CN106243182A - Enoxolone hydrogen sulfide donor reagent derivatives and synthetic method thereof and application - Google Patents
Enoxolone hydrogen sulfide donor reagent derivatives and synthetic method thereof and application Download PDFInfo
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- WIFHKZJKCUAIOL-WEVUPQLGSA-N CC(C)(C(CC[C@@]1(C)C(CC[C@@](C)(CC2)C3C[C@@]2(C)C(OCCOC(CCCC[C@H]2SSCC2)=O)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O Chemical compound CC(C)(C(CC[C@@]1(C)C(CC[C@@](C)(CC2)C3C[C@@]2(C)C(OCCOC(CCCC[C@H]2SSCC2)=O)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O WIFHKZJKCUAIOL-WEVUPQLGSA-N 0.000 description 1
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- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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Abstract
The invention discloses a kind of enoxolone hydrogen sulfide donor reagent derivatives and synthetic method thereof and application.The synthetic method of this derivant is: extracting liquorice subacid, α, and ω bis-bromoalkane and alkali react in aprotic polar solvent, obtain compound 1；Take compound 1, hydrogen sulfide donor reagent and alkali to react in aprotic polar solvent, obtain object crude product；Wherein, reaction is carried out under conditions of being heated or not heated.The majority of compounds that synthesis obtains in derivant has certain inhibitory activity to chronic myeloid leukemia cells K562, is expected to be used for the preparation of the medicine of corresponding antitumor drug and treatment chronic lymphocytic leukemia.The derivant that described synthesis obtains has a structure shown in following logical formula (I):Wherein, n is 2～8；R isOr
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of enoxolone-hydrogen sulfide donor reagent derivatives and
Synthetic method and application.
Background technology
Hydrogen sulfide is a new biological activity gas molecule after CO and NO in succession, is the important angle supporting life
Color, has irreplaceable physiological regulatory action in vital movement, and in control various kinds of cell, signal conductive process performance are long-pending
The regulation effect of pole.Potential therapeutic about hydrogen sulfide is applied and is concentrated mainly on nerve, cardiovascular system at present, such as treatment height
Blood pressure, treatment heart ischemia disease, treat atherosclerosis, be combined with nonsteroidal antiinflammatory drug, is used for reducing metabolism, preventing
Only conditions associated with hypoxia damage etc..
Hydrogen sulfide donor can hydrolyze in physiological conditions from putting out H2S or release under cysteine (GSH) acts on
H2S, GSH can accept the S sulphur atom of sulfide and form GSSH, is then urged by 3-mercaptopyruvate sulfurtransferase (3-MST)
Change and produce H2S。H2The research of the biological effect of S and signal path mechanism discloses it and relates at cardiovascular as signaling molecule
Physiological process multiple in body are all had an impact by the cell signalling of many organs such as system, nervous system, blood circulation.
Enoxolone is the primary pharmacological activity material of Radix Glycyrrhizae.In recent years, along with enoxolone pharmacological action research not
Disconnected deeply its pharmacological action is day by day realized, and including antitumor, antiinflammatory, antiviral, treatment cardiovascular disease, immunomodulating, resists
The multiple pharmacological effect such as oxidation.With natural product as lead compound, it is carried out structural modification and introduces the drug effect of corresponding activity
Group, and then carry out the pharmacology activity research in corresponding field, it has also become the study hotspot of new drug development.
Have not yet to see the derivant and synthesis side thereof enoxolone and hydrogen sulfide donor reagent being connected through alkane chain
Method and the relevant report of application.
Summary of the invention
The technical problem to be solved in the present invention is to provide the novel enoxolone-hydrogen sulfide donor reagent of a class formation and derives
Thing, and their synthetic method and application.
The present invention relates to have the enoxolone of structure-hydrogen sulfide donor reagent derivatives shown in following logical formula (I) or its
Pharmaceutically acceptable salt:
Wherein,
N is 2～8；
R is
The synthetic method of enoxolone of the present invention-hydrogen sulfide donor reagent derivatives is: extracting liquorice subacid, α, ω-
Two bromoalkanes and alkali react in aprotic polar solvent, obtain compound 1；Take compound 1, hydrogen sulfide donor reagent and alkali to exist
Aprotic polar solvent reacts, obtains object crude product；Wherein, reaction is carried out under conditions of being heated or not heated.
More specifically synthetic method, comprises the following steps:
1) extracting liquorice subacid, α, ω-two bromoalkane and alkali reacts in aprotic polar solvent, and gained reactant removes molten
Agent, residue is scattered in ethyl acetate, dichloromethane or ether, and scrubbed, anhydrous sodium sulfate is dried, and after filtration, collects filter
Liquid, filtrate obtains compound 1 after concentrating；
2) taking compound 1, hydrogen sulfide donor reagent and alkali to react in aprotic polar solvent, gained reactant removes molten
Agent, residue is scattered in ethyl acetate, dichloromethane or ether, and scrubbed, anhydrous sodium sulfate is dried, and after filtration, collects filter
Liquid, filtrate obtains object crude product after concentrating.
