CN112979672B

CN112979672B - 11, 20-dicarbonyl oridonin 14-O esterified series derivatives and application thereof

Info

Publication number: CN112979672B
Application number: CN202110242749.7A
Authority: CN
Inventors: 可钰; 王妮; 赵梦圆; 贾小苹; 刘宏民; 徐霞
Original assignee: Zhengzhou University
Current assignee: Zhengzhou University
Priority date: 2021-03-05
Filing date: 2021-03-05
Publication date: 2022-03-11
Anticipated expiration: 2041-03-05
Also published as: CN112979672A

Abstract

The invention relates to the field of natural products and pharmaceutical chemistry, and discloses an 11, 20-dicarbonyl economic oridonin 14-O esterified series derivative and application thereof. It is composed ofThe preparation method comprises the following steps: the oridonin (JOA) is used as a raw material, is oxidized by Jones reagent to obtain a target compound 11, 20-dicarbonyl oridonin, and is esterified with organic acid to obtain a series of derivatives on the premise of not damaging an active center. The compounds have antitumor activity and good water solubility, can be used for preparing anticancer drugs, and are applied to clinical treatment of esophageal cancer, gastric cancer, primary liver cancer, pancreatic cancer, breast cancer, acute myeloid leukemia and the like. It has the following general formula:

Description

11, 20-dicarbonyl oridonin 14-O esterified series derivatives and application thereof

Technical Field

The invention relates to the field of natural products and pharmaceutical chemistry, in particular to a Jiyuan rubescensine A compound which comprises the following components in percentage by weight: 11, 20-dicarbonyl economic oridonin 14-O esterification derivatives, and their synthesis method and application are provided.

Background

Rabdosia rubescens, rabdosia rubescens, lemongrass, snowflake and wild mint are perennial herbs or subshrubes of Rabdosia of Labiatae, and can be used as a whole plant. The medicinal parts are stems and leaves, and contain chemical components such as monoterpene, sesquiterpene, diterpene, triterpene, volatile oil, alkaloid, glycosides, amino acids, polysaccharide, flavone and steroid. Has effects in clearing away heat and toxic materials, relieving inflammation, and relieving pain, and can be used for relieving esophageal cancer, primary liver cancer, lung cancer, breast cancer, prostatic cancer, and bladder cancer.

The inventor obtains a lead compound with the framework of ent-kaurene diterpene from the original Rabdosia Rubescens (Hemsl.) Hara by a series of extraction and separation methods: oridonin (JOA). The alpha-methylene cyclopentanone structure is a group which is essential for the antineoplastic activity of the ent-kaurene diterpenoid compound, and in vitro activity research shows that the lead compound has good bioactivity, wider antineoplastic spectrum and good research value and significance.

Different substituents on the chemical structure of the compounds have important influence on the pharmacological activity. Therefore, the compound with good anti-tumor activity, high bioavailability, stable physicochemical property and low toxicity is hopefully obtained by the structural modification of the oridonin, and can be developed into a new medicine as soon as possible, thereby being beneficial to the research and development of new medicines with independent intellectual property rights in China.

Disclosure of Invention

The invention aims to provide a series of 11, 20-dicarbonyl economic oridonin 14-O esterified derivatives, and optically active bodies or racemates thereof, diastereoisomer mixtures or pharmaceutically acceptable salts thereof, and improve the anti-tumor effect and stability thereof, thereby providing possibility for clinical application thereof.

The invention also aims to provide a preparation method and application thereof in preparing antitumor drugs.

In order to realize the purpose of the invention, the invention esterifies 11, 20-dicarbonyl economic oridonin and organic acid to obtain a series of derivatives, improves the stability of the derivatives, and simultaneously retains or enhances the anti-tumor activity of the derivatives.

The structural general formula of the esterified 11, 20-dicarbonyl economic oridonin derivative provided by the invention is as follows:

r is organic acid esterified with 14-hydroxy group of oridonin.

The organic acid is selected from: phenylpropionic acid; cinnamic acid or cinnamic acid monosubstituted with C1-5 alkyl; pyrimidinecarboxylic acid; picolinic acid, pyridine acetic acid, pyridine acrylic acid, picolinic acid mono-substituted by methoxy group, C1-5 alkyl group, pyridine acetic acid mono-substituted by methoxy group, C1-5 alkyl group, pyridine acrylic acid mono-substituted by methoxy group, C1-5 alkyl group; nicotinic acid, isonicotinic acid; nicotinic acid mono-substituted with methoxy, C1-5 alkyl, halo; isonicotinic acid monosubstituted with halogen; indolecarboxylic acid, indoleacetic acid, indolepropionic acid, N-methyl-indolecarboxylic acid, N-methyl-indoleacetic acid, N-methyl-indolepropionic acid; indazolecarboxylic acid, indazoleacetic acid, indazolpropionic acid, and the like.

The organic acid is more preferably: phenylpropionic acid; cinnamic acid or cinnamic acid monosubstituted with methyl; 2-pyrimidinecarboxylic acid; 2-picolinic acid, 5-methoxy-2-picolinic acid, 5-methyl-2-picolinic acid, pyridine-4-acrylic acid; nicotinic acid, isonicotinic acid; nicotinic acid mono-substituted with methoxy, methyl, fluoro, chloro, bromo; 2-chloroisonicotinic acid; 2-indolecarboxylic acid, 3-indolepropionic acid, 3-indolecarboxylic acid, N-methyl-2-indolecarboxylic acid; 3-indazolecarboxylic acid and the like.

The esterified 11, 20-dicarbonyl economic oridonin derivative is obtained by the following synthetic route:

1. dissolving separated and purified oridonin (JOA) in acetone, adding Jones reagent for reaction, adding isopropanol for quenching reaction, and purifying by column chromatography to obtain mother nucleus 11, 20-dicarbonyl oridonin.

2. Dissolving the obtained mother nucleus 11, 20-dicarbonyl economic oridonin in dichloromethane, adding corresponding organic acid, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 4-Dimethylaminopyridine (DMAP) as catalysts under stirring for reaction, and purifying by column chromatography to obtain the target derivative.

The invention has the innovation points and advantages that: the invention selects oridonin (JOA) as a mother nucleus, and obtains the required derivative through oxidation and esterification processes, and the compound has anticancer activity and good water solubility, can be used for preparing antitumor drugs, is applied to clinical treatment of esophagus cancer, stomach cancer, cervical cancer, pancreatic cancer, breast cancer, acute myeloid leukemia and the like, and has good development prospect.

Detailed Description

The present invention is further illustrated by the following specific examples, but it should be noted that the scope of the present invention is not limited in any way by these examples.

