CN104910168A - Daphmalenine A O-(diethylamino) ethyl derivative, preparation method and uses thereof - Google Patents
Daphmalenine A O-(diethylamino) ethyl derivative, preparation method and uses thereof Download PDFInfo
- Publication number
- CN104910168A CN104910168A CN201510279765.8A CN201510279765A CN104910168A CN 104910168 A CN104910168 A CN 104910168A CN 201510279765 A CN201510279765 A CN 201510279765A CN 104910168 A CN104910168 A CN 104910168A
- Authority
- CN
- China
- Prior art keywords
- daphmalenine
- derivative
- acceptable salt
- preparation
- pharmacy acceptable
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the field of organic synthesis and pharmaceutical chemistry, particularly to a Daphmalenine A derivative, a preparation method of the Daphmalenine A derivative, and uses of the Daphmalenine A derivative in preparation of antitumor drugs. According to the present invention, the new Daphmalenine A derivative is synthesized, and the preparation method is disclosed; and the pharmacological experiment results show that the Daphmalenine A derivative has the antitumor effect and has the antitumor drug development value.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Daphmalenine A derivative, preparation method and its usage.
Background technology
Cancer is to one of maximum disease of human life's Health hazard, has a large amount of people to die from cancer every year.The research and development of cancer therapy drug are the focuses of study of pharmacy always.74% is had to be natural product or derivatives thereof in antitumor drug, if taxol and derivative thereof are exactly the current reasonable antitumor drug of effect clinically.Therefore, from natural product, find compound or lead compound and carry out structural modification and obtain its derivative, thus the potential drug obtaining high-efficiency low-toxicity there is important value most.
The Compound D aphmalenine A that the present invention relates to is one and within 2011, delivers (Yu Zhang et al., 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) compound, we have carried out structural modification to Compound D aphmalenine A, obtain a new Daphmalenine A derivative, and its anti-tumor activity is evaluated, it has anti-tumor activity.
Summary of the invention
The invention discloses a Daphmalenine A derivative, its structure is:
Daphmalenine A derivative (III) of the present invention is by method preparation below:
(1) Daphmalenine A (I) and glycol dibromide are obtained by reacting the O-bromotrifluoromethane derivative (II) of Daphmalenine A;
(2) O-bromotrifluoromethane derivative (II) and the diethylamine generation substitution reaction of Daphmalenine A obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
The preparation method of O-(diethylin) ethyl derivative (III) of further Daphmalenine A is: 419mg Compound D aphmalenine A (I) is dissolved in 10mL benzene by (1), the Tetrabutyl amonium bromide of 0.08g is added in solution, the glycol dibromide of 7.520g and 50% sodium hydroxide solution of 6mL; Mixture stirs 12h at 35 degrees Celsius; After 12h, reaction solution is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution; Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, moving phase is: sherwood oil/acetone=100:1.5, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromotrifluoromethane derivative (II) of Daphmalenine A.
(2) by Compound II per (263mg, 0.5mmol) be dissolved in the middle of 20mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassiumiodide (84mg, 0.5mmol) with diethylamine (1460 mg, 20mmol), mixture reflux 10h.After reaction terminates, reaction solution is poured in frozen water, with equivalent dichloromethane extraction four times, merge organic phase.Organic phase after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.(moving phase is product crude product purification by silica gel column chromatography: sherwood oil/acetone=100:1, v/v), collect the yellow yellow gummy solid (196.8mg, 76%) concentrating elution band namely to obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
Compound disclosed by the invention can make pharmacy acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, Daphmalenine A derivative (III) of the present invention has good antitumor action.Pharmacy acceptable salt of the present invention has same drug effect with its compound.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Embodiment
The preparation of embodiment 1 Compound D aphmalenine A
Document (the Yu Zhang et al. that the people such as preparation method's reference Yu Zhang of Compound D aphmalenine A (I) deliver, 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) method.
