CN116640125A - Xanthone and derivative, and preparation method and application thereof - Google Patents

Xanthone and derivative, and preparation method and application thereof Download PDF

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CN116640125A
CN116640125A CN202210137962.6A CN202210137962A CN116640125A CN 116640125 A CN116640125 A CN 116640125A CN 202210137962 A CN202210137962 A CN 202210137962A CN 116640125 A CN116640125 A CN 116640125A
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xanthone
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prodrug
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陈丽霞
李华
解慧茹
刘洋
郑梦竹
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Shenyang Pharmaceutical University
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Abstract

Xanthone and derivatives thereof, and a preparation method and application thereof belong to the technical field of medicines. Relates to a xanthone shown in a structural formula (I) or (II), or pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, a xanthone derivative which takes the xanthone shown in the structural formula (I) or (II) as a parent nucleus and is formed as a structural formula (IV) or (V), and a method for preparing the xanthone and the xanthone derivative. Also relates to the application of the xanthone and the xanthone derivative in preparing the medicine for treating and/or preventing diabetes, cancer and neurodegenerative diseases. In the structural formulas (I), (II), (IV) and (V), R 1 、R 2 、R 3 、E 3 And L is as described in the specification and claims.

Description

Xanthone and derivative, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, relates to xanthone and derivatives, and a preparation method and application thereof, and in particular relates to a compound and derivatives with antidiabetic activity, or pharmaceutically acceptable salts and solvates thereof, and a pharmaceutical composition containing the compound, wherein the parent nucleus is the xanthone and the derivatives. Also relates to a preparation method of the compound and application of the compound in preparing medicines for treating and/or preventing diabetes.
Background
Diabetes Mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia, caused by dysfunctions of insulin secretion and/or utilization due to multiple causes. Diabetes is a common and frequently occurring disease, and is a worldwide public health problem that seriously threatens human health. Diabetes is a clinical syndrome caused by a complex etiology of genetic and environmental factors, but its etiology and pathogenesis are not yet fully elucidated.
The double-substrate specific tyrosine phosphorylation regulating kinase A (DYRK 1A) belongs to the CMGC family, is positioned on a key region of chromosome 21, is regarded as a key target of Down syndrome, and is also a target of diseases such as neurodegenerative diseases, alzheimer disease, pancreatic cancer and the like. Wang P et al found that inhibition of DYRK1A protein promoted islet beta cell proliferation, and this finding correlated DYRK1A target with diabetes. DYRK1A affects islet beta cell proliferation by modulating important signaling pathways, and DYRK1A upregulation leads to nuclear NFAT phosphorylation, inOne step is phosphorylated by gsk3β and casein kinase and translocated into the cytosol; phosphorylation of p27kip, DREAM complex LIN52 results in cell cycle arrest; interaction with insulin receptor substrate 2 (IRS-2) promotes phosphorylation of insulin receptor substrate, resulting in degradation of IRS-2 proteasome, promoting beta cell apoptosis; upregulating IRS-1 protein expression, stabilizing IRS-1 by reducing IRS-1 ubiquitination; SMAD signals are inhibited, thereby reducing CDKN2B expression, resulting in a decrease in β cell number. Although it has been found that DYRK1A is inhibited by Ca 2+ The NFAT pathway and the tnfβ pathway cooperate to promote β cell proliferation, but small molecule inhibitors targeting DYRK1A to promote islet β cell proliferation are relatively few, and only harq, leucoetamine B, GNF4877, CC-401, OST167, etc. have been reported to promote islet β cell proliferation by inhibiting DYRK1A, but most of the studies on these small molecule inhibitors are still in preclinical research stage and have not entered clinical stage. Most of lead compounds for targeted inhibition of DYRK1A take the halmine as a parent nucleus to carry out subsequent structural optimization, and the toxic and side effects of the halmine parent nucleus and the non-specific selection of the halmine parent nucleus on kinase have not been well solved, so that the application prospect of the halmine parent nucleus is limited to a certain extent.
Proteolytic targeting chimeras (PROTAC) are a bifunctional small molecule in which a target protein ligand and an E3 ubiquitin ligase ligand are linked together by a linker arm to form a triplet compound. As a potential therapeutic approach, proteolytically targeted chimeras (PROTAC) are capable of degradation against specific proteins. Proteolytic targeting chimeras are a specific biofunctional molecule, typically a compound molecule that binds to a protein target, a recruiting E3 ubiquitin ligase ligand, and a linker. Induced by PROTAC, results in selective polyubiquitination of the protein of interest and subsequent degradation on the proteasome. Compared with the traditional small molecule inhibitors, PROTAC has various advantages, including acting without binding with the active site of target protein, degrading difficult-to-patent drug targets, having catalytic properties due to event-driven action, and acting at lower doses, thus having great potential in particular in the development of anticancer drugs.
Disclosure of Invention
The invention provides xanthone and a derivative thereof as well as a preparation method and application thereof, which are based on PROTAC technology to target and degrade a DYRK1A enzyme compound or pharmaceutically acceptable salt, hydrate or prodrug thereof as well as a preparation method and application thereof.
The primary object of the present invention is to provide a xanthone which is capable of directly inhibiting DYRK1A, or a compound which induces DYRK1A protein degradation, and also relates to a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug of the xanthone.
Meanwhile, a xanthone derivative formed by taking xanthone as a parent nucleus is provided.
Another object of the present invention is to provide a process for preparing the above xanthone and xanthone derivatives.
It is still another object of the present invention to provide the use of the above xanthone and xanthone derivatives for the preparation of a medicament for the treatment and/or prophylaxis of diabetes, cancer and neurodegenerative diseases.
The aim of the invention is achieved by the following technical scheme:
the structural formula of the xanthone is shown as (I) or (II):
the present invention provides xanthones of structural formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof:
wherein: r is R 1 、R 2 Independently represents hydrogen, deuterium, hydroxy, alkoxy, benzoyloxy, benzyloxy, p-toluenesulfonyloxy, methanesulfonyloxy, acetoxy, propynyloxy or one of the following structural formulae (III):
in the structural formula (III), T is selected from one of phenyl, piperazinyl, piperidinyl, heterocyclic groups and hydrocarbyl;
b is selected from one of O, S, C, H;
y is selected from one of-alkyl, -cycloalkyl, -Cl, -F, -H and Br;
R 1 more preferably:
R 3 one selected from H, D.
When R is 1 Or R is 2 In the case of formyloxy or benzoyloxy, xanthone having an ester group is formed; when R is 1 Or R is 2 The sulfonyl group and the p-toluenesulfonyloxy group are sulfonate, the formed xanthone with a sulfonic acid group forms a prodrug of xanthone, wherein the xanthone with an ester group and the xanthone with a sulfonic acid group form the xanthone, and the ester group or the sulfonic acid group can be hydrolyzed into a hydroxyl group in a body.