The step 1 of above-mentioned concrete synthetic method) and step 2) in, described washing is used hydrochloric acid, water the most successively, is satisfied
Wash with saline solution, or wash with hydrochloric acid, saturated aqueous common salt successively.
The structural formula synthesizing the compound 1 obtained in synthetic method of the present invention is as follows:
Wherein, n is 2～8.
Said method synthesizes the crude product that compound 1 is compound 1 obtained, in order to improve the purity of compound 1 simultaneously
Reduce in subsequent reactions and produce more by-product, preferably by the crude product of gained compound 1 through silica gel thin-layer chromatography or silica gel
Column chromatography is used further to subsequent operation after purification.Carried out silica gel thin-layer chromatography or on silica gel column chromatography time, generally with by body
Long-pending than be 2～10:1 petroleum ether (PE) and the eluent that forms of ethyl acetate (EA), collect eluent, eluent decompression
Solvent is evaporated off, obtains object after purification.The described petroleum ether of composition eluant and the volume ratio of ethyl acetate be preferably 2～
5:1.
Prepare by said method is the crude product of formula (I) compound, and the purification process of existing routine can be used to carry out it
Purification is to improve the purity of formula (I) compound.Generally use silica gel thin-layer chromatography or silica gel column chromatography to be purified, will make
When the target compound crude product silica gel thin-layer chromatography obtained or upper silica gel column chromatography, generally with by the oil that volume ratio is 2～10:1
The eluent that ether (PE) and ethyl acetate (EA) form, collects eluent, and eluent removes solvent under reduced pressure, obtains after purification
Object.The described petroleum ether of composition eluant and the volume ratio of ethyl acetate are preferably 2～5:1.
In synthetic method of the present invention, described α, ω-two bromoalkane can be glycol dibromide, 1,3-dibromo
Propane, 1,4-dibromobutane, pentamethylene bromide, 1,6-dibromo-hexane, 1,7-dibromo-heptane or 1,8-bis-bromooctane.
In synthetic method of the present invention, described alkali can be potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, carbon
Potassium hydrogen phthalate or cesium carbonate.When being chosen as cesium carbonate of alkali, it is possible to obtain higher productivity；Consider from cost and productivity,
Preferably alkali is potassium carbonate.
In synthetic method of the present invention, described aprotic polar solvent can be DMF
(DMF) one or more the combination, in toluene and pyridine, when the selection of aprotic polar solvent is more than above two
Combination time, the proportioning between them can be any proportioning.The consumption of described aprotic polar solvent usually can dissolve
Participate in the raw material of reaction.
In synthetic method of the present invention, described hydrogen sulfide donor reagent can be specifically 5-p-hydroxybenzene-1,
2-dithiole-3-thioketone (ADT-OH), (R)-thioctic acid (R-lipoic acid) or 4-hydroxythiobenzamide
(TBZ), their structural formula is the most as follows:
In synthetic method of the present invention, described enoxolone, α, the reaction of ω-two bromoalkane and alkali is preferably low
In or equal to carrying out under conditions of 40 DEG C, applicant finds in an experiment, when reaction is carried out under the conditions of 20～40 DEG C, permissible
Obtaining higher productivity in the short period of time, side reaction is less simultaneously；Described compound 1, hydrogen sulfide donor reagent and alkali
Reaction is carried out under conditions of less than or equal to 65 DEG C, more preferably carries out under the conditions of 35～65 DEG C, so can be shorter
Time in obtain higher productivity, and reduce the generation of by-product as far as possible.Under the conditions of above-mentioned limiting temperature, react the completeest
Entirely can pass through thin layer chromatography tracing detection.
In synthetic method of the present invention, described enoxolone, α, the ratio of the amount of the material of ω-two bromoalkane and alkali
For: 1:1～5:0.5～3；The ratio of the amount of the material of described compound 1, hydrogen sulfide donor reagent and alkali is: 1:1～3:1～5.
It has been found that in the reaction of compound 1, hydrogen sulfide donor reagent and alkali, add catalyst potassium iodide (KI)
The productivity of object can be improved further.The addition of described potassium iodide is 0.1～1 times of the amount of compound 1 material.
Compared with prior art, the enoxolone-hydrogen sulfide donor reagent that the invention provides a series of novel structure spreads out
Biology and synthetic method thereof, meanwhile, it is white to tumor cells of hepatocellular carcinoma strain and chronic myelognous that applicant has also investigated these derivants
The inhibitory activity of disorders of blood cell, result shows, wherein most compound has one to chronic myeloid leukemia cells K562
Fixed inhibitory activity, is expected to be used for the preparation of the medicine of corresponding antitumor drug and treatment chronic lymphocytic leukemia.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, to be more fully understood that present disclosure, but
The present invention is not limited to following example.
