CN102603858B - Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof - Google Patents
Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof Download PDFInfo
- Publication number
- CN102603858B CN102603858B CN201210052425.8A CN201210052425A CN102603858B CN 102603858 B CN102603858 B CN 102603858B CN 201210052425 A CN201210052425 A CN 201210052425A CN 102603858 B CN102603858 B CN 102603858B
- Authority
- CN
- China
- Prior art keywords
- betulin
- grams
- nitogen
- mole
- ywd
- 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.)
- Expired - Fee Related
Links
- 0 CC(C)[C@](CC1)C(C2CC3)[C@@]1(CO*)CC[C@@]2(C)[C@](C)(CC1)C3[C@@](C)(CC2)C1C(C)(C)C2O* Chemical compound CC(C)[C@](CC1)C(C2CC3)[C@@]1(CO*)CC[C@@]2(C)[C@](C)(CC1)C3[C@@](C)(CC2)C1C(C)(C)C2O* 0.000 description 1
Abstract
The invention relates to an azacycle-containing derivative of betulinol represented by a formula (1), wherein R1 are selected from the following substances, and R2 are selected from H and the following substances. The invention also provides a preparation method of the derivative, and a purpose of the derivative in preparing anti-tumor medicines.
Description
Technical field
The present invention relates to pharmaceutical chemistry and therapeutics field, be specifically related to nitogen-contained heterocycle derivant, preparation method and the purposes as antitumor drug thereof of betulin.
Background technology
Betulin (Betulin) (different name birch camphor, trochol) is needle crystal, molecular formula: C
30h
50o
2molecular weight 442.70, molecular structural formula:
Betulin belongs to the pentacyclic triterpene vinyl compound of lupinane type, and the derivative betulinic acid of betulin is a kind of substantially nontoxic antineoplastic compound, and that carries out taking betulin as lead compound is semi-synthetic, has obtained the derivative of biological activity excellence.Below provide part document as a reference.
PCT/US2005/041043?2005.11.14
PCT/US2005/032363?2005.9.12
PCT/US2005/032460?2005.9.12
PCT/FI2007/050318?2007.6.1
PCT/AT2004/000045?2004.2.11
US5962527A?1999.10.5
US20020052352?2002.5.2
WO9629068A?1996.9.26
PCT/IN1999/000043?1999.9.9
Bioorganic?&?Medicinal?Chemistry?Letters?19(2009)4814-4817
Bioorganic?&?Medicinal?Chemistry?17(2009)6241-6250
Bioorganic?&?Medicinal?Chemistry?18(2010)4385-4396
Chemistry?of?Natural?Compounds?6(2005)692-700
Bioorganic?&?Medicinal?Chemistry?13(2005)3447-3454
Summary of the invention
An object of the present invention is to provide the nitogen-contained heterocycle derivant of strong, the water-soluble betulin significantly improving of the novel anti-tumor activity of a class.
Another object of the present invention is to provide the preparation method of the nitogen-contained heterocycle derivant of such betulin.
A further object of the present invention is to provide the application as antitumor drug of the nitogen-contained heterocycle derivant of such betulin and composition thereof.
To achieve these goals, the present invention is to provide the there is formula nitogen-contained heterocycle derivant of betulin of (1).
The nitogen-contained heterocycle derivant of especially following concrete betulin:
The present invention also provides the method for the nitogen-contained heterocycle derivant of the described betulin of preparation: the hydroxyl of betulin and acid anhydrides carry out after acylation, react with corresponding acid amides, prepare corresponding compound; Described acid anhydrides is selected from MALEIC ANHYDRIDE, Tetra hydro Phthalic anhydride, and described acid amides is selected from N, N '-carbonyl dimidazoles, N, N '-carbonyl diurethane (1,2,4-triazole).
The invention provides and be applicable to antitumor medicine composition, comprise and implement acceptable carrier in treatment above-mentioned arbitrary betulin derivatives of significant quantity and pharmacodynamics, this pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.