The structural formula of the xanthone derivative or the pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof is shown as (IV) or (V):
wherein R is 1 、R 2 、R 3 Determined from xanthone forming a xanthone derivative;
E 3 is one of CRBN, VHL, MDM, CIAP, UBR7, RNF114, CBLB and KEAP1 in the E3 ligase ligand. When E is 3 Is a ligand of CRBN ligase selected from thalidomide and derivatives thereof, lenalidomide and derivatives thereof, pomalidomide and derivatives thereof;
more preferably E 3 The structure is any one of the structures shown in the following structural formula (VI):
wherein: in the structural formula (VI), W is selected from CH 2 、C＝O、SO 2 One of NH, N-alkyl;
x is selected from one of O, S;
z is selected from one of-alkyl, -cycloalkyl, -Cl, -F and H;
G. g' is independently selected from the group consisting of-H, alkyl, -OH, -CH 2 -one of the heterocycles;
R 1 selected from the group consisting of-H, -D, -F, -Cl, -Br, -I, -NO 2 、-CN、-NH 2 、-OH、-CH 3 、-CH 2 F、-CHF 2 、-CF 3 、-CH 2 D、-CHD 2 、-CD 3 、-CH 2 CH 3 One of the following;
q is selected from CH 2 、C＝O、-NH-C＝O、-NH 2 -one of NHBoc;
m is selected from one of amide group, ester group, carboxyl group and acyl chloride;
a is selected from piperazinyl, piperidinyl, heterocyclic groups or one of the linking groups shown in the following structural formula (VII);
wherein: the heterocyclic group is one of piperazinonyl, pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
The structural formula of the structural formula (VII) is as follows, wherein n is an integer of 0 to 3:
l is a connecting arm selected from one of a fatty chain, an aromatic chain, an ether chain and an amide chain; xanthone and E by covalent bond 3 Are connected to form a multifunctional molecular compound; more preferably, the structure of L is any one of the structures shown in the structural formula (VIII):
wherein, m is more preferably 1-10, and more preferably 1-5.
The xanthone derivative of the present invention is preferably a xanthone derivative represented by the following structural formula (IX) or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof:
wherein: r is R 1 Selected from the group consisting of-H, -D, -F, -Cl, -Br, -I, -NO 2 、-CN、-NH 2 、-OH、-CH 3 、-CH 2 F、-CHF 2 、-CF 3 、-CH 2 D、-CHD 2 、-CD 3 、-CH 2 CH 3 One of the following; r is R 1 More preferably H;
a is selected from piperazinyl, piperidinyl, heterocyclic or one of the linking groups of formula (VII), more preferably piperazinyl;
q is selected from CH 2 、C＝O、-NH-C＝O、-NH 2 -one of NHBoc; more preferably Q is-NH 2 or-NHBoc;
m is selected from one of amide group, ester group, carboxyl group and acyl chloride, more preferably ester group or amide group, and more particularly-COOCH 3 ；
L is any one of the structural formulae (VIII);
the xanthone and the xanthone derivative of the present invention are further preferably a xanthone derivative represented by the structural formula (X) or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof:
the xanthone or xanthone derivative may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention includes all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemates, are included within the scope of the present invention.
The pharmaceutically acceptable salts of xanthone or xanthone derivatives include addition salts with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, pyruvic acid, succinic acid.
Prodrugs of xanthones of the present invention are derivatives of formula (IX) which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or otherwise) following administration.
A pharmaceutical composition comprising at least one of the following: the xanthone, the stereoisomer of the xanthone, the pharmaceutically acceptable salt of the xanthone, the hydrate of the xanthone, the prodrug of the xanthone, the xanthone derivative, the stereoisomer of the xanthone derivative, the pharmaceutically acceptable salt of the xanthone, the hydrate of the xanthone, the prodrug of the xanthone; also included are pharmaceutically acceptable carriers, diluents, adjuvants, vehicles, or combinations thereof.
Wherein, the dosage form of the pharmaceutical composition is any one of injection, tablet or capsule.
A process for preparing xanthone or a xanthone derivative comprising the steps of:
step 1: dissolving 2, 4-dihydroxybenzoic acid in Eton reagent, adding phloroglucinol, and reacting at 80deg.C for two hours to obtain the final productA compound 1; the structural formula is as follows:
step 2: dissolving the compound 1 in a certain amount of acetone, adding potassium carbonate or sodium hydride as alkali, reacting at room temperature or heating to 60 ℃ for 6 hours to overnight, and carrying out hydroxyl etherification protection to obtain a compound 2; the structural formula is as follows:
dissolving the compound 1 in tetrahydrofuran, adding triethylamine as alkali, adding various halogenated compounds under ice bath to obtain R with different groups 1 And R is 2 A compound of (a);
dissolving the compound 1 in tetrahydrofuran, sequentially adding a Ru catalyst, copper acetate, a silver derivative and deuterium oxide, heating to 110-115 ℃ and reacting for 24-36 h to obtain a compound 10; the structural formula is as follows:
step 3: dissolving the compound 2 and an azide-connected E3 ligand in a solvent, and connecting through a Click reaction to obtain a series of compounds 1-5; the method comprises the following steps of: one of the compounds X1-nP-Tha (n=1-5), the compounds X1-nCH2-VHL2 (n=1, 3,5, 7), the compounds X1-nCH2-B4 (n=1, 3,5, 7), the compounds X1-nP-B5 (n=1-5), the compounds X1-nP-MDM2 (n=1-5);
step 4: deprotection of a compound of series 4 in ethyl acetate solution of HCl gives a compound of series 6; series 6 compound X1-nP-B5 (T) (n=1-5), corresponding to the structural formula:
according to the preparation method, the solvent is one or two of acetone, dichloromethane, THF and water; the benzoic acid comprises: 2,4, 6-trihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2,5, 6-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 2, 3-trihydroxybenzoic acid.
The reaction route using 2,4, 6-trihydroxybenzoic acid as the starting material is as follows:
the invention carries out a molecular mechanism of DYRK1A protein and synthesized series compounds to inhibit DYRK1A or induce DYRK1A protein degradation; the antidiabetic activity and mechanism of action of the derivatives, and the improving effect on islet function and glycolipid metabolism of diabetic animals, were studied at the cellular level and at the animal level.
The xanthone and the xanthone derivative thereof or the pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof and the application of the pharmaceutical composition thereof in preparing medicaments for treating or preventing diabetes, cancer and neurodegenerative diseases.
The xanthone and the derivative as well as the preparation method and the application thereof have the beneficial effects that:
the xanthone and the xanthone derivative can promote islet beta cell proliferation by inhibiting DYRK1A enzyme, take the xanthone as a parent nucleus, form the xanthone derivative through connecting arm L and E3 ligase ligand, can target and degrade DYRK1A enzyme, and have wide application prospect in preparing medicines for treating and/or preventing diabetes, cancer and neurodegenerative diseases by researching. The compounds 1,4,7,9, 10 and X1-CH2-V2 provided by the method can also effectively inhibit DYRK1A enzyme and effectively promote islet beta cell proliferation. Can solve the problem of drug resistance of diabetes. The method provides a new treatment mode for treating diabetes mellitus, cancer and neurodegenerative diseases mediated by islet beta cells.