Of the present invention have the ursolic acid of structure-hydrogen sulfide donor reagent derivatives shown in following logical formula (I) and press
State synthetic route to synthesize:
Wherein:
α, ω-two bromoalkane can be glycol dibromide, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromo penta
Alkane, 1,6-dibromo-hexane, 1,7-dibromo-heptane or 1,8-bis-bromooctane；
Aprotic polar solvent can be N,N-dimethylformamide, toluene or pyridine；
Alkali can be potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate；
Hydrogen sulfide donor reagent can be specifically 5-p-hydroxybenzene-1,2-dithiole-3-thioketone (ADT-OH),
(R)-thioctic acid (R-lipoic acid) or 4-hydroxythiobenzamide (TBZ), their structural formula is the most as follows:
N in compound 1 and compound 2 is 2～8；
R in compound 2 is
Embodiment 1: the synthesis of compound 1a
Enoxolone (500mg, 1.06mmol) is dissolved in dry DMF (5mL), adds 1,6-Bromofume (2.43mL,
5.3mmol)、K2CO3(146.28mg, 1.06mmol), 30 DEG C of reaction 24h.Remove solvent, residue dispersion ethyl acetate under reduced pressure
(50mL), in, successively with HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, post
Chromatography (VPE:VEA=2:1), obtain compound 1a (457mg, 75%, white solid).
Yield:457mg, 75%, white solid；Rf=0.461 (Petroluem ether:EtOAc=2:1)
.M.p 190-192℃.1H NMR(500MHz,CDCl3) δ (ppm): 5.69 (s, 1H, 12-H), 4.41 (dd, J=28.0,
5.9Hz,2H,OCH2), 3.53 (t, J=5.7Hz, 2H, OCH2), 3.21 (dd, J=11.0,5.2Hz, 1H, 3-H), 2.83-
2.71(m,1H,18-H),2.32(s,1H),2.21-0.63(m,20H),1.35,1.17,1.12,1.11,0.99,0.80and
0.79(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.2,169.2,128.8,
78.9,63.9,61.9,55.1,48.3,45.5,44.3,43.3,41.0,39.2,37.8,37.2,32.9,32.0,31.2,
29.2,28.6,28.2,27.4,26.6,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd
for C32H50BrO4,577.2893；found 577.2873.
Embodiment 2: the synthesis of compound 1b
Enoxolone (500mg, 1.06mmol) is dissolved in dry DMF (5mL), adds 1,8-dibromobutane (2.94mL,
5.3mmol)、K2CO3(146.28mg, 1.06mmol), 30 DEG C of reaction 24h.Remove solvent, residue dispersion ethyl acetate under reduced pressure
(50mL), in, successively with HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, post
Chromatography (VPE:VEA=2:1), obtain compound 1b (532mg, 83%, white solid).
Yield:532mg, 83%, white solid；Rf=0.515 (Petroluem ether:EtOAc=2:1)
.M.p 82-84℃.1H NMR(500MHz,CDCl3) δ (ppm): 5.61 (s, 1H, 12-H), 4.12 (t, J=6.3Hz, 2H,
OCH2), 3.43 (t, J=6.5Hz, 2H, OCH2), 3.21 (dd, J=11.1,5.1Hz, 1H, 3-H), 2.77 (d, J=13.5Hz,
1H,18-H),2.32(s,1H),2.13-0.61(m,24H),1.35,1.14,1.11,1.10and 0.98(5s,each 3H,5
×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.5 169.3,128.6,
78.8,63.5,61.9,55.0,48.5,45.5,44.1,43.3,41.1,39.2,37.8,37.2,33.1,32.8,31.9,
31.2,29.4,28.6,28.2,27.4,26.5,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+
calcd for C34H54BrO4,605.3206；found 605.3188.
Embodiment 3: the synthesis of compound 1c
Enoxolone (1.0g, 2.12mmol) is dissolved in dry DMF (5mL), adds 1,6-dibromo-hexane (1.62mL,
10.62mmol)、K2CO3(293.0mg, 2.12mmol), 30 DEG C of reaction 24h.Remove solvent, residue dispersion ethyl acetate under reduced pressure
(50ml), in, successively with HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, post
Chromatography (VPE:VEA=5:2), obtain compound 1c (929mg, 69%, white solid).
