CN100445288C - Bilobalide B derivatives and pharmaceutical application thereof - Google Patents
Bilobalide B derivatives and pharmaceutical application thereof Download PDFInfo
- Publication number
- CN100445288C CN100445288C CNB2006100399286A CN200610039928A CN100445288C CN 100445288 C CN100445288 C CN 100445288C CN B2006100399286 A CNB2006100399286 A CN B2006100399286A CN 200610039928 A CN200610039928 A CN 200610039928A CN 100445288 C CN100445288 C CN 100445288C
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- CN
- China
- Prior art keywords
- bilobalide
- ginkgolide
- derivates
- representative
- formyloxy
- 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.)
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- SQOJOAFXDQDRGF-ZMVGXLHTSA-N ginkgolide b Chemical class O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-ZMVGXLHTSA-N 0.000 title claims abstract description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- -1 propoxy- Chemical class 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 229930063422 Bilobalide A Natural products 0.000 claims description 20
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001118 alkylidene group Chemical group 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 3
- 238000002360 preparation method Methods 0.000 abstract description 13
- 125000002947 alkylene group Chemical group 0.000 abstract 4
- 239000004215 Carbon black (E152) Substances 0.000 abstract 2
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- 239000012188 paraffin wax Substances 0.000 abstract 2
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
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- 238000012856 packing Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 229940090044 injection Drugs 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000007689 inspection Methods 0.000 description 6
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000218628 Ginkgo Species 0.000 description 5
- 235000011201 Ginkgo Nutrition 0.000 description 5
- 235000008100 Ginkgo biloba Nutrition 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 description 4
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- 230000001105 regulatory effect Effects 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 210000004493 neutrocyte Anatomy 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
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- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 2
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention provides a bilobalide B derivative with a structural formula disclosed in the specification, wherein when R2 represents-COOH, R1 represents-X-and X represents alkylene with one to eight carbon atoms; the alkylene is not substituted or is substituted by straight-chain or branched paraffin hydrocarbon with one to five carbon atoms; when the R2 represents-NR3 R4, the R1 represents-XCO-and the X represents alkylene with one to five carbon atoms; the alkylene is not substituted or is substituted by straight-chain or branched paraffin hydrocarbon with one to five carbon atoms; R3 and R4 are the same or different and are both hydrogen, alkyl with one to eight carbon atoms or cycloalkyl with three or ten carbon atoms. The bilobalide B derivative is properly processed to be applied to medical preparation. Thus, the biological availability of an original compound can be greatly improved and medicinal therapeutic effect is increased.
Description
Technical field
The present invention relates to a kind of compound derivatives and preparation method thereof, and the application in pharmacy, relate in particular to bilobalide B derivates and preparation method thereof, and the application in pharmacy, medical technical field belonged to.
Background technology
Ginkgo is of long duration as medicinal plant, about 1000 Christian eras, and China's Ginkgo Leaf treatment asthma and bronchitis just used among the people.Along with going deep into of extract drugs process standardization and pharmacological action activity research, countries in the world, particularly European countries such as Germany, France have been widely used in Semen Ginkgo extrac (GBE) diseases such as treatment respiratory system, cardio-cerebrovascular.Bilobalide is a series of diterpene-kind compounds that are present in Ginkgo Leaf and the rhizome, the chemical property quite stable.Bilobalide is platelet activation factor (platelet-activating factor, PAF) strong antagonist, platelet activation factor is a very strong physiological regulation device, on a lot of physiological phenomenons, playing the part of important role, as irritated, inflammation and asthma or the like, therefore seeking the use that suitable substance P AF antagonist is used as in the medical treatment is very important problem of medical circle.
