CN109897048A - 10-Methoxycamptothecine glycinate, preparation method and purposes - Google Patents
10-Methoxycamptothecine glycinate, preparation method and purposes Download PDFInfo
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- CN109897048A CN109897048A CN201910229651.0A CN201910229651A CN109897048A CN 109897048 A CN109897048 A CN 109897048A CN 201910229651 A CN201910229651 A CN 201910229651A CN 109897048 A CN109897048 A CN 109897048A
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- methoxycamptothecine
- glycinate
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Abstract
The present invention provides 10-Methoxycamptothecine glycinate shown in formula (1), the present invention also provides the preparation method of the analog derivative and is preparing the purposes on anti-tumor drug.
Description
Technical field
The present invention relates to pharmaceutical chemistry and therapeutic field, and in particular to water-soluble 10-Methoxycamptothecine glycinate,
Preparation method and the usage.
Background technique
Camptothecine (Camptothecin, CPT) is to be extracted from China endemic plant camplotheca acuminata by Wall et al. for 1966
The alkaloid arrived.In the external activity screening of early stage, camptothecine shows stronger anti-tumor activity, to a variety of entity tumors
It is significantly inhibited with leukaemia.But camptothecine poorly water-soluble, toxic side effect are strong, therefore limit it in oncotherapy
On application.10-Methoxycamptothecine (10-methoxycamptothecin) is the natural derivative of camptothecine, antitumor work
Property be better than camptothecine, but toxicity is also stronger.The discovery camptothecine such as Hsiang Y. H. in 1985 is by inhibiting topoisomerase I
Cytotoxic activity is played, is attracted attention again.Many researchers start to devote repairing for camptothecine chemical structure
Decorations and improvement are dedicated to improving it in the intracorporal Absorption of people and enhancing therapeutic effect.So far, U.S.'s food and medicine pipe
Two kinds of camptothecin derivative listings of reason office (FDA) approved Topotecan and Irinotecan are for treating recurrent ovarian
Cancer, rectal/colon cancer.It is another there are many derivative for example 9-nitrocamptothecin, 9-aminocamptothecin, CKD-602, DX-9815f,
GI-147211 is carrying out the clinical research of different phase.The Alpha-hydroxy lactonic ring being closed in camptothecine structure is that it keeps anti-
The required structure of tumor promotion, but the facile hydrolysis open loop in human body of this Alpha-hydroxy lactonic ring forms carboxylate structure, this open loop
Form easily makes it lose anti-tumor activity in conjunction with human albumin.
10-Methoxycamptothecine chemical structural formula.
Summary of the invention
It is an object of the present invention to provide new high-efficiency low-toxicity, the sweet amino acid of the 10-Methoxycamptothecine of good water solubility
Ester.
It is a further object to provide the preparation methods of the sweet amino-acid ester of 10-Methoxycamptothecine.
It is also another object of the present invention to provide sweet amino-acid esters of 10-Methoxycamptothecine and combinations thereof as antitumor
The application of drug.
To achieve the goals above, the present invention is to provide the 10-Methoxycamptothecine glycine with structural formula (1)
Ester.
(1).
The preparation method of the 10-Methoxycamptothecine glycinate provided by the invention, 10-Methoxycamptothecine with
N- t-butoxycarbonyl glycine carries out esterification under the action of coupling agent and catalyst, handles to obtain using organic acid later
10-Methoxycamptothecine glycinate described in claim 1；The organic acid is acetic acid or trifluoroacetic acid.
The invention further relates to containing as on the compounds of this invention and pharmacodynamics of active constituent acceptable carriers it is various
Preparation.
" acceptable carriers in pharmacodynamics " refer to: one or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use, and have enough purity and sufficiently low toxicity.It is each in " compatibility " referred to herein as composition
Component energy and the compound of the present invention and they between mutually blend, and significantly reduce the drug effect of compound.In pharmacodynamics
Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato starch),
Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum, solid
Lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as oily beans, sesame oil, peanut oil, olive oil), polyalcohol
(such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as tween), lubricant (such as lauryl sodium sulfate), coloring
Agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The invention further relates to compound application in preparations of anti-tumor drugs of the present invention.
External activity screening experiment shows to have the 10-Methoxycamptothecine glycinate of structural formula (1) to have significantly
Antitumor action and good dose-dependence.
Specific embodiment
Further retouch elaboration in detail to present invention work below with reference to embodiment: the present invention is to provide with structural formula (1)
10-Methoxycamptothecine glycinate.
(1).
The preparation method of the 10-Methoxycamptothecine glycinate provided by the invention, 10-Methoxycamptothecine with
N- t-butoxycarbonyl glycine carries out esterification under the action of coupling agent and catalyst, handles to obtain using organic acid later
10-Methoxycamptothecine glycinate described in claim 1；The organic acid is acetic acid or trifluoroacetic acid.
