CN107793424A - Parthenolide derivative, its medical composition and its use - Google Patents

Parthenolide derivative, its medical composition and its use Download PDF

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CN107793424A
CN107793424A CN201610770862.1A CN201610770862A CN107793424A CN 107793424 A CN107793424 A CN 107793424A CN 201610770862 A CN201610770862 A CN 201610770862A CN 107793424 A CN107793424 A CN 107793424A
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cdcl
nmr
mhz
compound
cancer
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CN107793424B (en
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陈悦
张泉
杨忠金
邝蓓佳
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Accendatech Co Ltd
Nankai University
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Accendatech Co Ltd
Nankai University
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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
    • C07D493/04—Ortho-condensed systems

Abstract

The present invention relates to a kind of parthenolide derivative, particularly its medical composition and its use, formula（I）Shown parthenolide derivative medical compounds, for treating cancer disease, the compound parthenolide derivative containing therapeutically effective amount（I）And pharmaceutical composition or the composition with other cancer therapy drugs of pharmaceutically acceptable carrier, and the application in medicine, the particularly application in treating cancer medicine is prepared.

Description

Parthenolide derivative, its medical composition and its use
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, is related to parthenolide derivative, using it as active ingredient The pharmaceutical composition for the treatment of cancer or adjuvant therapy of tumors, and the medical compounds and composition are preparing anticancer or aided in anti- Application in cancer drug.
Background technology
Tumour great threat human health, and the people of the existing cancer patient in China about 2,000,000, annual new hair 1,600,000, this is One no small colony, antitumor research is the extremely challenging and significant field of current life science.It is past Treatment method lays particular emphasis on rooting out and killing to cancer cell, and at present, clinically conventional antineoplastic is mainly cell toxicant class Medicine, this kind anti-cancer drugs have the shortcomings that poor selectivity, toxic side effect are strong, are also easy to produce drug resistance, are typical double-sided blade medicines, And be difficult to eradicate cancer, the recurrence rate of many cancers is higher.The high relapse rate of malignant tumour is always to perplex oncologist Problem, increasing research confirms the tumor stem cells that minority can expand colony in tumor cell colonies be present.They Slow periodic state is generally in, it is low to chemotherapy drug susceptibility, it is the root of tumor recurrence.Therefore the discovery of tumor stem cell is given Oncotherapy brings new target, and possibility is provided thoroughly to cure cancer for the drug research of tumor stem cell.
In recent years, anti-cancer active compound is found from natural products and has become the exploitation focus of cancer therapy drug, preceding 20 Nian Jian, the whole world release Medicine small molecule new chemical entities in, there is 61% can trace back to natural products.Natural products is some Therapy field occurrence rate is very high：78% antimicrobial compound and 74% antitumoral compounds are all natural products, or from certain Individual natural products is derived, in practice it has proved that, unique effect of the natural products in cancer therapy drug discovery causes height weight again Depending on.There are resistance problems in the chemotherapeutics of traditional treatment tumour, especially tumor stem cell is more insensitive.Chinese herbal medicine for preventing is vast It is profound, high-efficiency low-toxicity, therefrom it is possible to filter out Efficient killing effect tumor stem cell, so as to treat the medicine of malignant tumour.
Sesquiterpene lactones compound parithenolide（Parthenolide）It is the compound extracted from feverfew, most Just it is used to treat skin infection, rheumatism and antimigraine.Recent studies suggest that parithenolide can suppress prostate cancer, The growth of the cancer cells such as breast cancer, stomach cancer, leukaemia cancer, kidney, lung cancer, adenocarcinoma of colon, medulloblastoma, in animal mould Parithenolide can also treat UV-induced cutaneum carcinoma in type.Its Study on mechanism is found, parithenolide can press down The activation of transcription factor NF-KB processed, its activity may be mainly derived from sulfydryl and little Bai on the Cys38 of p65/NF- κ B subunits Chrysanthemum lactone there occurs Michael addition reactions, due to NF- κ B be modulate tumor invasion and attack, transfer, drug resistance important gene, The activation for suppressing NF- κ B is possible to improve sensitiveness of the tumour for the Apoptosis caused by tumor suppression agent.Recently, New York sieve is cut The Jordan of this special University Medical College, C. doctor T. and its colleague have found that parithenolide can not damage normal do substantially In the case of cell, the stem cell for triggering acute and chronic myelomatosis is pointedly eliminated, it is possible to fundamentally Contain leukemia relapse, this unique mechanism of action of parithenolide, cause the extensive concern of people.
The content of the invention
The invention provides a kind of derivative of parithenolide, the formula containing effective dose（Ⅰ）Parthenolide derivative and The pharmaceutical composition of the treating cancer of pharmaceutical acceptable carrier or the composition with other cancer therapy drugs, and formula（Ⅰ）Lactone spreads out with a smile The application of biology or its pharmaceutical composition in treating cancer medicine is prepared.
In order to realize the above-mentioned purpose of the present invention, the present invention provides following technical scheme：
A kind of such as following formula（I）Compound,
（I）
Formula（I）Middle R is-CH2OR1、–C(O)R2Or heterocyclic radical,
R1For alkyl, aryl alkyl ,-C (O) R3, wherein R3For alkyl, cycloalkyl, alkenyl, aryl alkenyl, alkylalkenyl, substitution Base phenyl, ring group, the substituent in substituent phenyl is hydrogen, methoxyl group, cyano group, trifluoromethyl；
R2For hydroxyl, OR4Or-NR5R6
R4For alkyl, aryl alkyl, R5R6Respectively carbon number is 1-8 alkyl or-NR5R6Cyclization is
。
Purposes of the above-mentioned compound in the medicine for preparing treating cancer, wherein cancer is leukaemia.