The invention still further relates to described betulin derivatives in the application of preparing in antitumor drug.External activity screening experiment shows that described betulin derivatives has obvious antitumor action and good dose-dependence.Taking Proliferation of Human Ovarian Cell be XB1309 as subject cell strain, measured the half-inhibition concentration (IC50) of betulin derivatives, the results are shown in Table 1:
Table 1: betulin derivatives is the half-inhibition concentration of XB1309 to ovarian cancer tumor cell
Embodiment
Below in conjunction with embodiment, the present invention is done further to retouch in detail elaboration:
There is the betulin derivatives of formula (1) structure, in formula, R
1be selected from
r
2be selected from H,
Comprising following particular compound:
The method of the betulin derivatives described in preparation, the hydroxyl of betulin and acid anhydrides carry out after acylation, react with corresponding acid amides, prepare corresponding compound; Described acid anhydrides is selected from MALEIC ANHYDRIDE, Tetra hydro Phthalic anhydride, and described acid amides is selected from N, N '-carbonyl dimidazoles, N, N '-carbonyl (1,2,4-triazole).
Described a kind of pharmaceutical composition, contains described arbitrary betulin derivatives, and acceptable carrier in pharmacodynamics.
Described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.
Described betulin derivatives is in the application of preparing in antitumor drug.
Derivative of the present invention and preparation method be narration in more detail in following embodiment, but embodiment is not construed as limiting the invention.
Embodiment 1 prepares 28-betulin maleic acid monoesters
4.43 grams of (0.01 mole) betulins are dissolved in 100 milliliters of methylene dichloride, add 5 milliliters of triethylamines, 0.98 gram of (0.01 mole) MALEIC ANHYDRIDE, reflux 8 hours, cooling, recovery part solvent, debris adds frozen water, separates out a large amount of white solids, extract with methylene dichloride (50 milliliters × 3), washing, anhydrous sodium sulfate drying, filters, steaming vibrating dichloromethane, residue silica gel column chromatography (sherwood oil: ethyl acetate=1: 1), obtain 4.32 grams of oyster white 28-betulin maleic acid monoesters, yield 80%.
Embodiment 2 prepares 28-betulin maleic acid ester
4.43 grams of (0.01 mole) betulins are dissolved in 100 milliliters of methylene dichloride, add 10 milliliters of pyridines, 2.94 grams of (0.03 mole) MALEIC ANHYDRIDE, reflux 8 hours, cooling, recovery part solvent, debris adds frozen water, separate out a large amount of white solids, with methylene dichloride (50 milliliters × 3) extraction, washing, anhydrous sodium sulfate drying, filter, steaming vibrating dichloromethane, residue silica gel column chromatography (methyl alcohol: chloroform=1: 9), obtain white 3,4.78 grams of 28-betulin maleic acid esters, yield 75%.
Embodiment 3 prepares 28-betulin phthalic monoester
(1) 4.43 grams of (0.01 mole) betulins are dissolved in 100 milliliters of chloroforms, add 5 milliliters of pyridines, 1.48 grams of (0.01 mole) Tetra hydro Phthalic anhydrides, reflux 12 hours, cooling, recovery part solvent, debris adds frozen water, separates out a large amount of white solids, extract with chloroform (50 milliliters × 3), washing, anhydrous sodium sulfate drying, filters, boil off chloroform, residue silica gel column chromatography (sherwood oil: ethyl acetate=1: 2), obtain 4.38 grams of oyster white 28-betulin phthalic monoesters, yield 74%.
Embodiment 4 prepares 3,28-betulin Bisphthalate
4.43 grams of (0.01 mole) betulins are dissolved in 100 milliliters of chloroforms, add 10 milliliters of pyridines, 4.44 grams of (0.03 mole) Tetra hydro Phthalic anhydrides, reflux 18 hours, cooling, recovery part solvent, debris adds frozen water, separate out a large amount of white solids, with chloroform (50 milliliters × 3) extraction, washing, anhydrous sodium sulfate drying, filter, boil off chloroform, residue silica gel column chromatography (methyl alcohol: chloroform=2: 8), obtain white 3,7.18 grams of 28-betulin Bisphthalates, yield 68%.
Embodiment 5 prepares derivative YWD-1
2.70 grams of (0.005 mole) 28-betulin maleic acid monoesters are dissolved in 100 milliliters of tetrahydrofuran (THF)s; add 0.81 gram of (0.005 mole) N; N '-carbonyl dimidazoles; under nitrogen protection; room temperature reaction 1 hour, concentrating under reduced pressure desolventizes, enriched material silica gel column chromatography (sherwood oil: ethyl acetate=1: 2); obtain 1.75 grams of leukoderivative YWD-1, yield 59%.