Yield:929mg, 69%, white solid；Rf=0.452 (Petroluem ether:EtOAc=5:2)
.M.p 102-104℃.1H NMR(500MHz,CDCl3)δ(ppm):5.61(s,1H,12-H),4.08(m,2H,OCH2),3.39
(m,2H,CH2-Br), 3.20 (dd, J=11.1,5.2Hz, 1H, 3-H), 2.76 (d, J=13.5Hz, 1H, 18-H), 2.32 (s,
1H,10-H),2.09-0.69(m,35H),1.35,1.13,1.11,1.10and 0.98(5s,each 3H,5×CH3),0.79
(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.6,169.4,128.6,61.9,78.8,
64.4,55.0,48.5,45.5,44.1,43.3,41.2,39.2,37.9,37.2,33.9,32.9,32.7 31.9,31.2,
28.7,28.5,28.2,27.8,27.4,26.6,26.5,25.4,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/
z:[M+H]+calcd for C36H58BrO4,633.3519；found 633.3525.
Embodiment 4: the synthesis of compound 1d
Enoxolone (1.0g, 2.12mmol) is dissolved in dry DMF (5mL), adds 1,8-bis-bromooctane (1.62mL,
10.62mmol)、K2CO3(293.0mg, 2.12mmol), 30 DEG C of reaction 24h.Remove solvent, residue dispersion ethyl acetate under reduced pressure
(50mL), in, successively with HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, post
Chromatography (VPE:VEA=5:2), obtain compound 1d (984mg, 62%, white solid).
Yield:984mg, 62%, white solid；Rf=0.500 (Petroluem ether:EtOAc=5:2)
.M.p 67-69℃.1H NMR(500MHz,CDCl3)δ(ppm):5.62(s,1H,12-H),4.07(m,2H,OCH2),3.39
(m,2H,CH2-Br), 3.21 (dd, J=11.1,5.2Hz, 1H, 3-H), 2.77 (d, J=13.6Hz, 1H, 18-H), 2.32 (s,
1H,10-H),2.10-0.69(m,35H),1.35,1.13,1.12,1.11and 0.99(5s,each 3H,5×CH3),0.79
(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.6,169.4,128.6,78.9,64.6,
61.9,55.1,48.5,45.5,44.1,43.3,41.2,39.2,37.9,34.1,37.2,32.9,31.9,31.3,29.1,
28.7,28.8,28.7,28.6,28.3,28.2,27.4,26.6,26.5,26.0,23.5,18.8,17.6,16.5,
15.7.HRMS(ESI)m/z:[M+H]+calcd for C38H62BrO4,661.3831；found 661.3836.
Embodiment 5: the synthesis of compound 2a
Compound 1a (250mg, 0.43mmol) is dissolved in DMF (5mL), add (R)-lipoic acid (88.58mg,
0.43mmol)、K2CO3(178.02mg, 1.29mmol), 50 DEG C of reaction 24h.Residue is dispersed in ethyl acetate (50mL), successively
With HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, column chromatography for separation (VPE:
VEA=2:1), obtain compound 2a (231mg, 76%, faint yellow solid).
Yield:231mg, 76%, yellow solid；Rf=0.490 (Petroluem ether:EtOAc=2:1)
.M.p 64-66℃.1H NMR(500MHz,CDCl3)δ(ppm):5.62(s,1H,12-H),4.41-4.18(m,4H,2×
OCH2), 3.52 (dd, J=8.2,6.4Hz, 1H, 3-H), 3.25-2.98 (m, 3H), 2.75 (d, J=13.5Hz, 1H, 18-H),
2.44 (s, 1H), 2.33 (dd, J=14.7,7.2Hz, 3H), 2.14-0.60 (m, 26H), 1.34,1.13,1.10,1.09,
0.97,0.78and 0.77(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.1,176.2,
173.3,169.2,128.5,78.8,62.3,61.9,56.4,55.0,48.4,45.5,44.1,43.3,41.1,40.3,
39.2,38.6,37.8,37.2,34.6,34.0,32.8,31.9,31.2,28.8,28.7,28.3,28.2,27.3,26.5,
24.6,23.5,18.8,17.6,16.4,15.7,14.3.HRMS(ESI)m/z:[M+H]+calcd for C40H62ClO6S2,
737.3676；found 737.3696.
Embodiment 6: the synthesis of compound 2b
Compound 1b (250mg, 0.41mmol) is dissolved in DMF (5mL) F, add (R)-lipoic acid (85.12mg,
0.41mmol)、K2CO3(169.74mg, 1.23mmol), 50 DEG C of reaction 24h.Residue is dispersed in ethyl acetate (50mL), successively
With HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, column chromatography for separation (VPE:
VEA=2:1), obtain compound 2b (190mg, 63%, faint yellow solid).
