CN107840852A - Deuterated Agra shore dimethylamine fumarate, preparation method and its purposes in medicine preparation - Google Patents
Deuterated Agra shore dimethylamine fumarate, preparation method and its purposes in medicine preparation Download PDFInfo
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- CN107840852A CN107840852A CN201610825106.4A CN201610825106A CN107840852A CN 107840852 A CN107840852 A CN 107840852A CN 201610825106 A CN201610825106 A CN 201610825106A CN 107840852 A CN107840852 A CN 107840852A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
The present invention relates to one kind（Ⅰ）The deuterated Agra shore dimethylamine fumarate of formula structure, preparation method and its purposes in medicine preparation.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, the present invention relates to deuterated Agra shore dimethylamine fumarate,
Preparation method and its purposes in medicine preparation.
Background technology
Arglabin belongs to guaiaci lignum Sesquiterpene lactones compound, is from a kind of from the absinth for being grown on Kazakhstan
（Wormwood artemisia）Class plant Artemisia glabella Kar. et Kir. aerial part separation and Extraction obtains, its antitumaous effect
Principle is to suppress farnesyl transferase, and this is a kind of enzyme for determining oncogenic ras function, and scientist thinks this enzyme in people
Account for 20% -30% in the disease hair reason of class tumour, and Arglabin also show that good anti-different tumor cell lines activity and
Toxicity（Human tumor cell line IC50=0.9–5.0 μg mL–1）.In order to solve Arglabin water solubility problems, in C（13）Position
Putting and modified with dimethyl amine, Arglabin-DMA has been registered listing in the republic of Kazakhstan, for treating breast cancer,
Colon cancer, oophoroma and lung cancer.Arglabin and Arglabin-DMA structural formulas are shown below.
But Arglabin-DMA treatment window is small, and drug Clinical practice is made troubles, and Arglabin-DMA has very
Strong drawing is moist, limits its dosage form selection scope, Clinical practice is injection at present.
The content of the invention
The invention provides a kind of as follows（Ⅰ）The compound of formula structure,
（Ⅰ）.
It is described（Ⅰ）The preparation method of the compound of formula structure,
。
It is described（Ⅰ）Purposes of the compound of formula structure in the medicine for preparing treating cancer.
Described purposes, wherein cancer are selected from leukaemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, liver cancer, food
Road cancer, stomach cancer, bowel cancer, kidney, carcinoma of mouth, He Jiejin lymph cancers, cancer of pancreas, carcinoma of the colon and rectum, cervix cancer, non-hodgkin's
Lymph cancer, glioma, melanoma, carcinoma of urinary bladder, oophoroma, thyroid cancer or Kaposi sarcoma.
It is described（Ⅰ）Purposes of the compound of formula structure in the ancillary drug for preparing treating cancer.
Described purposes, wherein cancer are selected from leukaemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, liver cancer, food
Road cancer, stomach cancer, bowel cancer, kidney, carcinoma of mouth, He Jiejin lymph cancers, cancer of pancreas, carcinoma of the colon and rectum, cervix cancer, non-hodgkin's
Lymph cancer, glioma, melanoma, carcinoma of urinary bladder, oophoroma, thyroid cancer or Kaposi sarcoma.
A kind of pharmaceutical composition for treating cancer, described pharmaceutical composition contain the change described in the claim 1 of effective dose
Compound and pharmaceutically acceptable carrier or other cancer therapy drugs.
Described pharmaceutical composition, wherein cancer are selected from leukaemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, liver
It is cancer, cancer of the esophagus, stomach cancer, bowel cancer, kidney, carcinoma of mouth, He Jiejin lymph cancers, cancer of pancreas, carcinoma of the colon and rectum, cervix cancer, non-
He Jiejin lymph cancers, glioma, melanoma, carcinoma of urinary bladder, oophoroma, thyroid cancer or Kaposi sarcoma.
Described purposes, wherein the method for administration of the medicine is oral, for treating cancer.
The method of administration of described pharmaceutical composition, wherein described pharmaceutical composition is oral, for treating cancer.
Brief description of the drawings
The drop of the deuterated Agra shore dimethylamine fumarate of accompanying drawing 1 and Agra shore dimethylamine fumarate in blood plasma
Solution curve
Embodiment
In order to understand the present invention, the present invention is further illustrated with embodiment below, but do not limit the present invention.