And it has been found that xanthone derivatives have more excellent activity (0.5.+ -. 0.1. Mu. Mol) against DYRK1A enzyme to promote islet beta cell proliferation, thereby providing useful value in the treatment and/or prevention of diabetes.
Drawings
Results of microphoresis analysis of the compounds of FIG. 1 with DYRK1A protein. In standard treated capillaries, affinity of 1 (panel a), X1-CH2-V2 (panel b), 2 (panel c), 4 (panel d) to DYRK1A protein was measured by MST, and Kd values were calculated from the binding curves;
FIG. 2PROTAC mediates degradation of DYRK1A protein in INS-1 cells;
the compounds of FIG. 3 promote proliferation and regeneration of INS-1 cells; in the figure, (a) percentage of proliferation of INS-1 cells in the treatment group at various concentrations. The proliferation rates of the compound at 37.5 and 75 μm were 22.94± 20.62% and 31.46±14.38%, respectively, which are higher than those of the control (-0.57±5.06%). (b) Insulin levels in the culture supernatant were significantly elevated after treatment with compounds at concentrations of 9.375 to 300 μm. (c) Representative images of the effect of compounds (37.5 and 75. Mu.M) on INS-1 cell proliferation were stained with EdU and DAPI (magnification 400×). (d) Percentage of edu+ -INS-1 cells after compound treatment (n=3). P <0.05, < P <0.01, < P <0.001, # P +.0.01).
The effect of the compounds of FIG. 4 on proliferation and regeneration of STZ-treated INS-1 cells; in the figure, (a) percentage of proliferation of INS-1 cells in the treatment group at various concentrations. (b) Representative images of the effect of compounds (37.5 and 75. Mu.M) on INS-1 cell proliferation were stained with EdU (green) and DAPI (blue) (magnification 400×). (c) Percentage of edu+ -INS-1 cells after compound treatment (n=3). P <0.05, < P <0.01, < P <0.001, # P +.0.01).
The compounds of FIG. 5 modulate NFATc1 nuclear localization, stimulate INS-1 cell proliferation, and are involved in calcineurin/NFAT/DYRK 1A signaling pathway; (a) Representative images (400×) of the effect of compound (37.5 and 75 μm) treatment on INS-1 cell NFATc1 nuclear localization. (b) Compound-treated cell proliferation-related factors (Ccnd 1, ccnd2, ccnd3, CDK 4) mRNA expression levels (< P <0.05, < P < 0.01) compared to control.
The effect of the compounds of FIG. 6 on blood glucose control in db/db mice; (a) Immunofluorescent counterstaining analysis of insulin and glucagon expression levels in pancreatic tissue. (b) Western blot detects the expression levels of FOXO1, PDX1 and insulin in pancreatic tissues. The compound induces the production of PDX1 and reduces the expression of FOXO 1. Protein levels were quantified using grey value analysis of Image J software.
The effect of the compounds of fig. 7 on diabetic mice body weight, food intake, blood glucose levels, serum insulin levels, oral glucose tolerance test and blood lipid levels; (a) The body weight of each administration group was steadily increased, and there was no significant difference between the groups. (b) mice food intake was measured weekly for 6 consecutive weeks. (c) measuring blood glucose concentration weekly for 6 consecutive weeks. (d) quantitatively determining blood insulin levels. (n=8). ## P<0.01, compared to the normal group; * P (P)<0.05，**P<0.01, compared to the diabetic group. Metformin (200 mg/kg) and Harmine (200 mg/kg) were used as positive controls. The low dose group (75 mg/kg) and the high dose group (150 mg/kg) of the compound were used as administration groups. (e) oral glucose tolerance test. (f) area under glucose curve (AUC).
Detailed Description
The foregoing of the invention is further elaborated by the following specific embodiments in the form of examples. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
EXAMPLE 1 preparation of xanthone Compound 1
2,4, 6-Trihydroxybenzoic acid (940 mg,5 mmol) was dissolved in methanesulfonic acid solution of phosphorus pentoxide (Eton's reagent 12 mL), phloroglucinol (940 mg,7.5 mmol) was added, and the mixture was refluxed at 80℃for 2 hours, and the solution became dark red. Cooling to room temperature, adding ice water, stirring for 2 hr, filtering to remove filtrate, oven drying at 60deg.C, redissolving methanol, and purifying by open silica gel column chromatography (dichloromethane: methanol=50:1 elution) to obtain xanthone compound 1 in 30% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.91(d,J＝5.2Hz,2H),11.08(s,2H),6.34(dd,J＝7.7,2.2Hz,2H),6.18(t,J＝2.7Hz,2H)。
EXAMPLE 2 preparation of xanthone Compound 2
1,3,6, 8-tetrahydroxyxanthone (Compound 1 104.8mg,0.4mmol) was dissolved in acetone (6 mL), and potassium carbonate K was added 2 CO 3 (82.8 mg,0.6 mmol) and after stirring for 20min bromopropyne (47.6 mg,0.4 mmol) were added, the mixture was warmed to 65℃under reflux for 12h, cooled to room temperature, the acetone was evaporated, ethyl Acetate (EA) was redissolved, extracted with saturated aqueous HCl, and purified by open silica gel column chromatography (petroleum ether: ethyl acetate=5:1 elution) to give xanthone compound 2 as a white solid in 70% yield.
1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,2H),11.84(s,1H),6.64(d,J＝2.3Hz,1H),6.42(d,J＝2.3Hz,1H),6.32(d,J＝2.1Hz,1H),6.16(d,J＝2.1Hz,1H),4.96(d,J＝2.4Hz,2H),3.70(t,J＝2.4Hz,1H)。
EXAMPLE 3 preparation of xanthone Compound 3
Specific operation and preparation of proportioning reference xanthone compound 2
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.18(s,1H),7.50–7.32(m,5H),6.69(d,J＝2.3Hz,1H),6.52–6.45(m,1H),6.36(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,1H),5.26(s,2H)。
EXAMPLE 4 preparation of xanthone Compound 4
1,3,6, 8-tetrahydroxyxanthone (Compound 1 19mg,0.073 mmol) was dissolved in anhydrous tetrahydrofuran (THF 2 mL), potassium carbonate triethylamine (TEA 7.4mg,0.073 mmol) was added, acetyl chloride (5.7 mg,0.073 mmol) was added dropwise with stirring in an ice bath, DMAP was added as a catalyst, the reaction was allowed to proceed for about 20min (TLC monitoring), tetrahydrofuran was evaporated, ethyl Acetate (EA) was redissolved, and the mixture was extracted with saturated aqueous HCl, and purified by open silica gel column chromatography (Petroleum ether: ethyl acetate=5:1 elution) to give xanthone Compound 4 as a white solid in a yield of 70%.
