CN102603858A - 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
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- CN102603858A CN102603858A CN2012100524258A CN201210052425A CN102603858A CN 102603858 A CN102603858 A CN 102603858A CN 2012100524258 A CN2012100524258 A CN 2012100524258A CN 201210052425 A CN201210052425 A CN 201210052425A CN 102603858 A CN102603858 A CN 102603858A
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- SORYYJFDKGHNJH-KRTJEAQXSA-N CC(C)[C@H](CC1)C(C2CC3)[C@@]1(COC(/C=C\C([n]1cncc1)=O)=O)CC[C@@]2(C)[C@](C)(CC1)C3[C@@](C)(CC2)C1C(C)(C)[C@H]2OC(/C=C\C([n]1cncc1)=O)=O Chemical compound CC(C)[C@H](CC1)C(C2CC3)[C@@]1(COC(/C=C\C([n]1cncc1)=O)=O)CC[C@@]2(C)[C@](C)(CC1)C3[C@@](C)(CC2)C1C(C)(C)[C@H]2OC(/C=C\C([n]1cncc1)=O)=O SORYYJFDKGHNJH-KRTJEAQXSA-N 0.000 description 1
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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 the nitogen-contained heterocycle derivant, preparation method of betulol and as the purposes of antitumor drug.
Background technology
Betulol (Betulin) (different name birch camphor, trochol) is a needle crystal, molecular formula: C
30H
50O
2Molecular weight 442.70, molecular structural formula:
Betulol belongs to the pentacyclic triterpene vinyl compound of lupinane type, the verivate betulinic ncid of betulol is a kind of nontoxic basically antineoplastic compound, with the betulol be lead compound carry out semi-synthetic, obtained the excellent verivate of biological activity.Below provide the 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 one type of strong, water-soluble betulol that significantly improves of novel anti-tumor activity.
Another object of the present invention provides the preparation method of the nitogen-contained heterocycle derivant of such betulol.
A further object of the present invention provides the application as antitumor drug of nitogen-contained heterocycle derivant and the compsn thereof of such betulol.
To achieve these goals, the present invention is to provide the have formula nitogen-contained heterocycle derivant of betulol of (1).
In the formula, R
1Be selected from
R
2Be selected from H,
The nitogen-contained heterocycle derivant of especially following concrete betulol:
The present invention also provides the method for the nitogen-contained heterocycle derivant for preparing described betulol: after the hydroxyl of betulol and acid anhydrides carry out acylation, and with the corresponding amide reaction, the preparation corresponding compounds; 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, the 4-triazole).
The invention provides and be applicable to antitumor medicine composition; Comprise acceptable carrier on the above-mentioned arbitrary betulin derivatives of implementing the treatment significant quantity and the 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 the application of described betulin derivatives in the preparation antitumor drug.The external activity screening experiment shows that described betulin derivatives has obvious antineoplastic and good dose-dependent relationship.With Proliferation of Human Ovarian Cell is that XB1309 is the subject cell strain, has measured the half-inhibition concentration (IC50) of betulin derivatives, and the result sees table 1:
Table 1: betulin derivatives is to the half-inhibition concentration of oophoroma tumor clone XB1309
Embodiment
Below in conjunction with embodiment the present invention is done further to retouch in detail elaboration:
Betulin derivatives with formula (1) structure, in the formula, R
1Be selected from
R
2Be selected from H,
Comprising following particular compound:
The method for preparing described betulin derivatives, after the hydroxyl of betulol and acid anhydrides carry out acylation, with the corresponding amide reaction, the preparation corresponding compounds; 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, the 4-triazole).
Described a kind of pharmaceutical composition contains described arbitrary betulin derivatives, and acceptable carrier on the pharmacodynamics.
Described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.
The application of described betulin derivatives in the preparation antitumor drug.
Verivate 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 preparation 28-betulol maleic acid monoesters
4.43 gram (0.01 mole) betulols are dissolved in 100 milliliters of methylene dichloride, add 5 milliliters of triethylamines, 0.98 gram (0.01 mole) MALEIC ANHYDRIDE, reflux 8 hours; Cooling, the recovery part solvent, debris adds frozen water; Separate out a large amount of white solids, extract, washing with methylene dichloride (50 milliliters * 3); Anhydrous sodium sulfate drying filters steaming vibrating dichloromethane; Residue silica gel column chromatography (sherwood oil: ETHYLE ACETATE=1: 1), get oyster white 28-betulol maleic acid monoesters 4.32 grams, yield 80%.
Embodiment 2 preparation 28-betulol maleic acid esters
4.43 gram (0.01 mole) betulols are dissolved in 100 milliliters of methylene dichloride, add 10 milliliters of pyridines, 2.94 gram (0.03 mole) MALEIC ANHYDRIDEs, reflux 8 hours; Cooling, the recovery part solvent, debris adds frozen water, separates out a large amount of white solids; Extract washing, anhydrous sodium sulfate drying with methylene dichloride (50 milliliters * 3); Filter steaming vibrating dichloromethane, residue silica gel column chromatography (methyl alcohol: chloroform=1: 9); White 3,28-betulol maleic acid ester 4.78 grams, yield 75%.
