive resins AB-8 on the resistates earlier is 4 water flushing with pH value, is that 7.0 water washes with pH value then, uses ethanol elution at last, concentrated 15mg white solid.This white solid is dissolved in methyl alcohol and strong acidic ion resin and stirred 2 days, filters, and filtrate concentrates, and through the reversed-phase column purifying, the methanol wash-out is among the NaOH and obtain rubescensine A sodium sulfate.H1NMR(D2O)：6.25(s，1H)，5.87(s，1H)，5.10(s，1H)，4.36(d，J＝10.4Hz，1H)，4.20(d，J＝10.4Hz，1H)，4.11(m，1H)，3.79(d，J＝6.4Hz)，3.16(d，J＝9.4Hz，1H)，2.61(m，1H)，2.16(m，2H)，2.53(m，3H)，1.80-1.40(m，10H)，1.49(s，3H)，1.07(s，3H)。Under the room temperature, its solubleness in water is greater than 10g/100ml, with quantity of sample and rat anticoagulate plasma mixing, hatches under 37 ℃, extracts medicine in different time points with acetonitrile and carries out HPLC and analyze, and measuring the transformation period of medicine in blood is 1.2h.
Embodiment 6
When R1 represents SO
3Na, R2 represents SO
3Na, when R3 and R4 represented H, the preparation of the Oridonin derivative shown in the general formula 1: method obtained rubescensine A two sodium sulfate with embodiment 5.H1?NMR(D2O)：6.30(s，1H)，5.83(s，1H)，5.13(s，1H)，4.41(d，J＝10.4Hz，1H)，4.26(d，J＝10.4Hz，1H)，4.16(m，1H)，3.85(d，J＝6.4Hz)，3.24(d，J＝9.4Hz，1H)，2.63(m，1H)，2.20-1.40(m，10H)，1.36(s，3H)，1.10(s，3H)。Under the room temperature, its solubleness in water is greater than 12g/100ml, with quantity of sample and rat anticoagulate plasma mixing, hatches under 37 ℃, extracts medicine in different time points with acetonitrile and carries out HPLC and analyze, and measuring the transformation period of medicine in blood is 1.6h.
Embodiment 7
When R1 represents COCHNH
2CH
3When R2, R3 and R4 represent H; the preparation of the Oridonin derivative shown in the general formula 1: under nitrogen protection; t-BocNH-Ala (0.40mmol) is added to the rubescensine A (0.247mmol) of 100mg propylidene protection; DCC; in the mixture of catalytic amount DMAP and pyridine, be heated to 80 ℃ and stirred evaporate to dryness 24 hours.Macroporous adsorptive resins AB-8 on the resistates earlier is 4 water flushing with pH value, is that 7.0 water washes with pH value then, uses ethanol elution at last, concentrated white solid.This white solid is dissolved in methyl alcohol and strong acidic ion resin stirred 2 days, filters, and filtrate concentrates, through the reversed-phase column purifying, and the methanol wash-out, the HCl acidifying obtains the rubescensine A alanine ester.H1?NMR(D2O)：6.13(s，1H)，5.65(s，1H)，4.96(s，1H)，4.60(br?s，3H)，4.33(d，J＝10.4Hz，1H)，3.70(d，J＝6.0Hz，1H)，3.34(m，1H)，3.10(d，J＝10.0，1H)，2.51(m，2H)，2.47(m，3H)，2.53(m，3H)，2.20-1.40(m，10H)，1.78(d，3H)，1.33(s，3H)，1.27(s，3H)。Under the room temperature, its solubleness in water is greater than 10g/100ml, with quantity of sample and rat anticoagulate plasma mixing, hatches under 37 ℃, extracts medicine in different time points with acetonitrile and carries out HPLC and analyze, and measuring the transformation period of medicine in blood is 1h.
Claims (14)
1, following general formula (1) compound:
R1, R2, R3 and R4 represent separately separately: PO
3M
2, SO
3M, CO (CHX) nCO
2M, H or COR5;
Wherein:
M representation metal ion or amine salt ion NR6R7R8R9
+
R5 represents the alkyl of C1-C6, perhaps contains the substituted alkyl of water soluble group;
R6, R7, R8, R9 be representative separately separately: the alkyl of H, C1-C6 or substituted alkyl;
N＝1-5；
X represents H, OR10, NR11R12, CO
2M or CO
2NR6R7;
R11 and R12 be representative separately separately: the alkyl of H, C1-C6 or substituted alkyl, R10 are represented alkyl or the substituted alkyl of H, C1-C6.
2, compound according to claim 1, wherein R5 represents the alkyl of C1-C6, perhaps contains the substituted alkyl of water soluble group, and described water soluble group is: amido, carboxylic acid group, phosphate or sulfonic group.
3, compound according to claim 1, wherein M represents Li
+, Na
+, K
+, 1/2Mg
++, 1/2Ca
++Perhaps NR6R7R8R9
+
4, compound according to claim 1, wherein R1 represents CO (CH
2) nCO
2Na, R2, R3 and R4 represent H.
5, compound according to claim 1, wherein R1 represents PO
3Na
2, R2, R3 and R4 represent H.