Purposes of the above-mentioned compound in the ancillary drug for preparing treating cancer, wherein cancer is leukaemia.
A kind of pharmaceutical composition for treating cancer, wherein the formula containing effective dose（I）Compound and it can pharmaceutically connect The carrier received or other cancer therapy drugs.
It when the compounds of this invention is used as medicine, can directly use, or be used in the form of pharmaceutical composition.The medicine Composition contains 0.1-99%, and preferably 0.5-90% the compounds of this invention, remaining to people and is moved to be pharmaceutically acceptable The nontoxic and inert pharmaceutical acceptable carrier of thing and/or excipient or with other anti-cancer agent in combination medications.The composition of the present invention can To be prepared into parenteral solution, tablet and capsule etc..
Described pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and medicine Tetramune assistant agent.The pharmaceutical composition of the present invention is used in the form of per weight dose.The medicine of the present invention can be through note Penetrate and be administered with oral two kinds of forms, injection can be tablet and capsule such as intravenous injection and intramuscular injection, oral formulation.
Embodiment
In order to understand the present invention, the present invention is further illustrated with embodiment below, but is not meant to the protection of the limitation present invention Scope.
Embodiment 1：The synthesis of parithenolide analog
The preparation of compound 3,4,5 is according to the literature（J. Med. Chem., 2015,58, 7007−7020.）Side It is prepared by method.
Take compound 3（0.1 mmol）In bottle, 1 mL methylene chloride is added, starts to stir, adds three Ethamine（0.3 mmol）, cooled down under ice-water bath, then add acyl chlorides（0.15 mmol）, room temperature is raised to, stirring is until raw material disappears Lose, add 1 mL water, dichloromethane extraction, organic phase is washed with saturated common salt, anhydrous sodium sulfate drying, filtering, and decompression is dense Contracting, crude product pass through silica gel column chromatography（Petroleum ether:Ethyl acetate=4:1–2:1）Purifying, obtains object 6a ~ k.
6a:77% yield;1H NMR (400 MHz, CDCl3) δ 6.22 (d, J = 3.5 Hz, 1H), 5.67 (t, J = 8.1 Hz, 1H), 5.53 (d, J = 3.2 Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 4.44 (d, J = 12.5 Hz, 1H), 3.83 (t, J = 9.3 Hz, 1H), 2.92 – 2.85 (m, 1H), 2.83 (d, J = 9.5 Hz, 1H), 2.50 – 2.10 (m, 6H), 2.05 (d, J = 6.8 Hz, 3H), 1.71 – 1.61 (m, 1H), 1.52 (s, 3H), 1.09 (t, J = 12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.7, 169.4, 138.8, 134.9, 130.8, 120.2, 81.0, 66.9, 63.3, 60.0, 42.7, 36.6, 25.8, 24.5, 23.8, 21.0, 18.0; HRMS calcd forC17H26NO5 [M+NH4]+ 324.1805, found 324.1809.
6b:70% yield;1H NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (m, 5H), 6.14 (d, J = 3.5 Hz, 1H), 5.65 (t, J = 8.1 Hz, 1H), 5.33 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 11.8 Hz, 1H), 4.39 (d, J = 11.8 Hz, 1H), 4.06 (d, J = 11.2 Hz, 1H), 3.87 – 3.74 (m, 2H), 2.82 (d, J = 9.4 Hz, 1H), 2.80 – 2.70 (m, 1H), 2.40 – 2.12 (m, 6H), 1.63 – 1.55 (m, 1H), 1.53 (s, 3H), 1.08 (t, J = 12.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.5, 166.2, 145.7, 138.8, 135.1, 130.6, 122.2, 120.3, 81.1, 66.5, 63.3, 60.0, 42.7, 36.6, 25.8, 24.6, 23.9, 18.1, 18.0; HRMS (ESI) calcd for C19H24NaO5 [M+Na]+355.1516, found 355.1522.
6c:85% yield;1H NMR (400 MHz, CDCl3) δ 6.23 (d, J = 3.4 Hz, 1H), 5.65 (t, J = 8.0 Hz, 1H), 5.53 (d, J = 3.1 Hz, 1H), 4.65 (d, J = 12.5 Hz, 1H), 4.41 (d, J = 12.6 Hz, 1H), 3.84 (t, J = 9.3 Hz, 1H), 2.89 (dd, J = 11.8, 2.9 Hz, 1H), 2.84 (d, J = 9.4 Hz, 1H), 2.48 – 2.10 (m, 7H), 1.87 (m, 2H), 1.73 (m, 2H), 1.67 – 1.59 (m, 2H), 1.53 (s, 3H), 1.48 – 1.35 (m, 2H), 1.25 (m, 3H), 1.08 (t, J = 12.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.9, 169.5, 138.8, 135.2, 130.3, 120.4, 81.1, 66.4, 63.4, 60.1, 43.3, 42.8, 36.7, 29.2, 29.1, 25.8, 25.7, 25.5, 25.5, 24.5, 23.9, 18.1; HRMS (ESI) calcd for C22H30NaO5 [M+Na]+397.1985, found 397.1985.