Embodiment 6 prepares derivative YWD-2
2.70 grams of (0.005 mole) 28-betulin maleic acid monoesters are dissolved in 100 milliliters of tetrahydrofuran (THF)s; add 2.43 grams of (0.015 mole) N; N '-carbonyl dimidazoles; under nitrogen protection, heating reflux reaction 10 hours, is cooled to room temperature; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (ethyl acetate), obtains 2.37 grams of leukoderivative YWD-2, yield 70%.
Embodiment 7 prepares derivative YWD-3
By 3.19 grams of (0.005 moles) 3; 28-betulin maleic acid ester is dissolved in 100 milliliters of tetrahydrofuran (THF)s; add 2.43 grams of (0.015 mole) N; N '-carbonyl dimidazoles, under nitrogen protection, room temperature reaction 3 hours; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (2-butanone), obtains 2.42 grams of leukoderivative YWD-3, yield 66%.
Embodiment 8 prepares derivative YWD-4
2.70 grams of (0.005 mole) 28-betulin maleic acid monoesters are dissolved in 100 milliliters of tetrahydrofuran (THF)s; add 0.82 gram of (0.005 mole) N; N '-carbonyl diurethane (1,2,4-triazole); under nitrogen protection; room temperature reaction 5 hours, concentrating under reduced pressure desolventizes, enriched material silica gel column chromatography (sherwood oil: ethyl acetate=1: 3); obtain 1.88 grams of leukoderivative YWD-4, yield 70%.
Embodiment 9 prepares derivative YWD-5
2.70 grams of (0.005 mole) 28-betulin maleic acid monoesters are dissolved in 100 milliliters of tetrahydrofuran (THF)s; add 2.46 grams of (0.015 mole) N, N '-carbonyl diurethane (1,2; 4-triazole); under nitrogen protection, heating reflux reaction 10 hours, is cooled to room temperature; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (ethyl acetate), obtains 2.19 grams of leukoderivative YWD-5, yield 81%.
Embodiment 10 prepares derivative YWD-6
By 3.19 grams of (0.005 moles) 3; 28-betulin maleate is dissolved in 100 milliliters of tetrahydrofuran (THF)s, adds 2.46 grams of (0.015 mole) N, N '-carbonyl diurethane (1; 2; 4-triazole), under nitrogen protection, room temperature reaction 7 hours; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (2-butanone), obtains 2.14 grams of leukoderivative YWD-6, yield 58%.
Embodiment 11 prepares derivative YWD-7
2.95 grams of (0.005 mole) 28-betulin phthalic monoesters are dissolved in 150 milliliters of tetrahydrofuran (THF)s; add 0.81 gram of (0.005 mole) N; N '-carbonyl dimidazoles; under nitrogen protection; room temperature reaction 24 hours, concentrating under reduced pressure desolventizes, enriched material silica gel column chromatography (sherwood oil: ethyl acetate=3: 7); obtain 1.95 grams of leukoderivative YWD-7, yield 61%.
Embodiment 12 prepares derivative YWD-8
2.95 grams of (0.005 mole) 28-betulin phthalic monoesters are dissolved in 150 milliliters of tetrahydrofuran (THF)s; add 2.43 grams of (0.015 mole) N; N '-dicarbapentaborane diimidazole; under nitrogen protection, heating reflux reaction 16 hours, is cooled to room temperature; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (ethyl acetate), obtains 2.20 grams of leukoderivative YWD-8, yield 60%.
Embodiment 13 prepares derivative YWD-9
(2) by 3.69 grams of (0.005 moles) 3; 28-betulin Bisphthalate is dissolved in 150 milliliters of tetrahydrofuran (THF)s; add 2.43 grams of (0.015 mole) N; N '-dicarbapentaborane diimidazole, under nitrogen protection, room temperature reaction 11 hours; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (2-butanone), obtains 3.16 grams of leukoderivative YWD-9, yield 75%.
