CN108299435A - 13- ethanol amine matrine derivatives prepare and its application - Google Patents

13- ethanol amine matrine derivatives prepare and its application Download PDF

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Publication number
CN108299435A
CN108299435A CN201810086121.0A CN201810086121A CN108299435A CN 108299435 A CN108299435 A CN 108299435A CN 201810086121 A CN201810086121 A CN 201810086121A CN 108299435 A CN108299435 A CN 108299435A
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matrine
bromobenzyl
bromine
nmr
preparation
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王立升
孙朋
戴航
杜同同
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Guangxi University
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Guangxi University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses a kind of novel matrine derivative, including 13 hydramine substitution structures of matrine and benzyl, sulphonyl base class substitution product, also discloses the preparation method of the analog derivative and the application in pharmacy.

Description

13- ethanol amine matrine derivatives prepare and its application
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to 13- ethanol amines matrine derivative and preparation method, with And these compound application in preparations of anti-tumor drugs.
Background technology
Sophocarpine derives from legume herba sophorae alopecuroide aerial part, and radix sophorae etc. has extensive pharmacological action.Such as：It is right Nervous centralis is inhibited, also has anti-arrhythmia, anticancer, relievings asthma, easing pain and diminishing inflammation isoreactivity.
Matrine is one of representative component of Banlangen, derives from the dry root of legume kuh-seng, belongs to Fourth Ring quinoline Piperazine pyridine class.With extensive pharmacological action：It is antitumor, anti-arrhythmia, anti-inflammatory and antiviral etc..
Benzyl bromine is widely used in the manufacture of foaming agent as the important organic synthesis raw material of industry.The maximum of benzyl bromine is used Way is the benzylating reagent rolled into a ball as heteroatom functional, can effectively be rolled into a ball to various heteroatom functionals benzyl occurs under various conditions Base, to occupy important application status in organic synthesis.
Drug containing sulfonyl occupies suitable proportion in clinical treatment drug, and it is drug that sulfonyl, which is introduced into small molecule, One of Critical policies of molecular structure alteration.Application of the sulfonyl in SARS drug design, for structure, sulfonyl and carbonyl Base, carboxyl, tetrazole, phosphate have similar size and distribution of charges, can as they bioisostere and It is introduced into small molecule, to keep or enhance the bioactivity of small molecule；Sulfonyl has unique physicochemical properties, can To adjust the dissolubility and acid-base property of small molecule；And two hydrogen bond receptors can be provided, the rational sulfonyl that introduces can pass through increasing Add the interaction of hydrogen bond of small molecule and action target and improves the bioactivity of compound.
Have no the synthesis for having both the 13- ethanol amine matrine derivatives containing sulfonyl and benzyl bromine and antitumor activity Report.
Invention content
The technical problem to be solved in the present invention is to provide a kind of 13- ethanol amine matrines being used to prepare antitumor drug to spread out In terms of biology and its preparation.
13- ethanol amines matrine derivative of the present invention, structure are as follows：
Structural formula 1：
Structural formula 2：
Structural formula 3：
General structure 1：
General structure 2：
The present invention also provides the preparation method of above compound, this method uses following reaction route：
Compared with prior art, the advantageous effect that the present invention has：
The invention reside in a kind of antitumor drug being expected to as high-efficiency low-toxicity is provided, to mostly a kind for the treatment of of many patients Selection.
Specific implementation mode
Technical scheme of the present invention is further elaborated below by embodiment.
Embodiment 1
(1) preparation of SP-1：
The specific experimental method for preparing SP-1：
1.24g sophocarpine is sequentially added in reaction bulb, a small amount of water makees solvent.It is to be dissolved that suitable carbon is added later completely Sour potassium provides weakly alkaline environment, heats 10 minutes, is added slowly with stirring 0.4ml ethanol amines and (nitrogen of ethanol amine is utilized The big feature of electronegativity), TLC tracking and monitorings, until reaction solution is at green solution.It is cooled to room temperature, ethyl acetate extraction is added, Organic phase is taken to dry, through silica gel column chromatography [V (ethyl acetate): V (methanol)=1: 1] after concentration organic phase, purifying obtains 1.263g green oil object SP-1.Yield：82.2%.
