CN110483545B - Dihydroartemisinin oxime-containing phenol derivative, and synthesis method and application thereof - Google Patents

Dihydroartemisinin oxime-containing phenol derivative, and synthesis method and application thereof Download PDF

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CN110483545B
CN110483545B CN201910803240.8A CN201910803240A CN110483545B CN 110483545 B CN110483545 B CN 110483545B CN 201910803240 A CN201910803240 A CN 201910803240A CN 110483545 B CN110483545 B CN 110483545B
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杨大成
唐雪梅
潘建芳
范莉
周福委
李平
杨艳
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Abstract

The invention discloses a dihydroartemisinin oxime-containing phenol derivative, a synthesis method and application, and belongs to the technical field of chemical medicines. The derivatives or racemates, stereoisomers, tautomers and pharmaceutically acceptable salts thereof have the following general formula:

Description

Dihydroartemisinin oxime-containing phenol derivative, and synthesis method and application thereof
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a dihydroartemisinin oxime-containing phenol derivative, a synthesis method and application.
Background
Artemisinin is a terpenoid found in the plant Artemisia annua. Dihydroartemisinin (DHA) is a first-generation derivative of artemisinin, has a unique structure, shows better pharmaceutical properties than artemisinin, and is an important clinical antimalarial drug. Based on the special structure and excellent activity of DHA, the research on DHA is continuous at home and abroad, and the research is mainly focused on the design and synthesis of novel derivatives of DHA, the exploration of new activity of old DHA molecules or the activity research of new molecules at present. To date, a plurality of novel DHA derivatives have been synthesized, and part of artemisinin derivatives have been used in clinical tests for resisting breast cancer, colorectal cancer, non-small cell lung cancer and the like; researches also find that certain DHA derivatives show very good activity in resisting virus, bacteria, sensitization, HIV, cytomegalovirus, tuberculosis and other diseases, show the potential of multi-target molecules and are worthy of further research and development.
The Schiff base mainly refers to a class of organic compounds containing an imine characteristic group C ═ N, and is usually formed by condensation of primary amine and carbonyl, and by properly changing a substituent group, the Schiff base derivatives which are chain-shaped to ring-shaped, single to various, different in performance and variable in structure can be synthesized. Schiff base is an important organic intermediate, and can be used for preparing amine through reduction reaction; in organic synthesis, Schiff base can be used as a protecting group and a positioning group of aldehyde and ketone. Schiff base has important and wide pharmacological and physiological activities, and has attracted more and more attention of pharmaceutical workers in recent years. The amino acids, the amines, the semicarbazones, the thiosemicarbazones, the heterocycles, the hydrazones and the complexes thereof have unique medicinal effects of bacteriostasis, sterilization, antitumor, antivirus and the like.
Hydroxylamine is commonly used as a reducing agent in organic synthesis, and it specifically cleaves the peptide bond (Asn-Gly) between asparagine and glycine. Methoxyamine itself is used as an anti-shock vasoactive substance, mainly for massive hemorrhage, hypotension caused by trauma and surgery, shock caused by myocardial infarction and supraventricular tachycardia. Carboxymethyl hydroxylamine is an important organic intermediate, and is mainly used for introducing carboxyl into aldehyde ketone. Another important reaction of hydroxylamine, methoxyamine or carboxymethyl hydroxylamine is the condensation with carbonyl group to produce oxime, and many drugs on the market containing oxime structure, such as cefditoren pivoxil, cefdinir, cefixime, anticancer drug vorinostat, anticoagulant ximelagatran, quinolone antibacterial drug gemifloxacin, steroid contraceptive norgestimate, etc. Therefore, the synthesis of the oxime compound not only can synthesize organic new molecules with diverse structures, but also can obtain lead molecules with wide biological activity and even drugs.
The research of the literature finds that the derivatives of DHA are numerous, but no report is found at present for the oxime-containing phenol derivatives of dihydroartemisinin of DHA.
The invention provides a new medicament based on dihydroartemisinin oxime-containing phenol derivatives, and synthesis and application thereof, plays a promoting role in preparation and popularization of new medicaments and treatment of diseases, and can be applied to wider fields.
Disclosure of Invention
The invention provides a dihydroartemisinin oxime-containing phenol derivative, a synthesis method and application.
The invention provides a dihydroartemisinin oxime-containing phenol derivative, or a racemate, a stereoisomer, a tautomer and pharmaceutically acceptable salts thereof, wherein the dihydroartemisinin oxime-containing phenol derivative is represented by TM8, and the structural formula is as follows:
Figure RE-GDA0002228756440000021
wherein n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H or alkyl, R 3 Is H, alkyl or-CH 2 CO 2 H, m is 0, 1 or 2.
Preferably, n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 ，R 3 Is H, -CH 3 or-CH 2 CO 2 H, m ═ 0 or 2.
The invention also provides a synthetic method of the dihydroartemisinin oxime-containing phenolic derivative TM8, which is carried out according to the following reaction equation and comprises the following steps:
Figure RE-GDA0002228756440000022
wherein n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 ，R 3 Is H, -CH 3 or-CH 2 CO 2 H, m is 0 or 2;
adding raw materials TM4 and R 3 O-NH 2 ·HCl、EtOH、Et 3 And N, stirring, reacting for 0.5-30 h, and after the reaction is finished, performing post-treatment to obtain the dihydroartemisinin oxime-containing phenol derivative, namely TM 8.
It is preferable thatStarting materials TM4 and R 3 O-NH 2 The mass ratio of the substances is 1: 1-5, and the reaction temperature is 10-35 ℃.
Preferably, the synthesis of TM4 is performed according to the following reaction equation, comprising the steps of:
Figure RE-GDA0002228756440000031
wherein n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 M is 0 or 2;
adding raw materials containing carbonyl substituted phenol, IM1 and K 2 CO 3 And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 2-12.5 h, and after the reaction is finished, performing post-treatment to obtain the dihydroartemisinin and carbonyl-containing phenol conjugate, namely TM 4.
Preferably, the mass ratio of the raw material IM1 to the raw material phenol is 1:1.2, and the reaction temperature is 40-85 ℃.
The invention also provides application of the dihydroartemisinin oxime-containing phenol derivative or racemate, stereoisomer, tautomer and pharmaceutically acceptable salt thereof in medicaments for resisting tuberculosis, resisting diabetes, reducing fat and inhibiting interleukin-17.
Preferably, n ═ 3 and R in the structural formula of the derivative 1 Is H, R 2 Is H, R 3 H, m ═ 0 (represented by TM 8-1), n ═ 3, and R 1 is-OCH 3 、R 2 Is H, R 3 H, m ═ 0 (represented by TM 8-5), n ═ 2, and R 1 Is H, R 2 Is H, R 3 H, m ═ 0 (represented by TM 8-6), n ═ 2, and R 1 is-OCH 3 、R 2 Is H, R 3 H, m ═ 0 (represented by TM 8-8), n ═ 3, and R 1 is-OCH 3 、R 2 Is H, R 3 is-CH 3 M is 0 (represented by TM8-13 and TM 8-14), n is 2, and R is 1 is-OCH 3 、R 2 Is H, R 3 is-CH 3 And when m is 0 (represented by TM 8-18)Application in antituberculosis drugs.
Preferably, n ═ 3 and R in the structural formula of the derivative 1 Is H, R 2 Is H, R 3 Is H or-CH 2 CO 2 H. m is 0 (represented by TM8-3 and TM 8-21), n is 3, and R is 1 is-OCH 3 、R 2 Is H, R 3 is-CH 2 CO 2 H. m is 0 (represented by TM 8-23), and n is 2, R 1 Is H, R 2 Is H, R 3 is-CH 2 CO 2 H. Use of m-0 (denoted by TM 8-25) in antidiabetic medicaments;
n＝3、R 1 is H, R 2 Is H, R 3 is-CH 3 M is 0 (ortho-, meta-, or para-position, respectively represented by TM8-10, TM8-11, and TM 8-12), n is 2, and R is 1 Is H, R 2 Is H, R 3 is-CH 3 And m-0 (TM 8-15), for use in a lipid lowering drug.
n＝3、R 1 Is H, R 2 Is H, R 3 H, m ═ 0 (denoted by TM 8-3), n ═ 2, and R 1 Is H, R 2 Is H, R 3 H, m ═ 0 (TM 8-7), n ═ 3, and R 1 Is H, R 2 Is H, R 3 is-CH 3 M is 0 (ortho-meta, respectively represented by TM8-10 and TM 8-11), n is 2, and R is 1 Is H, R 2 Is H, R 3 is-CH 3 And m-0 (TM 8-16) in an interleukin-17 drug.
Compared with the prior art, the invention has the beneficial effects that: the invention provides dihydroartemisinin oxime-containing phenol derivatives, which are synthesized by mutually connecting dihydroartemisinin and carbonyl-containing phenol through a proper connecting structure and then reacting with hydroxylamine or substituted hydroxylamine, and have the advantages of simple synthesis method and higher synthesis yield; biological activity tests show that the derivative has various biological activities of resisting tuberculosis, resisting diabetes, reducing blood fat, inhibiting interleukin-17 and the like, and has good application prospect.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
EXAMPLE 1 preparation of Oxime-containing phenol derivatives of Dihydroartemisinin
(1) The preparation method of the intermediate IM1 is as follows:
Figure RE-GDA0002228756440000041
adding Dihydroartemisinin (DHA) and diethyl ether (Et) 2 O) and bromohydrin, adding boron trifluoride-diethyl ether (BF) under cooling in ice bath 3 ·Et 2 O), reacting for 5-20 h under stirring, and adding saturated NaHCO after the reaction is finished 3 Terminating the reaction, standing for layering, extracting the aqueous layer with ethyl acetate (EtOAc or EA), combining the organic phases, washing with saturated brine, anhydrous MgSO 4 Drying, filtering, decompressing and rotary-distilling the filtrate to remove the solvent to obtain a crude product, and recrystallizing the crude product by using a Petroleum Ether (PE) -EA mixed solvent to obtain an intermediate IM 1.