1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,1H),11.74(s,1H),11.29(s,1H),6.88(d,J＝2.0Hz,1H),6.64(d,J＝2.0Hz,1H),6.39(d,J＝2.1Hz,1H),6.24(d,J＝2.1Hz,1H),2.31(d,J＝3.3Hz,3H)。
EXAMPLE 5 preparation of xanthone Compound 5
Specific operations and preparation of proportioning reference xanthone Compound 4
1 H NMR(600MHz,DMSO-d 6 )δ12.10(s,1H),11.92(s,1H),11.76(s,1H),8.18–8.13(m,2H),7.78(t,J＝7.5Hz,1H),7.64(t,J＝7.8Hz,2H),7.07(d,J＝2.1Hz,1H),6.83(d,J＝2.1Hz,1H),6.39(d,J＝2.1Hz,1H),6.24(d,J＝2.1Hz,1H)。
EXAMPLE 6 preparation of xanthone Compound 6, xanthone Compound 7
Preparation of reference xanthone Compound 4 open silica gel column chromatography purification DCM
Xanthone compound 6: 1 H NMR(400MHz,DMSO-d 6 )δ11.92–11.81(m,2H),7.85(d,J＝8.1Hz,4H),7.51(d,J＝8.0Hz,4H),6.83(d,J＝2.2Hz,2H),6.53(d,J＝2.2Hz,2H),2.44(s,6H).
xanthone compound 7: 1 H NMR(600MHz,DMSO-d 6 )δ12.07(s,1H),11.65(s,1H),11.32(s,1H),7.87–7.82(m,2H),7.53–7.49(m,2H),6.78(d,J＝2.2Hz,1H),6.47(d,J＝2.2Hz,1H),6.39(d,J＝2.1Hz,1H),6.24(d,J＝2.1Hz,1H),2.43(s,3H)。
EXAMPLE 7 preparation of xanthone Compound 8 and xanthone Compound 9
Preparation of reference xanthone Compound 4 open silica gel column chromatography purification DCM
Xanthone compound 8: 1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,2H),7.12(d,J＝2.2Hz,2H),6.87(d,J＝2.2Hz,2H),3.54(s,6H).
xanthone compound 9: 1 H NMR(600MHz,DMSO-d 6 )δ12.14(s,1H),11.68(s,1H),11.36(s,1H),7.04(d,J＝2.2Hz,1H),6.80(d,J＝2.2Hz,1H),6.41(d,J＝2.1Hz,1H),6.26(d,J＝2.1Hz,1H),3.51(s,3H)。
EXAMPLE 8 preparation of xanthone Compound 10
1,3,6, 8-tetrahydroxyxanthone (Compound 1 20mg,0.076 mmol) was dissolved in anhydrous tetrahydrofuran (THF 2 mL), and [ RuCl ] was added sequentially 2 (p-cym)] 2 (2.3mg,0.0038mmol)、Cu(OAc) 2 (27.6mg,0.152mmol)、AgSbF 6 (10.4 mg,0.0304 mmol) and deuterium oxide (275 μl,15.2 mmol) were heated to 110deg.C and reacted for 24h, ethyl Acetate (EA) was diluted, filtered off with suction, the filtrate was extracted with EA/HCl saturated aqueous solution, and purified by open silica gel column chromatography (dichloromethane: methanol=50:1 elution) to give xanthone compound 10 as a pale yellow solid in 90% yield.
1 H NMR(600MHz,DMSO-d 6 )δ11.91(d,J＝3.3Hz,2H),11.08(s,2H),6.33(d,J＝1.5Hz,0.2H),6.18(d,J＝2.0Hz,0.2H).
Example 9 Synthesis of intermediate N3-nPEG-Tha (n=4)
58mg of thalidomide derivative (commercially available) was placed in a eggplant-shaped bottle, 3mL of DMF was added, 50mg of azido-PEG 4-amine (commercially available) and 47. Mu.L of DIPEA were added in sequence with stirring, the mixture was reacted at 90℃for 3 to 4 hours, 30mL of water and 30mL of ethyl acetate were added for extraction, the organic layer was dried over anhydrous sodium sulfate, and the concentrated solution was purified by silica gel column chromatography, and petroleum ether-ethyl acetate was eluted in a gradient of 1:2 to 1:4 to give a yellow oil with a yield of 60%.
1 H NMR(400MHz,CDCl3)δ8.81(br s,1H),7.48(dd,J＝8.0,7.2Hz,1H),7.09(d,J＝7.2Hz,1H),6.92(d,J＝8.8Hz,1H),6.49(t,J＝5.6Hz,1H),4.95–4.90(m,1H),3.72(t,J＝5.2Hz,2H),3.68–3.66(m,14H),3.48(q,J＝5.6Hz,2H),3.38(t,J＝5.0Hz,2H),2.88–2.72(m,3H),2.13–2.09(m,1H)；13C NMR(100MHz,CDCl3)δ171.6,169.4,168.8,167.8,146.9,136.1,132.6,116.9,111.7,110.3,70.8,70.74,70.71,70.7,70.65,70.62,70.1,69.6,50.8,48.9,42.5,31.5,22.9。
The first series of intermediates were prepared as in example 9
1 H NMR(600MHz,CDCl3)δ8.54(s,1H),7.49(dd,J＝8.2,7.4Hz,1H),7.10(d,J＝7.1Hz,1H),6.92(d,J＝8.5Hz,1H),6.50(t,J＝5.6Hz,1H),4.93(dd,J＝12.4,5.4Hz,1H),3.74(t,J＝5.4Hz,2H),3.71–3.66(m,6H),3.48(q,J＝5.5Hz,2H),3.38(t,J＝5.0Hz,2H),2.91–2.69(m,3H),2.11(ddd,J＝9.8,5.2,2.3Hz,1H).
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1 H NMR(600MHz,CDCl3)δ8.29(s,1H),7.49(dd,J＝8.5,7.1Hz,1H),7.10(d,J＝7.0Hz,1H),6.93(d,J＝8.5Hz,1H),4.92(dd,J＝12.4,5.3Hz,1H),3.73(t,J＝5.5Hz,2H),3.71–3.64(m,10H),3.48(t,J＝5.5Hz,2H),3.42–3.32(m,2H),2.95–2.66(m,3H),2.17–2.06(m,1H).