1H NMR (600MHz, Chloroform-d) δ 4.27 (dd, J=12.7,4.4Hz, 1H), 3.91 (ddd, J= 10.9,7.5,5.7Hz, 1H), 3.58 (t, J=5.1Hz, 2H), 3.11-2.93 (m, 2H), 2.88-2.61 (m, 4H), 2.49 (dd, J=17.0,4.5Hz, 1H), 2.28 (ddd, J=17.0,5.9,1.7Hz, 1H), 2.06 (t, J=3.0Hz, 1H), 1.96-1.85 (m, 3H), 1.83 (ddq, J=13.9,4.7,2.0Hz, 1H), 1.73-1.50 (m, 4H), 1.45 (tq, J= 8.5,4.7Hz, 2H), 1.40-1.29 (m, 4H), 1.20 (d, J=17.5Hz, 1H)13C NMR (151 MHz, CDCl3)δ 167.76,63.82,61.21,57.21,57.16,50.15,48.71,48.61,42.48,41.64,38.84,35.50, 31.01,27.70,26.57,21.12,20.67.MS m/z：308.75{[M+H]+}
(2) preparation of SP-14：
The specific experimental method for preparing SP-14：
0.4g SP-1 and 0.4ml 2- bromomethyl naphthalenes are sequentially added in reaction bulb, 1g potassium carbonate, DMF stirrings, which are added, to be made It is dissolved, and is stirred at room temperature and is started within 6 hours TLC detections, waits for that chloroform is added after reaction, and three are extracted with water until stirring evenly It is secondary, take organic phase to concentrate, concentration is finished through silica gel column chromatography [V (DCM)：V (methanol)=8: 1], it is yellowish green that purifying obtains 0.108g Color powder, yield：18.6%,
1H NMR (600MHz, Chloroform-d) δ 7.86-7.75 (m, 3H), 7.69 (s, 1H), 7.51-7.40 (m, 3H), 4.25 (dd, J=12.6,4.4Hz, 1H), 4.12-4.02 (m, 1H), 3.86-3.80 (m, 2H), 3.55 (t, J= 5.4Hz, 2H), 3.18-2.99 (m, 2H), 2.86-2.70 (m, 4H), 2.57 (ddd, J=16.9,5.1,2.3Hz, 1H), 2.43 (dd, J=16.9,11.4Hz, 1H), 2.16-2.00 (m, 2H), 1.98-1.87 (m, 4H), 1.87-1.76 (m, 2H), 1.64- 1.55 (m, 3H), 1.47-1.39 (m, 3H), 1.34-1.28 (m, 2H)13C NMR (151 MHz, CDCl3) δ 167.74, 136.65,133.34,132.85,128.48,127.73,127.60,127.00,126.24,125.82,64.22,58.92, 57.20,54.84,51.80,50.80,49.48,42.96,40.45,36.05,35.11,31.44,29.70,27.58, 26.76,26.21,21.14,20.65.MS m/z：448.49{[M+H]+}
(3) preparation of SP-17：
The specific experimental method for preparing SP-17：
0.4g SP-1 and 0.4ml 2- -4 '-bromomethylbiphenyls of cyano are sequentially added in reaction bulb, 1g potassium carbonate is added DMF is stirred to dissolve, and is stirred at room temperature and is started within 6 hours TLC detections, waits for that chloroform is added after reaction, until stirring evenly Three times with water extraction, organic phase is taken to concentrate, concentration is finished through silica gel column chromatography [V (DCM): V (methanol)=5: 1], and purifying obtains 0.201g yellow solids, yield：20%,
1H NMR (600MHz, Chloroform-d) δ 7.76 (dd, J=7.8,1.3Hz, 1H), 7.65 (td, J=7.7, 1.4Hz, 1H), 7.57-7.49 (m, 3H), 7.48-7.38 (m, 3H), 4.27 (dd, J=12.5,4.5Hz, 1H), 4.16-4.03 (m, 1H), 3.76 (s, 2H), 3.57 (d, J=5.6Hz, 2H), 3.10 (dddd, J=15.1,12.4,7.4,5.0Hz, 2H), 2.79-2.69 (m, 2H), 2.66-2.52 (m, 2H), 2.42 (dd, J=16.9,11.3Hz, 1H), 2.14 (s, 1H), 2.11- 2.04 (m, 1H), 2.00-1.86 (m, 4H), 1.76-1.53 (m, 4H), 1.53-1.32 (m, 6H), 1.29 (s, 1H)13C NMR (151 MHz, CDCl3) δ 167.72,145.07,140.00,137.22,133.75,132.84,130.00,129.01, 128.63,127.58,118.69,111.26,64.23,58.96,57.21,54.36,51.80,50.91,49.56,42.99, 40.54,36.07,35.01,31.65,29.69,27.59,26.74,26.42,22.69,21.15,20.64.MS m/z： 499.59{[M+H]+}
(4) preparation of SP-2：
The specific experimental method for preparing SP-2：