Example 1:

weighing JOA 300mg in a round bottom flask, adding 11mL of acetone to completely dissolve the acetone, adding 0.75mL of Jones reagent (6mL of acetone for dilution) under the stirring condition, reacting for 20min, monitoring a point plate, adding a certain amount of isopropanol to quench the reaction, performing reduced pressure spin drying after 20min, adding 30mL of ethyl acetate to dilute the reaction system, washing the reaction system with saturated NaCl solution for three times, performing back extraction on an aqueous phase with ethyl acetate for one time, combining organic phases, drying with anhydrous magnesium sulfate, concentrating, and performing column chromatography purification to obtain 270mg of target mother nucleus 11, 20-dicarbonyl economic oridonin with the yield of 74%.¹H NMR(400MHz,DMSO-d₆)δ6.14(s,1H),6.08(d,J＝2.9Hz,1H),5.79(s,1H),4.79(dd,J＝3.9,1.7Hz,1H),3.74–3.71(m,1H),3.10(d,J＝8.3Hz,1H),2.96(s,1H),2.92–2.83(m,2H),2.66(dd,J＝16.3,8.4Hz,1H),2.55(s,1H),1.76(ddd,J＝14.4,7.6,4.0Hz,1H),1.59(dp,J＝12.6,5.1,4.3Hz,2H),1.36(d,J＝11.6Hz,2H),1.09(td,J＝11.4,10.0,5.2Hz,1H),0.98(td,J＝14.0,4.4Hz,1H),0.81(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ204.50,200.41,174.32,148.15,121.28,72.87,70.54,58.52,57.72,46.51,45.35,42.97,41.08,33.81,30.56,28.28,23.36,19.10,18.21.HR-MS(ESI):Calculated for C₂₀H₂₄O_5.[M+H]⁺:345.1702,found:345.1688.

Example 2

Weighing 200mg of 11, 20-dicarbonyl economic oridonin, completely dissolving the oridonin in 10mL of dichloromethane, adding 113mg of phenylpropionic acid under stirring, and sequentially adding 144mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 9mg of 4-Dimethylaminopyridine (DMAP) serving as catalysts. After the reaction is monitored by a thin-layer chromatography plate, 30mL of dichloromethane is added to dilute the reaction system, the reaction system is washed three times by saturated sodium bicarbonate solution, water layers are combined and back-extracted once, organic phases are combined, anhydrous sodium sulfate is dried,concentrating, and purifying by column chromatography to obtain white solid product with yield of 83%.¹H NMR(400MHz,DMSO-d₆)δ7.26(d,J＝7.5Hz,2H),7.21–7.16(m,3H),6.21(s,1H),5.86(s,1H),4.77(d,J＝1.1Hz,1H),4.50(dd,J＝4.0,1.7Hz,1H),3.22(d,J＝8.3Hz,1H),3.19(s,1H),2.85(d,J＝1.9Hz,1H),2.82(d,J＝2.3Hz,1H),2.79(d,J＝7.2Hz,2H),2.73–2.66(m,3H),2.65(d,J＝1.9Hz,1H),1.71(ddd,J＝14.5,7.6,4.0Hz,1H),1.64–1.58(m,2H),1.39(d,J＝3.8Hz,1H),1.37–1.34(m,1H),1.09–1.01(m,2H),0.81(s,3H),0.70(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.35,198.37,173.89,171.06,146.10,139.94,128.29(*2),128.10(*2),126.10,122.77,72.99,72.27,58.86,56.06,46.51,45.22,43.05,39.77,38.50,34.60,33.79,30.51,29.99,28.13,23.12,18.97,18.14.HR-MS(ESI):Calculated for C₂₉H₃₂O_6.[M+NH₄]⁺:494.2543,found:494.2535.

Example 3

The same procedure as in example 2 was repeated except for using 109mg of cinnamic acid instead of phenylpropionic acid, to obtain a white solid product with a yield of 76%.¹H NMR(400MHz,DMSO-d₆)δ7.75(d,J＝1.8Hz,1H),7.73(s,1H),7.68(d,J＝16.0Hz,1H),7.44–7.41(m,3H),6.65(d,J＝16.0Hz,1H),6.26(d,J＝1.2Hz,1H),5.93(d,J＝1.1Hz,1H),4.90(d,J＝1.1Hz,1H),4.84–4.81(m,1H),3.45–3.42(m,1H),3.27(s,1H),2.94–2.87(m,2H),2.81(dd,J＝16.5,8.3Hz,1H),2.69(d,J＝16.4Hz,1H),1.82(ddd,J＝14.5,7.4,4.1Hz,1H),1.67(dd,J＝10.5,7.5Hz,1H),1.63–1.56(m,1H),1.42–1.39(m,1H),1.37(s,1H),1.11(d,J＝3.9Hz,1H),1.09–1.05(m,1H),0.82(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.41,198.60,173.94,165.00,146.23,146.19,133.66,130.84,128.89(*2),128.62(*2),122.95,116.70,73.46,72.49,58.96,56.27,46.62,45.36,43.21,38.59,33.84,30.53,28.18,23.11,18.97,18.16.HR-MS(ESI):Calculated for C₂₉H₃₀O_6.[M+NH₄]⁺:492.2386,found:492.2383.

Example 4

The same operation as in example 2 was carried out using 125mg of 4-methylcinnamic acid instead of phenylpropionic acid, to obtain a white solid product with a yield of 71%.¹H NMR(400MHz,DMSO-d₆)δ7.66–7.61(m,3H),7.23(d,J＝7.9Hz,2H),6.61–6.53(m,1H),6.26(s,1H),5.92(s,1H),4.89(d,J＝1.3Hz,1H),4.84–4.80(m,1H),3.42(d,J＝8.1Hz,1H),3.26(s,1H),2.94–2.86(m,2H),2.81(dd,J＝16.5,8.3Hz,1H),2.69(d,J＝16.3Hz,1H),2.33(s,3H),1.81(dq,J＝11.4,3.6Hz,1H),1.67(dd,J＝10.4,7.4Hz,1H),1.43–1.39(m,1H),1.37(s,1H),1.23(s,1H),1.12(dd,J＝14.3,3.9Hz,1H),1.08–1.03(m,1H),0.82(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.42,198.60,173.93,165.10,146.24,146.18,140.94,130.96,129.51(*2),128.63(*2),122.91,115.53,73.36,72.48,58.94,56.25,46.60,45.34,43.19,38.59,33.83,30.52,28.17,23.10,21.01,18.96,18.15.HR-MS(ESI):Calculated for C₃₀H₃₂O_6.[M+NH₄]⁺:506.2543,found:506.2536.