(2) DHA conjugates with carbonyl-containing phenols, which we refer to in this application as TM4, were prepared as follows:
Figure RE-GDA0002228756440000051
in a 100mL round-bottom flask were added 12mmol of a carbonyl-substituted phenol, 15mL of Dimethylformamide (DMF), and K 2 CO 3 (25mmol) and IM1(10mmol), stirring in water bath at 40-85 ℃ for reaction, and monitoring the reaction progress by TLC. After completion of the reaction, 20mL of water and EA15mL were added, the layers were separated, the aqueous layer was extracted with EA10mL, and the organic layers were combined, washed with 5mL of 2N NaOH (5 mL. times.2), and washed with 20mL of water (20 mL. times.2). Anhydrous MgSO (MgSO) 4 Drying, vacuum filtering, rotary steaming under reduced pressure to remove EA to obtain pale yellow mucus, and performing column chromatography to obtain solid pure product TM 4.
(3) The preparation method of TM8 is as follows:
Figure RE-GDA0002228756440000052
sequentially adding R into a 100mL round-bottom flask 3 O-NH 2 ·HCl1.2～3mmol、EtOH3mL、Et 3 And (3) stirring and reacting N3 mmol and TM 40.6-0.8 mmol, and monitoring the reaction progress by TLC. After the reaction was completed, 20mL of water and EA15mL were added, 1N HCl was added to adjust the pH to about 7, stirring was continued for 5min, the organic phase was separated and washed 1 time with 20mL of water. Anhydrous Na 2 SO 4 Drying, vacuum filtering, rotary evaporating under reduced pressure to remove EA to obtain near colorless mucus, and performing column chromatography (PE/EA is 3/1, v/v) to obtain pure TM 8.
Example 2 preparation of dihydroartemisinin oxime-containing phenolic derivatives TM 8-1. about. TM. 8-58
When n-2 or 3, R is prepared according to the method described in example 1 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 ，R 3 Is H, CH 3 Or CH 2 CO 2 A series of TM8-1 to TM8-58 products were prepared with H, m being 0 or 2, and the respective reaction conditions, yields, product yields, and product melting points are shown in table 1.
TABLE 1 results of synthetic experiments for TM8 series of compounds
Figure RE-GDA0002228756440000053
Figure RE-GDA0002228756440000061
Figure RE-GDA0002228756440000071
Figure RE-GDA0002228756440000081
Example 3 testing and characterization of TM8-1 through TM8-58
The series of products of examples 2TM 8-1-TM 8-58 were subjected to 1 H NMR(AV-300)、 13 C NMR (AV-75) and HR MS (Varian7.0T) were tested and characterized, and the data are shown below:
Figure RE-GDA0002228756440000091
TM8-1(E)-2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehydeoxime
1 H NMR(300MHz，CDCl 3 )δ:8.51(1H，s)，7.70(1H，d，J＝6.6Hz)，7.32(1H，t，J＝7.2Hz)，6.97-6.88(2H， m)，5.33(1H，s)，4.83(1H，d，J＝3.3Hz)，4.15-4.08(3H，m)，3.59-3.52(1H，m)，2.65-2.60(1H，m)， 2.39-2.28(1H，m)，2.13-1.04(12H，m)，1.43(3H，s)，0.89(3H，d，J＝7.5Hz)，0.86(3H，d，J＝6.3Hz). 13 C NMR(75MHz，CDCl 3 )δ:156.95，146.36，131.15，126.88，120.85，111.90，104.19，101.90，87.84， 81.12，65.16，64.33，52.50，44.40，37.28，36.44，34.58，30.95，29.29，26.19，24.65，24.60，20.42， 13.0.HR MScalcdforC 25 H 35 NO 7 [M+Na] + 484.2311，found 484.2310.
TM8-2(E)-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.10(1H，s)，7.31-7.29(1H，m)，7.14-7.11(2H，m)，6.94(1H，d，J＝ 8.1Hz)，5.29(1H，s)，4.82(1H，d，J＝3.0Hz)，4.17-4.05(3H，m)，3.54-3.45(1H，m)，2.64-2.59(1H， m)，2.38-2.28(1H，m)，2.10-1.10(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.81(3H，d，J＝5.1 Hz). 13 C NMR(75MHz，CDCl 3 )δ:159.35，150.18，133.51，129.88，120.02，116.77，111.95，104.19， 101.91，87.85，81.16，64.66，64.10，52.51，44.43，37.19，36.48，34.59，30.97，29.17，26.27，24.62， 24.62，20.46，13.12.HR MS calcd for C 25 H 35 NO 7 [M+H] + 462.2494，found 462.2494.
TM8-3(E)-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.08(1H，s)，7.51(2H，d，J＝8.7Hz)，6.91(2H，d，J＝8.4Hz)，5.29(1H， s)，4.82(1H，d，J＝3.3Hz)，4.16-4.06(3H，m)，3.59-3.45(1H，m)，2.64-2.59(1H，m)，2.39-2.28(1H， m)，2.10-1.11(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.81(3H，d，J＝5.1Hz). 13 C NMR(75MHz， CDCl 3 )δ:160.58，149.88，128.59，124.76，114.77，104.20，101.96，87.88，81.15，64.75，64.13，52.52， 44.43，37.22，36.49，34.62，30.98，29.16，26.29，24.68，24.60，20.49，13.13.HR MS calcd for C 25 H 35 NO 7 [M+Na] + 484.2311，found 484.2315.
TM8-4(E)-3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.06(1H，s)，7.22(1H，s)，7.00(1H，d，J＝8.1Hz)，6.84(1H，d，J＝ 8.1Hz)，5.29(1H，s)，4.82(1H，d，J＝3.0Hz)，4.17-4.11(3H，m)，3.90(3H，s)，3.55-3.45(1H，m)，2.64-2.59(1H， m)，2.40-2.29(1H，m)，2.13-1.11(12H，m)，1.45(3H，s)，0.88(3H，d，J＝7.2Hz)，0.83(3H，d，J＝5.7 Hz). 13 C NMR(75MHz，CDCl 3 )δ:150.32，150.09，149.70，125.04，121.53，112.00，108.24，104.11， 101.94，87.88，81.13，65.73，64.21，55.96，52.49，44.43，37.26，36.50，34.61，30.95，29.15，26.29， 24.71，24.58，20.49，13.11.HR MS calcd for C 26 H 37 NO 8 [M+Na] + 514.2417，found 514.2419.
TM8-5(E)-4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.05(1H，s)，7.21(1H，s)，7.03(1H，d，J＝8.1Hz)，6.86(1H，d，J＝ 8.1Hz)，5.27(1H，s)，4.82(1H，d，J＝3.0Hz)，4.19-4.11(3H，m)，3.89(3H，s)，3.55-3.48(1H，m)，2.63-2.58(1H， m)，2.39-2.29(1H，m)，2.13-1.10(12H，m)，1.43(3H，s)，0.87(3H，d，J＝7.2Hz)，0.82(3H，d，J＝4.8 Hz). 13 C NMR(75MHz，CDCl 3 )δ:151.22，150.05，148.83，124.89，121.63，111.01，109.42，104.07， 101.89，87.86，81.16，65.62，64.15，56.02，52.50，44.44，37.17，36.52，34.55，30.95，29.14，26.30， 24.70，24.61，20.47，13.11.HR MS calcd for C 26 H 37 NO 8 [M+Na] + 514.2417，found 514.2415.
TM8-6(E)-2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.49(1H，s)，7.72(1H，d，J＝7.8Hz)，7.34(1H，t，J＝7.5Hz)，6.99-6.90(2H， m)，5.48(1H，s)，4.90(1H，d，J＝3.0Hz)，4.26-4.14(3H，m)，3.58-3.45(1H，m)，2.68-2.63(1H，m)， 2.42-2.32(1H，m)，2.06-1.17(10H，m)，1.45(3H，s)，0.93-0.90(6H，m). 13 C NMR(75MHz，CDCl 3 )δ:156.93， 146.18，131.17，126.83，121.08，112.39，104.30，102.46，88.09，81.27，67.92，66.80，52.60，44.51， 37.42，36.50，34.58，30.95，26.26，24.68，24.54，20.42，13.07.
Figure RE-GDA0002228756440000101
TM8-7(E)-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.10(1H，s)，7.32-7.29(1H，m)，7.15-7.11(2H，m)，6.95-6.92(1H， m)，5.48(1H，s)，4.90(1H，d，J＝3.3Hz)，4.19-4.11(3H，m)，3.81-3.77(1H，m)，2.67-2.62(1H，m)，2.43-2.32(1H，m)，2.07-1.19(10H，m)，1.45(3H，s)，0.97-0.89(6H，m). 13 C NMR(75MHz，CDCl 3 )δ:159.20， 150.06，133.53，129.87，120.19，116.90，112.09，104.24，102.24，88.01，81.23，67.47，66.57，52.58， 44.48，37.49，36.47，34.66，30.95，26.24，24.77，24.48，20.43，13.04.
TM8-8(E)-3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.07(1H，s)，7.21(1H，s)，7.00(1H，d，J＝8.1Hz)，6.88(1H，d，J＝ 8.1Hz)，5.49(1H，s)，4.89(1H，d，J＝3.3Hz)，4.28-4.11(3H，m)，3.87(3H，s)，3.52-3.45(1H，m)，2.65-2.61(1H， m)，2.42-2.32(1H，m)，2.05-1.19(10H，m)，1.44(3H，s)，0.93(3H，d，J＝5.7Hz)，0.89(3H，d，J＝7.2 Hz). 13 C NMR(75MHz，CDCl 3 )δ:150.28，150.09，149.90，125.25，121.51，112.84，108.61，104.17， 102.25，88.02，81.27，68.23，66.54，55.98，52.61，44.53，37.34，36.52，34.77，30.96，26.27，24.79， 24.47，20.47，12.99.