Yield:190mg, 63%, yellow solid；Rf=0.431 (Petroluem ether:EtOAc=2:1)
.M.p 60-62℃.1H NMR(500MHz,CDCl3)δ(ppm):5.60(s,1H,12-H),4.09(m,4H,2×OCH2),
3.54 (dd, J=8.2,6.4Hz, 1H, 3-H), 3.21-3.02 (m, 3H), 2.75 (dd, J=13.3,3.3Hz, 1H, 18-H),
2.45 (s, 1H), 2.30 (dd, J=9.8,4.7Hz, 3H), 2.15-0.61 (m, 30H), 1.34,1.13,1.10,1.09and
0.98(5s,each 3H,5×CH3),0.78(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.2,
176.5,173.6,169.3,128.6,78.8,63.9,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.1,
40.3,39.2,38.6,37.8,37.2,34.7,34.1,32.8,31.9,31.2,28.8,28.7,28.5,28.2,27.4,
26.6,26.5,25.6,25.5,24.7,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd
for C42H66ClO6S2,765.3989；found 765.4008.
Embodiment 7: the synthesis of compound 2c
Compound 1c (500mg, 0.79mmol) is dissolved in DMF (5mL), add (R)-lipoic acid (163.0mg,
0.79mmol)、K2CO3(327.58mg, 2.37mmol), 50 DEG C of reaction 24h.Residue is dispersed in ethyl acetate (50mL), successively
With HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, column chromatography for separation (VPE:
VEA=3:1), obtain compound 2c (402mg, 67%, faint yellow solid).
Yield:402mg, 67%, yellow solid；Rf=0.339 (Petroluem ether:EtOAc=3:1)
.M.p 51-53℃.1H NMR(400MHz,CDCl3)δ(ppm):5.60(s,1H,12-H),4.05(m,4H,2×OCH2),
3.54 (dd, J=8.0,6.5Hz, 1H, 3-H), 3.25-3.03 (m, 3H), 2.75 (dd, J=10.1,3.4Hz, 1H, 18-H),
2.42(m,1H),2.29(m,2H),2.12-0.58(m,36H),1.35(s,3H,CH3),1.12–1.04(m,9H,3×CH3),
0.97(s,3H,CH3),0.77(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):200.2,176.5,173.6,
169.3,128.6,78.8,64.4,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.2,40.3,39.2,38.5,
37.8,37.2,34.7,34.2,32.8,31.9,31.2,28.6,28.2,27.4,26.5,25.8,25.6,24.8,23.5,
18.8,17.6,16.4,15.7.HRMS(ESI)m/z:[M+H]+calcd for C44H71O6S2,759.4692；found
759.4696.
Embodiment 8: the synthesis of compound 2d
Compound 1d (500mg, 0.76mmol) is dissolved in DMF (5mL), add (R)-lipoic acid (156.81mg,
0.76mmol)、K2CO3(315.12mg, 2.28mmol), 50 DEG C of reaction 24h.Residue is dispersed in ethyl acetate (50mL), successively
With HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, column chromatography for separation (VPE:
VEA=3:1), obtain compound 2d (475mg, 80%, faint yellow solid).
Yield:475mg, 80%, yellow solid；Rf=0.578 (Petroluem ether:EtOAc=3:1)
.M.p 52-54℃.1H NMR(400MHz,CDCl3)δ(ppm):5.60(s,1H,H-12),4.13-3.97(s,4H,2×
OCH2), 3.53 (m, 1H, 3-H), 3.27 (m, 3H), 2.74 (d, J=13.5Hz, 1H, 18-H), 2.42 (dd, J=12.5,
6.2Hz, 1H), 2.28 (dd, J=13.7,6.3Hz, 3H), 2.10-0.60 (m, 40H), 1.12-1.05 (m, 9H, 2 × CH3),
0.96(s,6H,2×CH3),0.77(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):200.2,176.5,
173.6,169.3,128.5,78.7,64.5,61.9,56.4,55.0,48.4,45.4,44.0,43.3,41.1,40.2,
39.2,38.5,37.8,37.1,34.6,34.1,32.8,31.9,31.2,29.1,28.8,28.7,28.6,28.5,28.2,
27.4,26.5,25.9,24.8,23.5,18.7,17.5,16.4,15.7.HRMS(ESI)m/z:[M+H]+calcd for
C46H75O6S2,787.5005；found 787.5019.
Embodiment 9: the synthesis of compound 2e
Compound 1c (500mg, 0.79mmol) is dissolved in DMF (5mL), add ADT-OH (178.57mg, 0.79mmol),
K2CO3(327.58mg, 2.37mmol), KI (13.28mg, 0.08mmol), 65 DEG C of reaction 24h.Residue is dispersed in ethyl acetate
(50mL), successively with HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, post layer
Analysis separates (VPE:VEA=3:1), obtain compound 2e (126mg, 21%, orange solids).