The synthesis of the O-bromotrifluoromethane derivative (II) of embodiment 2 Daphmalenine A
By Compound I (419mg, 1.00mmol) be dissolved in 10mL benzene, add in solution Tetrabutyl amonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-ethylene dibromide (7.520g, 40.00mmol) and 6mL.Mixture stirs 12h at 35 degrees Celsius.After 12h, reaction solution is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (moving phase is: sherwood oil/acetone=100:1.5, v/v), collects the yellow yellow solid (320mg, 61%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ3.84(d,J＝1.6Hz,2H),3.76–3.50(m,5H),3.42(s,2H),3.09(s,1H),2.99(s,1H),2.88(s,1H),2.70(s,1H),2.64(d,J＝19.1Hz,3H),2.45(d,J＝5.6Hz,3H),2.33(s,1H),2.19–2.12(m,5H),2.07(s,1H),1.97(d,J＝9.2Hz,3H),1.84–1.76(m,3H),1.69(s,1H),1.15(s,1H),1.04(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.71(s),211.07(s),176.65(s),66.24(s),65.38(s),63.59(s),59.42(s),54.79(s),52.18(s),46.22(s),46.01(s),45.50(s),45.27(s),40.33(s),37.86(s),37.61(s),36.27(s),34.26(s),30.89(s),28.52(s),26.04(s),25.24(s),8.50(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
25H
37BrNO
6:526.1804；found 526.1801.
The synthesis of O-(diethylin) ethyl derivative (III) of embodiment 3 Daphmalenine A
Compound II per (263mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassiumiodide (84mg, 0.5mmol) and diethylamine (1460mg, 20mmol), mixture reflux 10h.After reaction terminates, reaction solution is poured in frozen water, with equivalent dichloromethane extraction four times, merge organic phase.Organic phase after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.(moving phase is product crude product purification by silica gel column chromatography: sherwood oil/acetone=100:1, v/v), collect the yellow yellow gummy solid (196.8mg, 76%) concentrating elution band namely to obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
1H NMR(500MHz,DMSO-d6)δ3.78(s,1H),3.68(s,3H),3.45(s,2H),3.09(s,1H),2.94(d,J＝59.8Hz,5H),2.79(s,1H),2.71(d,J＝10.0Hz,2H),2.63(d,J＝1.4Hz,4H),2.43(t,J＝16.7Hz,3H),2.36(d,J＝5.9Hz,1H),2.19–2.12(m,5H),2.09–2.00(m,4H),1.90(dd,J＝10.7,8.0Hz,1H),1.85(d,J＝23.9Hz,1H),1.72(s,1H),1.65(s,1H),1.13(d,J＝7.0Hz,7H),1.06(s,3H).
13C NMR(125MHz,,DMSO-d6)δ219.80(s),211.16(s),176.74(s),66.30(s),63.64(s),61.62(s),59.51(s),54.88(s),52.27(s),51.99(s),47.76(s),46.30(s), 46.06(s),45.55(s),45.26(s),40.31(s),37.86(s),37.63(s),36.28(s),30.87(s),28.53(s),26.01(s),25.23(s),12.37(s),8.50(s).
HRMS(ESI):m/z[M+H]
+calcd for C
29H
47N
2O
6:519.3434；found:519.3429。
Embodiment 4 anti tumor activity in vitro screens
Screening cell strain is HepG2 (human liver cancer cell), PANC-1 (human pancreas cancer), MCF-7 (human breast cancer cell), SW620 (human colon cancer cell), A549 (human lung carcinoma cell), HGC-27 (gastric carcinoma cells), LO2 (people's normal liver parenchyma cell).
Triethylamine (compound IV) is commercially available analytical pure.
Experimental technique:
Take the logarithm cell in good condition in vegetative period, tryptic digestion, makes 5 × 10
4the suspension of cell/mL.Cell suspension is moved into 96 well culture plates, every hole 100 μ L, puts 37 DEG C, 5%CO
224h is cultivated under condition.
Test-compound III and triethylamine (compound IV) are mixed with certain density mother liquor with DMSO respectively, then derivative mother liquor are diluted to the diluent of different activity with RPMI1640 substratum.Remove old substratum, add the pastille substratum of different concns, every hole 100 μ L.Separately establish blank group.After drug effect 48h, inhale and abandon pastille substratum, add serum-free in every hole, without phenol red 1640 substratum 100 μ L, then add MTT solution (5mg/mL) 10 μ L, continue incubation 4h.