EXAMPLE 10 preparation of xanthone derivative X1-P-Tha (series 1, n=1)
Compound 2 (15 mg,0.050 mmol) was dissolved in tetrahydrofuran solution (2 mL), water (2 mL) was added, N3-nPEG-Tha (n=1) (21.4 mg,0.055 mmol), vcNa (29.7 mg,0.15 mmol), cuSO4 (10 mg,0.0625 mmol) were added separately, the reaction system was cloudy, the system was clarified soon, TLC was monitored for no work-up, ethyl acetate/HCl saturated aqueous solution extraction, and the organic layer was purified by open silica gel column chromatography (dichloromethane: methanol=30:1 elution) to give a yellow solid in 50% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),11.82(s,1H),11.15(s,1H),11.10(s,1H),8.23(s,1H),7.54(t,J＝7.8Hz,1H),7.06(d,J＝8.6Hz,1H),7.00(d,J＝7.1Hz,1H),6.69(d,J＝2.2Hz,1H),6.55(s,1H),6.45(d,J＝2.2Hz,1H),6.35(d,J＝2.1Hz,1H),6.20(d,J＝2.0Hz,1H),5.27(s,2H),5.04(dd,J＝12.9,5.4Hz,1H),4.58(t,J＝5.1Hz,2H),3.86(t,J＝5.1Hz,2H),3.60(t,J＝5.4Hz,2H),3.40(q,J＝5.9Hz,2H),2.88(ddd,J＝18.1,13.8,5.4Hz,1H),2.63–2.55(m,2H),1.99(s,1H). 13 C NMR(101MHz,DMSO-d 6 )δ182.68,173.24,170.53,169.38,167.71,166.46,165.55,162.49,162.20,157.71,157.41,146.75,142.07,136.62,132.50,125.89,117.79,111.14,109.67,102.03,101.07,98.99,98.44,94.79,94.17,69.31,69.10,62.34,60.23,49.93,49.02,31.44,22.60.
EXAMPLE 11 preparation of xanthone derivative X1-2P-Tha (series 1, n=2)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),11.82(s,1H),11.15(s,1H),11.09(s,1H),8.25(s,1H),7.51(dd,J＝8.6,7.1Hz,1H),7.05(d,J＝8.6Hz,1H),6.97(d,J＝7.0Hz,1H),6.68(d,J＝2.2Hz,1H),6.54(t,J＝5.8Hz,1H),6.44(d,J＝2.2Hz,1H),6.34(d,J＝2.1Hz,1H),6.20(d,J＝2.1Hz,1H),5.26(s,2H),5.04(dd,J＝12.7,5.4Hz,1H),4.55(t,J＝5.0Hz,2H),3.83(t,J＝5.1Hz,2H),3.59–3.52(m,6H),3.39(q,J＝5.7Hz,2H),2.88(ddd,J＝16.7,13.7,5.4Hz,1H),2.52(s,2H),2.03(ddt,J＝13.5,6.2,3.1Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ182.67,173.23,170.53,169.42,167.68,166.47,165.57,162.50,162.19,157.70,157.39,146.75,142.02,136.56,132.46,125.82,117.73,111.06,109.67,102.01,101.07,99.01,98.41,94.78,94.12,70.03,69.25,69.12,62.37,55.37,49.97,49.02,42.11,31.44,22.59.
EXAMPLE 12 preparation of xanthone derivative X1-3P-Tha (series 1, n=3)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),11.83(s,1H),11.15(s,1H),11.10(s,1H),8.25(s,1H),7.53(dd,J＝8.6,7.1Hz,1H),7.07(d,J＝8.6Hz,1H),6.99(d,J＝7.0Hz,1H),6.71(d,J＝2.3Hz,1H),6.55(t,J＝5.8Hz,1H),6.47(d,J＝2.2Hz,1H),6.35(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,1H),5.28(s,2H),5.04(dd,J＝12.7,5.4Hz,1H),4.55(t,J＝5.1Hz,2H),3.81(t,J＝5.1Hz,2H),3.59(t,J＝5.4Hz,2H),3.51(ddt,J＝15.8,5.9,3.6Hz,8H),3.42(d,J＝5.6Hz,2H),2.89(ddd,J＝17.3,13.5,5.3Hz,1H),2.63–2.52(m,2H),2.07–2.01(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ182.68,173.28,170.54,169.37,167.71,166.46,165.59,162.50,162.19,157.71,157.41,146.76,141.98,136.58,132.48,125.86,117.76,111.07,109.65,102.02,101.07,99.00,98.43,94.78,94.14,70.19,70.12,70.00,69.27,69.07,62.38,49.93,49.00,42.08,31.44,22.59.
EXAMPLE 13 preparation of xanthone derivative X1-4P-Tha (series 1, n=4)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),11.83(s,1H),11.38(s,1H),11.10(s,1H),8.25(s,1H),7.58–7.50(m,1H),7.09(d,J＝8.6Hz,1H),7.01(d,J＝7.1Hz,1H),6.71(d,J＝2.2Hz,1H),6.56(t,J＝5.8Hz,1H),6.47(d,J＝2.2Hz,1H),6.35(d,J＝2.1Hz,1H),6.20(d,J＝2.0Hz,1H),5.28(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),4.55(t,J＝5.1Hz,2H),3.82(t,J＝5.1Hz,2H),3.60(t,J＝5.4Hz,2H),3.55–3.39(m,16H),2.88(ddd,J＝17.6,14.0,5.4Hz,1H),2.63–2.51(m,2H),2.06–1.97(m,1H).
13 C NMR(101MHz,DMSO-d 6 )δ182.68,173.28,170.54,169.37,167.73,166.49,165.60,162.50,162.20,157.71,157.42,146.79,141.98,136.60,132.50,125.87,117.80,111.09,109.67,102.02,101.06,99.01,98.44,94.78,94.14,70.26,70.20,70.05,69.99,69.30,69.09,62.37,49.94,49.01,42.11,31.44,22.60.
EXAMPLE 14 preparation of xanthone derivative X1-5P-Tha (series 1, n=5)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),11.84(s,1H),11.16(s,1H),11.10(s,1H),8.25(s,1H),7.55(dd,J＝8.5,7.1Hz,1H),7.11(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.72(d,J＝2.3Hz,1H),6.58(t,J＝5.8Hz,1H),6.48(d,J＝2.2Hz,1H),6.36(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,1H),5.29(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),4.55(t,J＝5.1Hz,2H),3.82(t,J＝5.1Hz,2H),3.60(t,J＝5.4Hz,2H),3.57–3.49(m,6H),3.49–3.43(m,12H),2.95–2.82(m,1H),2.63–2.51(m,2H),2.06–1.99(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ182.70,173.28,170.54,169.38,167.74,166.47,165.61,162.51,162.21,157.73,157.43,146.82,141.98,136.63,132.52,125.88,117.84,111.10,109.67,102.03,101.09,99.01,98.45,94.79,94.16,70.27,70.21,70.04,69.98,69.31,69.09,62.37,49.93,49.01,42.13,31.44,22.60.