Example 5

The same procedure as in example 2 was repeated except for using 94mg of 4-pyrimidinecarboxylic acid instead of phenylpropionic acid to obtain a white solid product with a yield of 36%.¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),8.87(d,J＝5.1Hz,1H),7.74(d,J＝5.1Hz,1H),6.05(s,1H),5.70(s,1H),5.57–5.49(m,1H),4.88(s,1H),4.64–4.59(m,1H),2.64(dd,J＝19.7,11.2Hz,3H),2.52(s,1H),2.27(q,J＝2.0Hz,1H),1.48–1.37(m,2H),1.15(d,J＝12.0Hz,2H),1.00(s,1H),0.87(d,J＝12.5Hz,2H),0.59(s,3H),0.48(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.20,198.20,173.89,162.39,159.81,158.91,153.25,145.88,123.25,121.21,75.13,72.40,59.03,56.41,46.63,45.34,43.22,38.42,33.83,30.51,28.15,23.08,18.94,18.15.HR-MS(ESI):Calculated for C₂₅H₂₆N₂O_6.[M+H]⁺:451.1869,found:451.1901.

Example 6

The same procedure used in example 2 was repeated except for using 120mg of 2-indolecarboxylic acid instead of phenylpropionic acid to give the product as a white solid in a yield of 56%.¹H NMR(400MHz,DMSO-d₆)δ11.96(s,1H),7.67(d,J＝8.2Hz,1H),7.47(d,J＝8.4Hz,1H),7.29(t,J＝7.7Hz,1H),7.15(s,1H),7.09(t,J＝7.8Hz,1H),6.29(s,1H),5.93(s,1H),5.00(s,1H),4.97–4.92(m,1H),3.54(d,J＝8.3Hz,1H),2.97–2.88(m,2H),2.85(t,J＝8.4Hz,1H),2.72(d,J＝16.6Hz,1H),1.88–1.81(m,1H),1.72–1.60(m,2H),1.43–1.36(m,2H),1.25–1.05(m,3H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.34,198.46,173.97,159.79,146.17,137.74,126.52,125.58,125.26,122.90,122.24,120.42,112.58,109.23,74.01,72.57,59.12,56.37,46.65,45.49,43.30,38.60,33.85,30.52,28.20,23.09,18.94,18.16.HR-MS(ESI):Calculated for C₂₉H₂₉NO_6.[M+H]⁺:488.2073,found:488.2068.

Example 7

The same procedure used in example 2 was repeated except for using 132mg of N-methyl-2-indolecarboxylic acid instead of phenylpropionic acid to give a white solid as a product in 59% yield.¹H NMR(400MHz,DMSO-d₆)δ7.70(d,J＝8.1Hz,1H),7.59(d,J＝8.6Hz,1H),7.37(t,J＝7.7Hz,1H),7.20(s,1H),7.15(d,J＝7.6Hz,1H),6.30(s,1H),5.94(s,1H),5.04(d,J＝8.0Hz,1H),4.88–4.84(m,1H),3.98(s,3H),3.53(d,J＝8.2Hz,1H),2.94–2.88(m,2H),2.83(d,J＝8.3Hz,1H),2.73(d,J＝16.3Hz,1H),1.82(dd,J＝14.9,5.3Hz,1H),1.66(dd,J＝23.9,13.4Hz,2H),1.39(d,J＝12.2Hz,2H),1.23(s,1H),1.10(d,J＝13.5Hz,2H),0.83(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.40,198.54,173.96,159.65,146.22,139.57,125.92,125.50,125.08,122.98,122.48,120.75,110.96,110.68,73.67,72.62,58.90,56.41,46.55,45.34,43.21,39.77,38.61,33.84,31.52,30.52,28.17,23.18,18.96,18.16.HR-MS(ESI):Calculated for C₃₀H₃₁NO_6.[M+H]⁺:502.2230,found:502.2209.

Example 8

The same procedures used in example 2 were repeated except for using 143mg of 3-indolpropanic acid in place of phenylpropionic acid to give a product as a white solid in a yield of 45%.¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.48(d,J＝8.0Hz,1H),7.33(d,J＝8.1Hz,1H),7.05(d,J＝6.3Hz,2H),6.97(t,J＝7.5Hz,1H),6.18(s,1H),5.81(s,1H),4.77(s,1H),4.46(d,J＝3.3Hz,1H),3.22–3.15(m,2H),2.95–2.82(m,4H),2.79–2.73(m,2H),2.73–2.67(m,2H),2.61(d,J＝16.2Hz,1H),1.67(d,J＝10.6Hz,1H),1.59(q,J＝8.6,7.8Hz,3H),1.36(d,J＝12.4Hz,2H),1.23(s,1H),1.12–1.02(m,2H),1.02–0.95(m,1H),0.79(s,3H),0.69(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.39,198.35,173.91,171.44,146.12,136.18,126.69,122.68,122.29,120.94,118.21,118.16,112.43,111.28,72.82,72.31,58.84,56.06,46.47,45.17,43.00,39.74,38.50,34.07,33.78,30.51,28.11,23.04,20.16,18.99,18.13.HR-MS(ESI):Calculated for C₃₁H₃₃NO_6.[M+H]⁺:516.2386,found:516.2369.

Example 9

The same procedure as in example 2 was repeated except for using 120mg of 3-indolecarboxylic acid instead of phenylpropionic acid to obtain a white solid product with a yield of 43%.¹H NMR(400MHz,DMSO-d₆)δ11.96(s,1H),7.67(d,J＝8.2Hz,1H),7.47(d,J＝8.4Hz,1H),7.29(t,J＝7.7Hz,1H),7.15(s,1H),7.09(t,J＝7.8Hz,1H),6.29(s,1H),5.93(s,1H),5.00(s,1H),4.97–4.92(m,1H),3.54(d,J＝8.3Hz,1H),2.97–2.88(m,2H),2.85(t,J＝8.4Hz,1H),2.72(d,J＝16.6Hz,1H),1.88–1.81(m,1H),1.72–1.60(m,2H),1.43–1.36(m,2H),1.25–1.05(m,3H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.34,198.46,173.97,159.79,146.17,137.74,126.52,125.58,125.26,122.90,122.24,120.42,112.58,109.23,74.01,72.57,59.12,56.37,46.65,45.49,43.30,38.60,33.85,30.52,28.20,23.09,18.94,18.16.HR-MS(ESI):Calculated for C₂₉H₂₉NO_6.[M+H]⁺:488.2073,found:488.2077.

Example 10

The same procedure as in example 2 was repeated except for using 122mg of 3-indazolecarboxylic acid instead of phenylpropionic acid to obtain a white solid product with a yield of 24%.¹H NMR(400MHz,DMSO-d₆)δ7.93(d,J＝8.9Hz,2H),7.86(d,J＝8.6Hz,2H),7.51(t,J＝7.8Hz,2H),7.42(t,J＝7.7Hz,2H),6.14(s,1H),6.08(s,1H),5.79(s,1H),4.79(s,1H),3.73(s,2H),3.10(d,J＝8.2Hz,1H),2.96(s,1H),2.67(d,J＝7.9Hz,1H),2.55(s,1H),1.63–1.55(m,4H),1.23(s,2H),0.80(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ204.49,200.42,174.31,156.81,153.55,148.16,134.73,128.69,128.30,126.83,121.27,119.54,119.51,114.88,72.87,70.55,58.55,57.74,46.52,45.38,44.97,43.00,42.88,41.09,33.80,30.56,28.29,23.36,19.10,18.21.HR-MS(ESI):Calculated for C₂₈H₂₈N₂O_6.[M+H]⁺:489.2026,found:489.1987.