6d:95% yield;1H NMR (400 MHz, CDCl3) δ 6.23 (d, J = 3.5 Hz, 1H), 5.67 (t, J = 8.0 Hz, 1H), 5.53 (d, J = 3.2 Hz, 1H), 4.64 (d, J = 12.5 Hz, 1H), 4.43 (d, J = 12.5 Hz, 1H), 3.84 (t, J = 9.3 Hz, 1H), 2.93 – 2.85 (m, 1H), 2.84 (d, J = 9.5 Hz, 1H), 2.50 – 2.09 (m, 8H), 1.63 (m, 3H), 1.53 (s, 3H), 1.32 – 1.23 (m, 6H), 1.08 (t, J = 12.4 Hz, 1H), 0.86 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.6, 169.5, 138.8, 135.1, 130.6, 120.3, 81.1, 66.6, 63.4, 60.1, 42.7, 36.7, 34.4, 31.5, 28.9, 25.8, 25.0, 24.6, 23.9, 22.6, 18.1, 14.1; HRMS (ESI) calculated for C22H32NaO5 [M+Na]+ 399.2142, found 399.2145.
6e:99% yield;1H NMR (400 MHz, CDCl3) δ 8.05 – 7.96 (m, 2H), 7.61 – 7.53 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 6.21 (d, J = 3.5 Hz, 1H), 5.78 (t, J = 8.3 Hz, 1H), 5.52 (d, J = 3.2 Hz, 1H), 4.89 (d, J = 12.5 Hz, 1H), 4.72 (d, J = 12.6 Hz, 1H), 3.86 (t, J = 9.3 Hz, 1H), 2.95 (m, 1H), 2.89 (d, J = 9.4 Hz, 1H), 2.51 – 2.11 (m, 6H), 1.74 – 1.66 (m, 1H), 1.55 (s, 3H), 1.12 (t, J = 12.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 166.3, 138.6, 135.0, 133.3, 130.6, 129.8, 129.6, 128.6, 120.5, 81.0, 67.1, 63.3, 60.0, 42.8, 36.6, 25.8, 24.5, 23.9, 18.0; HRMS (ESI) calcd for C22H24NaO5 [M + Na+] 391.1516; found, 391.1520.
6f:91% yield;1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 7.9 Hz, 2H), 6.22 (d, J = 1.9 Hz, 1H), 5.77 (t, J = 8.2 Hz, 1H), 5.52 (s, 1H), 4.86 (d, J = 12.6 Hz, 1H), 4.70 (d, J = 12.6 Hz, 1H), 3.92 – 3.84 (m, 1H), 3.86 (s, 3H), 2.97 (t, J = 10.2 Hz, 1H), 2.90 (d, J = 9.3 Hz, 1H), 2.58 – 2.11 (m, 6H), 1.69 (t, J = 10.3 Hz, 1H), 1.56 (s, 3H), 1.13 (t, J = 13.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.5, 166.2, 163.8, 138.8, 135.3, 131.8, 130.5, 122.3, 120.6, 113.9, 81.2, 66.9, 63.5, 60.2, 55.7, 42.9, 36.8, 26.0, 24.7, 24.0, 18.2; HRMS (ESI) calcd for C23H26O6 [M+NH4]+ 416.2068, found 416.2071.
6g:93% yield;1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 7.9 Hz, 2H), 6.23 (d, J = 2.4 Hz, 1H), 5.78 (t, J = 8.2 Hz, 1H), 5.54 (s, 1H), 4.93 (d, J = 12.5 Hz, 1H), 4.75 (d, J = 12.5 Hz, 1H), 3.87 (t, J = 9.3 Hz, 1H), 2.93– 2.86 (m, 2H), 2.55 – 2.14 (m, 6H), 1.72 (t, J = 10.7 Hz, 1H), 1.55 (s, 3H), 1.11 (t, J = 13.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4,164.8,138.7,134.5,133.7,132.5,131.4,130.3,120.6,118.0,116.8,81.1, 67.8, 63.4, 60.1, 42.8, 36.7, 25.7, 24.4, 24.0, 18.1; HRMS (ESI) calcd for C23H23NO5 [M+NH4]+411.1914 found 411.1918.
6h:94% yield; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 1H), 7.82 (d,J = 7.3 Hz, 1H), 7.74 – 7.65 (m, 2H), 6.22 (d, J = 2.8 Hz, 1H), 5.86 (t, J = 8.3 Hz, 1H), 5.56 (d, J = 2.2 Hz, 1H), 5.29 (s, 1H), 4.97 – 4.84 (m, 2H), 3.87 (t, J = 9.3 Hz, 1H), 2.88 (m, 2H), 2.50 (d, J = 10.2 Hz, 3H), 2.38 – 2.14 (m, 3H), 1.77 – 1.69 (m, 1H), 1.56 (s, 3H), 1.13 (t, J = 13.0 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 169.5, 164.0, 138.7, 135.1, 134.5, 133.1, 132.8, 132.4, 132.3, 131.6, 120.7, 117.7, 112.8, 81.1, 68.6, 63.5, 60.1, 42.9, 36.7, 25.7, 24.5, 24.0, 18.1; HRMS (ESI) calcd for C23H23NO5 [M+NH4]+ 411.1914, found 411.1919.