TM8-9(E)-4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde oxime
1 H NMR(300MHz，CDCl 3 )δ:8.06(1H，s)，7.22(1H，s)，7.04(1H，d，J＝8.1Hz)，6.86(1H，d，J＝ 8.1Hz)，5.50(1H，s)，4.89(1H，d，J＝2.1Hz)，4.22-4.14(3H，m)，3.87(3H，s)，3.59-3.45(1H，m)，2.70-2.58(1H， m)，2.41-2.32(1H，m)，2.05-1.19(10H，m)，1.45(3H，s)，0.93(3H，d，J＝5.7Hz)，0.89(3H，d，J＝7.5 Hz). 13 C NMR(75MHz，CDCl 3 )δ:151.40，149.89，148.76，124.84，121.78，111.38，110.33，104.15， 102.22，88.00，81.28，68.20，66.59，56.01，52.60，44.54，37.31，36.51，34.75，30.95，26.25，24.78， 24.46，20.44，12.96.
TM8-10(E)-2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:8.47(1H，s)，7.79(1H，d，J＝7.8Hz)，7.31(1H，t，J＝7.8Hz)，6.96(1H， t，J＝7.5Hz)，6.87(1H，d，J＝8.1Hz)，5.30(1H，s)，4.81(1H，d，J＝3.3Hz)，4.10-4.04(3H，m)，3.97(3H， s)，3.58-3.50(1H，m)，2.64-2.59(1H，m)，2.39-2.29(1H，m)，2.11-1.02(12H，m)，1.43(3H，s)，0.99-0.95(6H， m). 13 C NMR(75MHz，CDCl 3 )δ:156.81，144.64，130.98，126.38，120.84，120.76，111.72，104.02，101.88， 87.73，81.03，65.00，64.24，61.86，52.45，44.32，37.20，36.41，34.51，30.89，29.25，26.18，24.56， 24.52，20.36，13.02.HR MS calcd for C 26 H 37 NO 7 [M+H] + 476.2648，found 476.2650.
TM8-11(E)-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:8.02(1H，s)，7.30-7.24(1H，m)，7.16(1H，s)，7.11(1H，d，J＝7.5Hz)， 6.92(1H，d，J＝8.1Hz)，5.28(1H，s)，4.82(1H，d，J＝3.3Hz)，4.17-4.02(3H，m)，3.97(3H，s)，3.54-3.47(1H， m)，2.64-2.59(1H，m)，2.38-2.28(1H，m)，2.10-1.10(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.5Hz)， 0.81(3H，d，J＝4.5Hz). 13 C NMR(75MHz，CDCl 3 )δ:159.30，148.51，133.58，129.76，120.12，116.66， 111.78，104.09，101.88，87.80，81.12，64.62，64.07，62.11，52.51，44.42，37.15，36.48，34.57，30.96， 29.17，26.29，24.61，20.44，13.11.HR MS calcd for C 26 H 37 NO 7 [M+Na] + 498.2468，found 498.2467.
TM8-12(E)-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:8.01(1H，s)，7.51(2H，d，J＝8.4Hz)，6.89(2H，d，J＝8.7Hz)，5.29(1H， s)，4.81(1H，d，J＝3.3Hz)，4.17-4.03(3H，m)，3.95(3H，s)，3.54-3.47(1H，m)，2.64-2.59(1H，m)，2.39-2.28(1H， m)，2.13-1.06(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.81(3H，d，J＝5.1Hz). 13 C NMR(75MHz， CDCl 3 )δ:160.46，148.32，128.57，124.87，114.69，104.16，101.94，87.86，81.14，64.71，64.13，61.94， 52.52，44.42，37.21，36.49，34.61，30.97，29.16，26.30，24.67，24.59，20.49，13.12.HR MS calcd for C 26 H 37 NO 7 [M+Na] + 498.2468，found 498.2469.
Figure RE-GDA0002228756440000121
TM8-13(E)-3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy [1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.99(1H，s)，7.24(1H，s)，6.97(1H，d，J＝7.5Hz)，6.83(1H，d，J＝8.1Hz)，5.29(1H，s)，4.81(1H，d，J＝3.0Hz)，4.15-4.11(3H，m)，3.96(3H，s)，3.91(3H，s)，3.55-3.45(1H， m)，2.64-2.59(1H，m)，2.40-2.29(1H，m)，2.14-1.12(12H，m)，1.43(3H，s)，0.88(3H，d，J＝7.5Hz)， 0.84(3H，d，J＝5.7Hz). 13 C NMR(75MHz，CDCl 3 )δ:150.22，149.68，148.52，125.14，121.54，111.96，108.21，104.07，101.94，87.86，81.12，65.72，64.23，61.96，56.00，52.51，44.43，37.26，36.50， 34.60，30.95，29.16，26.30，24.70，24.57，20.49，13.11.HR MS calcd for C 27 H 39 NO 8 [M+Na] + 528.2573， found 528.2571.
TM8-14(E)-4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.97(1H，s)，7.22(1H，s)，7.01(1H，d，J＝8.1Hz)，6.84(1H，d，J＝ 8.1Hz)，5.26(1H，s)，4.82(1H，d，J＝3.0Hz)，4.20-4.15(3H，m)，3.95(3H，s)，3.89(3H，s)，3.56-3.49(1H， m)，2.62-2.58(1H，m)，2.39-2.29(1H，m)，2.13-1.10(12H，m)，1.43(3H，s)，0.88(3H，d，J＝7.2Hz)， 0.82(3H，d，J＝4.2Hz). 13 C NMR(75MHz，CDCl 3 )δ:151.11，148.80，148.46，124.98，121.66，110.92， 109.36，103.98，101.86，87.82，81.12，65.61，64.12，61.92，55.98，52.49，44.43，37.13，36.50， 34.53，30.94，29.14，26.30，24.67，24.60，20.45，13.10.HR MS calcd for C 27 H 39 NO 8 [M+Na] + 528.2573， found 528.2573.
TM8-15(E)-2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:8.45(1H，s)，7.80(1H，d，J＝7.8Hz)，7.32(1H，t，J＝7.2Hz)，6.95(1H， t，J＝7.5Hz)，6.89(1H，d，J＝8.4Hz)，5.43(1H，s)，4.88(1H，d，J＝3.0Hz)，4.23-4.11(3H，m)，3.95(3H， s)，3.78-3.73(1H，m)，2.67-2.62(1H，m)，2.42-2.32(1H，m)，2.05-1.13(10H，m)，1.45(3H，s)，0.94-0.89(6H， m). 13 C NMR(75MHz，CDCl 3 )δ:156.82，144.44，131.07，126.38，121.13，121.08，112.28，104.21，102.50， 88.02，81.22，67.86，66.82，61.96，52.63，44.52，37.42，36.52，34.56，30.95，26.28，24.64，24.53， 20.47，13.07.
TM8-16(E)-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:8.02(1H，s)，7.30-7.25(1H，m)，7.17(1H，s)，7.11(1H，d，J＝7.5Hz)， 6.92(1H，d，J＝8.1Hz)，5.48(1H，s)，4.90(1H，d，J＝3.0Hz)，4.19-4.11(3H，m)，3.97(3H，s)，3.83-3.73(1H， m)，2.66-2.61(1H，m)，2.43-2.32(1H，m)，2.06-1.17(12H，m)，1.45(3H，s)，0.94-0.89(6H，m). 13 C NMR (75MHz，CDCl 3 )δ:159.20，148.49，133.56，129.79，120.36，116.85，111.90，104.17，102.20，87.98， 81.22，67.49，66.54，62.12，52.61，44.50，37.50，36.50，34.68，30.97，26.28，24.78，24.48，20.43， 13.05.
TM8-17(E)-3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.99(1H，s)，7.23(1H，s)，6.98(1H，d，J＝8.1Hz)，6.87(1H，d，J＝ 8.1Hz)，5.49(1H，s)，4.88(1H，d，J＝3.0Hz)，4.23-4.11(3H，m)，3.96(3H，s)，3.89(3H，s)，3.85-3.78(1H， m)，2.66-2.61(1H，m)，2.42-2.32(1H，m)，2.05-1.17(10H，m)，1.44(3H，s)，0.93(3H，d，J＝6.0Hz)， 0.89(3H，d，J＝7.5Hz). 13 C NMR(75MHz，CDCl 3 )δ:150.18，149.88，148.52，125.35，121.53，112.77， 108.52，104.11，102.21，88.00，81.25，68.20，66.52，61.97，56.00，52.61，44.53，37.32，36.52，34.76， 30.95，26.28，24.79，24.46，20.46，12.99.
TM8-18(E)-4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.98(1H，s)，7.26(1H，s)，7.02(1H，d，J＝8.4Hz)，6.84(1H，d，J＝ 8.1Hz)，5.50(1H，s)，4.89(1H，d，J＝3.3Hz)，4.27-4.17(3H，m)，3.95(3H，s)，3.86(3H，s)，3.82-3.78(1H， m)，2.66-2.61(1H，m)，2.42-2.32(1H，m)，2.05-1.17(10H，m)，1.44(3H，s)，0.93(3H，d，J＝6.3Hz)， 0.90(3H，d，J＝7.5Hz). 13 C NMR(75MHz，CDCl 3 )δ:151.24，148.68，148.36，124.92，121.81，111.19， 110.19，104.01，102.12，87.90，81.18，68.20，66.54，61.86，55.91，52.53，44.47，37.23，36.44，34.67， 30.89，26.20，24.70，24.38，20.35，12.90.
Figure RE-GDA0002228756440000141
TM8-19 2-(((E)-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.62(1H，s)，7.73(1H，d，J＝8.7Hz)，7.34(1H，t，J＝6.9Hz)，6.94(1H，t，J＝7.5Hz)，6.88(1H，d，J＝8.4Hz)，5.29(1H，s)，4.82(1H，d，J＝3.3Hz)，4.75(2H，s)，4.17-4.05(3H， m)，3.57-3.48(1H，m)，2.63-2.58(1H，m)，2.38-2.28(1H，m)，2.10-1.11(12H，m)，1.44(3H，s)，0.87(3H， d，J＝7.5Hz)，0.83(3H，d，J＝6.0Hz). 13 C NMR(75MHz，CDCl 3 )δ:174.51，157.18，147.25，131.71， 127.00，120.82，120.03，111.81，104.30，101.95，87.86，81.11，70.44，65.07，64.29，52.48，44.39， 37.28，36.42，34.57，30.94，29.25，26.14，24.65，24.58，20.42，13.09.