Example 11

The same procedure as in example 2 was repeated except for using 113mg of pyridine-4-acrylic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 85%.¹H NMR(400MHz,DMSO-d₆)δ8.64–8.62(m,2H),7.71–7.69(m,2H),7.66(d,J＝16.1Hz,1H),6.91(d,J＝16.1Hz,1H),6.27(d,J＝1.2Hz,1H),5.95–5.93(m,1H),4.93(d,J＝1.2Hz,1H),4.85–4.82(m,1H),3.47–3.43(m,1H),3.28(s,1H),2.94–2.87(m,2H),2.81(d,J＝8.3Hz,1H),2.70(d,J＝16.4Hz,1H),1.82(ddd,J＝14.5,7.5,4.1Hz,1H),1.70–1.65(m,1H),1.40(s,1H),1.37(s,1H),1.28(d,J＝16.4Hz,1H),1.14–1.10(m,1H),1.09–1.04(m,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.34,198.48,173.92,164.45,150.32(*2),146.12,143.43,140.76,123.05,122.26(*2),121.45,73.79,72.43,58.96,56.26,46.61,45.34,43.20,39.76,38.53,33.83,30.51,28.16,23.08,18.95,18.15.HR-MS(ESI):Calculated for C₂₈H₂₉NO_6.[M+H]⁺:476.2073,found:476.2065.

Example 12

The same procedure as in example 2 was repeated except for using 93mg of isonicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 79%.¹H NMR(400MHz,DMSO-d₆)δ8.82–8.80(m,2H),7.76–7.73(m,2H),6.29(d,J＝1.2Hz,1H),5.93(d,J＝1.1Hz,1H),5.07(d,J＝1.2Hz,1H),4.90–4.87(m,1H),3.54(dt,J＝8.3,1.3Hz,1H),2.91(dd,J＝4.1,1.8Hz,1H),2.88(d,J＝1.7Hz,1H),2.86–2.81(m,1H),2.73(d,J＝16.5Hz,1H),1.81(ddd,J＝14.7,7.6,4.2Hz,1H),1.68(dd,J＝10.5,7.5Hz,1H),1.63–1.56(m,1H),1.41(d,J＝8.3Hz,1H),1.37(s,1H),1.11(d,J＝4.1Hz,1H),1.09(d,J＝4.7Hz,1H),0.83(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.26,198.26,173.93,163.35,150.87(*2),145.93,135.65,123.18,122.48(*2),74.75,72.43,58.97,56.40,46.54,45.33,43.21,38.47,33.83,30.52,28.15,23.15,18.95,18.15.HR-MS(ESI):Calculated for C₂₆H₂₇NO_6.[M+H]⁺:450.1917,found:450.1931.

Example 13

The same procedure as in example 2 was repeated except for using 119mg of 2-chloroisonicotinic acid in place of phenylpropionic acid, to obtain a white solid product with a yield of 83%.¹H NMR(400MHz,DMSO-d₆)δ8.64(dd,J＝5.0,0.8Hz,1H),7.79(t,J＝1.1Hz,1H),7.77–7.75(m,1H),6.29(d,J＝1.3Hz,1H),5.93(d,J＝1.1Hz,1H),5.07(d,J＝1.1Hz,1H),4.97–4.94(m,1H),3.54(dt,J＝8.4,1.3Hz,1H),3.32(s,1H),2.91(p,J＝1.8Hz,1H),2.89–2.87(m,1H),2.86–2.81(m,1H),2.72(d,J＝16.4Hz,1H),1.83–1.76(m,1H),1.68(dd,J＝10.5,7.5Hz,1H),1.65–1.59(m,1H),1.41(d,J＝3.8Hz,1H),1.38–1.35(m,1H),1.25(d,J＝10.6Hz,1H),1.11(d,J＝3.7Hz,1H),1.10–1.06(m,1H),0.83(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.21,198.18,173.96,162.16,151.32,151.11,145.86,139.27,123.28,122.11,75.20,72.34,59.07,56.38,46.55,45.33,43.20,38.40,33.83,30.52,28.14,23.16,18.95,18.15.HR-MS(ESI):Calculated for C₂₆H₂₆ClNO_6.[M+H]⁺:484.1527,found:484.1559.

Example 14

The same procedure as in example 2 was repeated except for using 93mg of 2-picolinic acid instead of phenylpropionic acid to obtain a white solid product with a yield of 64%.¹H NMR(400MHz,DMSO-d₆)δ8.74(dt,J＝4.7,1.4Hz,1H),8.02–7.99(m,2H),7.69–7.65(m,1H),6.27(s,1H),5.93(s,1H),5.07(d,J＝1.2Hz,1H),4.84–4.81(m,1H),3.53(d,J＝8.2Hz,1H),3.32(s,1H),2.90(ddd,J＝15.1,8.3,3.9Hz,3H),2.84(d,J＝8.3Hz,1H),2.72(d,J＝16.5Hz,1H),1.84(ddd,J＝14.6,7.5,4.2Hz,1H),1.68(dd,J＝10.5,7.4Hz,1H),1.39(d,J＝11.7Hz,2H),1.10(tt,J＝9.0,3.8Hz,2H),0.82(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.32,198.44,173.90,163.32,150.01,146.05,137.66,127.92,125.30,123.11,74.51,72.52,58.97,56.38,46.65,45.36,43.24,38.49,33.85,30.51,28.16,23.08,18.94,18.15.HR-MS(ESI):Calculated for C₂₆H₂₇NO_6.[M+H]⁺:450.1917,found:450.1902.

Example 15

The same procedure used in example 2 was repeated except for using 116mg of 5-methoxy-2-picolinic acid instead of phenylpropionic acid to give the product as a white solid in 53% yield.¹H NMR(400MHz,DMSO-d₆)δ8.42(d,J＝3.0Hz,1H),7.99(d,J＝8.6Hz,1H),7.52(dd,J＝8.9,3.0Hz,1H),6.26(s,1H),5.92(s,1H),5.02(s,1H),4.79(d,J＝3.3Hz,1H),3.90(d,J＝2.6Hz,3H),3.50(d,J＝8.4Hz,1H),2.89(d,J＝10.9Hz,2H),2.83(d,J＝8.5Hz,1H),2.71(d,J＝16.4Hz,1H),1.73–1.58(m,3H),1.41–1.37(m,2H),1.23(s,1H),1.12–1.07(m,2H),0.82(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.37,198.50,173.90,162.90,158.38,146.13,138.58,138.22,126.99,123.01,120.13,74.15,72.55,58.94,56.36,56.03,46.64,45.35,43.23,39.76,38.54,33.85,30.51,28.17,23.07,18.94,18.15.HR-MS(ESI):Calculated for C₂₇H₂₉NO_7.[M+H]⁺:480.2022,found:480.1979.