Ginkgolide B (Ginkgolide B, GB) be from Ginkgo Leaf, extract a kind of six the ring cage structures diterpene compound, it is the strongest platelet activation factor (PAF) antagonist of finding so far, it participates in thrombosis directly, can stimulate coronary artery and cerebral arteries, cause their contraction, spasm, cause cardiac muscle and cerebral tissue ischemic.In recent years research finds that also stronger anti-inflammatory action is arranged.In inflammatory reaction, the LPA effect of the activated Phospholipase A2 of neutrophilic leukocyte membrane phospholipid is hydrolyzed into arachidonic acid (AA).AA further metabolism under the effect of 5-lipoxygenase (5-LO) is leukotriene (LTs) and hydroxyeicosatetraenoic acid products such as (HETEs), and wherein, some product is important inflammatory mediator, and the activation of Phospholipase A2 needs intracellular Ca2+ to participate in.Ginkgolide B has the effect that influences rat neutrophilic leukocyte arachidonic acid metabolism enzyme and intracellular free calcium.Its anti-inflammatory action may be relevant with the rising of the generation of the release of its inhibition neutrophilic leukocyte lysosomal enzyme, superoxide anion and intracellular Ca2+ level.
But Ginkgolide B is a kind of diterpene compound of six ring cage structures, rigid structure, and water insoluble, bioavailability is poor, causes giving full play to of drug effect to be restricted, and influences clinical application effect.
Summary of the invention
Technical problem: the invention provides the preparation method of bilobalide B derivates and this derivative, find out a kind of ginkgolide compounds that better has the PAF antagonistic action, it is not only oral, and effectively tool is long-lasting, and is water-soluble, and intravenously administrable is effective.
Technical scheme: bilobalide B derivates, its structural formula is:
R
2During representative-COOH,
R
1Representative-X-, the X representative has the alkylidene group of 1 to 8 carbon atom, and alkylidene group is not substituted or is had the straight or branched alkane replacement of 1 to 5 carbon atom; Preferred R
1Representative has the alkylidene group of 1 to 4 carbon atom, and alkylidene group is not substituted or is had the straight or branched alkane replacement of 1 to 3 carbon atom;
R
2Representative-NR
3R
4The time,
R
1Representative-XCO-, the X representative has the alkylidene group of 1 to 5 carbon atom, and alkylidene group is not substituted or is had the straight or branched alkane replacement of 1 to 5 carbon atom; R
3And R
4Identical or different, be hydrogen, have the alkyl of 1 to 8 carbon atom or have the cycloalkyl of 3 to 10 carbon atoms.Preferred R
1Representative-XCO, the X representative has the alkylidene group of 1 to 4 carbon atom, and alkylidene group is not substituted or is had the straight or branched alkane replacement of 1 to 3 carbon atom; R
3And R
4Identical or different, be hydrogen, have the alkyl of 1 to 4 carbon atom or have the cycloalkyl of 5 to 7 carbon atoms.
The bilobalide B derivates preferred compound is:
10-((sodium formiate base) methoxyl group)-Ginkgolide B,
10-((sodium formiate base) chloro methoxyl group)-Ginkgolide B,
10-((2 '-sodium formiate base)-oxyethyl group)-Ginkgolide B,
10-((3 '-sodium formiate base)-propoxy-)-Ginkgolide B,
10-((1 '-sodium formiate-1 '-sodium acetate base)-methoxyl group)-Ginkgolide B,
10-(dimethylin formyloxy)-Ginkgolide B,
10-(2 '-dimethylin acetoxyl)-Ginkgolide B,
10-(3 '-dimethylin propionyloxy)-Ginkgolide B,
10-(the first and second amido formyloxys)-Ginkgolide B,
10-(3 '-dimethylin acrylic)-Ginkgolide B,
10-(4 '-(sodium formiate base) benzyloxy)-Ginkgolide B,
10-(4 '-(sodium acetate base) benzyloxy)-Ginkgolide B,
10-(3 '-(sodium formiate base) benzyloxy)-Ginkgolide B,
10-(3 '-(sodium acetate base) benzyloxy)-Ginkgolide B,
10-(4 '-dimethylin benzoyloxy)-Ginkgolide B,
10-(4 ' dimethylamine-3-methyl-yl benzoic acid base)-Ginkgolide B.