TM8-20 2-(((E)-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.16(1H，s)，7.31-7.25(1H，m)，7.13-7.10(m)，6.95(1H，d，J＝7.8Hz)， 5.28(1H，s)，4.82(1H，d，J＝3.0Hz)，4.77(2H，s)，4.16-4.05(3H，m)，3.54-3.46(1H，m)，2.63-2.58(1H， m)，2.38-2.27(1H，m)，2.11-1.09(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.84-0.78(3H，m). 13 C NMR(75MHz，CDCl 3 )δ:174.73，159.30，150.62，132.78，129.84，120.47，117.16，112.22，104.19， 101.86，87.85，81.15，70.44，64.66，64.07，52.49，44.41，37.16，36.47，34.55，30.96，29.13，26.22， 24.61，20.42，13.10.HR MS calcd for C 27 H 37 NO 9 [M+Na] + 542.2366，found 542.2368.
TM8-21 2-(((E)-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.15(1H，s)，7.51(2H，d，J＝8.4Hz)，6.89(2H，d，J＝8.7Hz)，5.29(1H， s)，4.82(1H，d，J＝3.0Hz)，4.74(2H，s)，4.15-4.05(3H，m)，3.54-3.47(1H，m)，2.64-2.59(1H，m)，2.38-2.28(1H， m)，2.08-1.10(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.83-0.78(3H，m). 13 C NMR(75MHz， CDCl 3 )δ:175.24，160.89，150.44，129.01，124.00，114.74，104.21，101.92，87.87，81.14，70.31，64.74， 64.10，52.49，44.40，37.20，36.47，34.60，30.96，29.11，26.25，24.65，24.58，20.47，13.11.HR MS calcd for C 27 H 37 NO 9 [M+Na] + 542.2366，found 542.2368.
TM8-22 2-(((E)-(3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epo xy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.13(1H，s)，7.20(1H，s)，6.99(1H，d，J＝6.9Hz)，6.83(1H，d，J＝ 8.4Hz)，5.28(1H，s)，4.82(1H，d，J＝3.3Hz)，4.75(2H，s)，4.15-4.11(3H，m)，3.90(3H，s)，3.53-3.46(1H， m)，2.64-2.59(1H，m)，2.38-2.29(1H，m)，2.13-1.11(12H，m)，1.43(3H，s)，0.87(3H，d，J＝7.5Hz)， 0.83(3H，d，J＝5.7Hz). 13 C NMR(75MHz，CDCl 3 )δ:174.79，150.65，150.60，149.65，124.26，122.14， 111.88，108.39，104.12，101.89，87.87，81.12，70.33，65.70，64.18，56.01，52.47，44.40，37.23，36.48， 34.57，30.92，29.10，26.24，24.68，24.56，20.46，13.09.HR MS calcd for C 28 H 39 NO 10 [M+Na] + 572.2472， found 572.2473.
Figure RE-GDA0002228756440000151
TM8-23 2-(((E)-(4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epo xy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.12(1H，s)，7.18(1H，s)，7.02(1H，d，J＝8.1Hz)，6.84(1H，d，J＝ 8.1Hz)，5.26(1H，s)，4.82(1H，d，J＝2.7Hz)，4.74(2H，s)，4.16-4.11(3H，m)，3.89(3H，s)，3.53-3.48(1H， m)，2.69-2.50(1H，m)，2.37-2.28(1H，m)，2.12-1.13(12H，m)，1.43(3H，s)，0.87(3H，d，J＝7.2Hz)， 0.84-0.76(3H，m). 13 C NMR(75MHz，CDCl 3 )δ:174.64，151.55，150.56，148.80，124.15，122.22，110.92， 109.63，104.07，101.85，87.85，81.15，70.33，65.63，64.10，56.00，52.47，44.42，37.13，36.50，34.50， 30.94，29.08，26.26，24.68，24.61，20.44，13.09.R MS calcd for C 28 H 39 NO 10 [M+Na] + 572.2472，found 572.2474.
TM8-24 2-(((E)-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.59(1H，s)，7.76(1H，d，J＝7.5Hz)，7.35(1H，t，J＝7.2Hz)，6.98-6.90(2H， m)，5.42(1H，s)，4.90(1H，d，J＝3.0Hz,)，4.74(2H，s)，4.20-4.09(3H，m)，3.83-3.75(1H，m)，2.67-2.61(1H， m)，2.42-2.31(1H，m)，2.05-1.19(10H，m)，1.44(3H，s)，0.97-0.88(6H，m). 13 C NMR(75MHz，CDCl 3 ) δ:174.72，157.11，146.69，131.67，126.79，121.08，120.35，112.46，104.29，102.48，88.03，81.19， 70.41，67.98，66.87，52.58，44.46，37.43，36.47，34.53，30.91，26.16，24.66，24.51，20.41，13.03.
TM8-25 2-(((E)-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.17(1H，s)，7.31-7.26(1H，m)，7.15-7.10(2H，m)，6.94(1H，d，J＝ 8.1Hz)，5.48(1H，s)，4.91(1H，d，J＝3.0Hz)，4.77(2H，s)，4.19-4.11(3H，m)，3.83-3.76(1H，m)，2.66-2.61(1H， m)，2.42-2.32(1H，m)，2.11-1.17(10H，m)，1.45(3H，s)，0.93-0.89(6H，m). 13 C NMR(75MHz，CDCl 3 ) δ:174.88，159.17，150.60，132.73，129.84，120.71，117.37，112.21，104.25，102.15，88.01，81.23， 70.42，67.51，66.52，52.57，44.47，37.49，36.47，34.65，30.94，26.20，24.76，24.47，20.41，13.03.
TM8-26 2-(((E)-(3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-ep oxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.13(1H，s)，7.20(1H，s)，6.99(1H，d，J＝6.6Hz)，6.88-6.85(1H， m)，5.49(1H，s)，4.90(1H，d，J＝3.0Hz)，4.75(2H，s)，4.23-4.09(3H，m)，3.88(3H，s)，3.83-3.79(1H，m)，2.66-2.61(1H，m)，2.42-2.32(1H，m)，2.05-1.14(10H，m)，1.44(3H，s)，0.93(3H，d，J＝6.0Hz)， 0.89(3H，d，J＝7.2Hz). 13 C NMR(75MHz，CDCl 3 )δ:174.78，150.64，150.48，149.85，124.45，122.16， 112.64，108.72，104.18，102.19，88.03，81.27，70.34，68.17，66.48，56.03，52.60，44.52，37.32，36.51，34.75，30.94，26.23，24.78，24.46，20.46，12.98.
TM8-27 2-(((E)-(4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-ep oxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.12(1H，s)，7.23(1H，s)，7.03(1H，d，J＝8.4Hz)，6.84(1H，d，J＝ 8.4Hz)，5.50(1H，s)，4.89(1H，d，J＝3.0Hz)，4.74(2H，s)，4.25-4.09(3H，m)，3.87(3H，s)，3.82-3.78(1H， m)，2.64-2.61(1H，m)，2.42-2.32(1H，m)，2.05-1.17(10H，m)，1.44(3H，s)，0.97-0.88(6H，m). 13 C NMR (75MHz，CDCl 3 )δ:174.54，151.70，150.52，148.73，124.16，122.44，111.22，110.44，104.16，102.14， 88.01，81.28，70.34，68.27，66.50，55.99，52.59，44.53，37.30，36.50，34.73，30.95，26.21，24.77， 24.44，20.42，12.97.
TM8-28 2-(((E)-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dio xepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)amino)oxy)acetic acid
1 H NMR(300MHz，CDCl 3 )δ:8.16(1H，s)，7.51(2H，d，J＝8.4Hz)，6.89(2H，d，J＝8.7Hz)，5.47(1H， s)，4.90(1H，d，J＝3.3Hz)，4.74(2H，s)，4.18-4.09(3H，m)，3.81-3.77(1H，m)，2.66-2.61(1H，m)，2.42-2.32(1H， m)，2.05-1.19(12H，m)，1.45(3H，s)，0.94-0.88(6H，m). 13 C NMR(75MHz，CDCl 3 )δ:174.98，160.75， 150.41，129.00，124.12，114.90，104.26，102.23，88.03，81.22，70.32，67.49，66.50，52.59，44.46， 37.53，36.48，34.67，30.95，26.24，24.79，24.48，20.45，13.05.
Figure RE-GDA0002228756440000161
TM8-29(E)-1-(3-Methyl-2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy [1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone oxime
1 H NMR(300MHz，CDCl 3 )δ:7.33-7.26(2H，m)，6.97-6.88(2H，m)，5.43(1H，s)，4.82(1H，d，J＝ 3.3Hz)，4.14-4.02(3H，m)，3.53-3.47(1H，m)，2.63-2.58(1H，m)，2.40-2.29(1H，m)，2.25(3H，s)，2.18-1.06(12H， m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz,)，0.81(3H，d，J＝6.0Hz). 13 C NMR(151MHz，CDCl 3 )δ:156.91， 156.83，130.03，129.49，127.48，120.63，111.93，104.29，102.03，88.09，81.26，65.02，64.31，52.70， 44.59，37.19，36.61，34.72，31.06，29.48，26.29，24.70，24.66，20.35，15.45，13.10.