Example 16

The same procedure as in example 2 was repeated except for using 104mg of 5-methyl-2-picolinic acid instead of phenylpropionic acid to obtain a white solid product in 74% yield.¹H NMR(400MHz,DMSO-d₆)δ8.57(d,J＝2.1Hz,1H),7.90(d,J＝8.0Hz,1H),7.81(dd,J＝8.1,2.1Hz,1H),6.27(s,1H),5.92(s,1H),5.04(s,1H),4.80(q,J＝1.8Hz,1H),3.51(d,J＝8.2Hz,1H),2.91(td,J＝10.0,9.5,4.0Hz,2H),2.83(d,J＝8.2Hz,1H),2.72(d,J＝16.4Hz,1H),2.38(s,3H),1.83(dt,J＝14.2,4.7Hz,1H),1.71–1.66(m,1H),1.38(d,J＝12.4Hz,3H),1.23(s,1H),1.13–1.06(m,2H),0.81(d,J＝7.3Hz,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.33,198.48,173.90,163.34,150.44,146.08,143.73,138.25,137.57,124.94,123.07,74.36,72.53,58.96,56.37,46.65,45.36,43.24,38.50,33.85,30.51,28.17,23.08,18.94,18.15,18.08.HR-MS(ESI):Calculated for C₂₇H₂₉NO_6.[M+H]⁺:464.2073,found:464.2069.

Example 17

The same procedure as in example 2 was repeated except for using 93mg of nicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 73%.¹H NMR(400MHz,DMSO-d₆)δ8.99(dd,J＝2.4,1.1Hz,1H),8.84(dd,J＝4.8,1.7Hz,1H),8.20(dq,J＝8.1,2.2Hz,1H),7.60–7.55(m,1H),6.29(s,1H),5.92(s,1H),5.07(d,J＝1.4Hz,1H),4.94–4.89(m,1H),3.53(d,J＝8.1Hz,1H),2.95–2.91(m,1H),2.89–2.85(m,1H),2.82(d,J＝8.1Hz,1H),2.72(d,J＝17.2Hz,1H),1.84–1.77(m,1H),1.72–1.67(m,1H),1.64(d,J＝17.8Hz,1H),1.39(d,J＝11.7Hz,2H),1.27–1.23(m,1H),1.13(d,J＝10.8Hz,1H),1.10–1.04(m,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.32,198.44,173.90,163.32,150.01,146.05,137.66,127.92,125.30,123.11,74.51,72.52,58.97,56.38,46.65,45.36,43.24,38.49,33.85,30.51,28.16,23.08,18.94,18.15.HR-MS(ESI):Calculated for C₂₆H₂₇NO_6.[M+H]⁺:450.1917,found:450.1918.

Example 18

The same procedure as in example 2 was repeated except for using 116mg of 6-methoxynicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 84%.¹H NMR(400MHz,DMSO-d₆)δ8.67(d,J＝2.4Hz,1H),8.07(dd,J＝8.7,2.4Hz,1H),6.94(d,J＝8.7Hz,1H),6.28(s,1H),5.92(s,1H),5.02(s,1H),4.90(d,J＝3.5Hz,1H),3.93(s,3H),3.50(d,J＝8.8Hz,1H),3.31(s,1H),2.91(d,J＝13.8Hz,2H),2.81(d,J＝8.2Hz,1H),2.72(d,J＝16.4Hz,1H),1.81–1.76(m,1H),1.72–1.67(m,1H),1.66–1.61(m,1H),1.25(d,J＝11.5Hz,2H),1.11(s,1H),1.08(d,J＝6.4Hz,1H),0.83(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.34,198.38,173.95,166.70,163.21,149.78,146.09,139.68,122.95,118.26,110.90,73.97,72.52,58.94,56.38,53.98,46.50,45.35,43.19,38.59,33.82,30.51,28.17,23.17,18.95,18.16.HR-MS(ESI):Calculated for C₂₇H₂₉NO_7.[M+H]⁺:480.2022,found:480.2006.

Example 19

The same procedure as in example 2 was repeated except for using 104mg of 2-methylnicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 74%.¹H NMR(400MHz,DMSO-d₆)δ8.65–8.62(m,1H),8.08–8.04(m,1H),7.38(dd,J＝7.9,4.9Hz,1H),6.29(s,1H),5.94(s,1H),5.07(s,1H),4.85(d,J＝3.4Hz,1H),3.54(d,J＝8.1Hz,1H),3.32(s,1H),2.91(d,J＝13.6Hz,2H),2.83(d,J＝8.3Hz,1H),2.73(d,J＝16.4Hz,1H),2.64(s,3H),1.82–1.77(m,1H),1.69–1.65(m,1H),1.60(d,J＝14.2Hz,1H),1.41(d,J＝8.8Hz,1H),1.37(s,1H),1.12(d,J＝12.9Hz,1H),1.06(dd,J＝14.0,4.4Hz,1H),0.82(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.33,198.44,173.94,164.49,158.87,152.44,146.18,138.26,123.74,123.07,121.51,74.37,72.50,58.92,56.37,46.51,45.28,43.16,38.56,33.82,30.51,28.16,24.51,23.19,18.97,18.16.HR-MS(ESI):Calculated for C₂₇H₂₉NO_6.[M+H]⁺:464.2073,found:464.2076.

Example 20

The same procedure as in example 2 was repeated except for using 119mg of 2-chloronicotinic acid in place of phenylpropionic acid, to obtain a white solid product with a yield of 69%.¹H NMR(400MHz,DMSO-d₆)δ8.63–8.60(m,1H),8.21(d,J＝7.7Hz,1H),7.59(dd,J＝7.8,4.8Hz,1H),6.28(s,1H),5.95(s,1H),5.09(s,1H),4.86(d,J＝3.4Hz,1H),3.56(d,J＝8.2Hz,1H),2.93–2.88(m,2H),2.84(d,J＝8.8Hz,1H),2.73(d,J＝16.5Hz,1H),1.83–1.77(m,1H),1.69–1.61(m,2H),1.39(d,J＝12.5Hz,2H),1.25(d,J＝10.7Hz,1H),1.11(s,1H),1.07(s,1H),0.82(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.22,198.16,173.92,162.69,152.85,148.04,146.00,140.94,125.42,123.30,123.17,75.20,72.44,58.94,56.33,46.52,45.27,43.16,38.46,33.82,30.50,28.14,23.13,18.97,18.15.HR-MS(ESI):Calculated for C₂₆H₂₆ClNO_6.[M+H]⁺:484.1527,found:484.1559.