The invention further relates to containing as on the compounds of this invention and pharmacodynamics of active constituent acceptable carriers it is various
Preparation.
" acceptable carriers in pharmacodynamics " refer to: one or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use, and have enough purity and sufficiently low toxicity.It is each in " compatibility " referred to herein as composition
Component energy and the compound of the present invention and they between mutually blend, and significantly reduce the drug effect of compound.In pharmacodynamics
Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato starch),
Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum, solid
Lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as oily beans, sesame oil, peanut oil, olive oil), polyalcohol
(such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as tween), lubricant (such as lauryl sodium sulfate), coloring
Agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The invention further relates to compound application in preparations of anti-tumor drugs of the present invention.
The preparation of embodiment 1 10-Methoxycamptothecine -20-O- (N '-tertbutyloxycarbonyl) glycinate
0.52 gram of (N '-tertbutyloxycarbonyl) glycine is dissolved in 20 milliliters of dimethyl sulfoxides, 0.2 gram is added under stirring condition
10-Methoxycamptothecine, 0.4 gram of CDI and 0.06 gram of DMAP react 24 hours at room temperature, and filtering, filtrate is distilled with 100 milliliters
Water dilution, is precipitated white precipitate, and by precipitating filtering, washing, drying, pillar layer separation obtains 156 milligrams of faint yellow solids and (produces
Rate 78%).
1HNMR (400MHz, DMSO-d6, ppm): δ0.94 (3H, t, H-18), 1.32 (9H, s, t-
boc), 2.13 (2H, m, H-19), 3.81 (1H, dd, C-H), 3.90 (3H, s , OCH3), 3.98 (1H,
dd, C-H), 5.17 (2H, s, H-5), 5.48 (2H, s, H-17) ,7.13 (1H, s, H-14), 7.43
(1H, d, H-11), 7.44 (1H, t, N-H), 7.47 (1H, d, H-9), 7.97 (1H, d, H-12), 8.44
(1H, s, H-7)；ESIMS:m/z 533.3 (M+H)+。
The preparation of 2 10-Methoxycamptothecine -20-O- glycine ester hydrochloride of embodiment
100 milligrams of 10-Methoxycamptothecine -20-O- (N '-tertbutyloxycarbonyl) glycinate is dissolved in 20 milliliters of 4M HCl tetrahydros
It in furans, is stirred to react at room temperature 4 hours, is concentrated under reduced pressure and removes solvent, 100 milliliters of distillation water washings of concentrate filter, and collect
Filtrate, freeze-drying water removal will be lyophilized residue pillar layer separation (mobile phase are as follows: methylene chloride: methanol: water=10:1:0.05), obtain
To 0.46 milligram of faint yellow solid (yield 51%).
1HNMR (400MHz, DMSO-d6, ppm): δ0.94 (3H, t, H-18), 2.13 (2H, m, H-
19), 2.73(2H, t, N-H) 3.81 (1H, dd, C-H), 3.90 (3H, s, OCH3), 3.98 (1H, dd,
C-H), 5.17 (2H, s, H-5), 5.48 (2H, s, H-17) ,7.13 (1H, s, H-14), 7.43 (1H, d,
H-11),7.47 (1H, d, H-9), 7.97 (1H, d, H-12), 8.44 (1H, s, H-7)；ESIMS:m/z
429.7 (M+H)+。
Claims (5)
- The structural formula such as (1) of 1.10- methoxycamptothecine glycinate:(1).
- 2. a kind of method for preparing 10-Methoxycamptothecine glycinate described in claim 1, it is characterised in that 10- methoxy Base camptothecine and N- t-butoxycarbonyl glycine carry out esterification under the action of coupling agent and catalyst, later using organic Acid processing obtains 10-Methoxycamptothecine glycinate described in claim 1；The organic acid is acetic acid or trifluoro second Acid.
- 3. a kind of pharmaceutical composition contains acceptable carrier in any compound described in claim 1 and pharmacodynamics.
- 4. pharmaceutical composition according to claim 3, it is characterised in that the pharmaceutical composition can be tablet, capsule, ball Agent, injection, sustained release preparation, controlled release preparation or various particulate delivery systems.
- 5. compound application in preparation of anti-tumor drugs described in claim 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400619A (en) * | 2018-12-25 | 2019-03-01 | 东北林业大学 | 10-Methoxycamptothecine soluble derivative, preparation method and purposes |
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2019
- 2019-03-25 CN CN201910229651.0A patent/CN109897048A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400619A (en) * | 2018-12-25 | 2019-03-01 | 东北林业大学 | 10-Methoxycamptothecine soluble derivative, preparation method and purposes |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190618 |
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| WD01 | Invention patent application deemed withdrawn after publication |