0.4g SP-1 and 0.4ml p-bromobenzenesulfonyl chlorides are sequentially added in reaction bulb, 1g potassium carbonate, DMF stirrings, which are added, to be made It is dissolved, and is stirred at room temperature and is started within 6 hours TLC detections, waits for that chloroform is added after reaction, and three are extracted with water until stirring evenly It is secondary, take organic phase to concentrate, concentration is finished through silica gel column chromatography [V (DCM): V (methanol)=6: 1], and it is yellowish green that purifying obtains 0.263g Color powder, yield：38.6%,
1H NMR (600MHz, Chloroform-d) δ 7.71 (d, J=8.6Hz, 2H), 7.65 (d, J=8.5Hz, 2H), 4.23 (dd, J=12.6,4.5Hz, 1H), 4.12-4.00 (m, 2H), 3.79 (t, J=5.7Hz, 2H), 3.41-3.26 (m, 2H), 3.09 (t, J=12.5Hz, 1H), 2.91-2.74 (m, 2H), 2.49 (dd, J=16.9,11.6Hz, 1H), 2.36 (ddd, J=16.9,5.5,2.2Hz, 1H), 2.29-2.16 (m, 1H), 2.05 (dq, J=13.7,2.6Hz, 1H), 2.03-1.91 (m, 3H), 1.78-1.67 (m, 3H), 1.67 1 1.62 (m, 1H), 1.61-1.55 (m, 1H), 1.55-1.47 (m, 1H), 1.42 (d, J =11.4Hz, 2H), 1.33 (s, 1H), 1.29 (d, J=3.9Hz, 2H)13C NMR (151 MHz, CDCl3) δ 166.26, 139.24,132.68,128.54,127.99,123.96,123.42,64.18,62.43,57.17,51.58,48.52, 45.18,43.03,40.49,36.65,36.16,31.65,29.70,27.53,22.69,21.05,20.50.MS m/z： 526.50{[M+H]+}
Experimental method prepare compound SP-3~SP-5 of reference compound SP-2, compound SP-3~SP-5 Structural Identifications Data are as follows：
Compound SP-3：White solid, 44.6%,
1H NMR (600MHz, Chloroform-d) δ 7.94-7.87 (m, 2H), 7.35 (d, J=8.4Hz, 2H), 4.23 (dd, J=12.6,4.5Hz, 1H), 4.04 (dddd, J=27.2,11.8,5.5,2.7Hz, 2H), 3.81 (t, J=5.7Hz, 2H), 3.46-3.28 (m, 2H), 3.08 (t, J=12.4Hz, 2H), 2.80 (t, J=14.7Hz, 2H), 2.53 (dd, J= 16.9,11.6Hz, 1H), 2.41 (ddd, J=16.9,5.5,2.2Hz, 1H), 2.19 (s, 1H), 1.98 (dd, J=12.5, 4.7Hz, 2H), 1.74-1.60 (m, 4H), 1.59-1.54 (m, 1H), 1.50 (tq, J=8.1,4.5Hz, 1H), 1.47-1.40 (m, 1H), 1.40-1.28 (m, 2H), 1.25 (d, J=4.0Hz, 2H)13C NMR (151MHz, CDCl3) δ 166.25, 152.27,138.60,129.19,121.19,121.05,119.33,64.16,62.45,57.17,51.57,48.51, 45.21,43.04,40.46,36.85,36.17,31.43,29.69,28.62,27.54,26.56,21.07,20.46.MS m/ z：532.48{[M+H]+}
Compound SP-4：White powder, 26.8%,
1H NMR (600MHz, Chloroform-d) δ 7.94 (d, J=6.4Hz, 1H), 7.83-7.69 (m, 1H), 7.33- 7.24 (m, 1H), 4.23 (dd, J=12.6,4.5Hz, 1H), 4.06 (dtd, J=28.0,11.2,5.0Hz, 2H), 3.80 (d, J =6.0Hz, 2H), 3.34 (qq, J=16.8,5.4Hz, 2H), 3.10 (dd, J=23.4,10.7Hz, 2H), 2.93 (s, 1H), 2.81 (dd, J=20.3,11.6Hz, 3H), 2.54 (dd, J=16.9,11.6Hz, 1H), 2.40 (dd, J=17.1,5.4Hz, 1H), 2.21 (s, 1H), 1.98 (td, J=12.7,5.7Hz, 3H), 1.72 (q, J=14.5,12.8Hz, 2H), 1.62 (dd, J =31.0,12.7Hz, 2H), 1.41 (dt, J=20.9,16.5Hz, 3H), 1.26 (s, 2H)13C NMR (151 MHz, CDCl3) δ 166.19,159.81,137.46,129.94,127.40,117.62,64.15,62.30,57.17,51.57,48.65, 45.24,43.05,40.47,36.90,36.17,31.92,29.69,28.58,27.54,26.55,21.07,20.51.MS m/ z：500.48{[M+H]+}
Compound SP-5：Yellow solid, 40.6%,
1H NMR (600MHz, Chloroform-d) δ 7.86-7.68 (m, 2H), 7.06-6.91 (m, 2H), 4.38-4.30 (m, 1H), 4.21 (dd, J=12.5,4.5Hz, 1H), 4.09-4.02 (m, 1H), 3.86 (s, 3H), 3.76 (t, J=6.0Hz, 2H), 3.30 (q, J=6.6,5.9Hz, 2H), 3.08 (dt, J=19.4,12.5Hz, 1H), 2.86-2.74 (m, 2H), 2.55- 2.40 (m, 1H), 2.33 (ddd, J=16.9,5.5,2.2Hz, 1H), 2.23-2.14 (m, 1H), 2.07-1.89 (m, 4H), 1.78-1.54 (m, 5H), 1.53-1.41 (m, 2H), 1.41-1.15 (m, 3H)13C NMR (151 MHz, CDCl3) δ 166.60, 163.02,131.69,129.09,114.50,64.14,62.44,62.16,57.14,55.65,51.61,48.11,44.92, 42.98,41.35,40.39,36.61,36.14,29.63,28.45,27.53,26.55,21.05,20.48.MS m/z： 478.49{[M+H]+}
(5) preparation of SP-6
The specific experimental method for preparing SP-6：