6, compound according to claim 1, wherein R1 and R2 represent PO
3Na
2, R3 and R4 represent H.
7, compound according to claim 1, wherein R1 represents SO
3Na, R2 represent H or SO
3Na, R3 and R4 represent H.
8, according to the described compound of claim 1, wherein R1 represents COCHNH
2CH
3, R2, R3 and R4 represent H.
9, a kind of preparation method of compound shown in the general formula (1) according to claim 1 may further comprise the steps:
1) will insult in the winter first element under acidic conditions with reactive ketone, utilize hemiketal hydroxyl of rubescensine A and a hydroxyl to form the ketal protection, form the described compound of general formula (2), chemical equation is as follows:
R13 and R14 are from representing separately: alkyl or cyclic alkyl;
2) compound shown in the general formula (2) and acid-respons are formed soluble ester.
10, a kind of preparation according to claim 9 method of compound shown in the general formula (1) according to claim 1 wherein, with compound shown in the general formula (2) and the reaction of activatory carboxylic acid derivative, is formed with the ester of water soluble group.
11, a kind of preparation according to claim 9 method of compound shown in the general formula (1) according to claim 1 wherein, with compound shown in the general formula (2) and POCl3 reaction, is removed protection and salify through hydrolysis, is formed with the phosphate derivative of water soluble group.
12, a kind of preparation according to claim 9 method of compound shown in the general formula (1) according to claim 1; wherein; with compound shown in the general formula (2) and excessive POCl3 reaction, remove protection and salify through hydrolysis, be formed with the bisphosphate derivative of water soluble group.
13, a kind of preparation according to claim 9 method of compound shown in the general formula (1) according to claim 1; wherein; with compound shown in the general formula (2) and SO3-Py or excessive SO3-Py reaction, remove protection and salify through hydrolysis, form the sulfonate derivatives of water soluble group.
14, a kind of preparation according to claim 9 method of compound shown in the general formula (1) according to claim 1; amino acid reaction with compound shown in the general formula (2) and amino t-BOC protection; remove protection and salify through hydrolysis, form water-soluble propylhomoserin ester derivative.
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Cited By (6)
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|---|---|---|---|---|
| CN104017000A (en) * | 2013-03-01 | 2014-09-03 | 江苏恒瑞医药股份有限公司 | L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof |
| WO2014165841A1 (en) | 2013-04-05 | 2014-10-09 | The Board Of Regents Of The University Of Texas System | Oridonin analogs, compositions, and methods related thereto |
| CN104188988A (en) * | 2014-08-18 | 2014-12-10 | 深圳市健元医药科技有限公司 | Oridonin derivative injection and preparation process thereof |
| CN104327089A (en) * | 2014-10-16 | 2015-02-04 | 深圳市健元医药科技有限公司 | Water-soluble rubescensin a derivative and preparation method thereof |
| CN106866694A (en) * | 2017-02-22 | 2017-06-20 | 石家庄学院 | Oridonin Schiff base derivatives and its production and use |
| CN110627833A (en) * | 2019-11-03 | 2019-12-31 | 石家庄学院 | Oridonin derivative and preparation and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101139350B (en) * | 2007-10-15 | 2010-06-02 | 中国药科大学 | Oridonin derivative, preparation method and uses thereof |
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| CN104017000A (en) * | 2013-03-01 | 2014-09-03 | 江苏恒瑞医药股份有限公司 | L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof |
| CN104017000B (en) * | 2013-03-01 | 2017-01-04 | 江苏恒瑞医药股份有限公司 | ALANINE-(14-rubescensine A) ester trifluoroacetate and its production and use |
| WO2014165841A1 (en) | 2013-04-05 | 2014-10-09 | The Board Of Regents Of The University Of Texas System | Oridonin analogs, compositions, and methods related thereto |
| EP2981529A4 (en) * | 2013-04-05 | 2016-12-07 | Univ Texas | Oridonin analogs, compositions, and methods related thereto |
| US9725460B2 (en) | 2013-04-05 | 2017-08-08 | The Board Of Regents Of The University Of Texas System | Oridonin analogs, compositions, and methods related thereto |
| US10072022B2 (en) | 2013-04-05 | 2018-09-11 | The Board Of Regents Of The University Of Texas System | Oridonin analogs, compositions, and methods related thereto |
| CN104188988A (en) * | 2014-08-18 | 2014-12-10 | 深圳市健元医药科技有限公司 | Oridonin derivative injection and preparation process thereof |
| CN104327089A (en) * | 2014-10-16 | 2015-02-04 | 深圳市健元医药科技有限公司 | Water-soluble rubescensin a derivative and preparation method thereof |
| CN106866694A (en) * | 2017-02-22 | 2017-06-20 | 石家庄学院 | Oridonin Schiff base derivatives and its production and use |
| CN106866694B (en) * | 2017-02-22 | 2019-01-08 | 石家庄学院 | Oridonin Schiff base derivatives and its preparation method and application |
| CN110627833A (en) * | 2019-11-03 | 2019-12-31 | 石家庄学院 | Oridonin derivative and preparation and application thereof |
| CN110627833B (en) * | 2019-11-03 | 2024-04-19 | 石家庄学院 | Oridonin derivative, and preparation and application thereof |
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