TM8-30(E)-1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone oxime
1 H NMR(300MHz，CDCl 3 )δ:7.31-7.20(3H，m)，6.92(1H，d，J＝8.7Hz)，5.29(1H，s)，4.82(1H， d，J＝3.3Hz)，4.17-4.06(3H，m)，3.55-3.48(1H，m)，2.64-2.59(1H，m)，2.38-2.28(4H，m)，2.10-1.10(12H， m)，1.44(3H，s)，0.88(3H，d，J＝7.5Hz)，0.81(3H，d，J＝4.8Hz). 13 C NMR(151MHz，CDCl 3 )δ:159.25， 155.96，138.06，129.55，118.70，115.55，112.34，104.17，102.02，87.94，81.19，64.84，64.33，52.68， 44.59，37.30，36.62，34.72，31.06，29.38，26.31，24.72，24.68，20.45，13.11，12.23.
TM8-31(E)-1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone oxime
1 H NMR(300MHz，CDCl 3 )δ:7.58(2H，d，J＝8.4Hz)，6.90(2H，d，J＝8.7Hz)，5.31(1H，s)，4.82(1H， d，J＝3.0Hz)，4.15-4.05(3H，m)，3.55-3.48(1H，m)，2.64-2.59(1H，m)，2.39-2.27(4H，m,)，2.10-1.11(12H， m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.82(3H，d，J＝5.7Hz). 13 C NMR(151MHz，CDCl 3 )δ:160.10， 155.61，129.18，127.49，114.52，104.20，102.06，87.96，81.18，64.89，64.38，52.69，44.58，37.33， 36.61，34.76，31.05，29.37，26.32，24.76，24.66，20.44，13.12，12.09.
TM8-32(E)-1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propan-1-one oxime
1 H NMR(300MHz，CDCl 3 )δ:7.57(2H，d，J＝8.4Hz)，6.90(2H，d，J＝8.7Hz)，5.32(1H，s)，4.82(1H， d，J＝3.3Hz)，4.15-4.05(3H，m)，3.56-3.49(1H，m)，2.80(2H，q，J＝7.5Hz)，2.63-2.59(1H，m)，2.39-2.29(1H， m)，2.10-1.09(12H，m)，1.44(3H，s)，1.18(3H，t，J＝7.5Hz)，0.89(3H，d，J＝7.2Hz)，0.83(3H，d，J ＝6.0Hz). 13 C NMR(151MHz，CDCl 3 )δ:159.57，159.09，127.03，126.74，113.61，103.21，101.09，86.99， 80.20，63.91，63.45，51.72，43.60，36.38，35.63，33.78，30.07，28.42，25.33，23.78，23.68，19.46， 18.59，12.14，10.17.
TM8-33(E)-4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-one oxime
1 H NMR(300MHz，CDCl 3 )δ:7.09(2H，d，J＝8.4Hz)，6.82(2H，d，J＝8.4Hz)，5.33(1H，s)，4.81(1H， d，J＝3.3Hz)，4.13-4.00(3H，m)，3.55-3.48(1H，m)，2.80-2.74(2H，m)，2.67-2.45(3H，m)，2.40-2.29(1H， m)，2.08-1.26(12H，m)，1.19(3H，s)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.84(3H，d，J＝6.0Hz). 13 C NMR(151MHz，CDCl 3 )δ:158.15，157.55，133.31，129.30，114.64，104.17，102.05，87.96，81.20，64.86，64.58，52.70，44.60，38.02，37.32，36.62，34.76，31.93，31.06，29.54，26.30，24.76，24.63，20.46， 13.75，13.11.
TM8-34(E)-1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone oxime
1 H NMR(300MHz，CDCl 3 )δ:7.35-7.31(2H，m)，6.99-6.90(2H，m)，5.44(1H，s)，4.87(1H，d，J＝ 3.3Hz)，4.23-4.10(3H，m)，3.79-3.74(1H，m)，2.67-2.62(1H，m)，2.42-2.32(1H，m)，2.25(3H，s)，2.06-1.17(10H， m)，1.45(3H，s)，0.93-0.89(6H，m). 13 C NMR(151MHz，CDCl 3 )δ:157.18，156.91，130.27，129.72，127.21， 120.95，112.20，104.28，102.59，88.14，81.24，67.81，67.15，52.75，44.61，37.49，36.61，34.75，31.01， 26.29，24.82，24.59，20.45，15.39，13.05.
Figure RE-GDA0002228756440000181
TM8-35(E)-1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dio xepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone oxime
1 H NMR(300MHz，CDCl 3 )δ:7.32-7.26(1H，m)，7.22-7.20(2H，m)，6.93(1H，d，J＝8.1Hz)，5.49(1H， s)，4.90(1H，d，J＝2.7Hz)，4.19-4.11(3H，m)，3.84-3.77(1H，m)，2.67-2.60(1H，m)，2.43-2.32(1H， m)，2.28(3H，s)，2.05-1.19(10H，m)，1.45(3H，s)，0.94-0.89(6H，m). 13 C NMR(151MHz，CDCl 3 )δ:159.16， 155.95，138.12，129.57，118.90，115.88，112.42，104.23，102.33，88.09，81.27，67.65，66.68，52.78， 44.66，37.60，36.63，34.82，31.06，26.31，24.87，24.57，20.45，15.37，13.06.
TM8-36(E)-1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone oxime
1 H NMR(300MHz，CDCl 3 )δ:7.58(2H，d，J＝8.7Hz)，6.90(2H，d，J＝9.0Hz)，5.48(1H，s)，4.90(1H， d，J＝3.3Hz)，4.18-4.11(3H，m)，3.84-3.75(1H，m)，2.67-2.62(1H，m)，2.43-2.32(1H，m)，2.28(3H， s)，2.06-1.21(10H，m)，1.45(3H，s)，0.94-0.89(6H，m). 13 C NMR(151MHz，CDCl 3 )δ:159.99，155.62， 129.38，127.50，114.72，104.24，102.36，88.09，81.25，67.62，66.65，52.77，44.64，37.59，36.62，34.82， 31.04，26.30，24.88，24.56，20.45，13.05，12.12.
TM8-37(E)-1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propan-1-one oxime
1 H NMR(300MHz，CDCl 3 )δ:7.57(2H，d，J＝8.7Hz)，6.90(2H，d，J＝8.7Hz)，5.48(1H，s)，4.90(1H， d，J＝3.3Hz)，4.21-4.11(3H，m)，3.82-3.77(1H，m)，2.80(2H，q，J＝7.5Hz)，2.67-2.62(1H，m)，2.43-2.32(1H，m)，2.06-1.23(10H，m)，1.45(3H，s)，1.20(3H，t，J＝7.5Hz)，0.94-0.89(6H，m). 13 C NMR(151MHz， CDCl 3 )δ:159.76，159.02，127.17，126.80，113.81，103.25，101.38，87.12，80.28，66.63，65.66，51.81， 43.67，36.63，35.65，33.84，30.07，25.33，23.90，23.60，19.47，18.56，12.08，10.15.
TM8-38(E)-4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-one oxime
1 H NMR(300MHz，CDCl 3 )δ:7.10(2H，d，J＝8.7Hz)，6.82(2H，d，J＝8.4Hz)，5.47(1H，s)，4.90(1H， d，J＝3.3Hz)，4.18-4.09(3H，m)，3.80-3.75(1H，m)，2.80-2.75(2H，m)，2.67-2.41(3H，m)，2.43-2.32(1H， m)，2.06-1.17(10H，m)，1.91(3H，s)，1.45(3H，s)，0.94-0.89(6H，m). 13 C NMR(151MHz，CDCl 3 )δ:158.13， 157.47，133.51，129.33，114.91，104.21，102.31，88.08，81.28，67.61，66.71，52.79，44.67，38.03， 37.57，36.64，34.85，31.91，31.06，26.31，24.88，24.57，20.46，13.77，13.07.
TM8-39(E)-1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.33-7.27(2H，m)，6.94(1H，t，J＝7.8Hz)，6.88(1H，d，J＝8.1Hz)， 5.34(1H，s)，4.80(1H，d，J＝3.3Hz)，4.11-4.01(3H，m)，3.98(3H，s)，3.58-3.47(1H，m)，2.65-2.60(1H， m)，2.40-2.30(1H，m)，2.19(3H，s)，2.10-1.46(10H，m)，1.43(3H，s)，1.24-1.17(2H，m)，0.91-0.87(6H， m). 13 C NMR(75MHz，CDCl 3 )δ:156.87，156.61，130.15，129.73，127.13，120.70，111.71，104.14，102.09， 87.89，81.14，65.00，64.66，61.77，52.60，44.45，37.41，36.51，34.66，30.99，29.53，26.28，24.69， 24.62，20.44，16.19，13.14.
TM8-40(E)-1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.29-7.21(3H，m)，6.90(1H，d，J＝7.5Hz)，5.30(1H，s)，4.82(1H， d，J＝3.3Hz)，4.15-4.12(1H，m)，4.08(2H，t，J＝6.0Hz)，3.99(3H，s)，3.55-3.48(1H，m)，2.64-2.59(1H， m)，2.38-2.28(1H，m)，2.21(3H，s)，2.10-1.23(12H)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.821(3H， d，J＝5.7Hz). 13 C NMR(75MHz，CDCl 3 )δ:159.08，154.42，138.09，129.42，118.63，115.09，112.21， 104.10，101.90，87.83，81.15，64.60，64.16，62.03，52.53，44.45，37.16，36.51，34.59，30.98，29.24， 26.32，24.61，20.46，13.12，12.72.
Figure RE-GDA0002228756440000191
TM8-41(E)-1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.58(2H，d，J＝8.7Hz)，6.88(2H，d，J＝8.7Hz)，5.31(1H，s)，4.81(1H， d，J＝3.3Hz)，4.12-4.05(3H，m)，3.97(3H，s)，3.56-3.45(1H，m)，2.64-2.59(1H，m)，2.39-2.29(1H， m)，2.20(3H，s)，2.10-1.11(12H，m)，1.44(3H，s)，0.88(3H，d，J＝7.2Hz)，0.82(3H，d，J＝8.7Hz). 13 C NMR(75MHz，CDCl 3 )δ:159.84，154.19，129.20，127.40，114.30，104.12，101.95，87.85，81.12，64.67， 64.24，61.84，52.55，44.44，37.20，36.49，34.63，30.97，29.22，26.28，24.66，24.57，20.42，13.10， 12.56.