Example 15 preparation of intermediate N3-CH2-VHL2 (n=1)
50.3mg of azido-CH 2-carboxylic acid are placed in a eggplant-shaped bottle, 5mL of DCM is added, 159mg of EDCI, 112mg of HoBt, 289 mu L of DIPEA and 200mg of compound VHL2 hydrochloride are added in sequence under ice bath stirring, 30mL of water and 30mL of dichloromethane are added for extraction, an organic layer is dried with anhydrous sodium sulfate, a crude product is obtained after concentration, and an organic layer is purified by open silica gel column chromatography (dichloromethane: methanol=25:1 elution) to obtain a yellow solid with the yield of 60%.
1 H NMR(400MHz,CDCl3)δ8.70(s,1H),7.38(q,J＝8.5Hz,4H),7.02(d,J＝8.6Hz,1H),5.14–5.03(m,1H),4.73(t,J＝7.8Hz,1H),4.57(d,J＝8.7Hz,2H),3.63(dd,J＝11.3,3.7Hz,1H),2.60–2.50(m,4H),2.08(dd,J＝19.9,6.3Hz,1H),1.48(d,J＝6.9Hz,3H),1.06(s,8H).
The second series of intermediate preparation procedures was as in example 15
1 H NMR(400MHz,CDCl3)δ8.70(s,1H),7.46–7.33(m,5H),6.59(d,J＝8.9Hz,1H),5.15–5.04(m,1H),4.68(t,J＝7.9Hz,1H),4.60(d,J＝8.9Hz,1H),4.51(s,1H),4.02(d,J＝11.3Hz,1H),3.65(dd,J＝11.2,3.8Hz,1H),3.40–3.25(m,3H),2.52(s,3H),2.47–2.21(m,4H),2.06(dd,J＝9.0,2.6Hz,1H),1.89(dt,J＝12.6,6.7Hz,3H),1.48(d,J＝6.9Hz,3H),1.04(s,9H).
1 H NMR(400MHz,CDCl3)δ8.68(s,1H),7.36(q,J＝8.3Hz,4H),6.11(d,J＝8.8Hz,1H),4.72(t,J＝8.0Hz,1H),4.64–4.47(m,3H),4.33(dd,J＝14.9,5.1Hz,1H),3.60(dd,J＝11.4,3.5Hz,1H),3.26(t,J＝6.8Hz,2H),2.61–2.54(m,1H),2.53(d,J＝6.5Hz,3H),2.22(t,J＝7.5Hz,2H),2.14(d,J＝8.2Hz,1H),1.60(ddd,J＝22.1,15.0,7.4Hz,4H),1.44–1.33(m,2H),0.97–0.88(m,9H).
EXAMPLE 16 preparation of xanthone derivative X1-CH2-VHL2 (series 2, n=1)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.20(s,1H),8.99(s,1H),8.54(d,J＝9.1Hz,1H),8.45(d,J＝7.8Hz,1H),8.25(s,1H),7.48–7.33(m,4H),6.74(d,J＝2.3Hz,1H),6.49(d,J＝2.3Hz,1H),6.37(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,1H),5.35–5.23(m,4H),5.13(s,1H),4.94(p,J＝7.1Hz,1H),4.55–4.41(m,1H),4.28(s,1H),3.66–3.51(m,3H),2.46(s,3H),2.05(d,J＝10.3Hz,1H),1.79(ddd,J＝12.9,8.7,4.5Hz,1H),1.39(d,J＝7.0Hz,3H),0.97(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,171.00,169.36,166.50,165.64,162.52,162.23,157.74,157.45,151.95,148.22,145.10,141.81,131.58,130.17,129.30,127.19,126.85,102.05,101.08,99.02,98.45,94.80,94.16,69.24,62.29,59.11,57.43,56.92,51.84,48.19,38.18,35.99,26.81,22.90,16.45.
EXAMPLE 17 preparation of xanthone derivative X1-3CH2-VHL2 (series 2, n=3)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),8.99(s,1H),8.39(d,J＝7.8Hz,1H),8.30(s,1H),7.97(d,J＝9.2Hz,1H),7.47–7.35(m,4H),6.73(d,J＝2.3Hz,1H),6.49(d,J＝2.2Hz,1H),6.37(d,J＝2.1Hz,1H),6.21(d,J＝2.0Hz,1H),5.29(s,2H),5.13(s,1H),4.92(p,J＝6.8Hz,1H),4.52(d,J＝9.3Hz,1H),4.43–4.35(m,3H),4.29(s,1H),3.62(d,J＝3.3Hz,2H),2.46(s,3H),2.24(dh,J＝29.3,7.6Hz,2H),2.11–2.00(m,3H),1.80(ddd,J＝12.9,8.5,4.6Hz,1H),1.38(d,J＝7.0Hz,3H),1.23(d,J＝4.8Hz,1H),0.94(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,171.49,171.08,169.97,166.51,165.62,162.52,162.21,157.74,157.46,151.95,148.22,145.11,142.13,130.15,129.28,126.84,125.38,102.07,101.09,99.03,98.46,94.80,94.15,69.24,62.43,59.02,57.04,56.75,49.57,48.16,38.18,35.64,32.08,26.90,26.60,22.89,16.44.
EXAMPLE 18 preparation of xanthone derivative X1-5CH2-VHL2 (series 2, n=5)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.19(s,1H),8.98(s,1H),8.38(d,J＝7.8Hz,1H),8.29(s,1H),7.83(d,J＝9.3Hz,1H),7.45–7.36(m,4H),6.73(d,J＝2.3Hz,1H),6.48(d,J＝2.3Hz,1H),6.37(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,1H),5.28(s,2H),5.12(s,1H),4.92(p,J＝7.2Hz,1H),4.52(d,J＝9.4Hz,1H),4.42(t,J＝8.1Hz,1H),4.37(t,J＝7.1Hz,2H),4.28(s,1H),3.61(d,J＝3.4Hz,2H),2.51(p,J＝1.8Hz,3H),2.25(dt,J＝14.6,7.5Hz,1H),2.14(h,J＝7.4Hz,1H),2.06–2.00(m,1H),1.87–1.79(m,3H),1.52(tt,J＝14.0,6.8Hz,3H),1.37(d,J＝7.0Hz,3H),1.23(s,1H),0.92(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ182.72,172.33,171.08,170.05,166.50,165.63,162.52,162.21,157.74,157.45,151.94,148.21,145.11,142.04,130.15,129.28,126.84,125.30,102.05,101.09,99.02,98.46,94.79,94.16,69.23,62.43,59.01,56.82,56.74,49.81,48.15,38.20,35.64,35.07,29.90,26.90,25.96,25.24,22.89,16.44.