Most preferred compound is:
10-((sodium formiate base) methoxyl group)-Ginkgolide B,
10-((sodium formiate base) chloro methoxyl group)-Ginkgolide B,
10-((3 '-sodium formiate base)-propoxy-)-Ginkgolide B,
10-(dimethylin formyloxy)-Ginkgolide B,
10-(the first and second amido formyloxys)-Ginkgolide B,
A kind of method for preparing bilobalide B derivates, it is included under the condition that alkali and organic solvent exist with the Ginkgolide A is the synthetic Ginkgolide A derivative of raw material, and wherein the selected scope of alkali comprises alkaline carbonate, alkali metal hydrocarbonate, triethylamine, Ag
2O, alkali metal hydroxide, MH, MNH
2, wherein M is a basic metal; The selected scope of wherein said organic solvent comprises second eyeball, tetrahydrofuran (THF), acetone, ethyl acetate, dimethyl formamide, dimethyl sulfoxide (DMSO), pyridine, diox, methyl alcohol, ethanol, 2-methyl cellosolve and their mixture; Wherein said synthesizing at 0～110 ℃ carries out.
Bilobalide B derivates can with the negatively charged ion salify on any pharmacy meaning.
Ion salify on bilobalide B derivates and any pharmacy meaning is hydrochloride, vitriol, mesylate, maleate, citrate, phosphoric acid salt.
Bilobalide B derivates adds suitable pharmaceutical excipient, makes and is applicable to clinical pharmaceutical preparation.
Pharmaceutical preparation is tablet, orally disintegrating tablet, dispersible tablet, slow-release tablet, capsule, sustained and controlled release capsule, oral liquid, freeze-dried powder, aseptic subpackaged powder pin, solvent crystallization powder pin, injection liquid, large vol 5% glucose infusion liquid, large vol 10% glucose infusion liquid, the transfusion of large vol sodium-chlor, the transfusion of large vol N.F,USP MANNITOL, the transfusion of large vol Xylitol.
Beneficial effect: the present invention is to be parent with the Ginkgolide B, through structural modification, becomes the nitrogen containing derivative of Ginkgolide B, has improved water-solublely, improves bioavailability, heightens the effect of a treatment; Especially behind its salify, it is water-soluble, bioavailability and curative effect all are improved largely and strengthen.
Have platelet activation factor (PAF) antagonistic action, can be used for disease prevention and the clinical treatments relevant such as ishemic stroke, inflammation, asthma with the PAF factor.
Embodiment
Synthetic and the structural identification of embodiment 1.10-((sodium formiate base) methoxyl group)-Ginkgolide B
With bromoacetic acid 1.47g, salt of wormwood 20g, 300mg Ginkgolide B, add successively in the 40mL acetonitrile, logical rare gas element stirs reflux 2 hours. and the mixture acid solution is handled, concentrating under reduced pressure, the chloroform dissolving is filtered, and filtrate concentrates.(elutriant: chloroform/methanol=20/1) separate, get product 142mg (yield 42%), then it is dissolved in an amount of saturated solution of sodium bicarbonate, transfer pH to 9.0, remove by filter insolubles, the filtrate drying obtains expecting compound to the products therefrom column chromatography.
1H-NMR(DMSO-d6)δ6.22(brs，1H)，6.05(s，1H)，5.24(d，1H)，4.96(s，1H)，4.81(brs，2H)，4.50(d，1H)，4.04(d，1H)，2.81(q，1H)，2.30(d，2H)，2.05～1.64(m，3H)，1.10(d，3H)，0.96(s，9H)。
Synthetic and the structural identification of embodiment 2.10-((3 '-sodium formiate base) propoxy-) Ginkgolide B
With bromo-butyric acid 1.77g, salt of wormwood 2.0g, 300mg Ginkgolide B, add successively in the 40mL acetonitrile, logical rare gas element stirs reflux 2 hours. and the mixture acid solution is handled, concentrating under reduced pressure, the chloroform dissolving is filtered, and filtrate concentrates.The products therefrom column chromatography (elutriant: chloroform/methanol=20/1) separate, get product 132mg (yield 35%), then it is dissolved in an amount of saturated solution of sodium bicarbonate, transfer pH to 9.0, remove by filter insolubles, the filtrate drying obtains expecting compound.
1H-NMR(CDCl
3)δ5.95(brs，1H)，5.59(s，1H)，5.43(d，1H)，4.78(s，1H)，4.70(brs，1H)，4.46(d，1H)，3.86(d，1H)，2.67(q，1H)，2.42(d，2H)，2.23(d，2H)，2.01～1.55(m，3H)，1.05(d，3H)，0.97(s，9H).