TM8-42(E)-1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propan-1-one O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.58(2H，d，J＝8.7Hz)，6.88(2H，d，J＝8.7Hz)，5.33(1H，s)，4.81(1H， d，J＝3.3Hz)，4.14-4.11(1H，m)，4.07(2H，t，J＝6.0Hz)，3.96(3H，s)，3.55-3.47(1H，m)，2.71(2H， q，J＝7.5Hz)，2.64-2.58(1H，m)，2.40-2.29(1H，m)，2.10-1.23(12H)，1.44(3H，s)，1.13(3H，t，J＝7.5 Hz)，0.88(3H，d，J＝7.2Hz)，0.83(3H，d，J＝6.0Hz). 13 C NMR(75MHz，CDCl 3 )δ:159.79，159.29， 128.10，127.58，114.37，104.14，101.97，87.88，81.15，64.68，64.30，61.83，52.56，44.45，37.26，36.49， 34.64，30.98，29.26，26.30，24.67，24.58，20.45，20.01，13.13，11.40.
TM8-43(E)-4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-one O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.10(2H，d，J＝8.7Hz)，6.82(2H，d，J＝8.4Hz)，5.33(1H，s)，4.81， 4.13-4.06(1H，m)，4.02(2H，t，J＝6.0Hz)，3.84(3H，s)，3.55-3.48(1H，m)，2.78-2.71(2H，m)，2.64-2.55(1H， m)，2.47-2.42(2H，m)，2.40-2.29(1H，m)，2.08-1.12(12H，m)，1.85(3H，s)，1.44(3H，s)，0.88(3H，d， J＝7.5Hz)，0.84(3H，d，J＝6.0Hz). 13 C NMR(75MHz，CDCl 3 )δ:157.40，157.11，133.28，129.30，114.42， 104.10，101.93，87.87，81.15，64.61，64.39，61.24，52.55，44.46，38.14，37.19，36.50，34.64，32.17， 30.99，29.36，26.30，24.67，24.56，20.46，14.31，13.12.
TM8-44(E)-1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.34-7.29(2H，m)，6.95(1H，t，J＝7.5Hz)，6.89(1H，d，J＝8.1Hz)， 5.42(1H，s)，4.86(1H，d，J＝3.3Hz)，4.22-4.08(3H，m)，3.97(3H，s)，3.81-3.73(1H，m)，2.67-2.62(1H，m)，2.43-2.32(1H，m)，2.19(3H，s)，2.08-1.18(10H，m)，1,45(3H，s)，0.92(3H，d，J＝6.0Hz)，0.90(3H， d，J＝7.2Hz). 13 C NMR(75MHz，CDCl 3 )δ:156.84，156.63，130.22，129.82，127.18，120.95，111.89， 104.25，102.64，88.06，81.21，67.60，67.21，61.82，52.65，44.50，37.50，36.54，34.66，30.96，26.31，24.77，24.54，20.52，16.09，13.06.
TM8-45(E)-1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.30-7.20(3H，m)，6.90(1H，d，J＝7.8Hz)，5.49(1H，s)，4.91(1H， d，J＝3.3Hz)，4.19-4.15(3H，m)，4.00(3H，s)，3.83-3.75(1H，m)，2.67-2.62(1H，m)，2.43-2.32(1H， m)，2.21(3H，s)，2.08-1.17(10H，m)，1,45(3H，s)，0.93-0.90(6H，m). 13 C NMR(75MHz，CDCl 3 )δ:158.98， 154.49，138.09，129.46，118.81，115.49，112.20，104.15，102.17，87.98，81.23，67.48，66.53，62.02， 52.63，44.52，37.50，36.50，34.69，30.97，26.28，24.78，24.48，20.43，13.06，12.78.
TM8-46(E)-1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.58(2H，d，J＝8.7Hz)，6.88(2H，d，J＝8.7Hz)，5.48(1H，s)，4.90(1H， d，J＝3.3Hz)，4.18-4.12(3H，m)，3.98(3H，s)，3.81-3.77(1H，m)，2.67-2.59(1H，m)，2.43-2.32(1H， m)，2.20(3H，s)，2.08-1.17(10H，m)，1,45(3H，s),0.94-0.89(6H，m). 13 C NMR(75MHz，CDCl 3 )δ:159.77， 154.31，129.37，127.45，114.51，104.19，102.24，88.02，81.24，67.49，66.53，61.90，52.65，44.52， 37.53，36.52，34.70，30.98，26.31，24.81，24.49，20.47，13.07，12.67.
Figure RE-GDA0002228756440000211
TM8-47(E)-1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propan-1-one O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.57(2H，d，J＝8.7Hz)，6.88(2H，d，J＝9.0Hz)，5.48(1H，s)，4.90(1H， d，J＝3.3Hz)，4.20-4.10(3H，m)，3.96(3H，s)，3.85-3.77(1H，m)，2.72(2H，q，J＝7.5Hz)，2.67-2.55(1H， m)，2.43-2.32(1H，m)，2.06-1.21(10H，m)，1.45(3H，s)，1.12(3H，t，J＝7.5Hz)，0.94-0.89(6H，m). 13 C NMR(75MHz，CDCl 3 )δ:159.72，159.37，128.27，127.63，114.58，104.17，102.23，88.00，81.22，67.47， 66.51，61.83，52.65，44.52，37.52，36.52，34.70，30.97，26.28，24.80，24.49，20.45，20.03，13.05， 11.35.
TM8-48(E)-4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-one O-methyl oxime
1 H NMR(300MHz，CDCl 3 )δ:7.11(2H，d，J＝7.8Hz)，6.82(2H，d，J＝7.8Hz)，5.48(1H，s)，4.90(1H， d，J＝3.3Hz)，4.18-4.06(3H，m)，3.84(3H，s)，3.82-3.76(1H，m)，2.79-2.71(2H，m)，2.66-2.57(1H， m)，2.47-2.32(3H，m)，2.08-1.17(10H，m)，1.85(3H，s)，1.45(3H，s)，0.94-0.89(6H，m). 13 C NMR(75MHz， CDCl 3 )δ:157.33，157.18，133.48，129.34，114.68，104.17，102.20，88.00，81.25，67.46，66.61，61.26， 52.64，44.53，38.14，37.50，36.52，34.72，32.17，30.99，26.30，24.80，24.50，20.47，14.32，13.07. 13 C NMR151MHz，CDCl 3 δ:173.03，159.36，156.84，130.51，129.73，126.55，120.72，111.97，104.43， 102.21，87.97，81.16，70.38，65.14，64.88，52.65，44.55，37.40，36.53，34.72，31.00，29.54，26.11， 24.74，24.63，20.39，16.61，13.07.
TM8-49 2-(((E)-(1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.31(1H，td，J＝1.8and7.8Hz)，7.26(1H，dd，J＝1.8and7.8Hz)， 6.94(1H，td，J＝1.2and7.8Hz)，6.89(1H，d，J＝8.4Hz)，5.36(1H，s)，4.81(1H，d，J＝3.6Hz)，4.73(2H， s)，4.15-4.00(3H，m)，3.54-3.51(1H，m)，2.62-2.59(1H，m)，2.34(1H，td，J＝4.2and13.8Hz)，2.29(3H， s)，2.06-2.03(2H，m)，1.86-1.81(1H，m)，1.72-1.68(2H，m)，1.52-1.50(1H，m)，1.44(3H，s)，1.43-1.40(2H， m)，1.27-1.17(4H，m)，0.88-0.87(6H，m). 13 C NMR(151MHz，CDCl 3 )δ:173.03，159.36，156.84，130.51， 129.73，126.55，120.72，111.97，104.43，102.21，87.97，81.16，70.38，65.14，64.88，52.65，44.55， 37.40，36.53，34.72，31.00，29.54，26.11，24.74，24.63，20.39，16.61，13.07.
TM8-50 2-(((E)-(1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.28-7.25(1H，m)，7.21-7.18(2H，m)，6.93-6.91(1H，m)，5.30(1H， s)，4.81(1H，d，J＝3.0Hz)，4.77-4.06(3H，m)，3.57-3.50(1H，m)，2.64-2.60(1H，m)，2.35-2.28(4H， m)，2.10-1.98(2H，m)，1.83-1.76(1H，m)，1.71-1.64(2H，m)，1.49-1.45(1H，m)，1.43(3H，s)，1.42-1.24(4H， m)，0.88(3H，d，J＝7.2Hz)，0.81(3H，d，J＝6.0Hz). 13 C NMR(151MHz，CDCl 3 )δ:174.20，159.18， 157.04，137.34，129.51，118.92，115.70，112.67，104.20，101.98，87.94，81.18，70.49，64.85，64.33， 52.64，44.55，37.25，36.59，34.68，31.03，29.33，26.26，24.69，24.66，20.41，15.28，13.09.
TM8-51 2-(((E)-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.28-7.25(1H，m)，7.21-7.18(2H，m)，6.93-6.91(1H，m)，5.30(1H， s)，4.81(1H，d，J＝3.0Hz)，4.77-4.06(3H，m)，3.57-3.50(1H，m)，2.64-2.60(1H，m)，2.35-2.28(4H， m)，2.10-1.98(2H，m)，1.83-1.76(1H，m)，1.71-1.64(2H，m)，1.49-1.45(1H，m)，1.43(3H，s)，1.42-1.24(4H， m)，0.88(3H，d，J＝7.2Hz)，0.81(3H，d，J＝6.0Hz). 13 C NMR(151MHz，CDCl 3 )δ:173.89，160.41， 157.01，128.33，127.78，114.49，104.21，102.04，87.96，81.16，70.41，64.90，64.37，52.67，44.56， 37.32，36.59，34.73，31.03，29.33，26.27，24.74，24.64，20.40，14.32，13.10.