Example 21

The same procedure as in example 2 was repeated except for using 119mg of 5-chloronicotinic acid in place of phenylpropionic acid, to obtain a white solid product with a yield of 63%.¹H NMR(400MHz,DMSO-d₆)δ8.92(dd,J＝3.4,2.2Hz,2H),8.27(t,J＝2.2Hz,1H),6.29(s,1H),5.93(s,1H),5.07(d,J＝1.2Hz,1H),5.03–4.99(m,1H),3.54(d,J＝8.1Hz,1H),2.92(dt,J＝4.6,2.3Hz,1H),2.88(d,J＝4.4Hz,1H),2.83(d,J＝8.2Hz,1H),2.72(d,J＝16.4Hz,1H),2.51(d,J＝2.1Hz,1H),1.80–1.75(m,1H),1.68(dd,J＝10.4,7.5Hz,1H),1.60(d,J＝12.8Hz,1H),1.40(d,J＝2.7Hz,1H),1.37(s,1H),1.11(d,J＝3.5Hz,1H),1.09–1.07(m,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.26,198.24,173.99,152.76,148.28,145.93,136.32,131.35,123.18,74.90,72.38,59.08,56.37,46.54,45.35,43.20,38.47,33.82,30.52,28.16,23.18,18.96,18.16.HR-MS(ESI):Calculated for C₂₆H₂₆ClNO_6.[M+H]⁺:484.1527,found:484.1508.

Example 22

Using 152mg of 5The procedure of example 2 was otherwise identical, except that nicotinic acid bromide was used instead of phenylpropionic acid, to give a white solid product in 71% yield.¹H NMR(400MHz,DMSO-d₆)δ8.99(d,J＝2.3Hz,1H),8.96(d,J＝2.0Hz,1H),8.37(t,J＝2.1Hz,1H),6.30(s,1H),5.93(s,1H),5.07(d,J＝1.1Hz,1H),5.02–4.99(m,1H),3.54(d,J＝8.1Hz,1H),2.92(dt,J＝4.2,2.1Hz,1H),2.90–2.87(m,1H),2.83(d,J＝8.2Hz,1H),2.73(d,J＝16.4Hz,1H),2.52(d,J＝2.2Hz,1H),1.78(dt,J＝11.6,4.2Hz,1H),1.70–1.66(m,1H),1.63(d,J＝14.5Hz,1H),1.40(s,1H),1.37(s,1H),1.11(d,J＝3.5Hz,1H),1.09–1.06(m,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.26,198.24,173.99,162.31,154.87,148.54,145.94,139.03,126.28,123.18,120.25,74.88,72.38,59.08,56.37,46.55,45.34,43.19,38.47,33.82,30.52,28.16,23.18,18.95,18.16.HR-MS(ESI):Calculated for C₂₆H₂₆BrNO_6.[M+H]⁺:528.1022,found:528.1010.

Example 23

The same procedure as in example 2 was repeated except for using 106mg of 5-fluoronicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 83%.¹H NMR(400MHz,DMSO-d₆)δ8.89(d,J＝2.8Hz,1H),8.86(t,J＝1.7Hz,1H),8.12(ddd,J＝8.9,2.9,1.7Hz,1H),6.30–6.28(m,1H),5.93(d,J＝1.1Hz,1H),5.07(d,J＝1.2Hz,1H),5.01–4.99(m,1H),3.55(d,J＝8.1Hz,1H),2.92(dt,J＝4.8,2.4Hz,1H),2.89(d,J＝4.5Hz,1H),2.83(d,J＝8.2Hz,1H),2.73(d,J＝16.5Hz,1H),2.51(d,J＝2.0Hz,1H),1.78(dt,J＝11.5,4.2Hz,1H),1.71–1.68(m,1H),1.63–1.57(m,1H),1.41(d,J＝8.0Hz,1H),1.38(s,1H),1.11(d,J＝3.6Hz,1H),1.10–1.07(m,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.26,198.21,173.98,162.45,159.91,157.36,146.25,146.21,145.92,142.89,142.66,126.13,123.81,123.61,123.16,74.91,72.41,59.07,56.38,46.53,45.36,43.21,39.77,38.47,33.82,30.52,28.16,23.17,18.95,18.16.HR-MS(ESI):Calculated for C₂₆H₂₆FNO_6.[M+H]⁺:468.1822,found:468.1804.

Example 24

The same procedure as in example 2 was repeated except for using 104mg of 5-methylnicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 65%.¹H NMR(400MHz,DMSO-d₆)δ8.79(d,J＝2.1Hz,1H),8.68(d,J＝2.1Hz,1H),8.03(d,J＝2.4Hz,1H),6.29(d,J＝1.3Hz,1H),5.93(d,J＝1.1Hz,1H),5.05(d,J＝1.2Hz,1H),4.95–4.92(m,1H),3.55–3.51(m,1H),2.93(dt,J＝4.5,2.3Hz,1H),2.89(dd,J＝4.6,2.3Hz,1H),2.83(d,J＝8.2Hz,1H),2.73(d,J＝16.4Hz,1H),2.51(d,J＝2.0Hz,1H),2.37(s,3H),1.84–1.77(m,1H),1.69(dd,J＝10.5,7.5Hz,1H),1.65–1.59(m,1H),1.40(s,1H),1.38–1.35(m,1H),1.11(d,J＝3.7Hz,1H),1.09(d,J＝4.6Hz,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.30,198.36,173.96,163.61,154.56,147.30,146.01,136.93,133.57,124.12,123.10,74.43,72.47,59.01,56.38,46.56,45.36,43.22,38.52,33.83,30.51,28.17,23.19,18.95,18.16,17.58.HR-MS(ESI):Calculated for C₂₇H₂₉NO_6.[M+H]⁺:464.2073,found:464.2064.

Example 25

The same procedure as in example 2 was repeated except for using 152mg of 2-bromonicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 73%.¹H NMR(400MHz,DMSO-d₆)δ8.57(dd,J＝4.7,2.0Hz,1H),8.12(dd,J＝7.7,2.0Hz,1H),7.60(dd,J＝7.7,4.7Hz,1H),6.27(s,1H),5.96(d,J＝1.1Hz,1H),5.08(d,J＝1.1Hz,1H),4.87(dd,J＝4.0,1.7Hz,1H),3.57(d,J＝8.2Hz,1H),3.32(s,1H),2.91(d,J＝2.2Hz,1H),2.88(d,J＝3.3Hz,1H),2.86–2.83(m,1H),2.73(d,J＝16.4Hz,1H),1.82–1.77(m,1H),1.67(d,J＝2.9Hz,1H),1.37(s,1H),1.23(s,1H),1.11(d,J＝4.3Hz,1H),1.07(s,1H),0.82(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.21,198.14,173.93,163.33,152.96,145.98,140.12,138.85,128.44,123.41,123.28,75.30,72.43,58.98,56.31,46.51,45.26,43.16,40.01,38.43,33.83,30.52,28.13,23.14,18.99,18.15.HR-MS(ESI):Calculated for C₂₆H₂₆BrNO_6.[M+H]⁺:528.1022,found:528.1003.