6i:91% yield;1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 7.9 Hz, 2H), 6.24 (s, 1H), 5.79 (t, J = 8.1 Hz, 1H), 5.54 (s, 1H), 4.93 (d, J = 12.5 Hz, 1H), 4.75 (d, J = 12.5 Hz, 1H), 3.87 (t, J = 9.2 Hz, 1H), 2.90 (m, 2H), 2.54 – 2.12 (m, 6H), 1.75 – 1.65 (m, 1H), 1.56 (s, 3H), 1.12 (t, J = 13.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 165.2, 138.7, 134.9 (q, J = 31.0 Hz), 134.7, 133.2, 131.1, 130.2, 125.7 (q, J =4.0 Hz), 123.7 (q, J = 271.0 Hz), 120.6, 81.1, 67.6, 63.4, 60.1, 42.8, 36.7, 25.8, 24.5, 24.0, 18.1; HRMS (ESI) calcd for C23H23F3O5 [M+NH4]+ 454.1836, found 454.1834.
6j:92% yield;1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 16.0 Hz, 1H), 7.50 (m, 2H), 7.45 – 7.32 (m, 3H), 6.41 (d, J = 16.0 Hz, 1H), 6.23 (d, J = 3.4 Hz, 1H), 5.73 (t, J = 8.2 Hz, 1H), 5.55 (d, J = 3.1 Hz, 1H), 4.78 (d, J = 12.5 Hz, 1H), 4.60 (d, J = 12.6 Hz, 1H), 3.86 (t, J = 9.3 Hz, 1H), 3.04 – 2.92 (m, 1H), 2.88 (d, J = 9.4 Hz, 1H), 2.55 – 2.10 (m, 6H), 1.73 – 1.65 (m, 1H), 1.54 (s, 3H), 1.11 (t, J = 12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 166.6, 145.6, 138.8, 135.0, 134.1, 130.7, 130.6, 129.0, 128.1, 120.3, 117.4, 81.1, 66.9, 63.3, 60.0, 42.7, 36.7, 25.8, 24.6, 23.9, 18.0; HRMS (ESI) calcd forC24H30NO5 [M+NH4]+ 412.2118, found 412.2118.
6k:85% yield;1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 4.9 Hz, 1H), 7.11 (t, J = 4.3 Hz, 1H), 6.22 (d, J = 3.4 Hz, 1H), 5.78 (t, J = 8.3 Hz, 1H), 5.52 (d, J = 3.0 Hz, 1H), 4.86 (d, J = 12.4 Hz, 1H), 4.70 (d, J = 12.5 Hz, 1H), 3.86 (t, J = 9.3 Hz, 1H), 2.96 (dd, J = 14.9, 5.8 Hz, 1H), 2.89 (d, J = 9.4 Hz, 1H), 2.51 – 2.14 (m, 6H), 1.74 – 1.65 (m, 1H), 1.55 (s, 3H), 1.12 (t, J = 12.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.5, 162.0, 138.8, 134.9, 133.9, 133.3, 133.0, 131.3, 128.1, 120.6, 81.1, 67.3, 63.4, 60.1, 42.9, 36.7, 25.9, 24.8, 24.0, 18.2; HRMS (ESI) calcd for C20H22O5S [M+NH4]+392.1526 found 392.1530.
Take compound 3（0.15 mmol）In reaction bottle, 1 mL methylene chloride is added, starts to stir at room temperature, according to It is secondary to take silver oxide（0.30 mmmol）With corresponding halogenated hydrocarbons（0.6 mmol）Add, react 48 hours, see original from TLC plates Material is basic to disappear, and adds the mL of ethyl acetate 3, is filtered by diatomite, ethyl acetate is washed, and is concentrated under reduced pressure, crude product silicagel column Chromatography purifies（Petroleum ether：Ethyl acetate=5:1–2:1）, obtain object 7a ~ d.
7a:84% yield;1H NMR (400 MHz, CDCl3) δ 6.21 (d, J = 3.4 Hz, 1H), 5.61 (t, J = 7.9 Hz, 1H), 5.52 (d, J = 3.0 Hz, 1H), 4.02 (d, J = 11.5 Hz, 1H), 3.83 (t, J = 9.3 Hz, 1H), 3.70 (d, J = 11.5 Hz, 1H), 3.29 (s, 3H), 2.88 (m, 1H), 2.84 (d, J = 9.5 Hz, 1H), 2.45 – 2.08 (m, 6H), 1.68 – 1.60 (m, 1H), 1.53 (s, 3H), 1.08 (t, J = 12.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.6, 139.1, 136.9, 129.2, 120.0, 81.2, 75.7, 63.5, 60.1, 58.0, 42.9, 36.8, 25.8, 24.4, 23.7, 18.0; HRMS calcd for C16H26NO4 [M+NH4]+ 296.1856, found 296.1859.