Synthetic and the structural identification of embodiment 3.10-((sodium formiate base) chlorine methoxyl group)-Ginkgolide B
With dichloro acetic acid 1.45g, salt of wormwood 2.0g, potassiumiodide 400g, Ginkgolide B 300mg, add successively in the 40mL acetonitrile, logical rare gas element stirs reflux 2 hours. and the mixture acid solution is handled, concentrating under reduced pressure, the chloroform dissolving is filtered, and filtrate concentrates.The products therefrom column chromatography (elutriant: chloroform/methanol=20/1) separate, get product 161mg (yield 45%), then it is dissolved in an amount of saturated solution of sodium bicarbonate, transfer pH to 9.0, remove by filter insolubles, the filtrate drying obtains expecting compound.
1H-NMR(DMSO-d6)δ6.42(brs，1H)，6.15(s，1H)，5.38(d，1H)，5.05(ABq，2H)，4.80(brs，1H)，4.60(d，1H)，4.19(d，1H)，2.88(q，1H)，2.61(d，H)，2.15～1.71(m，3H)，1.12(d，3H)，0.99(s，9H)。
Synthetic and the structural identification of embodiment 4.10-(4 '-dimethylin formyloxy)-Ginkgolide B
The 300mg Ginkgolide B is dissolved in the 30mL pyridine, adds dimethylin formyl chloride 1.60g, stir, stirring at room 4 hours, the mixture acid solution is handled, chloroform extraction, washing, anhydrous sodium sulfate drying concentrates.Products therefrom column chromatography (elutriant: chloroform/methanol=20/1) separate, get product 120mg (yield 38%).
1H-NMR(DMSO-d
6)δ6.35(brs，1H)，6.07(s，1H)，5.35(d，1H)，5.17(s，1H)，4.88(brs，1H)，4.59(d，1H)，4.15(d，1H)，2.81(q，1H)，2.20(dd，6H)，2.15(s，1H)，1.95(dd，1H)，1.86(ddd，1H)，1.14(d，3H)，1.05(s，9H).
Synthetic and the structural identification of embodiment 5.10-(the first and second amido formyloxys)-Ginkgolide B
The 300mg Ginkgolide B is dissolved in the 30mL pyridine, adds the first and second amido formyl chloride 1.81g, stir, stirring at room 4 hours, the mixture acid solution is handled, chloroform extraction, washing, anhydrous sodium sulfate drying concentrates.Products therefrom column chromatography (elutriant: chloroform/methanol=20/1) separate, get product 104mg (yield 32%).
1H-NMR(DMSO-d
6)δ6.28(brs，1H)，6.02(s，1H)，5.26(d，1H)，5.06(s，1H)，4.81(brs，1H)，4.50(d，1H)，4.10(d，1H)，3.22～3.34(m，2H)，2.81(q，1H)，2.30(d，2H)，2.15(s，3H)，2.08(s，3H)，1.91(dd，1H)，1.82(ddd，1H)，1.10(d，3H)，1.02(s，9H).
Embodiment 6.10-((3 '-sodium formiate base) propoxy-)-ginkgolide B lyophilized powder injection preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g, glycine 80g, N.F,USP MANNITOL 160g, add the injection water to 4000ml (1000 component), stir and be heated to 70 ℃ and make dissolving, add the 4g needle-use activated carbon, coarse filtration is taken off charcoal, intermediate content is measured with the smart filter of 0.22um millipore filtration in the back, and qualified back can is in 10ml control cillin bottle, adorn 4ml approximately for every bottle, partly be pressed into the butyl rubber match.Put into Freeze Drying Equipment and carry out lyophilize according to pre-designed freeze-drying curve.Drying process compresses plug after finishing, the plastic-aluminum combination cover rolls lid, promptly gets 10-((3 '-sodium formiate base) propoxy-)-ginkgolide B lyophilized powder injection.
The aseptic subpackaged powder pin preparation of embodiment 7,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g, add N.F,USP MANNITOL, dextran or lactose 460g, mix (1000 component).Measure intermediate content, the aseptic subpackaged device in qualified back
Divide to be filled in the 10ml cillin bottle, adorn 0.5g approximately for every bottle, tamponade, roll the plastic-aluminum combination cover, promptly get 10-((3 '-sodium formiate base) propoxy-)-aseptic subpackaged powder pin of Ginkgolide B.