Embodiment 3 preparation 28-betulol phthalic monoesters
(1) 4.43 gram (0.01 mole) betulols is dissolved in 100 milliliters of chloroforms, adds 5 milliliters of pyridines, 1.48 gram (0.01 mole) Tetra hydro Phthalic anhydrides, reflux 12 hours; Cooling, the 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: ETHYLE ACETATE=1: 2), get oyster white 28-betulol phthalic monoester 4.38 grams, yield 74%.
Embodiment 4 preparations 3,28-betulol Bisphthalate
4.43 gram (0.01 mole) betulols are dissolved in 100 milliliters of chloroforms, add 10 milliliters of pyridines, 4.44 gram (0.03 mole) Tetra hydro Phthalic anhydrides, reflux 18 hours, cooling; The recovery part solvent, debris adds frozen water, separates out a large amount of white solids, extracts with chloroform (50 milliliters * 3); Washing, anhydrous sodium sulfate drying filters, and boils off chloroform; The residue silica gel column chromatography (methyl alcohol: chloroform=2: 8), white 3,28-betulol Bisphthalate 7.18 grams, yield 68%.
Embodiment 5 preparation verivate YWD-1
2.70 gram (0.005 mole) 28-betulol maleic acid monoesters are dissolved in 100 milliliters of THFs, add 0.81 gram (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: ETHYLE ACETATE=1: 2); Get 1.75 gram leukoderivative YWD-1, yield 59%.
Embodiment 6 preparation verivate YWD-2
2.70 gram (0.005 mole) 28-betulol maleic acid monoesters is dissolved in 100 milliliters of THFs, adds 2.43 gram (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 (ETHYLE ACETATE) gets 2.37 gram leukoderivative YWD-2, yield 70%.
Embodiment 7 preparation verivate YWD-3
With 3.19 gram (0.005 moles) 3,28-betulol maleic acid ester is dissolved in 100 milliliters of THFs, adds 2.43 gram (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) gets 2.42 gram leukoderivative YWD-3, yield 66%.
Embodiment 8 preparation verivate YWD-4
2.70 gram (0.005 mole) 28-betulol maleic acid monoesters are dissolved in 100 milliliters of THFs, add 0.82 gram (0.005 mole) N, N '-carbonyl diurethane (1; 2, the 4-triazole), under nitrogen protection; Room temperature reaction 5 hours, concentrating under reduced pressure desolventizes, enriched material silica gel column chromatography (sherwood oil: ETHYLE ACETATE=1: 3); Get 1.88 gram leukoderivative YWD-4, yield 70%.
Embodiment 9 preparation verivate YWD-5
2.70 gram (0.005 mole) 28-betulol maleic acid monoesters are dissolved in 100 milliliters of THFs, add 2.46 gram (0.015 mole) N, N '-carbonyl diurethane (1; 2, the 4-triazole), under nitrogen protection; Heating reflux reaction 10 hours is cooled to room temperature, and concentrating under reduced pressure desolventizes; Enriched material silica gel column chromatography (ETHYLE ACETATE) gets 2.19 gram leukoderivative YWD-5, yield 81%.
Embodiment 10 preparation verivate YWD-6
With 3.19 gram (0.005 moles) 3,28-betulol maleate is dissolved in 100 milliliters of THFs, adds 2.46 gram (0.015 mole) N; N '-carbonyl diurethane (1,2, the 4-triazole); Under nitrogen protection, room temperature reaction 7 hours, concentrating under reduced pressure desolventizes; Enriched material silica gel column chromatography (2-butanone) gets 2.14 gram leukoderivative YWD-6, yield 58%.
Embodiment 11 preparation verivate YWD-7
2.95 gram (0.005 mole) 28-betulol phthalic monoesters are dissolved in 150 milliliters of THFs, add 0.81 gram (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: ETHYLE ACETATE=3: 7); Get 1.95 gram leukoderivative YWD-7, yield 61%.
Embodiment 12 preparation verivate YWD-8
2.95 gram (0.005 mole) 28-betulol phthalic monoesters are dissolved in 150 milliliters of THFs, add 2.43 gram (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 (ETHYLE ACETATE) gets 2.20 gram leukoderivative YWD-8, yield 60%.
Embodiment 13 preparation verivate YWD-9
(2) with 3.69 gram (0.005 moles) 3,28-betulol Bisphthalate is dissolved in 150 milliliters of THFs, adds 2.43 gram (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) gets 3.16 gram leukoderivative YWD-9, yield 75%.