7b:75% yield;1H NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (m, 5H), 6.14 (d, J = 3.5 Hz, 1H), 5.65 (t, J = 8.1 Hz, 1H), 5.33 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 11.8 Hz, 1H), 4.39 (d, J = 11.8 Hz, 1H), 4.06 (d, J = 11.2 Hz, 1H), 3.87 – 3.74 (m, 2H), 2.82 (d, J = 9.4 Hz, 1H), 2.80 – 2.70 (m, 1H), 2.40 – 2.12 (m, 6H), 1.63 – 1.55 (m, 1H), 1.53 (s, 3H), 1.08 (t, J = 12.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.6, 138.9, 138.0, 137.1, 129.6, 128.6, 128.2, 128.0, 120.1, 81.2, 73.0, 72.4, 63.5, 60.1, 42.9, 36.9, 25.7, 24.4, 23.8, 18.1; HRMS (ESI) calcd for C22H26NaO4 [M+Na]+ 377.1723 , found 377.1728
7c:82% yield;1H NMR (400 MHz, CDCl3) δ7.24 (d, J = 8.5 Hz, 2H), 6.87 (d,J = 8.5 Hz, 2H), 6.13 (d, J = 3.5 Hz, 1H), 5.63 (t, J = 8.1 Hz, 1H), 5.32 (d,J = 3.1 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.32 (d, J = 11.5 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.79 (br s, 4H), 3.77 (t, J = 4.4 Hz, 1H), 2.81 (d, J = 9.4 Hz, 1H), 2.79 – 2.71 (m, 1H), 2.38 – 2.09 (m, 6H), 1.57 (d, J = 13.7 Hz, 1H), 1.52 (s, 3H), 1.07 (t, J = 12.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.5, 159.4, 138.9, 137.1, 130.0, 129.7, 129.4, 119.9, 113.9, 81.1, 72.6, 71.9, 63.4, 60.1, 55.3, 42.9, 36.8, 25.6, 24.3, 23.7, 18.0; HRMS calcd forC23H32NO5 [M+NH4]+ 402.2275, found 402.2269.
7d:91% yield;1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 6.18 (d, J = 3.1 Hz, 1H), 5.67 (t, J = 8.1 Hz, 1H), 5.38 (d, J = 2.6 Hz, 1H), 4.58 (d, J = 12.4 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 4.11 (d, J = 11.3 Hz, 1H), 3.84 (t, J = 9.5 Hz, 2H), 2.81 (d, J = 9.4 Hz, 1H), 2.79 – 2.71 (m, 1H), 2.47 – 2.09 (m, 6H), 1.63 (dd, J = 18.6, 7.6 Hz, 1H), 1.54 (s, 3H), 1.09 (t, J = 12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 142.1, 138.9, 136.7, 130.0 (q, J =33.0 Hz), 129.9,127.8,125.4（q,J = 4.0 Hz）124.1 (q,J = 271.0 Hz), 120.0, 81.1, 73.5, 71.3, 63.4, 60.0, 42.9, 36.8, 25.7, 24.3, 23.8, 18.0; HRMS calcd for C23H29F3NO4 [M+NH4]+ 440.2049, Found 440.2044.
Compound 4 is taken successively（27 mg, 0.103 mmol）With 2- aminothiophenols（13 μL, 0.124 mmol）Add reaction In bottle, it is dissolved in 1mL tetrahydrofurans, starts to stir at room temperature, take TCCA（14 mg, 0.062 mmol）Add In the solution of stirring, being kept for 4 hours, find out that display raw material point disappears from TLC plates, add 3mL water, ethyl acetate extracts, This is washed organic phase with watery hydrochloric acid, water and saturated common salt, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, crude product silicagel column Chromatography, obtain target compound 8 (22.7 mg, 60%)1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 6.55 (t, J = 8.5 Hz, 1H), 6.10 (d, J = 3.3 Hz, 1H), 5.43 (d, J = 2.8 Hz, 1H), 3.86 (t, J = 9.4 Hz, 1H), 3.25 – 3.13 (m, 1H), 3.03 (dd, J = 14.6, 7.1 Hz, 1H), 2.90 (d, J = 9.5 Hz, 1H), 2.84 – 2.73 (m, 1H), 2.60 (m, 2H), 2.51 – 2.42 (m, 1H), 2.30 (dd, J = 13.0, 5.2 Hz, 1H), 1.71(m, 1H), 1.61 (s, 3H), 1.30 (t, J = 13.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.6, 168.8, 154.0, 138.6, 137.04, 137.01, 134.0, 126.4, 125.8, 123.2, 121.6, 120.4, 82.0, 63.3, 59.8, 42.4, 36.8, 26.2, 25.4, 25.1, 18.2; HRMS (ESI) calcd for C21H22NO3S [M+H]+368.1315 found 368.1314.
Compound 5 is taken successively（0.03 mmol）And potassium carbonate（11 mg, 0.08 mmol）In reaction bottle, add 1mL's Reaction dissolvent DMF, start to stir at room temperature, halogenated hydrocarbons (0.16 mmol) is added into the solution of stirring, kept for 5 hours, from TLC finds out that raw material point disappears, and adds 5 mL water, is extracted with ethyl acetate three times, and organic phase semi-saturation salt is washed three times, nothing Aqueous sodium persulfate is dried, and filtering, is concentrated under reduced pressure, crude product silica gel column chromatography（Petroleum ether：Ethyl acetate=3:1–1:1）Purifying, Obtain target compound 9a ~ 9c.
9a:95% yield;1H NMR (400 MHz, CDCl3) δ 6.80 (t, J = 8.8 Hz, 1H), 6.20 (d, J = 3.1 Hz, 1H), 5.53 (d, J = 2.4 Hz, 1H), 3.79 (t, J = 9.4 Hz, 1H), 3.73 (s, 3H), 2.77 (d, J = 9.6 Hz, 1H), 2.72 (m, 1H), 2.65 – 2.55 (m, 2H), 2.41 (m, 3H), 2.22 (m, 1H), 1.60 (td, J = 13.3, 6.0 Hz, 1H), 1.53 (s, 3H), 1.17 (t, J = 13.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 167.5, 141.3, 138.6, 133.3, 120.4, 81.7, 62.9, 59.6, 51.9, 42.3, 36.0, 25.9, 24.5, 23.7, 18.0; HRMS (ESI) calcd for C16H20NaO5 [M + Na+] 315.1203, found 315.1208.