Embodiment 1：The preparation of deuterated Agra shore dimethylamine fumarate
1st, the preparation of deuterated dimethylamine agueous solution
3.03 g dimethylamine hydrochlorides are added in 100 ml stand up reaction bottle, add 4 ml heavy water, stir lower clarify.Oil pump steams
Dry solvent, white solid is obtained, operate 3 times repeatedly, obtain deuterated dimethylamine hydrochloride.3.67 g sodium hydroxides add 100
In ml stand up reaction bottle, 3 ml heavy water are added, after dissolving（Heat release is obvious）, oil pump is evaporated, repeats once, obtain sticky
Deuterated sodium hydroxide.The deuterated dimethylamine hydrochlorides of 3.03 g are added in 100 ml single port bottles, 10 ml heavy water are added, under stirring
Deuterated sodium hydroxide is added, regulation pH is 9-10（It is standby）.
2nd, Agra shore（0.0967 g, 0.39 mmol）Add in 50 ml stand up reaction bottle, add 2.5 ml deuterated methanols（It is single
It is deuterated）, under ar gas environment, the deuterated dimethylamine heavy aqueous solutions of 2.5 ml are added dropwise, reaction is stirred 1 hour at room temperature, TLC inspections
Survey raw material to disappear, decompression steams deuterated methanol, stands, and aqueous phase has solid precipitation, filters, and room temperature obtains white solid after drying
0.0695 g, yield：58.64 %, purity（HPLC）：94.310 % .
MS：293.2;
1HNMR（400 MZ, CDCl3）：δ 5.55 （br s, 1H）, 4.03-3.98 (t, J=10.2 Hz, 1H),
2.85-2.82
(d, J=10.5 Hz, 1H), 2.78-2.72 (dd, J=17.6 Hz, 1H), 2.71-2.55 (dd, J=13.0
Hz, 2H), 2.24 (s, 6H), 2.15-2.02 (m, 2H), 2.00-1.85(m, 5H), 1.65-1.60 (m,
1H), 1.51-1.41 (m, 1H), 1.33 (s, 3H)。
3rd, fumaric acid（0.2091 g, 1.80 mmol）It is added in 100 ml stand up reaction bottle.5 ml ethyl acetate are added, are added
20 ml D-DMA-AGLB are added dropwise to after flowing back in heat（0.7836 g 2.88 mmol）Ethyl acetate solution, reaction solution are gradually muddy
It is turbid, there is white solid precipitation.After backflow 2 hours, room temperature is down to, filters, is dried to obtain 0.5103 g white solids at room temperature.Receive
The purity of rate 68.91%（HPLC）：99.094 %.
1H NMR（400MHz, DMSO-d6）：δ 6.62(s, 2H), 5.59 (s, 1H), 3.97-3.92 (t, 1H),
2.92-2.89 (d, 1H), 2.77-2.72 (d, 1H), 2.68-2.56 (m, 2H), 2.00-1.85 (m, 5H),
1.65-1.60 (m, 1H), 1.51-1.41 (m, 1H), 1.33 (s, 3H)；13CNMR:（400 MHz, DMSO-d6）
δ 177.8, 166.8, 140.7, 134.6, 124.7, 82.5, 72.4, 62.6, 58.0, 52.4, 51.7,
46.1, 39.5, 33.6, 22.79, 22.72, 18.3。
Embodiment 2：Deuterated Agra shore dimethylamine fumarate and conversion of the Agra shore dimethylamine fumarate in blood plasma
Experiment
10 mg test compounds are weighed with a ten thousandth balance precision, are dissolved in 10 ml solvents（The mixing of acetonitrile and water is molten
Agent）In, 1 mg/ml solution for standby is made.It is put into the accurate solution 200 μ L that draw of liquid-transfering gun in 1.5 mL EP pipes, with shifting
After liquid rifle accurate addition 800 μ L blank plasmas vortex removes 0 min samples after mixing, it is put into rapidly in 37 DEG C of waters bath with thermostatic control.
Afterwards respectively in the h point in time sampling of 15min, 30 min, 45 min, 1 h, 2 h, 3 h, 5 h, 24.
Sampling operation：Precision draws 40 μ L detected solutions, is rapidly added the μ L of protein precipitation solvent acetonitrile 160, adds 10 μ L and steams
Distilled water and 10 μ L carbamazepine internal standard solutions（32 μ g/mL, acetonitrile solution）, it is vortexed after 1 min, in 5000 r/min centrifuges
10 min are centrifuged, are then put into -20 DEG C of preservations rapidly.The μ L of supernatant 20 are taken, are then analyzed with HPLC.Record test compound
And the peak area of internal standard compound, and calculate its ratio.Each sample, which does parallel test three times, averages and is contrasted.