Example 26

The same procedure as in example 2 was repeated except for using 104mg of 4-methylnicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 73%.¹H NMR(400MHz,DMSO-d₆)δ8.80(s,1H),8.61(d,J＝5.1Hz,1H),7.39(d,J＝5.2Hz,1H),6.30(s,1H),5.94(s,1H),5.10(d,J＝1.2Hz,1H),4.86(dd,J＝4.0,1.7Hz,1H),3.55(d,J＝8.1Hz,1H),3.32(s,1H),2.93–2.87(m,2H),2.82(d,J＝8.2Hz,1H),2.73(d,J＝16.3Hz,1H),2.47(s,3H),1.83–1.77(m,1H),1.69–1.64(m,1H),1.63–1.57(m,1H),1.40(s,1H),1.37(s,1H),1.23(s,1H),1.11(d,J＝3.5Hz,1H),1.08(d,J＝4.0Hz,1H),0.82(s,3H),0.71(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.35,198.45,173.96,164.05,152.83,150.74,149.10,146.23,126.62,124.45,123.06,74.26,72.54,58.88,56.40,46.46,45.27,43.14,38.61,33.82,30.52,28.16,23.21,20.53,18.98,18.16.HR-MS(ESI):Calculated for C₂₇H₂₉NO_6.[M+H]⁺:464.2073,found:464.2072.

Example 27

The same procedure as in example 2 was repeated except for using 106mg of 6-fluoronicotinic acid in place of phenylpropionic acid, to obtain a white solid product with a yield of 56%.¹H NMR(400MHz,DMSO-d₆)δ8.72(d,J＝2.6Hz,1H),8.40(td,J＝8.1,2.5Hz,1H),7.36(dd,J＝8.6,2.6Hz,1H),6.29(s,1H),5.93(s,1H),5.07(s,1H),4.97–4.94(m,1H),3.54(d,J＝8.1Hz,1H),3.32(s,1H),2.92(ddt,J＝15.6,13.5,2.5Hz,3H),2.83(d,J＝8.2Hz,1H),2.73(d,J＝16.4Hz,1H),1.83–1.76(m,1H),1.71–1.66(m,1H),1.60(dt,J＝14.4,3.8Hz,1H),1.41(d,J＝4.5Hz,1H),1.37(s,1H),1.25(d,J＝12.0Hz,1H),1.11(d,J＝3.6Hz,1H),1.08(t,J＝3.7Hz,1H).¹³C NMR(101MHz,DMSO-d₆)δ203.25,198.25,173.95,164.22,162.40,149.91,149.74,145.96,143.42,143.32,123.47,123.10,110.42,110.05,74.58,72.43,59.03,56.38,46.53,45.35,43.20,39.77,38.51,33.82,30.50,28.16,23.16,18.94,18.16.HR-MS(ESI):Calculated for C₂₆H₂₆FNO_6.[M+H]⁺:468.1822,found:468.1811.

Example 28

The same procedure as in example 2 was repeated except for using 152mg of 6-bromonicotinic acid in place of phenylpropionic acid to obtain a white solid product with a yield of 63%.¹H NMR(400MHz,DMSO-d₆)δ8.78(d,J＝2.4Hz,1H),8.10(dd,J＝8.4,2.5Hz,1H),7.84(d,J＝8.4Hz,1H),6.28(s,1H),5.92(s,1H),5.06(d,J＝1.2Hz,1H),4.93(dd,J＝4.0,1.7Hz,1H),3.53(d,J＝8.2Hz,1H),3.31(s,1H),2.93–2.86(m,2H),2.82(d,J＝8.2Hz,1H),2.72(d,J＝16.4Hz,1H),1.81–1.74(m,1H),1.70–1.65(m,1H),1.59(d,J＝14.0Hz,1H),1.41(d,J＝4.0Hz,1H),1.39–1.35(m,1H),1.11(d,J＝3.2Hz,1H),1.08(d,J＝4.4Hz,1H),0.83(s,3H),0.71(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ203.27,198.24,173.95,162.82,151.05,146.59,145.94,139.81,128.50,124.39,123.15,74.65,72.40,59.02,56.38,46.53,45.33,43.19,38.49,33.82,30.52,28.15,23.16,18.96,18.15.HR-MS(ESI):Calculated for C₂₆H₂₆BrNO_6.[M+H]⁺:528.1022,found:528.1007.

Example 29

The same procedures as in the example were carried out except that 106mg of 2-fluoronicotinic acid was used in place of phenylpropionic acid2, obtaining a white solid product with the yield of 55 percent.¹H NMR(400MHz,DMSO-d₆)δ8.52–8.49(m,1H),8.36(ddd,J＝9.6,7.6,2.0Hz,1H),7.53(ddd,J＝7.5,4.8,1.6Hz,1H),6.28(s,1H),5.93(d,J＝1.1Hz,1H),5.07(d,J＝1.2Hz,1H),4.88–4.85(m,1H),3.53(d,J＝8.1Hz,1H),3.31(s,1H),2.91(dt,J＝4.1,2.2Hz,1H),2.89–2.85(m,1H),2.83(d,J＝8.2Hz,1H),2.72(d,J＝16.5Hz,1H),1.81(ddd,J＝14.5,7.5,4.1Hz,1H),1.68(dd,J＝10.5,7.5Hz,1H),1.60(d,J＝13.7Hz,1H),1.41(d,J＝4.2Hz,1H),1.37(s,1H),1.21–1.13(m,1H),1.11(d,J＝3.3Hz,1H),1.10–1.06(m,1H),0.82(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.27,198.18,173.92,161.12,152.58,152.42,145.94,143.59,123.06,122.55,122.50,112.19,74.71,72.42,58.91,56.34,46.55,45.32,43.19,38.46,33.83,30.51,28.15,23.13,18.95,18.15.HR-MS(ESI):Calculated for C₂₆H₂₆FNO_6.[M+H]⁺:468.1822,found:468.1807.