Embodiment 14 preparation verivate YWD-10
(2) 2.95 gram (0.005 mole) 28-betulol phthalic monoesters are dissolved in 150 milliliters of THFs, add 0.82 gram (0.005 mole) N, N '-carbonyl diurethane (1; 2, the 4-triazole), under nitrogen protection; Room temperature reaction 24 hours, concentrating under reduced pressure desolventizes, enriched material silica gel column chromatography (sherwood oil: ETHYLE ACETATE=1: 4); Get 2.18 gram leukoderivative YWD-10, yield 68%.
Embodiment 15 preparation verivate YWD-11
2.95 gram (0.005 mole) 28-betulol phthalic monoesters are dissolved in 150 milliliters of THFs, add 2.46 gram (0.015 mole) N, N '-carbonyl diurethane (1; 2, the 4-triazole), under nitrogen protection; Heating reflux reaction 16 hours is cooled to room temperature, and concentrating under reduced pressure desolventizes; Enriched material silica gel column chromatography (ETHYLE ACETATE) gets 2.16 gram leukoderivative YWD-11, yield 58%.
Embodiment 16 preparation verivate YWD-12
With 3.69 gram (0.005 moles) 3,28-betulol phthalic ester is dissolved in 150 milliliters of THFs, adds 2.46 gram (0.015 mole) N; N '-carbonyl diurethane (1,2, the 4-triazole); Under nitrogen protection, room temperature reaction 5 hours, concentrating under reduced pressure desolventizes; Enriched material silica gel column chromatography (2-butanone) gets 3.48 gram leukoderivative YWD-12, yield 82%.
Embodiment 17
Verivate YWD-2 is dissolved in the ethanol of minimum volume, this verivate can also be dissolved in methyl alcohol, Virahol, DMSO 99.8MIN. or any other The suitable solvent.It is in the 2-hydroxypropyl beta-cyclodextrin aqueous solution of 30 mg/ml that this dissolved betulin derivatives is added concentration with little aliquots containig; And carry out supersound process at low temperatures until obtaining clear soln; Remove organic solvent through rotary evaporation, gained solution is filtered, sterilizes.With final solution freeze-drying.
Claims (6)
1. the nitogen-contained heterocycle derivant of the betulol shown in the formula (1)
Wherein, R
1Be selected from
R
2Be selected from H,
2. the nitogen-contained heterocycle derivant of betulol as claimed in claim 1 is specially following compound:
3. a method for preparing the nitogen-contained heterocycle derivant of claim 1 or 2 described betulols is characterized in that: after betulol and acid anhydrides carry out acylation, with the corresponding amide reaction, prepare corresponding compounds again; 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, the 4-triazole).
4. pharmaceutical composition contains the nitogen-contained heterocycle derivant of claim 1 or 2 described arbitrary betulols and acceptable carrier on the pharmacodynamics thereof.
5. pharmaceutical composition as claimed in claim 4 can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.
6. according to claim 1 or claim 2 the nitogen-contained heterocycle derivant of each described betulol is in the application of preparation in the antitumor drug.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105837652A (en) * | 2016-04-12 | 2016-08-10 | 哈尔滨理工大学 | Betulinic acid-phosphatide composites, and preparing method and uses thereof |
| CN105884853A (en) * | 2016-04-11 | 2016-08-24 | 哈尔滨理工大学 | Phospholipid analogue containing betulinic acid, preparing method and application |
| 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 |
| CN115626946A (en) * | 2022-09-26 | 2023-01-20 | 湖南省中医药研究院 | Betulol-carprofen derivative, self-assembled nanoparticles thereof and application of betulin-carprofen derivative in preparation of anti-lung cancer drugs |
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| 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 |
| US20050014730A1 (en) * | 2003-04-02 | 2005-01-20 | Carlson Robert M. | 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 |
| 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 |
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2012
- 2012-03-02 CN CN201210052425.8A patent/CN102603858B/en not_active Expired - Fee Related
Patent Citations (5)
| 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 |
| US20050014730A1 (en) * | 2003-04-02 | 2005-01-20 | Carlson Robert M. | Anti-fungal formulation of triterpene and essential oil |
| 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 |
| 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 |
Cited By (5)
| 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 |
| CN105884853A (en) * | 2016-04-11 | 2016-08-24 | 哈尔滨理工大学 | Phospholipid analogue containing betulinic acid, preparing method and application |
| CN105837652A (en) * | 2016-04-12 | 2016-08-10 | 哈尔滨理工大学 | Betulinic acid-phosphatide composites, and preparing method and uses thereof |
| CN115626946A (en) * | 2022-09-26 | 2023-01-20 | 湖南省中医药研究院 | Betulol-carprofen derivative, self-assembled nanoparticles thereof and application of betulin-carprofen derivative in preparation of anti-lung cancer drugs |
| 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 |
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| CN102603858B (en) | 2014-07-02 |
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