EXAMPLE 19 preparation of xanthone derivative X1-7CH2-VHL2 (series 2, n=7)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.85(s,1H),11.18(s,1H),8.99(s,1H),8.38(d,J＝7.8Hz,1H),8.29(s,1H),7.79(d,J＝9.3Hz,1H),7.47–7.30(m,4H),6.73(d,J＝2.2Hz,1H),6.48(d,J＝2.2Hz,1H),6.37(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,1H),5.28(s,2H),5.11(d,J＝3.5Hz,1H),4.98–4.86(m,1H),4.52(d,J＝9.3Hz,1H),4.45–4.34(m,3H),4.28(s,1H),3.61(d,J＝3.5Hz,2H),2.45(s,3H),2.24(dt,J＝14.7,7.6Hz,1H),2.16–2.07(m,1H),2.09–1.97(m,1H),1.79(qd,J＝8.4,7.8,4.9Hz,2H),1.46(dh,J＝13.9,7.2Hz,2H),1.37(d,J＝7.0Hz,3H),1.22(d,J＝8.7Hz,7H),0.93(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ182.72,172.50,171.09,170.07,166.48,165.62,162.52,162.21,157.74,157.45,151.99,145.11,130.16,129.28,125.33,102.05,101.10,99.03,98.48,94.80,94.18,69.22,62.43,59.00,56.80,56.72,49.88,48.16,38.19,35.65,35.27,30.13,28.91,28.54,26.90,26.20,25.75,22.88,16.44.
Example 20 preparation of intermediate N3-5CH2-B4 (n=5)
56.3mg of azido-5 CH 2-carboxylic acid in a eggplant-shaped bottle, 5mL of DCM was added, 214mg of EDCI, 150.7mg of HoBt, 309. Mu.L of TEA and 200mg of compound B4 hydrochloride were added sequentially under ice bath stirring, 30mL of water and 30mL of dichloromethane were added for extraction, the organic layer was dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by silica gel column chromatography, and the organic layer was purified by open silica gel column chromatography (dichloromethane: methanol=50:1 elution) to give an oil with a yield of 70%.
1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.6Hz,1H),7.27(dd,J＝8.1,6.1Hz,2H),7.21(t,J＝7.6Hz,3H),6.56(d,J＝8.1Hz,1H),4.57(td,J＝8.9,5.0Hz,1H),4.29–4.13(m,2H),3.72(s,2H),3.28(t,J＝6.8Hz,1H),3.22(t,J＝6.9Hz,2H),3.11(dd,J＝13.8,5.8Hz,1H),2.96(dd,J＝13.8,9.9Hz,1H),2.35(t,J＝7.4Hz,1H),2.12–2.01(m,2H),1.71–1.39(m,9H),1.31–1.21(m,3H),0.97–0.87(m,6H).
EXAMPLE 21 preparation of xanthone derivative X1-CH2-B4 (series 3, n=1)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.26(d,J＝8.9Hz,1H),8.06(s,1H),7.87(d,J＝8.5Hz,1H),7.32–7.17(m,5H),6.75(d,J＝2.3Hz,1H),6.50(d,J＝2.3Hz,1H),6.40–6.30(m,2H),6.20(dd,J＝10.8,2.1Hz,1H),5.29(s,2H),5.12(d,J＝16.3Hz,1H),4.99(d,J＝16.2Hz,1H),4.41–4.31(m,1H),4.24–4.18(m,1H),3.91(dd,J＝5.8,2.5Hz,1H),3.61(d,J＝2.3Hz,3H),2.86(dd,J＝13.3,7.4Hz,1H),2.66(dd,J＝13.3,7.4Hz,1H),2.00(q,J＝7.4Hz,1H),1.76–1.54(m,2H),0.91–0.80(m,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.74,173.16,172.15,166.50,165.65,165.13,162.53,162.23,157.76,157.47,141.84,138.87,129.64,128.76,126.78,126.71,102.07,101.10,99.03,98.47,94.80,94.18,71.01,62.29,54.19,52.40,51.98,50.12,37.31,24.62,23.25,21.63.
EXAMPLE 22 preparation of xanthone derivative X1-3CH2-B4 (series 3, n=3)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.92(d,J＝59.5Hz,2H),8.23(s,1H),7.85(d,J＝8.4Hz,1H),7.65(d,J＝8.8Hz,1H),7.32–7.12(m,6H),6.73(d,J＝2.2Hz,1H),6.48(d,J＝2.3Hz,1H),6.35(d,J＝2.1Hz,1H),6.19(d,J＝2.1Hz,2H),5.28(s,2H),4.39–4.31(m,1H),4.24(dt,J＝10.6,6.7Hz,3H),3.87(s,1H),3.60(s,3H),2.82(dd,J＝13.4,6.9Hz,1H),2.66(dd,J＝13.3,8.0Hz,1H),2.02(s,4H),1.53–1.32(m,2H),1.24(d,J＝7.4Hz,1H),0.86–0.72(m,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.67,173.18,172.42,171.05,165.61,162.52,162.22,157.77,157.47,142.07,139.25,129.67,128.61,126.54,125.37,102.07,101.02,99.09,98.46,94.85,94.17,71.66,70.25,62.40,53.62,52.37,50.04,49.41,37.36,32.37,26.45,24.48,23.24,21.58。
EXAMPLE 23 preparation of xanthone derivative X1-5CH2-B4 (series 3, n=5)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.84(s,1H),11.20(s,1H),8.28(s,1H),7.84(d,J＝8.5Hz,1H),7.52(dd,J＝8.8,3.4Hz,1H),7.32–7.14(m,5H),6.71(d,J＝2.3Hz,1H),6.46(d,J＝2.2Hz,1H),6.36(d,J＝2.1Hz,1H),6.27–6.18(m,2H),5.26(s,2H),4.35(q,J＝8.6,6.9Hz,3H),4.18(qd,J＝7.6,2.5Hz,1H),3.85(s,1H),3.61(s,3H),2.85–2.76(m,1H),2.64(dd,J＝13.3,7.7Hz,1H),2.11–1.89(m,2H),1.77(p,J＝7.3Hz,2H),1.59–1.38(m,5H),1.23(s,2H),0.81(dd,J＝20.2,6.2Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,173.20,172.47,172.04,166.51,165.61,162.52,162.21,157.73,157.44,142.05,139.25,129.65,128.62,126.54,125.27,102.04,101.07,99.02,98.44,94.79,94.13,71.61,62.41,53.64,52.38,50.07(d,J＝10.2Hz),49.76,37.30,35.34,29.96,25.85,25.04,24.48,23.29,21.63。
EXAMPLE 24 preparation of xanthone derivative X1-7CH2-B4 (series 3, n=7)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.84(s,1H),11.19(s,1H),8.29(s,1H),7.85(d,J＝8.5Hz,1H),7.48(d,J＝8.9Hz,1H),7.30–7.13(m,5H),6.71(d,J＝2.2Hz,1H),6.47(d,J＝2.3Hz,1H),6.36(d,J＝2.1Hz,1H),6.21(d,J＝2.1Hz,2H),5.28(s,2H),4.35(q,J＝10.1,8.4Hz,3H),4.18(qd,J＝7.7,2.4Hz,1H),3.86(d,J＝2.7Hz,1H),3.61(s,3H),2.81(dd,J＝13.3,7.1Hz,1H),2.66(dd,J＝13.3,7.7Hz,1H),1.99(qt,J＝14.5,7.6Hz,2H),1.79(p,J＝7.2Hz,2H),1.69–1.26(m,7H),1.23–1.16(m,4H),0.82(dd,J＝21.6,6.3Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.68,173.20,172.48,172.21,166.58,165.60,162.51,162.20,157.73,157.43,142.06,139.24,129.63,128.59,126.51,125.29,102.03,101.04,99.04,98.46,94.80,94.15,71.69,62.42,53.63,52.37,50.03,49.88,37.28,35.59,30.15,28.88,28.67,26.19,25.54,24.49,23.29,21.65。
Example 25 preparation of intermediate N3-2P-B5 (n=2)
In a eggplant-shaped bottle, 5mL of DCM is added, 188mg of EDCI, 132mg of HoBt, 272 mu L of TEA and 94 mu L of azido-2 PEG-NH2 are sequentially added under ice bath stirring, 30mL of water and 30mL of dichloromethane are added for extraction, an organic layer is dried by anhydrous sodium sulfate, a crude product is obtained after concentration, and the organic layer is purified by open silica gel column chromatography (dichloromethane: methanol=50:1 elution) to obtain oily matter with the yield of 70%.