Embodiment 8,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B injection liquid preparation
Take by weighing 10-(3 '-sodium formiate base)-third oxygen Ginkgolide B 8g, glycine 80g between weighing, add the injection water to 10000ml (1000 component), stir and be heated to 60 ℃ and make dissolving, regulating the pH value with Citric Acid or Sodium Citrate is 6.0～8.0, adds the 10g needle-use activated carbon, and coarse filtration is taken off charcoal, filter with the 0.22um millipore filtration is smart the back, measure intermediate content, qualified back can is adorned 10ml for every bottle approximately in the 10ml cillin bottle, compress butyl rubber plug, roll lid.100 ℃ of flowing steam sterilizations 30 minutes, lamp inspection packing is promptly; If sterile filling, rolls lid at tamponade, lamp inspection packing promptly.
Embodiment 9,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B large vol glucose injection preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g between weighing, glycine 2.5kg, Calcium Disodium Edetate 100g, glucose 12.5kg, add the injection water and stir and be heated to 60 ℃ to 250L (1000 bottles of amounts) and make dissolving, regulating the pH value with Citric Acid or Sodium Citrate is 6.0～8.0, add the 250g needle-use activated carbon, coarse filtration is taken off charcoal, filter with the 0.22um millipore filtration is smart the back, measure intermediate content, qualified back can is in 250ml vial or the soft bag of PVC, adorn 255ml approximately for every bottle or every bag, add butyl rubber plug, roll lid or sealing by fusing.100 ℃ of flowing steam sterilizations 30 minutes, lamp inspection packing is promptly; If sterile filling, lamp inspection packing promptly.
Embodiment 10,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B large vol sodium chloride injection preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g between weighing, glycine 1000g, Calcium Disodium Edetate 40g, sodium-chlor 900g, add the injection water and stir and be heated to 60 ℃ to 100L (1000 bottles of amounts) and make dissolving, regulating the pH value with Citric Acid or Sodium Citrate is 6.0～8.0, add the 100g needle-use activated carbon, coarse filtration is taken off charcoal, filter with the 0.22um millipore filtration is smart the back, measure intermediate content, qualified back can is in 100ml vial or the soft bag of PVC, adorn 102ml approximately for every bottle or every bag, add butyl rubber plug, roll lid or sealing by fusing.100 ℃ of flowing steam sterilizations 30 minutes, lamp inspection packing is promptly; If sterile filling, lamp inspection packing promptly.
Embodiment 11,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B tablet preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g, Microcrystalline Cellulose 50g, micropowder silica gel 9.5g, Magnesium Stearate 0.5g (adding) mixes, with 60% ethanolic soln as tackiness agent, 18 eye mesh screens are granulated, 60 ℃ dry to moisture be the whole grain of 1.5%, 20 eye mesh screen, add Magnesium Stearate 0.5g, mix, measure intermediate, the flat stamping of qualified back 7#, back bag film-coat shading, packing promptly
Embodiment 12,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B capsule preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 40g, Microcrystalline Cellulose 50g, micropowder silica gel 9.5g, Magnesium Stearate 0.5g (adding), mix, as tackiness agent, 18 eye mesh screens are granulated with 5% starch slurry, 60 ℃ dry to moisture be 1.0%, the whole grain of 16 eye mesh screens, add Magnesium Stearate 0.5g, mix
Measure intermediate, qualified back can is in 3# opaque capsule shell, and aluminium-plastic bubble plate packing promptly.
Embodiment 13,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B orally disintegrating tablet preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g, Avicel PH301 170g, low-substituted hydroxypropyl cellulose (L-HPC) 35g, sodium starch glycolate (CMSNa) 5g, control pressure 1.98 * 10
3N is flat towards direct compression with 9#, and the two-layer compound aluminum plastic film is packed promptly.
Embodiment 14,10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B oral liquid preparation
Take by weighing 10-((3 '-sodium formiate base) propoxy-)-Ginkgolide B 8g, glycine 100g, P-hydroxybenzoic acid 2g and propylparaben 1g are dissolved in earlier in the 100ml dehydrated alcohol, after add water to 10L, 60 ℃ of stirrings make dissolving, regulating the pH value with Citric Acid or Sodium Citrate is 6.0～8.0, check intermediate, can in the brown oral liquid bottle of 10mL, tamponade, roll lid, packing promptly.