Yield:126mg, 21%, orange solid；Rf=0.352 (Petroluem ether:EtOAc=3:1)
.M.p 92-94℃.1H NMR(400MHz,CDCl3) δ (ppm): 7.60 (d, J=8.8Hz, 2H, Ar-H), 7.39 (s, 1H, Ar-
H), 6.96 (d, J=8.8Hz, 2H, Ar-H), 5.63 (s, 1H, 12-H), 4.22-3.97 (m, 4H, 2 × OCH2),3.23(dd,J
=10.9,5.3Hz, 1H, 3-H), 2.79 (d, J=13.5Hz, 1H, 18-H), 2.34 (s, 1H, 9-H), 2.13-0.69 (m,
29H),1.19-1.09(m,9H,3×CH3),1.01(s,6H,2×CH3),0.81(s,6H,2×CH3).13C NMR(100MHz,
CDCl3)δ(ppm):215.1,200.3,176.6,173.3,169.5,162.6,134.6,128.7,128.6,124.0,
115.6,78.8,68.3,64.4,61.9,55.0,48.6,45.5,44.1,43.3,41.2,39.2,37.8,37.2,32.9,
31.9,31.2,29.0,28.8,28.7,28.5,28.2,27.4,26.54,26.51,25.9,25.7,23.5,18.8,17.6,
16.5,15.7.HRMS(APCl)m/z:[M+H]+calcd for C45H63O5S3,779.3838；found 779.3820.
Embodiment 10: the synthesis of compound 2f
Compound 1d (500mg, 0.76mmol) is dissolved in DMF (5mL), add ADT-OH (169.74mg, 0.76mmol),
K2CO3(315.12mg, 2.28mmol), KI (13.28mg, 0.08mmol), 65 DEG C of reaction 24h.Residue is dispersed in ethyl acetate
(50mL), successively with HCl (1N), water, saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and filters, filtrate reduced in volume, post layer
Analysis separates (VPE:VEA=3:1), obtain compound 2f (118mg, 19%, orange solids).
Yield:118mg, 19%, orange solid；Rf=0.369 (Petroluem ether:EtOAc=3:1)
.M.p 87-89℃.1H NMR(400MHz,CDCl3) δ (ppm): 7.60 (d, J=8.8Hz, 2H, Ar-H), 7.39 (s, 1H),
6.96 (d, J=8.8Hz, 2H, Ar-H), 5.64 (s, 1H, 12-H), 4.14-3.98 (m, 4H, 2 × OCH2), 3.22 (dd, J=
10.7,5.3Hz, 1H, 3-H), 2.78 (d, J=13.5Hz, 1H, 18-H), 2.34 (s, 1H, 9-H), 2.17-0.64 (m, 33H),
1.16-1.10(m,9H,3×CH3),1.00(s,3H,CH3),0.80(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ
(ppm):215.2,200.3,176.6,173.3,169.4,162.7,134.6,128.7,128.6,124.0,115.6,78.8,
68.5,64.6,61.9,55.1,48.5,45.5,44.1,43.3,41.2,39.2,37.9,37.2,32.9,31.9,31.3,
29.3,29.2,29.1,28.7,28.5,28.2,27.4,26.6,26.5,26.0,26.0,23.5,18.8,17.6,16.5,
15.7.HRMS(APCl)m/z:[M+H]+calcd for C47H67O5S3,807.4151；found 807.4118.
Embodiment 11: the synthesis of compound 2g
Compound 1c (250mg, 0.39mmol) is dissolved in DMF (5mL), adds TBZ (60.35mg, 0.39mmol), K2CO3
(28mg, 0.2mmol), KI (6.30mg, 0.04mmol), 35 DEG C of reaction 12h.Residue is dispersed in ethyl acetate (50mL), depends on
Secondary HCl (1N), water, saturated aqueous common salt wash, and anhydrous sodium sulfate is dried, and filter, filtrate reduced in volume, column chromatography for separation (VPE:
VEA=3:1), obtain compound 2g (91mg, 32%, light yellow solid).
Yield:91mg, 32%, yellow solid；Rf=0.267 (Petroluem ether:EtOAc=3:1)
.M.p 119-120℃.1H NMR (500MHz, DMSO-d6) δ (ppm): 9.30 (s, 1H, NH), 8.23 (s, 1H, NH), 7.48
(d, J=8.8Hz, 2H, Ar-H), 6.99 (d, J=8.9Hz, 2H, Ar-H), 5.40 (s, 1H, 12-H), 4.02 3.96 (m, 4H,
2×OCH2), 2.98 (d, J=4.5Hz, 1H, 3-H), 2.55 (d, J=13.2Hz, 1H, 18-H), 2.30 (s, 1H), 2.18
0.63(m,28H),1.08,0.89and 0.72(3s,each 3H,3×CH3,1.00and 0.67(2s,each 6H,4×
CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):199.1,191.7,175.9,169.5,161.6,134.2,126.4,
120.9,115.0,76.6,67.8,63.9,61.2,54.1,48.1,44.9,43.6,42.9,37.4,36.7,32.1,31.6,
30.4,29.1,28.7,28.6,28.5,28.32,28.28,28.2,27.8,27.0,26.1,25.8,25.6,25.4,23.0,
22.2,18.4,17.2,16.2,16.1.HRMS(ESI)m/z:[M+Na]+calcd for C43H64NO5S,706.4505；
found 706.4500.