0.4g SP-1 and 0.4ml is sequentially added in reaction bulb to trifluoromethoxy cylite, DMF is added in 1g potassium carbonate It stirs to dissolve, is stirred at room temperature and starts within 6 hours TLC detections, wait for that chloroform is added after reaction, water is used until stirring evenly Extraction three times, takes organic phase to concentrate, and concentration is finished through silica gel column chromatography [V (DCM): V (methanol)=6: 1], and purifying obtains 0.174g yellow solids, yield：27.8%,
1H NMR (600MHz, Chloroform-d) δ 7.34-7.29 (m, 2H), 7.17 (d, J=8.1Hz, 2H), 4.26 (dd, J=12.6,4.5Hz, 1H), 4.15-4.03 (m, 1H), 3.68 (s, 2H), 3.54 (t, J=5.5Hz, 2H), 3.15- 2.98 (m, 2H), 2.80 (dd, J=26.4,11.3Hz, 2H), 2.74-2.65 (m, 2H), 2.59-2.46 (m, 2H), 2.40 (dd, J=16.9,11.2Hz, 1H), 2.13 (s, 1H), 2.05-1.99 (m, 1H), 1.99-1.86 (m, 4H), 1.85-1.74 (m, 1H), 1.73-1.52 (m, 3H), 1.52-1.37 (m, 4H)13C NMR (151 MHz, CDCl3) δ 167.60,148.39, 138.10,129.69,129.55,121.30,121.09,119.60,64.23,59.03,57.19,53.94,51.71, 50.98,49.62,42.96,40.63,36.09,35.02,29.69,27.57,26.73,26.40,21.13,20.62.MS m/ z：482.44{[M+H]+}
Experimental method the prepare compound SP-7~SP-25, compound SP-7~SP-13, SP-15 of reference compound SP-6 ~SP-16, SP-18~SP-25 Structural Identification data are as follows：
Compound SP-7：White solid, 33.6%,
1H NMR (600MHz, Chloroform-d) δ 7.35-7.31 (m, 2H), 7.19 (d, J=8.0Hz, 2H), 4.26 (dd, J=12.6,4.5Hz, 1H), 4.08 (dd, J=11.8,5.1Hz, 1H), 3.71-3.57 (m, 2H), 3.52 (t, J= 5.4Hz, 2H), 3.13-3.01 (m, 2H), 2.80 (dd, J=27.4,11.2Hz, 2H), 2.69 (t, J=5.4Hz, 2H), 2.61-2.49 (m, 1H), 2.40 (dd, J=16.9,11.4Hz, 1H), 2.12 (s, 1H), 2.05 (d, J=13.9Hz, 1H), 1.95 (q, J=10.6Hz, 2H), 1.79 (td, J=13.1,5.5Hz, 2H), 1.74-1.55 (m, 3H), 1.42 (q, J= 4.8Hz, 6H), 1.29 (d, J=2.2Hz, 2H), 1.26 (s, 9H)13C NMR (151 MHz, CDCl3) δ 167.85,150.30, 136.08,128.03,125.47,123.36,115.83,64.33,58.74,57.23,54.12,51.83,50.72,49.35, 42.97,40.54,36.10,35.21,34.50,31.66,31.38,29.70,27.61,26.81,26.21,22.69, 21.16 20.66.MS m/z：454.53{[M+H]+}
Compound SP-8：Greenish yellow solid, 20.7%,
1H NMR (600MHz, Chloroform-d) δ 7.38 (dd, J=7.4,2.0Hz, 1H), 7.36 (dd, J=7.6, 1.7Hz, 1H), 7.26-7.18 (m, 2H), 4.27 (dd, J=12.5,4.4Hz, 1H), 4.15-4.04 (m, 1H), 3.88-3.73 (m, 2H), 3.50 (q, J=5.3Hz, 2H), 3.13-2.99 (m, 2H), 2.85-2.76 (m, 2H), 2.75-2.67 (m, 2H), 2.63-2.51 (m, 2H), 2.43 (dd, J=16.9,11.5Hz, 1H), 2.18-2.05 (m, 2H), 1.99-1.90 (m, 2H), 1.90-1.76 (m, 3H), 1.70-1.64 (m, 2H), 1.64-1.56 (m, 1H), 1.51-1.38 (m, 4H), 1.38-1.21 (m, 3H).13C NMR (151 MHz, CDCl3) δ 167.68,136.49,133.99,130.46,129.87,128.66,126.92, 64.32,59.00,57.24,52.31,51.81,50.96,50.15,42.97,40.53,36.16,35.10,29.66, 27.63,26.81,26.25,21.17,20.67.MS m/z：432.42{[M+H]+}
Compound SP-9：Yellow solid, 24.3%,
1H NMR (600MHz, Chloroform-d) δ 7.32 (d, J=8.0Hz, 2H), 7.18 (dd, J=8.4,7.7Hz, 1H), 4.30 (dd, J=12.5,4.5Hz, 1H), 4.18-4.07 (m, 1H), 4.05-3.95 (m, 2H), 3.37 (t, J= 4.8Hz, 2H), 3.11 (dddd, J=15.5,12.7,7.8,5.2Hz, 2H), 2.81 (dd, J=24.1,11.2Hz, 2H), 2.77-2.70 (m, 1H), 2.70-2.64 (m, 2H), 2.59-2.51 (m, 1H), 2.17 (s, 1H), 2.09 (dq, J=13.3, 2.5Hz, 1H), 1.96 (t, J=12.0Hz, 2H), 1.88 (td, J=13.0,6.1Hz, 1H), 1.81-1.63 (m, 4H), 1.51 (dq, J=13.7,4.9,4.4Hz, 2H), 1.48-1.39 (m, 2H), 1.36-1.28 (m, 1H), 1.26 (s, 2H)13C NMR (151 MHz, CDCl3) δ 167.77,136.66,133.98,129.41,128.78,64.36,58.72,57.24,51.85, 50.84,50.36,49.98,43.01,40.60,36.22,34.76,31.92,31.44,30.31,29.69,27.65, 26.77,21.18,20.67.MS m/z：466.53{[M+H]+}
