Summary of the invention
First object of the present invention is to provide the multiple novel derivative of Cucurbitacin B and E and their salt; Second object of the present invention is to provide the preparation method of the novel derivative of Cucurbitacin B and E.
The invention provides the novel derivative of six kinds of Cucurbitacin Bs, the novel derivative of six kinds of Cucurbitacin Es and their pharmacy acceptable salt,
The chemical structure of these novel derivatives is as follows:
The Cucurbitacin B derivative of formula I, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,6H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 573[M+H]
+。
The Cucurbitacin B derivative of formula II, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,8H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H),0.9(t,J=8.4,3H).MS 587[M+H]
+。
The Cucurbitacin B derivative of formula III, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,12H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 575[M+H]
+。
The Cucurbitacin B derivative of formula IV, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,12H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H),0.9(t,J=8.4,3H).MS 587[M+H]
+。
The Cucurbitacin B derivative of formula V, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),5.03(m,1H),4.08(m,1H),3.79-3.49(m,5H),3.40(m,1H),2.85(m,1H),2.27-2.02(m,8H),1.85-1.69(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H).MS 721[M+H]
+。
The Cucurbitacin B derivative of formula VI, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ5.51(t,J=8.4Hz,1H),5.03(m,1H),4.08(m,1H),3.79-3.49(m,5H),3.40(m,1H),2.85(m,1H),2.27-2.02(m,12H),1.85-1.69(m,4H),1.60-1.46(m,2H),1.47(s, 6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H).MS 723[M+H]
+。
The Cucurbitacin E derivative of formula X, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.66(s,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 571[M+H]
+。
The Cucurbitacin E derivative of formula XI, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.66(s,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.32-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,6H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H),0.90(t,J=8.4,3H).MS 585[M+H]
+。
The Cucurbitacin E derivative of formula XII, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ6.66(s,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,8H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 573[M+H]
+。
The Cucurbitacin E derivative of formula XIII, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ6.66(s,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.32-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,10H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H),0.90(t,J=8.4,3H).MS 585[M+H]
+。
The Cucurbitacin E derivative of formula XIV, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.66(s,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),5.03(m,1H),3.79-3.49(m,5H),3.40(m,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,6H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H).MS 719[M+H]
+。
The Cucurbitacin E derivative of formula XV, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ6.66(s,1H),5.51(t,J=8.4Hz,1H),5.03(m,1H),3.79-3.49(m,5H),3.40(m,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,10H),2.16(m,1H),2.04-2.02(m,2H),1.86- 1.71(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H).MS721[M+H]
+。
, formula II(B-2), formula III (B-3), formula IV(B-4 likes I(B-1)) Cucurbitacin B derivative and formula X(E-1), formula XI(E-2), formula XI(E-3), formula XIII(E-4) the synthetic route of Cucurbitacin E derivative as follows:
, Cucurbitacin B derivative formula VI(B-6) and formula XIV(E-5 likes V(B-5)), formula XV(E-6) the synthetic route of Cucurbitacin E derivative as follows:
Newfound above-mentioned six kinds of Cucurbitacin B derivatives and six kinds of Cucurbitacin E derivatives and their salt, owing to thering is common basic structure with Cucurbitacin B, E respectively, so character is also substantially the same with Cucurbitacin B, E, there is preferably anticancer, antiviral, anti-inflammatory and protect the liver dirty effect, and toxic side effect is lower.
Embodiment
In conjunction with above-mentioned synthetic route, further set forth the present invention.
(1) B-1-1's is synthetic: by (559 milligrams of existing Cucurbitacin Bs, 1.0 mmoles) be dissolved in 10 ml methanol, then the lithium hydroxide aqueous solution (1 milliliter) that adds 1N, stirring at room 2 hours, concentrated, resistates dissolves with methylene dichloride, with soda lye wash, organic layer is dry concentrated, obtains 502 milligrams of white solids, yield 97.2%.
(2) B-1's is synthetic: by synthetic B-1-1(51.6 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add propionyl chloride (10 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 42 milligrams of white solids, yield 74%.
(3) E-1-1's is synthetic: by (557 milligrams of existing Cucurbitacin Es, 1.0 mmoles) be dissolved in 10 ml methanol, then the lithium hydroxide aqueous solution (1 milliliter) that adds 1N, stirring at room 2 hours, concentrated, resistates dissolves with methylene dichloride, with soda lye wash, organic layer is dry concentrated, obtains 498 milligrams of white solids, yield 96.8%.