Claims (8)
1, bilobalide B derivates, its structural formula is:
R
2During representative-COOH,
R
1Representative has the alkylidene group of 1 to 8 carbon atom, and alkylidene group is not substituted or is had the straight or branched alkane replacement of 1 to 5 carbon atom;
R
2Representative-NR
3R
4The time,
R
1Representative-CO, R
3And R
4Identical or different, be hydrogen, have the alkyl of 1 to 8 carbon atom or have the cycloalkyl of 3 to 10 carbon atoms.
2, bilobalide B derivates according to claim 1, wherein said bilobalide B derivates compound is selected from:
10-((formyloxy) methoxyl group)-Ginkgolide B,
10-((3 '-formyloxy) propoxy-)-Ginkgolide B,
10-(dimethylin formyloxy)-Ginkgolide B,
10-(the first and second amido formyloxys)-Ginkgolide B.
3. a bilobalide B derivates is characterized in that this bilobalide B derivates is 10-((formyloxy) chloro methoxyl group)-Ginkgolide B.
4, a kind of method for preparing bilobalide B derivates as claimed in claim 1, it is included under the condition that alkali and organic solvent exist with the Ginkgolide B is the synthetic bilobalide B derivates of raw material, wherein the selected scope of alkali is Ag
2O, triethylamine, alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide, MH, MNH
2, wherein M is a basic metal; The selected scope of wherein said organic solvent is a tetrahydrofuran (THF), acetone, ethyl acetate, dimethyl formamide, dimethyl sulfoxide (DMSO), pyridine ， diox, methyl alcohol, ethanol, 2-methyl cellosolve and their mixture; Wherein said synthesizing at 0～110 ℃ carries out.
5, the salt that negatively charged ion became on a kind of bilobalide B derivates as claimed in claim 1 and any pharmacy meaning.
6, the salt that negatively charged ion became on bilobalide B derivates according to claim 5 and any pharmacy meaning is characterized in that salt is hydrochloride, vitriol, mesylate, maleate, citrate or phosphoric acid salt.
7, a kind of bilobalide B derivates according to claim 1 adds the clinical pharmaceutical preparation that is applicable to that suitable pharmaceutical excipient makes.
8, bilobalide B derivates according to claim 7 adds the clinical pharmaceutical preparation that is applicable to that suitable pharmaceutical excipient makes, and it is characterized in that pharmaceutical preparation is tablet, capsule, oral liquid, freeze-dried powder, aseptic subpackaged powder pin, solvent crystallization powder pin, injection liquid.
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| CN101323621B (en) * | 2007-06-11 | 2012-04-25 | 秦引林 | Process for synthesizing ginkgolide B derivative |
| CN101675925B (en) * | 2008-09-17 | 2012-05-23 | 秦引林 | Methanesulfonic amine ginkgolide B injection and preparation method thereof |
| CN102068426B (en) * | 2009-11-24 | 2013-01-02 | 秦引林 | New application of Ginkgolide B derivative in medicament preparation |
| CN103127059A (en) * | 2011-11-29 | 2013-06-05 | 秦引林 | Oral administration preparation composed of bilobalide B derivative and preparation method thereof |
| CN104098584B (en) * | 2013-04-03 | 2017-01-18 | 广东东阳光药业有限公司 | Ginkgolide B derivative and application thereof in medicines |
| CN105367582B (en) * | 2014-08-11 | 2019-06-25 | 广东东阳光药业有限公司 | Bilobalide B derivates and its application in drug |
| CN106892930B (en) | 2015-12-18 | 2020-02-18 | 成都百裕金阁莱药业有限公司 | Bilobalide B derivative and preparation method and application thereof |
| CN107304214B (en) * | 2016-04-18 | 2021-04-06 | 浙江康恩贝制药股份有限公司 | Water-soluble ginkgolide B carbamate derivative and preparation method and application thereof |
| CN117567480A (en) * | 2019-04-24 | 2024-02-20 | 复旦大学 | Ginkgolide B derivative and salt thereof, and preparation method and application thereof |
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| CN1837212A (en) | 2006-09-27 |
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