Embodiment 14 prepares derivative YWD-10
(2) 2.95 grams of (0.005 mole) 28-betulin phthalic monoesters are dissolved in 150 milliliters of tetrahydrofuran (THF)s; add 0.82 gram of (0.005 mole) N; N '-carbonyl diurethane (1,2,4-triazole); under nitrogen protection; room temperature reaction 24 hours, concentrating under reduced pressure desolventizes, enriched material silica gel column chromatography (sherwood oil: ethyl acetate=1: 4); obtain 2.18 grams of leukoderivative YWD-10, yield 68%.
Embodiment 15 prepares derivative YWD-11
2.95 grams of (0.005 mole) 28-betulin phthalic monoesters are dissolved in 150 milliliters of tetrahydrofuran (THF)s; add 2.46 grams of (0.015 mole) N, N '-carbonyl diurethane (1,2; 4-triazole); under nitrogen protection, heating reflux reaction 16 hours, is cooled to room temperature; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (ethyl acetate), obtains 2.16 grams of leukoderivative YWD-11, yield 58%.
Embodiment 16 prepares derivative YWD-12
By 3.69 grams of (0.005 moles) 3; 28-betulin phthalic ester is dissolved in 150 milliliters of tetrahydrofuran (THF)s, adds 2.46 grams of (0.015 mole) N, N '-carbonyl diurethane (1; 2; 4-triazole), under nitrogen protection, room temperature reaction 5 hours; concentrating under reduced pressure desolventizes; enriched material silica gel column chromatography (2-butanone), obtains 3.48 grams of leukoderivative YWD-12, yield 82%.
Embodiment 17
Derivative YWD-2 is dissolved in the ethanol of minimum volume, this derivative can also be dissolved in methyl alcohol, Virahol, dimethyl sulfoxide (DMSO) or any other suitable solvent.Add concentration in the 2-hydroxypropyl beta-cyclodextrin aqueous solution of 30 mg/ml taking little aliquots containig the betulin derivatives of this dissolving, and carry out supersound process until obtain clear soln at low temperatures, remove organic solvent by rotary evaporation, by gained solution filter, sterilizing.By final solution freeze-drying.
Claims (6)
3. a method of preparing the nitogen-contained heterocycle derivant of the betulin described in claim 1 or 2, is characterized in that: betulin and acid anhydrides carry out after acylation, then reacts with corresponding acid amides, prepares corresponding compound; Described acid anhydrides is selected from MALEIC ANHYDRIDE, Tetra hydro Phthalic anhydride; Described acid amides is selected from N, N '-carbonyl dimidazoles, N, N '-carbonyl diurethane (1,2,4-triazole).
4. a pharmaceutical composition, the nitogen-contained heterocycle derivant that contains the arbitrary betulin described in claim 1 or 2, and acceptable carrier in pharmacodynamics.
5. pharmaceutical composition as claimed in claim 4, it is tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.
6. the nitogen-contained heterocycle derivant of the betulin described in any one as claimed in claim 1 or 2 is in the application of preparing in antitumor drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210052425.8A CN102603858B (en) | 2012-03-02 | 2012-03-02 | Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210052425.8A CN102603858B (en) | 2012-03-02 | 2012-03-02 | Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102603858A CN102603858A (en) | 2012-07-25 |
CN102603858B true CN102603858B (en) | 2014-07-02 |
Family
ID=46521679
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210052425.8A Expired - Fee Related CN102603858B (en) | 2012-03-02 | 2012-03-02 | Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102603858B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104292468B (en) * | 2014-09-28 | 2017-05-10 | 哈尔滨理工大学 | Amphiprotic compound containing betulinic acid and preparation method and application thereof |
CN105884853B (en) * | 2016-04-11 | 2017-10-20 | 哈尔滨理工大学 | Phospholipid analogues, Preparation method and use containing betulinic acid |
CN105837652B (en) * | 2016-04-12 | 2017-10-13 | 哈尔滨理工大学 | Betulinic acid phosphatide complexes, Preparation method and use |
CN115626946B (en) * | 2022-09-26 | 2024-04-09 | 湖南省中医药研究院 | Betulol-carprofen derivative, self-assembled nano particles thereof and application of derivative in preparation of anti-lung cancer drugs |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002026762A1 (en) * | 2000-09-29 | 2002-04-04 | Regents Of The University Of Minnesota | Triterpenes having antibacterial activity |