Embodiment 12: the synthesis of compound 2h
Compound 1d (250mg, 0.38mmol) is dissolved in DMF (5mL), adds TBZ (57.80mg, 0.38mmol), K2CO3
(28mg, 0.20mmol), KI (6.30mg, 0.04mmol), 35 DEG C of reaction 12h.Residue is dispersed in ethyl acetate (50mL), depends on
Secondary HCl (1N), water, saturated aqueous common salt wash, and anhydrous sodium sulfate is dried, and filter, filtrate reduced in volume, column chromatography for separation (VPE:
VEA=3:1), obtain compound 2h (107mg, 39%, light yellow solid).
Yield:107mg, 39%, yellow solid；Rf=0.206 (Petroluem ether:EtOAc=3:1)
.M.p 117-119℃.1H NMR(500MHz,DMSO-d6)δ(ppm):9.63(s,1H,NH),9.31(s,1H,NH),7.94
(d, J=8.9Hz, 2H, Ar-H), 6.91 (d, J=8.9Hz, 2H, Ar-H), 5.42 (s, 1H, 12-H), 4.01 (m, 4H, 2 ×
OCH2), 3.01 (dd, J=11.4,4.4Hz, 1H, 3-H), 2.58 (s, 1H, 18-H), 2.31 (s, 1H), 2.15-0.64 (m,
32H),1.09,0.90and 0.73(3s,each 3H,3×CH3),1.02and 0.68(2s,each 6H,4×CH3).13C
NMR(125MHz,DMSO-d6)δ(ppm):199.0,198.5,175.8,169.4,161.4,131.1,129.5,127.4,
113.4,76.6,67.7,63.9,61.2,59.8,54.1,48.1,44.9,43.6,42.9,37.4,36.7,32.1,31.5,
30.4,28.5,28.2,27.8,27.0,26.1,25.8,25.4,25.2,23.0,20.8,18.4,16.2,16.0,
14.4.HRMS(ESI)m/z:[M+Na]+calcd for C45H68NO5S,734.4818；found 734.4816.
Embodiment 13: the synthesis of compound 2a
Repeat embodiment 5, except for the difference that: substitute DMF with toluene, substitute K with cesium carbonate2CO3, and temperature is changed into 40 DEG C
Reaction 12h.
Products therefrom (228mg, 75%, faint yellow solid) it is accredited as compound 2a through nuclear-magnetism, the following institute of its structural formula
Show:
Embodiment 14: the synthesis of compound 2b
Repeat embodiment 6, except for the difference that: substitute DMF with pyridine, substitute K with potassium bicarbonate2CO3, and add being equivalent to
The catalyst KI of the amount of compound 1b material 0.5 times.
Products therefrom (166mg, 55%, faint yellow solid) it is accredited as compound 2b through nuclear-magnetism, the following institute of its structural formula
Show:
Embodiment 15: the synthesis of compound 2e
Repeat embodiment 9, except for the difference that: substitute DMF with toluene, substitute K with sodium carbonate2CO3, and it is added without catalyst KI,
Residue is scattered in dichloromethane.
Products therefrom (72mg, 12%, orange solids) it is accredited as compound 2e through nuclear-magnetism, its structural formula is as follows:
Embodiment 16: the synthesis of compound 2f
Repeat embodiment 10, except for the difference that: the compositions of use toluene and DMF (is pressed the volume ratio of 1:1 by toluene and DMF
Composition) substitute DMF, substitute K with triethylamine2CO3, and it is added without catalyst KI, residue is scattered in ether.
Products therefrom (62mg, 10%, orange solids) it is accredited as compound 2f through nuclear-magnetism, its structural formula is as follows:
Embodiment 16: the synthesis of compound 2h
Repeat embodiment 12, except for the difference that: (pressed the volume of 1:5 by picolin and toluene by the compositions of pyridine and toluene
Than composition) substitute DMF, substitute K with sodium bicarbonate2CO3, and it is added without catalyst KI.
Products therefrom (49mg, 18%, light yellow solid) it is accredited as compound 2h through nuclear-magnetism, the following institute of its structural formula
Show:
Applicant is thin to people's tumor cells of hepatocellular carcinoma strain and chronic lymphocytic leukemia to compound 2a～2h of the present invention
The proliferation inhibition activity of born of the same parents is tested:
1, cell strain is cultivated with cell
Human liver cancer cell BEL-7402, chronic myeloid leukemia cells K562 and Human normal hepatocyte are selected in this experiment
3 kinds of human cell's strains such as L-O2.
All cells strain is all cultivated containing 10wt% calf blood, 100U/mL penicillin, the RPMI-of 100U/mL streptomycin
In RPMI-1640, put 37 DEG C containing volumetric concentration 5%CO2Incubator is cultivated.