Suck supernatant liquor in each hole, every hole adds DMSO 150 μ L, dark place vibration 10min, crystallisate is fully dissolved, microplate reader measures the absorbance value (OD value) in each hole, 490nm place, calculates the proliferation inhibition rate of cell: inhibiting rate (%)=(1-medication group mean OD value/blank group mean OD value) × 100%.Application SPSS16.0 software carries out data processing and calculates the half-inhibition concentration (IC of cancer cell multiplication
50), the results are shown in Table 1.
Table 1 compound III is to the in-vitro multiplication restraining effect of 7 kinds of cancer cells
As shown in table 1 result, synthesized compound III all has certain inhibited proliferation to different tumour cells; And for the IC of normal hepatic parenchymal cells LO2
50very large (>40 μM), illustrates that security is very high.For substituted radical derived compound IV, as shown in Table 1 for its IC of all tumour cells
50all very large, the IC of individual tumor cell
50be greater than 40 μMs, but compound IV is to the IC of LO2
50but be only 2.1 μMs.For the related activity of Compound I see application for a patent for invention: Daphmalenine A derivative, preparation method and its usage.Compound I and compound IV for the activity of the application's compound III without any instruction and enlightenment.Derivative synthesized by explanation shows good antitumour activity, has the potentiality of exploitation cancer therapy drug.
The preparation of embodiment 5 Compound II per involved in the present invention and III tablet
Get the one in the middle of 20 g of compound III or its pharmacy acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of embodiment 6 Compound II per involved in the present invention and III capsule
Get the one in the middle of 20 g of compound III or its pharmacy acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (7)
1. one kind has Daphmalenine A derivative and the pharmacy acceptable salt thereof of structure shown in formula III:
2. the preparation method of Daphmalenine A derivative as claimed in claim 1, is characterized by:
(1) Daphmalenine A (I) and glycol dibromide are obtained by reacting the O-bromotrifluoromethane derivative (II) of Daphmalenine A;
(2) O-bromotrifluoromethane derivative (II) and the diethylamine generation substitution reaction of Daphmalenine A obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
3. the preparation method of Daphmalenine A derivative as claimed in claim 2, is characterized by:
(1) 419mg Compound D aphmalenine A (I) is dissolved in 10mL benzene, in solution, adds the Tetrabutyl amonium bromide of 0.08g, the glycol dibromide of 7.520g and 50% sodium hydroxide solution of 6mL; Mixture stirs 12h at 35 degrees Celsius; After 12h, reaction solution is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution; Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, moving phase is: sherwood oil/acetone=100:1.5, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromotrifluoromethane derivative (II) of Daphmalenine A;
(2) the O-bromotrifluoromethane derivative (II) of the Daphmalenine A of 263mg is dissolved in the middle of 20mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassiumiodide of 84mg and the diethylamine of 1460mg, mixture reflux 10h; After reaction terminates, reaction solution is poured in 20mL frozen water, with equivalent dichloromethane extraction four times, merge organic phase; Organic phase after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, moving phase is: sherwood oil/acetone=100:1, v/v, collects the yellow gummy solid that namely brown concentrated elution band obtains O-(diethylin) ethyl derivative (III) of Daphmalenine A.
4. Daphmalenine A derivative as claimed in claim 1 and pharmacy acceptable salt thereof are preparing the application in antitumor drug.
5. Daphmalenine A derivative as claimed in claim 4 and pharmacy acceptable salt thereof are preparing the application in antitumor drug, it is characterized by: described tumour is digestive system tumor.
6. Daphmalenine A derivative as claimed in claim 5 and pharmacy acceptable salt thereof are preparing the application in antitumor drug, it is characterized by: described digestive system tumor is liver cancer, carcinoma of the pancreas, colorectal carcinoma or cancer of the stomach.