9b:93% yield;1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 10.0 Hz, 5H), 6.86 (t, J = 8.4 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 5.29 (d, J = 12.1 Hz, 1H), 5.24 (d, J = 3.1 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 3.76 (t, J = 9.4 Hz, 1H), 2.77 (d, J = 9.5 Hz, 1H), 2.71 – 2.29 (m, 6H), 2.23 (m, 1H), 1.59 – 1.54 (m, 1H), 1.52 (s, 3H), 1.19 (td, J = 12.9, 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 166.9, 141.5, 138.2, 135.8, 133.4, 128.8, 128.6, 128.5, 120.4, 81.7, 66.7, 62.9, 59.6, 42.2, 36.0, 25.9, 24.5, 23.7, 18.0. HRMS (ESI) calcd for C22H24NaO5 [M + Na+] 391.1516, found 391.1522.
9c:99% yield;1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 6.87 (t, J = 8.8 Hz, 1H), 6.14 (d, J = 3.0 Hz, 1H), 5.31 (dd, J = 14.2, 7.5 Hz, 2H), 5.14 (d, J = 12.7 Hz, 1H), 3.78 (t, J = 9.4 Hz, 1H), 2.77 (d, J = 9.5 Hz, 1H), 2.71 – 2.34 (m, 6H), 2.28 – 2.19 (m, 1H), 1.57 (m, 1H), 1.54 (s, 3H), 1.19 (t, J = 12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 166.8, 142.1, 139.9, 138.5, 133.3, 130.7(q, J = 33.0 Hz), 128.6, 125.8 (q, J = 4.0 Hz), 124.0(q, J = 271.0 Hz), 120.4, 81.7, 65.8, 63.0, 59.7, 42.4, 36.1, 25.9, 24.7, 23.8, 18.1; HRMS (ESI) calcd for C23H25F3O4 [M+NH4]+ 454.1836, Found 454.1835.
Compound 5 is taken successively（50 mg, 0.18 mmol）And triethylamine（74µL, 0.54 mmol）In reaction bottle, 3 are added ML dry toluene, stirring is opened at room temperature, then successively by oxalyl chloride（30µL, 0.36 mmol）And DMF（20µL）Add In the reaction solution of stirring, kept for 1 hour, be concentrated under reduced pressure, again with toluene azeotropic removes unnecessary oxalyl chloride three times, obtains crude product acyl Chlorine.Into the reaction bulb containing above-mentioned acyl chlorides, 3 mL dry toluene and triethylamine are sequentially added（74µL, 0.54 mmol）, Start to stir at room temperature, then by corresponding amine（0.22 mmol）Add in the reaction solution of stirring, kept for 4 hours, from TLC plates On find out basic disappearance, add 3 mL saturated sodium bicarbonate solution, be extracted with ethyl acetate three times, the organic phase of merging is according to this Washed, anhydrous sodium sulfate drying, filtering, be concentrated under reduced pressure with water and saturated common salt, crude product silica gel column chromatography separating purification, just Obtain corresponding target compound 10a ~ 10j.
10a:46% yield;1H NMR (400 MHz, CDCl3) δ 6.18 (d, J = 3.4 Hz, 1H), 5.71 (t, J = 8.3 Hz, 1H), 5.44 (d, J = 3.0 Hz, 1H), 3.82 (t, J = 9.4 Hz, 1H), 3.59 – 3.42 (m, 1H), 3.01 (m, 7H), 2.52 – 2.15 (m, 6H), 1.65 – 1.58 (m, 1H), 1.55 (s, 3H), 1.17 (t, J = 12.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 171.0, 169.7, 139.2, 138.1, 130.6, 119.9, 80.9, 63.3, 59.9, 42.7, 36.5, 26.8, 25.4, 23.7, 18.0; HRMS (ESI) calcd forC17H24NO4 [M+H]+ 306.1700, found 306.1702.
10b:48% yield;1H NMR (400 MHz, CDCl3) δ 6.15 (d, J = 3.5 Hz, 1H), 5.64 (t, J = 7.9 Hz, 1H), 5.39 (d, J = 3.2 Hz, 1H), 3.82 (t, J = 9.4 Hz, 1H), 3.72 – 3.61 (m, 1H), 3.52 – 3.22 (m, 4H), 3.03 (d, J = 9.4 Hz, 1H), 2.50 – 2.12 (m, 6H), 1.63 (m, 1H), 1.53 (s, 3H), 1.13 (t, J = 7.1 Hz, 7H); 13C NMR (101 MHz, CDCl3) δ 170.5, 169.7, 139.2, 138.7, 129.3, 119.6, 80.9, 63.3, 59.8, 42.7 (br), 42.5, 39.0 (br), 36.6, 26.9, 25.7, 23.6, 18.0, 14.5 (br), 12.9 (br); HRMS (ESI) calcd forC19H28NO4 [M+H]+ 334.2013, found 334.2015.
10c:43% yield;1H NMR (400 MHz, CDCl3) δ 6.14 (d, J = 2.8 Hz, 1H), 5.62 (t, J = 8.2 Hz, 1H), 5.37 (d, J = 3.1 Hz, 1H), 3.81 (t, J = 9.4 Hz, 1H), 3.75 – 3.62 (m, 1H), 3.39 (br s, 1H), 3.27 – 3.06 (m, 3H), 3.02 (d, J = 9.3 Hz, 1H), 2.48 – 2.10 (m, 6H), 1.69 – 1.53 (m, 5H), 1.52 (s, 3H), 1.13 (t, J = 12.8 Hz, 1H), 0.86 (d, J = 7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.0, 169.7, 139.2, 138.7, 129.5, 119.5, 80.9, 63.3, 59.8, 50.0 (br), 45.9 (br), 42.4, 36.6, 26.9, 25.7, 23.6 (br), 22.2 (br), 20.7, 18.0, 11.4 (br), 11.2 (br); HRMS (ESI) calcd forC21H32NO4 [M+H]+ 362.2326, found 362.2333.