Chromatographic condition：
Chromatographic column：Inertsil ODS-SP, 5 μm, 4.6 × 150 mm
Flow velocity：1 mL/min
Column temperature：37 ℃
Sample size：20 μL
Wavelength：210 nm
Mobile phase：Mobile phase A：10% acetonitrile and 90%-0.1% H3PO4 aqueous solution mixed solutions
Mobile phase B：70% acetonitrile and 30%-0.1% H3PO4 aqueous solution mixed solutions
Elution requirement：
Experimental result：
As shown in the above formula, deuterated Agra shore dimethylamine fumarate can in blood plasma with Agra shore dimethylamine fumarate
Slowly to decompose, active medicine Agra shore is discharged, by accompanying drawing 1 it can be seen that deuterated Agra shore dimethylamine fumaric acid
The degradation rate of salt is significantly less than the degradation rate of Agra shore dimethylamine fumarate.It is possible thereby to infer, this is due to
Deuterated Agra shore dimethylamine fumarate carbonyl α positions it is deuterated in action, can become degraded using isotope effect
Must be relatively slow, make active medicine to keep the certain density time longer under certain condition, so that efficacy time is more
It is long, reach more preferable slow release effect.
Embodiment 3：Oral deuterated Agra shore dimethylamine fumarate maximum tolerated dose
Medicament is prepared：
The deuterated Agra shore dimethylamine fumarates of 60mg accurately are weighed, are separately added into 0.3ml physiological saline, piping and druming is mixed repeatedly
It is even, form it into the suspension of no obvious not tolerant.Its matched doses is 2000mg/kg, standby.
Deuterated Agra shore dimethylamine fumarate is accurately weighed, 40mg, is separately added into 0.4ml physiological saline, piping and druming is mixed repeatedly
It is even, form it into the suspension of no obvious not tolerant.Its matched doses is 1000mg/kg, standby.
Testing program：
Appoint take one it is healthy, the b/c mouse of no abnormal behavior, claim its body weight, be administered by 0.1ml/10g body weight, dosage is
2000mg/kg, give observation post administration its ability to act, and toxic reaction, and the death time.
If dead, appoint take one it is healthy, the b/c mouse of no abnormal behavior, claim its body weight, be administered by 0.1ml/10g body weight, dosage
For 1500mg/kg（1.3 times of acquisitions are diluted by 2000mg/kg）, give observation post administration its ability to act, and toxic reaction, and it is dead
Time
If dead, appoint take one it is healthy, the b/c mouse of no abnormal behavior, claim its body weight, be administered by 0.1ml/10g body weight, dosage
For 1000mg/kg, give observation post administration its ability to act, and toxic reaction, and the death time.It is in office to take 1 health if not dead
, the b/c mouse of no abnormal behavior, claim its body weight, be administered by 0.1ml/10g body weight, dosage 1000mg/kg, to observation post administration
Its ability to act and abnormal response, 48h is observed, whether dead seen.
Result of the test
Conclusion (of pressure testing)：Deuterated Agra shore dimethylamine fumarate is can be seen that in mouse experiment from above-mentioned result of the test
Maximum tolerated dose is more than 1000 mg/kg.Better than the listing medicine Agra shore dimethylamine hydrochloride of injection（120 mg/kg）,
And oral Agra shore dimethylamine fumarate（750 mg/kg）.
The purposes and method of the present invention is described by specific embodiment.Those skilled in the art can use for reference this
The links such as the appropriate feed change of content of invention, process conditions realize corresponding other purposes, and its correlation changes all without de-
From present disclosure, all similar replacements and change it will become apparent to those skilled in the art that all by regarding
To be included within the scope of the present invention.
Claims (10)
- It is 1. a kind of as follows（Ⅰ）The compound of formula structure,（Ⅰ）.
- 2. compound according to claim 1, its preparation method,。
- 3. purposes of the compound according to claim 1 in the medicine for preparing treating cancer.
- 4. purposes according to claim 3, wherein cancer are selected from leukaemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, large intestine Cancer, lung cancer, liver cancer, cancer of the esophagus, stomach cancer, bowel cancer, kidney, carcinoma of mouth, He Jiejin lymph cancers, cancer of pancreas, carcinoma of the colon and rectum, son Cervical carcinoma, non-hodgkin's lymph cancer, glioma, melanoma, carcinoma of urinary bladder, oophoroma, thyroid cancer or Kaposi sarcoma.