Figure RE-GDA0002228756440000221
Figure RE-GDA0002228756440000231
TM8-52 2-(((E)-(4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-ylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.58(2H，d，J＝8.4Hz)，6.89(2H，d，J＝9.0Hz)，5.30(1H，s)，4.81(1H，d，J＝3.0Hz)，4.74(2H，s)，4.15-4.06(3H，m)，3.53-3.48(1H，m)，2.63-2.60(1H，m)，2.33(1H，td，J＝ 4.2and13.8Hz)，2.29(3H，s)，2.08-1.99(2H，m)，1.82-1.78(1H，m)，1.71-1.65(2H，m)，1.50-1.46(1H， m)，1.43(3H，s)，1.42-1.33(2H，m)，1.30-1.26(4H，m)，0.88(3H，d，J＝7.2Hz)，0.82(3H，d，J＝6.0Hz). 13 C NMR(151MHz，CDCl 3 )δ:174.18，161.72，160.29，127.94，127.32，114.54，104.20，102.02，87.95， 81.16，70.42，64.87，64.39，52.66，44.54，37.32，36.57，34.72，31.02，29.33，26.24，24.72，24.62， 20.45，20.39，13.08，11.29.
TM8-53 2-(((E)-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.56(2H，d，J＝9.0Hz)，6.89(2H，d，J＝9.0Hz)，5.31(1H，s)，4.81(1H， d，J＝3.6Hz)，4.73(2H，s)，4.14-4.06(3H，m)，3.54-3.50(1H，m)，2.79(2H，q，J＝7.2Hz)，2.63-2.58(1H， m)，2.33(1H，td，J＝4.2and13.8Hz)，2.09-1.99(2H，m)，1.83-1.78(1H，m)，1.73-1.66(2H，m)，1.51-1.48(1H， m)，1.43(3H，s)，1.42-1.33(2H，m)，1.27-1.14(7H)，0.88(3H，d，J＝7.8Hz)，0.83(3H，d，J＝6.6Hz). 13 C NMR(151MHz，CDCl 3 )δ:173.97，160.03，157.55，133.06，129.32，114.62，104.18，102.01，87.96， 81.18，69.91，64.85，64.58，52.68，44.58，37.83，37.31，36.60，34.74，31.77，31.04，29.50，26.25， 24.74，24.61，20.45，14.82，13.09.
TM8-54 2-(((E)-(1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.08(2H，d，J＝9.0Hz)，6.82(2H，d，J＝8.4Hz)，5.34(1H，s)，4.81(1H， d，J＝3.6Hz)，4.59(2H，s)，4.10-4.07(1H，m)，4.02(2H，t，J＝6.6Hz)，3.54-3.50(1H，m)，2.80-2.75(2H， m)，2.67-2.46(3H，m)，2.34(1H，td，J＝4.2and14.4Hz)，2.04-2.02(2H，m)，1.93(3H，s)，1.83-1.77(1H， m)，1.74-1.70(2H，m)，1.52-1.49(2H，m)，1.43(3H，s)，1.42-1.36(2H，m)，1.30-1.15(4H，m)，0.88(3H， d，J＝7.8Hz)，0.85(3H，d，J＝6.6Hz). 13 C NMR(151MHz，CDCl 3 )δ:173.28，159.13，156.83，130.56， 129.85，126.67，121.02，112.50，104.38，102.56，88.09，81.22，70.37，68.02，67.10，52.66，44.52， 37.49，36.54，34.70，30.93，26.16，24.79，24.54，20.41，16.48，12.98.
TM8-55 2-(((E)-(1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.33(1H，td，J＝1.8and8.4Hz)，7.29(1H，dd，J＝1.8and7.2Hz)， 6.96(1H，td，J＝0.6and7.2Hz)，6.92(1H，d，J＝7.8Hz)，5.41(1H，s)，4.87(1H，d，J＝1.8Hz)，4.74(2H， s)，4.20-4.10(3H，m)，3.82-3.78(1H，m)，2.66-2.61(1H，m)，2.37(1H，td，J＝3.6and 14.4Hz)， 2.29(3H，s)，2.06-2.02(2H，m)，1.90-1.85(1H，m)，1.75-1.67(2H，m)，1.59-1.55(1H，m)，1.51-1.43(2H， m)，1.45(3H，s)，1.28-1.23(2H，m)，0.93(3H，d，J＝6Hz)，0.88(3H，d，J＝7.2Hz). 13 C NMR(151MHz， CDCl 3 )δ:174.09，159.04，156.84，137.42，129.48，119.10，116.03，112.62，104.22，102.23，88.04， 81.22，70.50，67.61，66.62，52.70，44.58，37.51，36.56，34.74，30.99，26.18，24.81，24.50，20.37， 13.18，12.99.
TM8-56 2-(((1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]diox epino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethyl)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.29-7.26(1H，m)，7.23-7.19(2H，m)，6.92(1H，dd，J＝1,8and8.4Hz)， 5.48(1H，s)，4.90(1H，d，J＝3.6Hz)，4.77(2H，s)，4.19-4.10(3H，m)，3.81-3.77(1H，m)，2.65-2.63(1H， m)，2.37(1H，td，J＝4.2and14.4)，2.30(3H，s)，2.05-2.02(2H，m)，1.89-1.85(1H，m)，1.77(1H，qd，J ＝3.6and14.4Hz)，1.71-1.67(1H，m)，1.57-1.54(1H，m)，1.52-1.40(2H，m)，1.44(3H，s)，1.27-1.23(2H， m)，0.92(3H，d，J＝6.0Hz)，0.90(3H，d，J＝7.2Hz). 13 C NMR(151MHz，CDCl 3 )δ:174.45，160.27， 156.93，128.54，127.79，114.66，104.25，102.30，88.09，81.23，70.39，67.61，66.61，52.74，44.60， 37.57，36.60，34.78，31.02，26.23，24.85，24.53，20.42，13.04，13.03.
TM8-57 2-(((E)-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.56(2H，d，J＝9.0Hz)，6.89(2H，d，J＝8.4Hz)，5.47(1H，s)，4.89(1H， d，J＝3.6Hz)，4.73(2H，s)，4.18-4.10(3H，m)，3.82-3.77(1H，m)，2.80(2H，q，J＝7.8Hz)，2.66-2.61(1H， m)，2.37(1H，td，J＝4.2and14.4Hz)，2.06-2.02(2H，m)，1.90-1.85(1H，m)，1.77(1H，qd，J＝4.2and13.8 Hz)，1.71-1.67(1H，m)，1.57-1.55(1H，m)，1.50-1.43(2H，m)，1.44(3H，s)，1.27-1.23(2H，m)，1.18(3H， t，J＝7.8Hz)，0.93(3H，d，J＝6.0Hz)，0.90(3H，d，J＝7.2Hz). 13 C NMR(151MHz，CDCl 3 )δ:173.80， 161.54，160.03，127.84，127.40，114.59，104.11，102.16，87.94，81.10，70.32，67.45，66.46，52.60， 44.47，37.43，36.45，34.64，30.88，26.09，24.71，24.40，20.34，15.13，12.88，11.12.
TM8-58 2-(((E)-(4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-ylidene)amino)oxy)acetic acid
1 H NMR(600MHz，CDCl 3 )δ:7.08(2H，d，J＝8.4Hz)，6.82(2H，d，J＝8.4Hz)，5.48(1H，s)，4.90(1H，d，J＝3.0Hz)，4.57(2H，s)，4.15-4.08(3H，m)，3.81-3.77(1H，m)，2.81-2.76(2H，m)，2.67-2.47(3H， m)，2.37(1H，td，J＝4.2and13.8Hz)，2.05-2.02(1H，m)，1.93(3H，s)，1.90-1.85(1H，m)，1.82-1.77(2H， m)，1.73-1.69(1H，m)，1.59-1.56(1H，m)，1.50-1.44(2H，m)，1.43(3H，s)，1.30-1.23(2H，m)，0.93(3H， d，J＝6.6Hz)，0.91(3H，d，J＝7.8Hz). 13 C NMR(151MHz，CDCl 3 )δ:160.54，159.84，157.26，133.11， 129.24，114.80，104.11，102.15，87.97，81.13，69.77，67.47，66.56，52.62，44.51，37.64，37.42，36.48， 34.68，31.59，30.91，26.09，24.72，24.41，20.30，14.66，12.91.
example 4 test of antitubercular Activity of TM8 target molecule
American Gift pharmaceutical (EliLillyand company) tested the anti-tuberculosis activity of the TM 8-1-TM 8-27 samples prepared in example 2 by first testing the percentage inhibition of Mycobacterium tuberculosis by a single concentration of sample; secondly, screening out high-activity molecules to carry out multi-concentration test; finally, various cells were tested. The test results are shown in table 2.
TABLE 2 partial TM8 series of target molecules against Mycobacterium tuberculosis H 37 Inhibition of Rv (antitubercular)
Figure RE-GDA0002228756440000251
As can be seen from Table 2, the screening results of the antituberculosis activity show that 7 of 27 compounds have more than 50% of target molecule activity at the test concentration of 20 μ M sample, and show moderate inhibition effect on mycobacterium tuberculosis; most importantly, the antituberculotic activity of the dihydroartemisinin is weak, when the dihydroartemisinin and the oxime phenol structure coexist, the antituberculotic activity of 12 molecules in 27 target compounds exceeds that of DHA, and the DHA oxime phenol derivative is found to have the antituberculotic activity for the first time and has the potential of further developing into medicaments.
Example 5 glucagon-like peptide-1 (GLP-1) Activity assay of TM8 target molecule
GLP-1 activity of the target molecule was tested by American Gift pharmacy. The study tested the results of GLP-1 secretion by the target molecule. The experimental procedure was as follows:
before the experiment, the culture medium of the human NCI-H716 cells was changed to a differentiation medium. On the day of the experiment, the cells were first washed 2 times with HBSS buffer containing BSA and DPP-IV inhibitor (final concentrations 0.1% and 1%, respectively) and then resuspended with this buffer (HBSS buffer containing BSA and DPP-IV inhibitor at final concentrations 0.1% and 1%, respectively). Next, cells were seeded at a density of 10000 cells/50. mu.L/well into poly-D-lysine-coated black-bottomed 384-well plates.