Compound SP-1 0：White powder, 43.7%,
1H NMR (600MHz, Chloroform-d) δ 7.42 (d, J=8.7Hz, 1H), 6.98 (d, J=3.1Hz, 1H), 6.69 (dd, J=8.7,3.1Hz, 1H), 4.27 (dd, J=12.5,4.5Hz, 1H), 4.10 (ddd, J=11.5,6.0, 2.3Hz, 1H), 3.78 (s, 3H), 3.74 (s, 2H), 3.57-3.45 (m, 2H), 3.13-3.03 (m, 2H), 2.80 (dd, J= 26.1,11.4Hz, 2H), 2.73 (td, J=5.4,3.8Hz, 2H), 2.60 (ddd, J=16.8,5.0,2.3Hz, 1H), 2.49- 2.40 (m, 2H), 2.16-2.06 (m, 2H), 2.01-1.90 (m, 2H), 1.89-1.74 (m, 4H), 1.74-1.52 (m, 3H), (1.52-1.40 m, 4H)13C NMR (151 MHz, CDCl3) δ 167.66,159.12,139.22,133.63,116.30, 114.23,114.16,64.31,59.26,57.24,55.47,55.10,51.77,51.25,50.66,42.93,40.58, 36.15,35.36,29.70,27.64,26.86,26.27,21.18,20.68.MS m/z：506.64{[M+H]+}
Compound SP-1 1：Yellow solid, 23%,
1H NMR (600MHz, Chloroform-d) δ 7.28-7.22 (m, 2H), 7.02 (t, J=8.6Hz, 2H), 4.28 (dd, J=12.5,4.5Hz, 1H), 4.17-4.03 (m, 1H), 3.66 (s, 2H), 3.54 (t, J=5.4Hz, 2H), 3.16- 2.99 (m, 2H), 2.82 (dd, J=27.2,11.2Hz, 2H), 2.74-2.64 (m, 2H), 2.55 (ddd, J=16.9,5.1, 2.3Hz, 1H), 2.41 (dd, J=16.9,11.3Hz, 1H), 2.15 (s, 1H), 2.08-2.01 (m, 1H), 2.01-1.92 (m, 2H), 1.90-1.76 (m, 4H), 1.66 (tt, J=31.1,15.1Hz, 3H), 1.53-1.39 (m, 3H), 1.36-1.29 (m, 1H).13C NMR (151MHz, CDCl3) δ 167.65,161.25,134.90,129.85,129.79,115.53,115.39, 64.26,58.87,57.20,53.89,51.75,50.79,49.44,42.97,40.57,36.11,35.04,29.70, 27.59,26.78,26.29,21.15,20.64.MS m/z：416.51{[M+H]+}
Compound SP-1 2：Greenish yellow solid, 18%,
1H NMR (600MHz, Chloroform-d) δ 7.31 (td, J=7.6,1.8Hz, 1H), 7.25 (dtd, J=7.5, 5.5,2.7Hz, 1H), 7.11 (t, J=7.4Hz, 1H), 7.07-7.00 (m, 1H), 4.27 (dd, J=12.6,4.5Hz, 1H), 4.08 (td, J=13.3,11.9,6.1Hz, 1H), 3.73 (q, J=14.1Hz, 2H), 3.54 (t, J=5.4Hz, 2H), 3.14- 3.00 (m, 2H), 2.82 (dt, J=26.3,14.1Hz, 2H), 2.75-2.63 (m, 3H), 2.54 (ddd, J=17.0,5.1, 2.3Hz, 1H), 2.41 (dd, J=16.9,11.3Hz, 1H), 2.21-1.89 (m, 6H), 1.88-1.77 (m, 2H), 1.76- 1.53 (m, 3H), 1.52-1.40 (m, 4H)13C NMR (151 MHz, CDCl3) δ 167.75,162.12,130.72,129.14, 126.06,124.21,115.65,64.30,58.79,57.22,51.77,50.67,49.70,47.89,42.92,40.58, 36.12,35.19,29.69,27.61,26.69,26.13,21.14,20.63.MS m/z：416.48{[M+H]+}
Compound SP-1 3：White powder, 51.3%,
1H NMR (600MHz, Chloroform-d) δ 7.31-7.27 (m, 1H), 7.06 (d, J=7.6Hz, 1H), 7.01 (dd, J=9.5,2.4Hz, 1H), 6.95 (td, J=8.4,2.6Hz, 1H), 4.26 (dd, J=12.5,4.5Hz, 1H), 4.09 (ddt, J=12.2,6.2,3.0Hz, 1H), 3.68 (s, 2H), 3.54 (q, J=4.7,4.3Hz, 2H), 3.13-3.00 (m, 2H), 2.90-2.75 (m, 2H), 2.71 (td, J=5.3,2.6Hz, 2H), 2.62-2.51 (m, 1H), 2.39 (dd, J=16.9, 11.3Hz, 2H), 2.13 (d, J=3.0Hz, 1H), 2.04 (ddd, J=19.2,14.7,4.7Hz, 1H), 1.95 (tdd, J= 11.3,7.2,2.6Hz, 2H), 1.80 (dq, J=12.6,6.5Hz, 2H), 1.63-1.51 (m, 2H), 1.42 (d, J=7.2Hz, 2H), 1.38-1.32 (m, 2H), 1.29 (d, J=4.6Hz, 2H)13C NMR (151 MHz, CDCl3) δ 167.57,163.88, 142.15,130.14,123.74,115.07,114.23,64.27,58.99,57.23,51.76,51.05,49.75,42.98, 40.58,36.12,35.02,31.93,29.70,27.61,26.78,26.36,21.16,20.66.MS m/z：416.5l{[M+ H]+}
Compound SP-1 5：Yellow solid, 14.7%,
1H NMR (600MHz, Chloroform-d) δ 7.23 (t, J=7.8Hz, 1H), 6.90-6.85 (m, 1H), 6.83 (t, J=2.0Hz, 1H), 6.79 (ddd, J=8.2,2.7,0.9Hz, 1H), 4.26 (dd, J=12.5,4.5Hz, 1H), 4.15- 4.04 (m, 1H), 3.80 (s, 3H), 3.69-3.63 (m, 2H), 3.52 (t, J=5.4Hz, 2H), 3.07 (tq, J=11.7, 2.5Hz, 2H), 2.80 (dd, J=27.8,11.3Hz, 2H), 2.70 (t, J=5.4Hz, 2H), 2.54 (ddd, J=16.9, 5.1,2.3Hz, 2H), 2.44-2.36 (m, 1H), 2.12 (s, 1H), 2.10-2.03 (m, 1H), 1.98-1.90 (m, 2H), 1.76 (s, 3H), 1.63 (d, J=15.1Hz, 1H), 1.43 (dt, J=9.7,3.0Hz, 5H), 1.35-1.28 (m, 1H)13C NMR (151 MHz, CDCl3) δ 167.75,159.87,140.99,129.61,120.53,113.98,112.54,64.29,58.86, 57.23,55.21,54.63,51.78,50.97,49.67,42.95,40.53,36.10,35.21,29.70,27.61, 26.81,26.20,21.16,20.67.MS m/z：428.51{[M+H]+}