- 5. purposes of the compound according to claim 1 in the ancillary drug for preparing treating cancer.
- 6. purposes according to claim 5, wherein cancer are selected from leukaemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, large intestine Cancer, lung cancer, liver cancer, cancer of the esophagus, stomach cancer, bowel cancer, kidney, carcinoma of mouth, He Jiejin lymph cancers, cancer of pancreas, carcinoma of the colon and rectum, son Cervical carcinoma, non-hodgkin's lymph cancer, glioma, melanoma, carcinoma of urinary bladder, oophoroma, thyroid cancer or Kaposi sarcoma.
- 7. a kind of pharmaceutical composition for treating cancer, described pharmaceutical composition contains described in the claim 1 of effective dose Compound and pharmaceutically acceptable carrier or other cancer therapy drugs.
- 8. pharmaceutical composition according to claim 7, wherein cancer are selected from leukaemia, breast cancer, prostate cancer, nasopharynx Cancer, colorectal cancer, lung cancer, liver cancer, cancer of the esophagus, stomach cancer, bowel cancer, kidney, carcinoma of mouth, He Jiejin lymph cancers, cancer of pancreas, nodus hemorrhoidalis Intestinal cancer, cervix cancer, non-hodgkin's lymph cancer, glioma, melanoma, carcinoma of urinary bladder, oophoroma, thyroid cancer or Ka Boxi meat Knurl.
- 9. according to the purposes described in any one of claim 3 to 6, wherein the method for administration of the medicine is oral, for controlling Treat cancer.
- 10. the method for administration of the pharmaceutical composition according to claim 7 or 8, wherein described pharmaceutical composition is oral, with For treating cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610825106.4A CN107840852A (en) | 2016-09-18 | 2016-09-18 | Deuterated Agra shore dimethylamine fumarate, preparation method and its purposes in medicine preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610825106.4A CN107840852A (en) | 2016-09-18 | 2016-09-18 | Deuterated Agra shore dimethylamine fumarate, preparation method and its purposes in medicine preparation |
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| Publication Number | Publication Date |
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| CN107840852A true CN107840852A (en) | 2018-03-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610825106.4A Pending CN107840852A (en) | 2016-09-18 | 2016-09-18 | Deuterated Agra shore dimethylamine fumarate, preparation method and its purposes in medicine preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113185562A (en) * | 2021-04-27 | 2021-07-30 | 中国科学院昆明植物研究所 | Artemisinin A-P, pharmaceutical composition thereof, and preparation method and application thereof |
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|---|---|---|---|---|
| CN103417532A (en) * | 2012-05-16 | 2013-12-04 | 天津尚德药缘科技有限公司 | Sesquiterpene lactone compound and uses of derivative thereof in preparation of drugs |
| CN103622954A (en) * | 2012-08-22 | 2014-03-12 | 龙海波 | Applications of sesquiterpene lactone compound and derivative of sesquiterpene lactone compound in treatment of diabetes |
| CN103833766A (en) * | 2012-11-23 | 2014-06-04 | 天津尚德药缘科技有限公司 | Arglabin dimethylamine fumarate and application thereof to medicament preparation |
-
2016
- 2016-09-18 CN CN201610825106.4A patent/CN107840852A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417532A (en) * | 2012-05-16 | 2013-12-04 | 天津尚德药缘科技有限公司 | Sesquiterpene lactone compound and uses of derivative thereof in preparation of drugs |
| CN103622954A (en) * | 2012-08-22 | 2014-03-12 | 龙海波 | Applications of sesquiterpene lactone compound and derivative of sesquiterpene lactone compound in treatment of diabetes |
| CN103833766A (en) * | 2012-11-23 | 2014-06-04 | 天津尚德药缘科技有限公司 | Arglabin dimethylamine fumarate and application thereof to medicament preparation |
Non-Patent Citations (2)
| Title |
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| 刘洁: "氘代药物进展", 《化工设计通讯》 * |
| 执业药师考试命题研究组编写: "《药学专业知识 1》", 31 March 2015 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113185562A (en) * | 2021-04-27 | 2021-07-30 | 中国科学院昆明植物研究所 | Artemisinin A-P, pharmaceutical composition thereof, and preparation method and application thereof |
| CN113185562B (en) * | 2021-04-27 | 2023-09-19 | 中国科学院昆明植物研究所 | Artemisinin A-P and pharmaceutical composition thereof, and preparation method and application thereof |
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