10d:54% yield;1H NMR (400 MHz, CDCl3) δ 6.15 (d, J = 3.5 Hz, 1H), 5.62 (t, J = 7.7 Hz, 1H), 5.38 (d, J = 3.2 Hz, 1H), 3.81 (t, J = 9.4 Hz, 1H), 3.72 – 3.56 (m, 1H), 3.43 (m, 1H), 3.27 – 3.08 (m, 3H), 3.02 (d, J = 9.4 Hz, 1H), 2.51 – 2.10 (m, 6H), 1.62 (m, 1H), 1.53 (s, 3H), 1.50 (m, 4H), 1.27 (m, 4H), 1.14 (t, J = 12.4 Hz, 1H), 0.90 (t, J = 7.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.8, 169.6, 139.2, 138.7, 129.5, 119.5, 80.9, 63.2, 59.8, 48.0 (br), 44.1 (br), 42.4, 36.5, 31.1 (br), 29.6 (br), 26.9, 25.7, 23.6, 20.2 (br), 20.0 (br), 17.9, 13.8 (br); HRMS (ESI) calcd forC23H36NO4 [M+H]+ 390.2639, found 390.2643.
10e:78% yield;1H NMR (400 MHz, CDCl3) δ 6.15 (d, J = 3.5 Hz, 1H), 5.78 (t, J = 7.6 Hz, 1H), 5.45 (d, J = 3.2 Hz, 1H), 3.80 (t, J = 9.4 Hz, 1H), 3.58 – 3.46 (m, 1H), 3.46 – 3.27 (m, 4H), 2.98 (d, J = 9.5 Hz, 1H), 2.61 – 2.48 (m, 1H), 2.45 – 2.35 (m, 1H), 2.34 – 2.13 (m, 4H), 1.96 – 1.76 (m, 4H), 1.66 – 1.55 (m, 1H), 1.52 (s, 3H), 1.13 (t, J = 12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.6, 169.4, 139.1, 139.0, 130.9, 120.0, 81.0, 63.2, 59.9, 48.3, 45.8, 42.8, 36.4, 26.6, 26.3, 24.8, 24.2, 23.7, 17.9; HRMS (ESI) calcd forC19H26NO4 [M+H]+ 332.1856, found 332.1863.
10f:78% yield;1H NMR (400 MHz, CDCl3) δ 6.15 (d, J = 3.1 Hz, 1H), 5.65 (t, J = 8.1 Hz, 1H), 5.43 (d, J = 2.7 Hz, 1H), 3.82 (t, J = 9.4 Hz, 1H), 3.46 (m, 5H), 3.00 (d, J = 9.4 Hz, 1H), 2.43 (d, J = 7.9 Hz, 2H), 2.34 – 2.12 (m, 4H), 1.67 – 1.60 (m, 3H), 1.55 – 1.45 (m, 7H), 1.14 (t, J = 12.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.8, 169.5, 139.2, 138.3, 129.8, 120.0, 80.9, 63.3, 60.0, 47.9, 42.7, 36.6, 26.9, 25.7, 24.6, 23.7, 18.0; HRMS (ESI) calcd for C20H28NO4 [M+H]+ 346.2013 found 346.2014.
10g:51% yield;1H NMR (400 MHz, CDCl3) δ 6.16 (d, J = 3.5 Hz, 1H), 5.66 (t, J = 8.2 Hz, 1H), 5.43 (d, J = 3.2 Hz, 1H), 4.49 (s, 1H), 3.82 (t, J = 9.4 Hz, 1H), 3.81 – 3.66 (m, 1H), 3.51 (br s, 1H), 3.00 (d, J = 9.4 Hz, 1H), 2.98 – 2.80 (m, 1H), 2.72 – 2.54 (m, 1H), 2.44 (m, 2H), 2.38 – 2.11 (m, 5H), 1.76 – 1.54 (m, 5H), 1.53 (s, 3H), 1.14 (t, J = 12.8 Hz, 1H), 0.94 (d, J = 5.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.6, 169.5, 139.1, 138.2, 129.8, 119.8, 80.9, 63.3, 59.9, 47.0 (br), 42.6, 41.90 (br), 36.5, 34.40 (br), 31.1, 26.8, 25.7, 23.7, 21.7, 18.0. HRMS (ESI) calcd for C21H30NO4 [M+H]+ 360.2169, found 360.2169.
10h:53% yield;1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.4 Hz, 2H), 7.21 (m, 3H), 6.20 (d, J = 3.4 Hz, 1H), 5.73 (t, J = 8.2 Hz, 1H), 5.47 (d, J = 3.0 Hz, 1H), 4.72 (br s, 1H), 3.98 (br s, 1H), 3.85 (t, J = 9.4 Hz, 1H), 3.56 (br s, 1H), 3.13 (br m, 1H), 3.03 (d, J = 9.4 Hz, 1H), 2.85 – 2.70 (m, 2H), 2.49 (m, 2H), 2.36 – 2.15 (m, 4H), 1.94 (m, 2H), 1.66 (m, 3H), 1.55 (s, 3H), 1.18 (t, J = 12.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.6, 144.9, 139.2, 138.1, 130.0, 128.7, 126.7, 126.67, 119.9, 80.9, 63.3, 59.9, 42.7, 36.5, 33.6 (br), 26.9, 25.7, 23.8, 18.0; HRMS (ESI) calcd forC26H32NO4 [M+H]+ 422.2326, found 422.2322.