2, the preparation of testing compound
Purity >=95% of test medicine used, is configured to 200 μ after being diluted by its DMSO liquid storage physiological buffer
The whole solution of mol/L, wherein final concentration≤1% of cosolvent DMSO, test compound under this concentration raw to various tumor cells
Long suppression degree.
3, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumor cell of trophophase, after trypsinization, join with the culture fluid containing 10% calf serum
Make the cell suspension that concentration is 5000/mL, be inoculated in 96 well culture plates with every hole 190 μ L, make cell density to be measured extremely
1000～10000 holes (edge hole is filled with aseptic PBS)；
(2) 5%CO2, to hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer, every hole adds the medicine 10 of finite concentration gradient
μ L, each Concentraton gradient sets 4 multiple holes；
(3) 5%CO2, hatch 48 hours for 37 DEG C, observe under inverted microscope；
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h；
(5) terminating cultivating, carefully suck culture fluid in hole, every hole adds the DMSO of 150 μ L and fully dissolves first a ceremonial jade-ladle, used in libation precipitation, shakes
After swinging device mixing, being 570nm at microplate reader wavelength, reference wavelength is the optical density value that 450nm measures each hole；
(6) arranging zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolution of same concentrations are situated between control wells simultaneously
Matter, culture fluid, MTT, DMSO).
(7) according to the optical density value (OD value) recorded, judging living cells quantity, OD value is the biggest, and cytoactive is the strongest.Profit
With formula:
The computerized compound suppression ratio to each cell strain growth, its result is as shown in the following Table 1.
Table 1: each compound IC to different cell strains50Value (μM)
Note: experimental data is the meansigma methods of 3 experiments, Nd represents that this cell detection is lived by test-compound less than suppression
Property.
Claims (10)
1. there is the enoxolone of structure-hydrogen sulfide donor reagent derivatives shown in following logical formula (I) or it is pharmaceutically acceptable
Salt:
Wherein,
N is 2～8；
R is
2. the synthetic method of enoxolone described in claim 1-hydrogen sulfide donor reagent derivatives, it is characterised in that: extracting liquorice
Subacid, α, ω-two bromoalkane and alkali react in aprotic polar solvent, obtain compound 1；Take compound 1, hydrogen sulfide donor
Reagent and alkali react in aprotic polar solvent, obtain object crude product；Wherein, reaction is under conditions of being heated or not heated
Carry out.
Synthetic method the most according to claim 2, it is characterised in that: comprise the following steps:
1) extracting liquorice subacid, α, ω-two bromoalkane and alkali reacts in aprotic polar solvent, and gained reactant removes solvent,
Residue is scattered in ethyl acetate, dichloromethane or ether, and scrubbed, anhydrous sodium sulfate is dried, and after filtration, collects filtrate,
Filtrate obtains compound 1 after concentrating；
2) taking compound 1, hydrogen sulfide donor reagent and alkali to react in aprotic polar solvent, gained reactant removes solvent,
Residue is scattered in ethyl acetate, dichloromethane or ether, and scrubbed, anhydrous sodium sulfate is dried, and after filtration, collects filtrate,
Filtrate obtains object crude product after concentrating.
4. according to the synthetic method described in Claims 2 or 3, it is characterised in that: gained compound 1 is through silica gel thin-layer chromatography or silicon
Subsequent operation it is used further to after gel column chromatography eluting.
5. according to the synthetic method described in Claims 2 or 3, it is characterised in that: also include being purified object crude product
Step: specifically prepared object crude product is carried out silica gel thin-layer chromatography or silica gel column chromatography, obtain object after purification.
6. according to the synthetic method described in Claims 2 or 3, it is characterised in that: described α, ω-two bromoalkane be 1,2-dibromo
Ethane, 1,3-dibromopropane, 1,4-dibromobutane, pentamethylene bromide, 1,6-dibromo-hexane, 1,7-dibromo-heptane or 1,8-bis-
Bromooctane.
7. according to the synthetic method described in Claims 2 or 3, it is characterised in that: described alkali is potassium carbonate, triethylamine, carbonic acid
Sodium, sodium bicarbonate, potassium bicarbonate or cesium carbonate；Described aprotic polar solvent is N,N-dimethylformamide, toluene and pyrrole
One or more combination in pyridine.
8. according to the synthetic method described in Claims 2 or 3, it is characterised in that: described hydrogen sulfide donor reagent is that 5-is to hydroxyl
Base phenyl-1,2-dithiole-3-thioketone, (R)-thioctic acid or 4-hydroxythiobenzamide.
9. according to the synthetic method described in Claims 2 or 3, it is characterised in that: at compound 1, hydrogen sulfide donor reagent and alkali
Reaction in, add catalyst potassium iodide.
10. enoxolone described in claim 1-hydrogen sulfide donor reagent derivatives is being prepared antitumor drug and is being treated chronic
Application in the medicine of myelomatosis.
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