Preparing a compound to be tested: the test compound was initially at a concentration of 40 μ M and diluted down in a 3-fold gradient.
Compound dose-response curve determination: the above formulated compounds were added to 384-well plate wells that had been previously seeded with cells, and then incubated at 37 ℃ for 2 hours. Upon stimulation with the compound, the cells secrete GLP-1 into the culture medium. GLP-1 secreted by the cells was quantified using the AlphaLISAassay kit in 384 well plate format. The signal was collected using a full-function microplate reader Envision from Perkin Elmer. The amount of GLP-1 polypeptide synthesized by the cell is calculated by fitting the collected signal to a GLP-1 standard curve.
Calculation of percent relative agonism: relative percent agonism was determined by dividing the signal obtained at each data point for the remaining test compounds by the highest signal (Maximum response) for the standard compound, using as the standard the compound that stimulates the cell to secrete the most GLP-1. The calculation formulas of the excitation ratio (stimulation (%)) and the inhibition ratio (inhibition (%)) are as follows:
Figure RE-GDA0002228756440000261
where Max and Min are defined based on the highest signal and lowest signal for each experiment. IC (integrated circuit) 50 Or EC 50 Is calculated by fitting the calculated activation or inhibition ratio to a standard 4 parameter logistic and non-linear regression fitting equation. The results of the experiment are shown in tables 3 and 4.
TABLE 3 GLP-1 percent agonist Activity of a portion of TM8 target Compound
Figure RE-GDA0002228756440000262
Figure RE-GDA0002228756440000271
TABLE 4 EC for GLP-1 agonistic activity of the TM8 target compound in part 50 Value of
Figure RE-GDA0002228756440000272
As can be seen from Table 3, the GLP-1 agonistic activity of DHA on mSTC-1 was almost nil (-1.8%) at a sample concentration of 20. mu.M, but 5 targeting events were observedThe activity of the compound is more than 20 percent, and the GLP-1 agonistic activity of TM8-3 with the best activity reaches 70.8 percent. At the same time, R is found 3 is-CH 2 The target compound of COOH has better activity than other groups, and all four compounds of TM8-21, TM8-23, TM8-25 and TM8-26 contain-CH 2 COOH, and GLP-1 agonistic activity of more than 20%. Table 4 results show the EC of TM8-3 50 Values, which exhibit the strongest GLP-1 agonistic activity towards mSTC-1, have potential for further development as a drug.
Example 6 investigation of the hypolipidemic Activity of TM8
Proprotein convertase subtilisin/kexin type 9 (PCSK 9) is a lipid metabolism regulator protein found in 2003. A great deal of research shows that PCSK9 can mediate the degradation of low-density lipoprotein receptor and regulate the cholesterol level of plasma low-density lipoprotein. Therefore, therapeutic approaches to inhibit or reduce PCSK9 levels are effective in treating hypercholesterolemia and have been the focus of hypercholesterolemia research.
The American Gift pharmaceutical company tested PCSK9 inhibitory activity against part of TM8, and the PCSK9 inhibitory activity of the target molecule was measured at a sample concentration of 5. mu.M, and the results of the activity are shown in Table 5.
TABLE 5 results of inhibition Activity of PCSK9(Eff-2) for a TM8 target Compound
Figure RE-GDA0002228756440000281
Figure RE-GDA0002228756440000291
The results in Table 5 show that at 5. mu.M concentration, 8 of the 27 DHA-containing phenolic oxime derivatives (target molecules) had an inhibitory activity of more than 67% against Basal _ PCSK9HepG2, and among them, the inhibitory activity of TM8-10 and TM8-11 was more than 91%, showing strong inhibitory activity. Also at 5 μ M concentration, the Basal _ PCSK9HepG2 Cell Health values of the 27 target molecules tested were very low, showing little cytotoxicity.
As can be seen from Table 5, 4 compounds were tested for multiple rounds of activity, with better PCSK9 ELISA RPH SP inhibitory activity in the last round, and with the best inhibitory activity being TM8-12 at a sample concentration of 20. mu.M, with an average of 87.36%. These show the good potential application value of the molecules.
EXAMPLE 7 study of the inhibitory Activity of TM8 on interleukin IL-17
Interleukin-17 (IL-17) activity of compounds of TM8 was tested against the Open Innovation Drug Discovery (OIDD) program, the American Gift Inc. The results are shown in Table 6
TABLE 6 IL-17 Activity results for a TM8 partial target Compound
Figure RE-GDA0002228756440000292
Figure RE-GDA0002228756440000301
Table 6 the activity results show: the target molecules of TM8 series have excellent inhibitory effect on IL-17 at sample concentration of 10 μ M, and all the molecules have IL-17 secretion inhibitory activity of over 50% and low cytotoxicity (1: (<20%); tested molecules, IC's for IL-17 and IL-5 50 There is a difference (1-fold or even more than 10-fold) and low IC 50 <1 mu M; in addition, the tested molecules showed very low cytotoxicity (EC) against anti CD3/anti CD28/IL23_ PBMC 50 >30 μ M). In the second round of testing on HEK-293 cells, both tests differed in their results and IC 50 There are high and low, and the lowest reaches 0.04074 μ M. 5 target compounds enter the second round of test and show good application potential. The invention discovers for the first time that the conjugate of DHA and carboxyl-containing phenol/ester phenol/amido phenol has the bioactivity of inhibiting IL-17 and has the potential of being further developed into a medicament.
The undescribed parts of the present invention are the same as or practiced with the prior art.
The above disclosure is only for a few specific embodiments of the present invention, however, the present invention is not limited to the above embodiments, and any variations that can be made by those skilled in the art are intended to fall within the scope of the present invention.

Claims (9)

1. Dihydroartemisinin oxime-containing phenolic derivatives, and pharmaceutically acceptable salts thereof, characterized in that the dihydroartemisinin oxime-containing phenolic derivatives are represented by TM8 and have the following structural formula:
Figure FDA0003679544910000011
wherein n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 ，R 3 Is H, -CH 3 or-CH 2 CO 2 H, m is 0, 1 or 2.
2. The method for synthesizing dihydroartemisinin oxime-containing phenolic derivatives as claimed in claim 1, wherein the synthesis of TM8 is carried out according to the following reaction equation, comprising the following steps:
Figure FDA0003679544910000012
wherein n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 ，R 3 Is H, -CH 3 or-CH 2 CO 2 H, m is 0 or 2;
adding raw materials TM4 and R 3 O-NH 2 ·HCl、EtOH、Et 3 And N, stirring, reacting for 0.5-30 h, and after the reaction is finished, performing post-treatment to obtain the dihydroartemisinin oxime-containing phenol derivative, namely TM 8.
3. The method for synthesizing dihydroartemisinin oxime-containing phenolic derivatives as claimed in claim 2, wherein the starting materials TM4 and R 3 O-NH 2 The mass ratio of (A) to (B) is 1: 1-5, and the reaction temperature is 10-35 ℃.
4. A method for the synthesis of oxime-containing phenolic derivatives of dihydroartemisinin as claimed in claim 3, wherein the reaction temperature is 19-23 ℃.
5. The method for synthesizing dihydroartemisinin oxime-containing phenolic derivatives as claimed in claim 2, wherein the synthesis of TM4 is carried out according to the following reaction equation, comprising the following steps:
Figure FDA0003679544910000021
wherein n is 2 or 3, R 1 Is H or-OCH 3 ，R 2 Is H, -CH 3 or-CH 2 CH 3 M is 0 or 2;
adding raw materials containing carbonyl substituted phenol, IM1 and K 2 CO 3 And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 2-12.5 h, and after the reaction is finished, performing post-treatment to obtain the dihydroartemisinin and carbonyl-containing phenol conjugate, namely TM 4.
6. The synthesis method according to claim 5, wherein the mass ratio of the raw material IM1 to the raw material phenol is 1:1.2, and the reaction temperature is 40-85 ℃.
7. Use of a dihydroartemisinin oxime-containing phenolic derivative as claimed in claim 1 and its pharmaceutically acceptable salts for the preparation of antitubercular, antidiabetic, lipid lowering and interleukin-17 inhibiting medicaments.
8. The use of dihydroartemisinin oxime-containing phenolic derivatives as claimed in claim 7, wherein n-3, R in the formula of the derivatives 1 Is H, R 2 Is H, R 3 H, m is 0, n is 3, R 1 is-OCH 3 、R 2 Is H, R 3 H, m ═ 0, n ═ 2, R 1 Is H, R 2 Is H, R 3 H, m is 0, n is 2, R 1 is-OCH 3 、R 2 Is H, R 3 H, m is 0, n is 3, R 1 is-OCH 3 、R 2 Is H, R 3 is-CH 3 、m＝0，n＝2、R 1 is-OCH 3 、R 2 Is H, R 3 is-CH 3 And m is 0, in the preparation of antituberculosis drugs.
9. Use of a dihydroartemisinin oxime-containing phenol derivative according to claim 7, wherein n-3, R in the formula of said derivative 1 Is H, R 2 Is H, R 3 Is H or-CH 2 CO 2 H、m＝0，n＝3、R 1 is-OCH 3 、R 2 Is H, R 3 is-CH 2 CO 2 H. m is 0, and n is 2, R 1 Is H, R 2 Is H, R 3 is-CH 2 CO 2 H. The use of a compound wherein m is 0 for the manufacture of a medicament for treating diabetes;
n＝3、R 1 is H, R 2 Is H, R 3 is-CH 3 、m＝0，n＝2、R 1 Is H, R 2 Is H, R 3 is-CH 3 The application of the compound when m is 0 in preparing a lipid-lowering medicine;
n＝3、R 1 is H, R 2 Is H, R 3 H, m is 0, n is 2, R 1 Is H, R 2 Is H, R 3 H, m is 0, n is 3, R 1 Is H, R 2 Is H, R 3 is-CH 3 、m＝0，n＝2、R 1 Is H, R 2 Is H, R 3 is-CH 3 The application of the compound when m is 0 in preparing medicines for inhibiting interleukin-17.
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