Compound SP-1 6：Yellow solid, 24.4%,
1H NMR (600MHz, Chloroform-d) δ 6.45 (d, J=2.3Hz, 2H), 6.35 (t, J=2.3Hz, 1H), 4.26 (dd, J=12.6,4.5Hz, 1H), 4.09 (ddd, J=11.2,6.0,2.5Hz, 1H), 3.78 (s, 6H), 3.67-3.56 (m, 2H), 3.53 (t, J=5.5Hz, 2H), 3.13-3.03 (m, 2H), 2.87-2.74 (m, 2H), 2.70 (td, J=5.4, 1.9Hz, 2H), 2.67-2.59 (m, 1H), 2.54 (ddd, J=16.9,5.1,2.2Hz, 1H), 2.40 (dd, J=16.9, 11.2Hz, 1H), 2.18-2.10 (m, 2H), 2.06 (dq, J=13.4,2.6Hz, 1H), 1.95 (tdd, J=11.5,7.5, 2.7Hz, 2H), 1.82 (tdd, J=19.4,18.1,8.9,4.2Hz, 2H), 1.73-1.53 (m, 4H), 1.51-1.39 (m, 4H).13C NMR (151 MHz, CDCl3) δ 167.79,160.98,141.96,106.33,106.10,99.00,98.92, 64.26,59.03,58.28,57.21,55.30,54.90,51.75,51.15,49.86,42.90,40.56,36.08, 35.35,29.68,27.61,26.79,26.15,21.14,20.65.MSm/z：458.50{[M+H]+}
Compound SP-1 8：Greenish yellow solid, 15.8%,
1H NMR (600MHz, Chloroform-d) δ 7.34-7.25 (m, 1H), 7.22 (t, J=8.2Hz, 2H), 4.27 (dd, J=12.6,4.5Hz, 1H), 4.18-4.01 (m, 1H), 3.68 (q, J=14.3Hz, 2H), 3.54 (t, J=5.4Hz, 2H), 3.18-2.95 (m, 2H), 2.81 (dd, J=26.5,11.2Hz, 2H), 2.70 (t, J=5.7Hz, 2H), 2.64-2.47 (m, 2H), 2.40 (dd, J=16.9,11.1Hz, 1H), 2.15 (s, 1H), 2.11-1.90 (m, 5H), 1.81 (dd, J=13.1, 6.0Hz, 2H), 1.76-1.53 (m, 4H), 1.45 (s, 3H)13C NMR (151 MHz, CDCl3) δ 167.58,161.79, 160.13,131.73,127.57,125.40,121.35,119.14,64.25,58.99,57.21,51.67,50.94, 49.98,47.56,40.64,36.10,35.27,29.69,27.60,26.70,26.14,21.13,20.62.MS m/z： 494.45{[M+H]+}
Compound SP-1 9：Yellow solid 43.4%,
1H NMR (600MHz, Chloroform-d) δ 7.32-7.26 (m, 2H), 7.25-7.19 (m, 2H), 4.26 (dd, J =12.5,4.5Hz, 1H), 4.08 (ddt, J=13.9,9.4,4.6Hz, 1H), 3.75-3.58 (m, 2H), 3.52 (t, J= 5.5Hz, 2H), 3.12-2.99 (m, 2H), 2.88-2.75 (m, 2H), 2.69 (t, J=5.5Hz, 2H), 2.63-2.47 (m, 2H), 2.39 (dd, J=16.9,11.2Hz, 1H), 2.17-2.12 (m, 1H), 2.11-2.00 (m, 3H), 1.99-1.91 (m, 2H), 1.84-1.76 (m, 2H), 1.70-1.61 (m, 2H), 1.45-1.39 (m, 3H), 1.38-1.33 (m, 1H)13C NMR (151 MHz, CDCl3) δ 167.65,137.85,133.01,129.59,128.73,64.22,59.04,57.20,54.04, 51.71 50.99,49.67,42.94,40.58,36.09,35.12,31.92,31.50,29.69,27.59,26.76, 26.26,21.13,20.63.MS m/z：432.45{[M+H]+}
Compound SP-20：Yellow solid, 26.7%,
1H NMR (600MHz, Chloroform-d) δ 7.44 (q, J=3.3,2.5Hz, 1H), 7.39 (dt, J=7.3, 1.8Hz, 1H), 7.24-7.16 (m, 2H), 4.26 (dd, J=12.6,4.5Hz, 1H), 4.09 (ddd, J=12.4,6.1, 3.0Hz, 1H), 3.66 (s, 2H), 3.54 (t, J=5.4Hz, 2H), 3.13-2.99 (m, 2H), 2.90-2.74 (m, 2H), 2.70 (td, J=5.4,3.2Hz, 2H), 2.53 (ddd, J=16.9,5.0,2.3Hz, 1H), 2.38 (dd, J=16.9,11.2Hz, 1H), 2.14 (s, 1H), 2.11-2.00 (m, 2H), 2.01-1.86 (m, 4H), 1.81 (td, J=13.2,5.3Hz, 2H), 1.74-1.54 (m, 3H), 1.42 (d, J=8.2Hz, 2H), 1.39-1.32 (m, 1H), 1.29 (d, J=2.0Hz, 1H)13C NMR (151 MHz, CDCl3) δ 167.61,141.84,131.15,130.18,126.83,122.74,64.25,59.10, 57.21,54.22,51.73,51.03,49.70,42.95,40.61,36.08,35.00,29.69,27.59,26.79, 26.40,21.14,20.65.MS m/z：476.44{[M+H]+}
Compound SP-21：Greenish yellow solid, 25.5%,