(4) E-1's is synthetic: by synthetic E-1-1(51.4 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add propionyl chloride (10 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 47 milligrams of white solids, yield 83%.
(5) B-2's is synthetic: by synthetic B-1-1(51.6 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add butyryl chloride (10 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 45 milligrams of white solids, yield 77%.
(6) E-2's is synthetic: by synthetic E-1-1(51.4 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add butyryl chloride (11 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 50 milligrams of white solids, yield 86%.
(7) B-3's is synthetic: by compd B-1(57.2 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 56.9 milligrams of white solids, yield 99%.
(8) B-4's is synthetic: by compd B-2(58.4 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 55.2 milligrams of white solids, yield 94%.
(9) E-3's is synthetic: by compd E-1(57 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 56.1 milligrams of white solids, yield 98.4%.
(10) E-4's is synthetic: by compd E-2(58.2 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 56.5 milligrams of white solids, yield 97%.
(11) G-1's is synthetic: by (1.8 grams of glucose, 10 mmoles) be dissolved in 20 milliliters of acetone, then add (2.1 grams of 1,1-Propanal dimethyl acetals, 20 mmoles) and sulfuric acid (1), stirring at room 1 hour, is concentrated into the greatest extent, and resistates is with acetic acid ethyl dissolution, with water washing, organic layer is dry concentrated, obtains 2.13 grams of colorless oil, yield 82%.
(12) B-5-1's is synthetic: by (559 milligrams of existing Cucurbitacin Bs, 1 mmole), synthetic G-1(260 milligram, 1 mmole), zinc oxide (81.5 milligrams, 1 mmole) is dissolved in 10 ml methanol, stirring at room one hour, be concentrated into the greatest extent, resistates, with acetic acid ethyl dissolution, washs with saturated brine, organic layer is dry concentrated, residuum, with column chromatography purification, obtains 624 milligrams of white solids, yield 78%.
(13) B-5's is synthetic: by synthetic B-5-1(400 milligram, 0.5 mmole) be dissolved in 10 milliliters of toluene, then add tosic acid (86 milligrams, 0.5 mmole), stirring at room 18 hours, react complete, in reaction solution, add saturated sodium bicarbonate aqueous solution washing, organic layer is dry concentrated, and resistates is with column chromatography purification, obtain 248 milligrams of white solids, yield 69%.
(14) E-5-1's is synthetic: by (556 milligrams of existing Cucurbitacin Es, 1 mmole), synthetic G-1(260 milligram, 1 mmole), zinc oxide (81.5 milligrams, 1 mmole) is dissolved in 10 ml methanol, stirring at room one hour, be concentrated into the greatest extent, resistates, with acetic acid ethyl dissolution, washs with saturated brine, organic layer is dry concentrated, residuum, with column chromatography purification, obtains 606 milligrams of white solids, yield 76%.
(15) E-5's is synthetic: by synthetic E-5-1(400 milligram, 0.5 mmole) be dissolved in 10 milliliters of toluene, then add tosic acid (86 milligrams, 0.5 mmole), stirring at room 18 hours, react complete, in reaction solution, add saturated sodium bicarbonate aqueous solution washing, organic layer is dry concentrated, and resistates is with column chromatography purification, obtain 240 milligrams of white solids, yield 67%.
(16) B-6's is synthetic: by compd B-5(72 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 68.6 milligrams of white solids, yield 95%.
(17) E-6's is synthetic: by compd E-5(72 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 69.8 milligrams of white solids, yield 97%.
The Cucurbitacin B novel derivative B-1 making, B-2, B-3, B-4, B-5, B-6 and Cucurbitacin E novel derivative E-1, E-2, E-3, E-4, E-5, E-6, function is identical with existing Cucurbitacin B, E respectively, the effect that has anticancer, antiviral, anti-inflammatory and protect the liver.In other words, the method for pharmacology of these Cucurbitacin Bs and E novel derivative of studying is with existing Cucurbitacin B, E, therefore be not repeated herein, the pharmacological action report of relevant existing Cucurbitacin B, E is specifically referring to following disclosed document:
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