Example 30

The same procedure used in example 2 was repeated except for using 116mg of 2-methoxy-3-picolinic acid instead of phenylpropionic acid to give the product as a white solid in a yield of 42%.¹H NMR(400MHz,DMSO-d₆)δ8.41(dd,J＝4.9,2.0Hz,1H),8.08(dd,J＝7.6,2.0Hz,1H),7.14–7.10(m,1H),6.26(d,J＝1.4Hz,1H),5.92(d,J＝1.1Hz,1H),5.00(d,J＝1.3Hz,1H),4.86(dd,J＝4.0,1.7Hz,1H),3.89(d,J＝4.1Hz,1H),3.87(d,J＝1.9Hz,3H),3.48(d,J＝8.6Hz,1H),3.29(s,1H),2.94–2.91(m,1H),2.89(d,J＝2.0Hz,1H),2.81(d,J＝8.3Hz,1H),2.71(d,J＝16.5Hz,1H),1.86–1.81(m,1H),1.68(dd,J＝10.6,7.5Hz,1H),1.62–1.54(m,1H),1.41(d,J＝4.1Hz,1H),1.37(s,1H),1.24(d,J＝5.0Hz,1H),1.11(s,1H),1.08(d,J＝4.6Hz,1H),0.83(s,3H),0.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ203.38,198.33,173.95,163.20,161.44,151.62,146.15,141.37,122.80,116.97,112.43,74.13,72.57,58.81,56.32,53.69,46.53,45.33,43.18,38.51,33.84,30.51,28.17,23.13,18.97,18.16.HR-MS(ESI):Calculated for C₂₇H₂₉NO_7.[M+H]⁺:480.2022,found:480.2043.

Example 37: the anti-tumor activity evaluation of the 11, 20-dicarbonyl economic oridonin derivative synthesized by the invention on four cells of a human esophageal cancer cell TE-1, a human pancreatic cancer cell SW-1990, a human cervical cancer cell Hela and a human esophageal cancer cell Ec109 is as follows: the contents are all mass% contents, not specifically stated.

Experimental methods

Taking oridonin as a positive control, selecting the four cancer cells to determine the antiproliferative activity of the synthesized compound for 72 hours: digesting the cells in logarithmic growth phase by pancreatin containing 0.25% EDTA to prepare cell suspension with the concentration of 1-10 x 10^ 4/mL, inoculating the cells into a 96-well plate according to 1000-10000 cells/hole, adding 100 mu L of cell suspension into the fast top wall of each hole, and after the inoculation is finished, placing the 96-well plate in a position with the volume percentage content of 5% CO₂In a 37 ℃ humidity incubator. Discarding supernatant in clean plate after 24h, adding 200 μ L culture solution containing different drug concentrations into each well, arranging three parallel wells according to a certain concentration gradient for each compound, adding 200 μ L blank culture solution into control group, and adding 5 vol% CO₂And culturing for 72 hours in a humidity incubator at 37 ℃. Adding 100 μ L of 30% TCA solution into each well, and fixing at 4 deg.C for 60 min; washing with deionized water for 3-4 times, and air drying; adding 0.4% SRB 100 μ L per well, and dyeing at room temperature for 30 min; washing with 1% acetic acid for 3 times, and air drying; adding 150 μ L of Tris base into each well, shaking with a flat plate shaker for 15min, measuring absorbance density (OD) with a microplate reader, and detecting wavelength of 540 nm. Using the solvent control treated cells as a control group, calculating the inhibition rate of the compound on the cells according to the following formula, and calculating the half inhibition concentration IC according to the middle effect equation₅₀: inhibition (%) - (control group OD average-administration group OD average)/control group OD average 100%

11, 20-dicarbonyl economic source oridonin derivative with anti-tumor activity

Ori is oridonin; JOA is JIYUANWANGCAOZIA; O-JOA is 11, 20-dicarbonyl oridonin.

The above experimental results show that: the compound has better in-vitro anti-tumor activity, can be used for preparing anti-tumor drugs, and is applied to clinical treatment of esophagus cancer, stomach cancer, cervical cancer, pancreatic cancer, breast cancer, acute myeloid leukemia and the like. The compound of the invention is used as an active ingredient for preparing a new anticancer drug, and has potential application value.

Drug solubility test

According to solubility test of 'Chinese pharmacopoeia' 2020 edition, the invention selects normal saline, methanol, ethanol, acetone, ethyl acetate, dichloromethane and petroleum ether as solvents, and the result shows that most compounds are easy to dissolve in dichloromethane, and the solubility of the compounds can reach 200 mg/mL.

Test for stability of drug

The compound 10 with the best antitumor activity was tested for stability according to the guidelines of the drug stability test in the 'Chinese pharmacopoeia' 2020 edition, and the results are shown in the following table:

compound 10 influencing factor test (1 test sample)

Accelerated test and Long term test of Compound 10 (3 test batches)

Claims

The 14-O esterified derivative of the oridonin 11, 20-dicarbonyl is characterized by having a structure shown in a general formula I:

r is a group formed by esterifying organic acid and 14-hydroxyl of oridonin;

the organic acid is selected from: phenylpropionic acid; cinnamic acid or cinnamic acid monosubstituted with C1-5 alkyl; pyrimidinecarboxylic acid; picolinic acid, pyridine acetic acid, pyridine acrylic acid, picolinic acid monosubstituted by methoxy and C1-5 alkyl, pyridine acetic acid monosubstituted by methoxy and C1-5 alkyl, and pyridine acrylic acid monosubstituted by methoxy and C1-5 alkyl; nicotinic acid, isonicotinic acid; nicotinic acid mono-substituted with methoxy, C1-5 alkyl, halo; isonicotinic acid monosubstituted with halogen; indolecarboxylic acid, indoleacetic acid, indolepropionic acid, N-methyl-indolecarboxylic acid, N-methyl-indoleacetic acid, N-methyl-indolepropionic acid; indazolecarboxylic acid, indazoleacetic acid or indazolepropanoic acid.
2. The esterified 11, 20-dicarbonyl oridonin 14-O derivative of claim 1, wherein the organic acid is selected from the group consisting of: phenylpropionic acid; cinnamic acid or cinnamic acid monosubstituted with methyl; 2-pyrimidinecarboxylic acid; 2-picolinic acid, 5-methoxy-2-picolinic acid, 5-methyl-2-picolinic acid, pyridine-4-acrylic acid; nicotinic acid, isonicotinic acid; nicotinic acid mono-substituted with methoxy, methyl, fluoro, chloro or bromo; 2-chloroisonicotinic acid; 2-indolecarboxylic acid, 3-indolepropionic acid, 3-indolecarboxylic acid, N-methyl-2-indolecarboxylic acid; 3-indazolecarboxylic acid.
3. The esterified 11, 20-dicarbonyl oridonin 14-O derivative of claim 1, selected from the group consisting of:
4. the use of the esterified 11, 20-dicarbonyl oridonin 14-O derivative according to any one of claims 1-3 for the manufacture of a medicament for the treatment of esophageal, pancreatic or cervical cancer, comprising the esterified derivative as an active ingredient.