1H NMR (600MHz, Chloroform-d) δ 6.88 (d, J=6.2Hz, 3H), 4.26 (dd, J=12.5, 4.4Hz, 1H), 4.08 (ddd, J=11.8,6.2,2.2Hz, 1H), 3.65-3.56 (m, 2H), 3.55-3.51 (m, 2H), 3.06 (tdd, J=11.8,5.0,2.4Hz, 2H), 2.80 (dd, J=29.3,11.4Hz, 2H), 2.72-2.64 (m, 3H), 2.52 (ddd, J=16.9,5.1,2.3Hz, 1H), 2.42-2.34 (m, 1H), 2.29 (s, 6H), 2.12 (d, J=3.5Hz, 1H), 2.06 (dq, J=13.4,2.5Hz, 1H), 2.01 (s, 2H), 1.97-1.93 (m, 1H), 1.87-1.83 (m, 1H), 1.78 (td, J=12.9,6.0Hz, 1H), 1.73-1.54 (m, 3H), 1.47 (dt, J=13.8,5.0Hz, 1H), 1.42 (dd, J=8.6, 3.0Hz, 1H), 1.38-1.32 (m, 1H), 1.29 (d, J=0.9Hz, 1H)13C NMR (151 MHz, CDCl3) δ 167.87, 139.02,138.09,128.96,126.07,64.31,58.70,57.23,54.46,51.84,50.59,49.21,42.95, 40.48,36.09,35.13,31.92,30.32,29.69,27.61,26.82,26.07,22.69,21.29,21.16, 20.68.MS m/z：426.42{[M+H]+}
Compound SP-22：Green solid, 30.5%,
1H NMR (600MHz, Chloroform-d) δ 7.17-7.06 (m, 2H), 7.00 (ddd, J=8.0,3.9, 1.9Hz, 1H), 4.26 (dd, J=12.6,4.5Hz, 1H), 4.09 (ddt, J=12.3,6.3,3.1Hz, 1H), 3.64 (s, 2H), 3.54 (q, J=5.5Hz, 2H), 3.13-2.99 (m, 2H), 2.88-2.75 (m, 2H), 2.69 (t, J=5.5Hz, 2H), 2.57-2.47 (m, 2H), 2.38 (dd, J=16.8,11.2Hz, 1H), 2.14 (t, J=3.0Hz, 1H), 2.03 (dq, J= 13.4,2.7Hz, 1H), 1.98 (s, 2H), 1.85-1.76 (m, 2H), 1.75-1.53 (m, 4H), 1.48 (dt, J=13.7, 4.8Hz, 1H), 1.44 (dd, J=11.8,3.2Hz, 2H), 1.39-1.32 (m, 1H), 1.29 (d, J=1.3Hz, 1H)13C NMR (151 MHz, CDCl3) δ 167.55,151.29,150.28,136.58,123.94,117.34,116.86,64.21, 59.24,57.19,53.84,51.68,51.17,49.83,42.94,40.65,36.10,35.08,29.69,27.59, 26.76,26.38,21.14,20.64.MS m/z：434.49{[M+H]+}
Compound SP-23：Greenish yellow solid, 15.7%,
1H NMR (600MHz, Chloroform-d) δ 7.90 (d, J=7.9Hz, 2H), 7.52 (d, J=7.9Hz, 2H), 4.26 (dd, J=12.6,4.5Hz, 1H), 4.11 (d, J=9.6Hz, 1H), 3.85-3.69 (m, 2H), 3.56 (t, J= 5.5Hz, 2H), 3.07 (s, 3H), 2.89-2.76 (m, 2H), 2.73 (t, J=5.5Hz, 2H), 2.55 (ddd, J=16.9, 5.1,2.1Hz, 1H), 2.41 (dd, J=16.9,10.9Hz, 1H), 2.15 (s, 1H), 2.05 (d, J=12.9Hz, 1H), 2.02-1.88 (m, 4H), 1.82 (dd, J=19.9,9.7Hz, 1H), 1.64 (dq, J=29.3,17.1,12.8Hz, 3H), 1.45-1.40 (m, 4H), 1.40-1.32 (m, 1H), 1.29-1.24 (m, 5H)13C NMR (151 MHz, CDCl3) δ 167.46, 146.40,139.51,128.99,127.71,64.17,59.42,57.16,54.42,51.59,50.34,44.55,42.88, 40.71,36.05,35.36,31.92,30.19,29.69,27.56,26.78,22.69,21.11.MS m/z：476.50{[M+ H]+}
Compound SP-24：White powder, 32.2%,
1H NMR (600MHz, Chloroform-d) δ 7.78 (d, J=19.0Hz, 3H), 4.24 (dd, J=12.6, 4.5Hz, 1H), 4.09 (ddd, J=11.2,5.9,2.6Hz, 1H), 3.92-3.79 (m, 2H), 3.60 (t, J=5.7Hz, 2H), 3.14-2.95 (m, 3H), 2.87-2.67 (m, 4H), 2.55 (ddd, J=16.9,5.0,2.1Hz, 1H), 2.40 (dd, J= 16.9,10.9Hz, 1H), 2.13 (t, J=2.9Hz, 1H), 2.07 (dq, J=13.6,2.7Hz, 1H), 1.96 (tdd, J= 12.2,9.2,2.7Hz, 2H), 1.84 (ddt, J=15.7,11.4,5.2Hz, 2H), 1.72-1.59 (m, 3H), 1.51-1.39 (m, 4H), 1.39-1.31 (m, 1H), 1.30-1.19 (m, 1H)13C NMR (151 MHz, CDCl3) δ 167.48,142.85, 132.03,131.81,131.59,131.37,128.08,125.98,124.18,122.37,121.14,120.56,64.11, 59.99,57.12,54.28,51.60,50.22,42.84,40.67,36.03,35.10,27.54,26.63,21.05, 20.56.MS m/z：534.45{[M+H]+}
Compound SP-25：White powder, 40%,
1H NMR (600MHz, Chloroform-d) δ 7.54 (dd, J=8.1,1.5Hz, 1H), 7.41 (dd, J=7.7, 1.7Hz, 1H), 7.28 (td, J=7.9,1.7Hz, 1H), 7.13 (td, J=7.7,1.8Hz, 1H), 4.26 (dd, J=12.6, 4.5Hz, 1H), 4.14-4.03 (m, 1H), 3.79 (s, 2H), 3.49 (t, J=5.6Hz, 2H), 3.16-2.98 (m, 2H), 2.87-2.66 (m, 4H), 2.59 (ddt, J=17.0,4.7,2.3Hz, 1H), 2.42 (dd, J=16.9,11.4Hz, 1H), 2.20-2.03 (m, 2H), 1.95 (dp, J=12.1,4.4,3.9Hz, 2H), 1.82 (td, J=13.2,5.8Hz, 2H), 1.76- 1.54 (m, 4H), 1.51-1.38 (m, 4H), 1.38-1.29 (m, 1H), 1.27 (d, J=17.7Hz, 1H)13C NMR(151 MHz, CDCl3) δ 167.74,138.18,133.09,130.52,128.86,127.51,124.07,64.26,59.25, 57.20,55.00,51.77,51.17,50.38,42.92,40.52,36.12,35.15,29.67,27.60,26.78, 26.36,21.13,20.63.MS m/z：476.44{[M+H]+}
The 13- ethanol amine matrine derivative purity prepared through the invention is 98% or more.