CN1373769A (en) * | 1999-09-09 | 2002-10-09 | 达布尔研究基金会 | Betulinic acid derivs, having antiangiogenic activity, processes for producing such derivs. and their use for treating tumor associated angiogenesis |
CN101084234A (en) * | 2004-09-10 | 2007-12-05 | 康乃尔研究基金会有限公司 | Betulinol derivatives as anti-cancer agents |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004089357A2 (en) * | 2003-04-02 | 2004-10-21 | Regents Of The University Of Minnesota | Anti-fungal formulation of triterpene and essential oil |
US20060252733A1 (en) * | 2005-04-07 | 2006-11-09 | Novelix Pharmaceuticals, Inc. | Betulin, betulin derivatives, betulinic acid and betulinic acid derivatives as novel therapeutics in the treatment of disease of lipid and/or glucose metabolism |
-
2012
- 2012-03-02 CN CN201210052425.8A patent/CN102603858B/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1373769A (en) * | 1999-09-09 | 2002-10-09 | 达布尔研究基金会 | Betulinic acid derivs, having antiangiogenic activity, processes for producing such derivs. and their use for treating tumor associated angiogenesis |
WO2002026762A1 (en) * | 2000-09-29 | 2002-04-04 | Regents Of The University Of Minnesota | Triterpenes having antibacterial activity |
CN101084234A (en) * | 2004-09-10 | 2007-12-05 | 康乃尔研究基金会有限公司 | Betulinol derivatives as anti-cancer agents |
Also Published As
Publication number | Publication date |
---|---|
CN102603858A (en) | 2012-07-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104447777B (en) | A kind of capsaicin-camptothecin cancer therapy drug conjugate and its preparation method and application | |
CN102603858B (en) | Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof | |
CN109575099A (en) | Dammarane saponins member derivative and its preparation method and application | |
CN102040592B (en) | Coumarin azole compound with antimicrobial activity, and preparation method and medicinal application thereof | |
CN103980276A (en) | Quercetin caffeine eutectic | |
CN104151391A (en) | Oleanolic acid derivative having antineoplastic effect, preparation method and purpose thereof | |
CN103880856B (en) | Bisabolane sesquiterpene derivant and pharmaceutical composition thereof and its application in pharmacy | |
CN111333694B (en) | Application of hederagenin derivative in medicine for resisting myocardial anoxia reoxygenation injury | |
CN104004037B (en) | 8-position methylamine like derivative of baicalin and ester thereof and preparation method thereof | |
CN105622497A (en) | Isoliquiritigenin pyrazinamide eutectic crystal and preparation method thereof | |
CN102908340B (en) | Isolicoflavonol-containing antitumor drug and application thereof | |
CN107286220A (en) | Dihydromyricetin derivative of 1,2,4 triazoles coupling and its preparation method and application | |
CN101029034B (en) | Polyenic taxol soluble derivative, its preparation and use | |
CN102690317B (en) | Derivant of 30-halogenated betulinic acid and preparation method and application thereof | |
CN101182345B (en) | Ursolic acid oxazoline new drugs having antiphlogistic activity and preparation method thereof | |
CN104211650A (en) | Ligustrazine fumarate, and preparation method and medicinal composition thereof | |
CN109734768B (en) | Deacetylated cedilanid glucose-based modified compound liposome and application thereof | |
CN101085804A (en) | Method for preparing lonicera macranthoides hypo-saponin B and application of the same in curing liver cancer, breast carcinoma and cervical cancer | |
CN102344482A (en) | Betulinol derivant, preparation method and usage | |
CN104546881A (en) | Application of degalactotigonin and derivative thereof in preparation of broad-spectrum antitumor medicine | |
CN103172555B (en) | Indole alkaloid compound separated from rhizoma cimicifugae as well as preparation method and application thereof | |
CN104402964A (en) | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof | |
CN106187806A (en) | A kind of α-crocetin derivant GX F and preparation method thereof and the application in prevention or treatment cardiovascular and cerebrovascular disease | |
CN106187949A (en) | A kind of α-crocetin derivant GX B and preparation method thereof and the application in prevention or treatment cardiovascular and cerebrovascular disease | |
CN107304223A (en) | Bortezomib crystal form and its production and use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140702 Termination date: 20210302 |
|
CF01 | Termination of patent right due to non-payment of annual fee |