10i:73% yield; 1H NMR (400 MHz, CDCl3) δ 6.19 (d, J = 3.0 Hz, 1H), 5.71 (t, J = 8.2 Hz, 1H), 5.45 (d, J = 2.4 Hz, 1H), 3.83 (t, J = 9.4 Hz, 1H), 3.57 (m, 9H), 2.99 (d, J = 9.4 Hz, 1H), 2.50 – 2.14 (m, 6H), 1.66 (t, J = 12.9 Hz, 1H), 1.54 (s, 3H), 1.16 (t, J = 12.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.7, 169.5, 138.9, 137.4, 130.9, 120.0, 80.7, 67.0, 63.2, 59.8, 42.6, 36.4, 26.8, 25.6, 23.7, 18.0; HRMS (ESI) calcd for C19H26NO5 [M+H]+348.1805, found 348.1807.
10j:66% yield;1H NMR (400 MHz, CDCl3) δ 6.19 (d, J = 3.5 Hz, 1H), 5.72 (t, J = 7.8 Hz, 1H), 5.45 (d, J = 3.2 Hz, 1H), 3.84 (t, J = 9.4 Hz, 1H), 3.46 (m, 9H), 3.00 (d, J = 9.4 Hz, 1H), 2.58 – 2.46 (m, 1H), 2.43 – 2.17 (m, 5H), 1.68 (m, 1H), 1.56 (s, 3H), 1.47 (s, 9H), 1.18 (t, J = 12.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 169.9, 169.5, 154.5, 139.0, 137.6, 130.9, 119.8, 80.7, 80.5, 63.2, 59.8, 43.9 (br), 42.6, 36.4, 29.7, 29.3, 28.4, 27.2, 26.8, 25.7, 23.7, 17.9; HRMS (ESI) calcd for C24H38N3O6 [M+NH4]+ 464.2755, found 464.2758.
Embodiment 2：The pharmacological action of parthenolide derivative
Various cancer cells are made into 2 × 105/ mL cell suspensions, add in 24 orifice plate round bottom Tissue Culture Plates, be separately added into implementation Compound synthesized by example 1, each hole of test concentrations 5, puts 37 DEG C, 5%CO2Cultivated 18 hours under the conditions of saturated humidity, use MTT Method measures absorbance in the nm wavelength of enzyme detector 570（A）Value, calculate suppression of the compounds of this invention to test cancer cell Effect.
The inhibitory activity of compound prepared by the embodiment 1 of table 1 to various cancer cells（IC50, μM）
Continued 1
Continued 2
Cell 10c 10d 10e 10f 10g 10h 10i 10j
HL-60 1.0 3.7 4.0 1.8 6.3 2.2 3.9 5.1
KG1a 2.0 1.4 1.8 3.2 1.6 2.2 29.9 1.7
Data above is the average value of result three times.
Wherein HL-60, KG1a represent acute leukemia cellses strain, high expression CD34+ Acute myelocytic leukemia cell line respectively.
Active testing result shows that the compound of screening shows stronger inhibitory activity to subject cell.
Embodiment 3：Parenteral solution
Compound prepared by embodiment 1 is with after a small amount of DMSO dissolvings, and routinely plus water for injection, refined filtration, embedding sterilizing are made Parenteral solution.
Embodiment 4：Tablet
Compound prepared by embodiment 1 is 5 according to weight ratio with excipient:1 ratio adds excipient, pelletizing press sheet, obtains piece Agent.
Embodiment 5：Capsule
Compound prepared by embodiment 1 is 5 according to weight ratio with excipient:1 ratio adds excipient, and capsule is made.
Compound, purposes and the method for the present invention is described by specific embodiment.People in the art Member can use for reference the links such as the appropriate feed change of present disclosure, process conditions to realize corresponding other purposes, and it is related Change all without departing from present disclosure, all similar replacements and change are aobvious and easy to those skilled in the art See, be considered as being included within the scope of the present invention.

Claims (4)

  1. It is 1. a kind of such as following formula（I）Compound,
    （I）
    Formula（I）Middle R is-CH2OR1、–C(O)R2Or heterocyclic radical,
    R1For alkyl, aryl alkyl ,-C (O) R3, wherein R3For alkyl, cycloalkyl, alkenyl, aryl alkenyl, alkylalkenyl, substitution Base phenyl, ring group, the substituent in substituent phenyl is hydrogen, methoxyl group, cyano group, trifluoromethyl；
    R2For hydroxyl, OR4Or-NR5R6
    R4For alkyl, aryl alkyl, R5R6Respectively carbon number is 1-8 alkyl or-NR5R6Cyclization is
    。
  2. 2. purposes of the compound in the medicine for preparing treating cancer described in claim 1, wherein cancer is leukaemia.
  3. 3. purposes of the compound in the ancillary drug for preparing treating cancer described in claim 1, wherein cancer is leukaemia.
  4. A kind of 4. pharmaceutical composition for treating cancer, wherein compound and medicine described in the claim 1 containing effective dose Acceptable carrier or other cancer therapy drugs on.
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