7. Daphmalenine A derivative as claimed in claim 4 and pharmacy acceptable salt thereof are preparing the application in antitumor drug, it is characterized by: described tumour is mammary cancer or lung cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510279765.8A CN104910168A (en) | 2015-05-27 | 2015-05-27 | Daphmalenine A O-(diethylamino) ethyl derivative, preparation method and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510279765.8A CN104910168A (en) | 2015-05-27 | 2015-05-27 | Daphmalenine A O-(diethylamino) ethyl derivative, preparation method and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104910168A true CN104910168A (en) | 2015-09-16 |
Family
ID=54079659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510279765.8A Pending CN104910168A (en) | 2015-05-27 | 2015-05-27 | Daphmalenine A O-(diethylamino) ethyl derivative, preparation method and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104910168A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160399A (en) * | 2022-06-22 | 2022-10-11 | 延边大学 | Soapbark acid compound and preparation method and medical application thereof |
-
2015
- 2015-05-27 CN CN201510279765.8A patent/CN104910168A/en active Pending
Non-Patent Citations (5)
| Title |
|---|
| YU ZHANG，等: "Daphmalenines A and B: Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense", 《EUR. J. ORG. CHEM.》 * |
| 叶海亚，等: "牛耳枫果实中的生物碱成分", 《云南植物研究》 * |
| 张于，等: "脉叶虎皮楠的生物碱成分研究", 《天然产物研究与开发》 * |
| 李震宇，等: "虎皮楠生物碱研究进展", 《有机化学》 * |
| 杨廷全，等: "长序虎皮楠果实中的一个新的生物碱", 《云南植物研究》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160399A (en) * | 2022-06-22 | 2022-10-11 | 延边大学 | Soapbark acid compound and preparation method and medical application thereof |
| CN115160399B (en) * | 2022-06-22 | 2023-10-27 | 延边大学 | Soap-skin acid compound, preparation method and medical application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101878218A (en) | Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof | |
| CN104095857B (en) | The application in preparing anti-hepatic fibrosis medicines of the diethylamine derivative of Cleistanone Cleistanone | |
| CN104086617B (en) | Close dimethylamine derivative, the preparation method and its usage of flowers and trees ketone Cleistanone | |
| CN107793424A (en) | Parthenolide derivative, its medical composition and its use | |
| CN105418490B (en) | Purposes of the mustargen base piperlongumine class compound in medicine | |
| CN103450133B (en) | Scopoletin derivatives with anti-tumor activity, and preparation method and application thereof | |
| CN102827116B (en) | Alpha-aryl-gamma-methylene butene lactone compounds, and synthesis method and application thereof | |
| CN104910168A (en) | Daphmalenine A O-(diethylamino) ethyl derivative, preparation method and uses thereof | |
| CN102924450A (en) | 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof | |
| CN104804010A (en) | Daphmalenine A derivative as well as preparation method and application | |
| CN104744556B (en) | O-(the 1H-tetrazole base) ethyl derivative of Cleistanone, preparation method and its usage | |
| CN105367575A (en) | Folic acid compound, and preparation method and pharmaceutical application thereof | |
| CN104844680B (en) | O-(benzimidazolyl) ethyl derivative of Cleistanone, preparation method and its usage | |
| CN106632297A (en) | Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof | |
| CN105418597B (en) | 1,3- dihydroxy Xanthone derivative and its purposes in medicine | |
| CN107445931A (en) | Alantolactone derivative, its pharmaceutical composition and its production and use | |
| CN104327063B (en) | Acridine oxadiazole derivative, preparation method and uses thereof | |
| CN104557916B (en) | 2-substituted-beta-carboline compounds and application thereof in preparing drugs for preventing or treating tumors | |
| CN104974135B (en) | Targeting DNA has the Sai-Mi-Xi-Bu derivative containing benzene-naphthalene diimide structure of antitumor activity, pharmaceutical composition and its preparation method and application | |
| CN105343079A (en) | Composition and application of composition in anti-tumor medicines | |
| CN109206473B (en) | C12 and C13 substituted oleanolic acid derivatives, and preparation and application thereof | |
| CN105213373A (en) | Compositions and the application in antitumor drug thereof | |
| CN104098594B (en) | Biotin-podophyllotoxin esterification derivative and pharmaceutical composition thereof and its preparation method and application | |
| CN103709135B (en) | Ton ketone derivatives and its preparation method and application | |
| CN103896824B (en) | Dehydroabietic acid indole derivatives, preparation method and its usage |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150916 |
|
| RJ01 | Rejection of invention patent application after publication |