Following table 1 gives the structural formula for preparing target compound：
The invention also includes the 13- ethanol amines matrine derivative application in preparations of anti-tumor drugs.It is preferred that , the tumour is liver cancer and cervical carcinoma.
The excellent effect that embodiment 2 is further illustrated the present invention below by way of experiment.
Pharmacological evaluation：
Human hepatocarcinoma cells (HepG2) and human cervix cancer cells (Hela) culture are dual anti-in 10% fetal calf serum and 1% DMEM high glucose mediums in；All cells are all placed in 37 DEG C, in the cell incubator of 5%CO2.
It is tested, will be cultivated with basis after matrine, sophocarpine, the dissolving of 13- ethanol amine matrine derivatives with mtt assay Base is diluted to mother liquor.Take 0.5 × 106The above cell strain of a exponential phase, is inoculated in 96 orifice plates, (about per sky 100uL 5000 cells), if blank group, control group and administration group (100uM), every group sets 4 parallel holes.It is placed in 37 DEG C, 5% (V/V) CO2Incubator in, the drug of same concentration is added afterwards for 24 hours, continues to cultivate 48h, supernatant is removed before terminating, is added per empty 30uL5mg/mLMTT, incubator remove MTT after being incubated 4h and 100uLDMSO are added per hole, are placed in low speed on shaking table and shake 10min makes crystalline material fully dissolve, and measures each hole absorbance (OD) value at 490nm wavelength with microplate reader, calculates cell Proliferation inhibition rate, cell proliferation inhibition rate=(1- samples OD values/control group OD values) × 100%.
Above-mentioned experiment is repeated 3 times, and SPSS fit equations is used in combination to calculate IC50It is worth, is compared between group and is examined using t Method, P ＜ 0.05 are that difference is significant.
Experimental result：
Inhibition of 2 target compound of table to HepG2 and Hela cell Proliferations
The Pharmacological experiment result shows that：
The serial 13- ethanol amines matrine derivative of synthesis has antitumor activity effect, is being with matrine, sophocarpine Comparison medicine in the case of being administered simultaneously with the SP series compounds of synthesis, is found, all changes by comparing their inhibiting rate The activity for closing object is better than comparison medicine matrine and sophocarpine in various degree, and wherein SP-8, SP-18, SP-20, SP-21 is to liver cancer (HepG2)IC50Value is respectively less than 100.SP-7, SP-8, SP-15, SP-18, SP-19 are to cervical carcinoma (Hela) IC50Value is respectively less than 100, the compound activity after modification is significantly improved.

Claims (7)

1. a kind of 13- ethanol amines matrine derivative, which is characterized in that the compound has following structure：
Structural formula 1：
Structural formula 2：
Structural formula 3：
General structure 1：
General structure 2：
2. the preparation method of matrine ethanolamine derivant SP-1 according to claim 1, which is characterized in that with sophocarpine For starting material, electrophilic conjugated system is formed under alkaline condition, then the conjugate addition reaction occurred with nucleophilic group.
3. the preparation method of 13- ethanol amine matrine derivatives SP-2~SP-25 according to claim l, feature exist In using SP-1 ethanol amines matrine as starting material, sodium carbonate or potassium carbonate provide weak basic condition, and 2- bromomethyls are then added Naphthalene, 2- cyano -4 '-bromomethylbiphenyl, benzene sulfonyl chloride class compound or the reaction of cylite class compound, react up to 13- second Hydramine matrine derivative.
4. the preparation method of 13- ethanol amines matrine derivative SP-2~SP-25 according to claim 3, feature exist In the benzene sulfonyl chloride class compound includes 4- bromobenzene sulfonyl chlorides, 4- (trifluoromethoxy) benzene sulfonyl chloride, the chloro- 4- fluorobenzene sulphurs of 3- Acyl chlorides and to Methoxybenzenesulfonyl chloride.
5. the preparation method of 13- ethanol amines matrine derivative SP-2~SP-25 according to claim 3, feature exist In cylite class compound includes 4- trifluoromethoxies bromobenzyl, 4- tertiary butyl benzyls bromine, 2- bromine chlorides, 2,6- benzyl dichlorides bromide, 2- Bromo- 5- methoxyl groups bromobenzyl, 4- fluorine bromobenzyl, 2- fluorine bromobenzyl, 3- fluorine bromobenzyl, 3- methoxybenzyls bromine, 3,5- dimethoxys bromobenzyl, 4- Bromo- 2- fluorobenzyl bromides, 4- bromine chlorides, 3- bromobenzyls bromine, 3,5- dimethyl bromobenzyl, 3,4- difluorobenzyl bromides, 4- sulfonyloxy methyl benzyls bromine, 3,5- Bistrifluoromethylbenzyl bromine and 2- bromobenzyl bromines.
6. the preparation method of matrine ethanolamine derivant SP-1 according to claim 2, which is characterized in that the nucleophilic Group is provided by ethanol amine.
7. requiring the 13- ethanol amines matrine derivative in the application for preparing anticancer drug according to right 1.
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WO2020035010A1 (en) * 2018-08-14 2020-02-20 上海星叶医药科技有限公司 MATRINE α-KETOAMINE COMPOUNDS, PREPARATION METHOD THEREFOR AND USE THEREOF
CN110818713A (en) * 2018-08-14 2020-02-21 上海星叶医药科技有限公司 Matrine α -ketoamine compound and preparation method and application thereof

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Application publication date: 20180720