1 H NMR(400MHz,CDCl 3 )δ7.33–7.27(m,2H),7.23(d,J＝7.5Hz,3H),6.57(s,1H),5.01(d,J＝8.0Hz,1H),4.45(d,J＝4.7Hz,1H),4.13(s,1H),3.98(s,1H),3.67–3.60(m,2H),3.59–3.52(m,2H),3.37(dd,J＝21.2,16.4Hz,3H),3.18(d,J＝13.9Hz,1H),3.03(s,1H),1.43–1.33(m,8H),0.95–0.86(m,6H).
Other intermediates are fed and operated as above
1 H NMR(400MHz,CDCl 3 )δ7.32–7.27(m,2H),7.25–7.19(m,3H),6.67(s,1H),5.58(s,1H),5.04(d,J＝8.2Hz,1H),4.45(dd,J＝11.6,6.5Hz,1H),4.09(dd,J＝26.7,24.2Hz,2H),3.71–3.58(m,7H),3.55(dd,J＝9.4,5.0Hz,2H),3.51–3.43(m,2H),3.39(dd,J＝11.6,6.6Hz,3H),3.07(d,J＝40.9Hz,2H),1.62(dt,J＝15.9,10.2Hz,3H),1.38(s,9H),0.91(dd,J＝12.5,6.1Hz,6H).
1 H NMR(400MHz,CDCl 3 )δ7.31–7.26(m,2H),7.22(dd,J＝8.6,4.5Hz,3H),6.88(s,1H),5.04(s,1H),4.48(s,1H),4.13(s,2H),3.70–3.50(m,16H),3.40(dd,J＝18.6,13.7Hz,4H),3.02(d,J＝16.1Hz,2H),1.71(dd,J＝11.1,6.4Hz,2H),1.64–1.51(m,2H),1.38(d,J＝11.6Hz,8H),0.92(dd,J＝11.3,6.2Hz,6H)。
EXAMPLE 26 preparation of xanthone derivative X1-P-B5 (series 4, n=1)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.84(s,1H),11.18(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.61(d,J＝9.0Hz,1H),7.21(ddt,J＝18.3,14.1,7.2Hz,5H),6.71(d,J＝2.3Hz,1H),6.47(d,J＝2.2Hz,1H),6.36(d,J＝2.2Hz,1H),6.23–6.15(m,2H),5.99(s,1H),5.28(s,2H),4.55(t,J＝5.1Hz,2H),4.34(td,J＝9.2,5.2Hz,1H),3.96(ddt,J＝12.4,8.5,4.3Hz,1H),3.81(q,J＝5.2,4.4Hz,3H),3.42(t,J＝5.9Hz,2H),3.18(q,J＝5.8Hz,2H),2.78(s,1H),2.67(dd,J＝13.3,7.7Hz,1H),1.60–1.49(m,2H),1.28(s,9H),1.22(s,1H),0.83(dd,J＝16.0,6.4Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.69,172.32,172.02,166.52,165.61,162.51,162.21,157.72,157.43,155.33,142.05,139.18,129.68,128.58,126.46,125.86,102.02,101.05,99.02,98.42,94.79,94.13,78.03,71.88,69.11,68.89,62.34,54.93,50.75,49.88,42.06,38.83,38.04,28.56,24.43,23.59,22.14。
EXAMPLE 27 preparation of xanthone derivative X1-2P-B5 (series 4, n=2)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.84(s,1H),11.17(s,1H),8.25(s,1H),8.14–8.03(m,1H),7.60(d,J＝9.0Hz,1H),7.31–7.13(m,5H),6.72(d,J＝2.3Hz,1H),6.48(d,J＝2.3Hz,1H),6.36(d,J＝2.1Hz,1H),6.23–6.14(m,2H),5.98(d,J＝6.1Hz,1H),5.29(s,2H),4.55(t,J＝5.2Hz,2H),4.35(td,J＝9.0,5.1Hz,1H),4.00–3.85(m,1H),3.83(q,J＝6.8,5.1Hz,3H),3.51(dd,J＝6.1,3.5Hz,2H),3.45(dd,J＝6.1,3.6Hz,2H),3.36(s,2H),3.18(q,J＝5.9Hz,2H),2.78(dd,J＝13.3,7.2Hz,1H),2.66(dd,J＝13.3,7.7Hz,1H),1.58–1.49(m,2H),1.28(s,9H),1.15(s,1H),0.83(dd,J＝15.2,6.4Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,172.28,171.96,166.50,165.62,162.51,162.21,157.73,157.43,155.33,142.01,139.18,129.68,128.59,126.47,125.86,102.03,101.07,99.01,98.45,94.79,94.15,78.03,71.86,69.91,69.85,69.30,69.11,62.36,54.94,50.74,49.92,42.13,38.99,38.03,28.57,24.42,23.59,22.16。
EXAMPLE 28 preparation of xanthone derivative X1-3P-B5 (series 4, n=3)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.84(s,1H),11.18(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.60(d,J＝9.0Hz,1H),7.31–7.14(m,5H),6.71(d,J＝2.3Hz,1H),6.47(d,J＝2.2Hz,1H),6.36(d,J＝2.1Hz,1H),6.23–6.14(m,2H),5.99(s,1H),5.29(s,2H),4.56(t,J＝5.2Hz,2H),4.35(td,J＝9.1,5.2Hz,1H),3.95(dtd,J＝10.0,7.5,2.5Hz,1H),3.86–3.79(m,3H),3.52(dd,J＝6.1,3.5Hz,2H),3.46(d,J＝6.7Hz,4H),3.37(t,J＝5.9Hz,4H),3.18(q,J＝6.0Hz,2H),2.79(dd,J＝13.2,7.2Hz,1H),2.67(dd,J＝13.3,7.7Hz,1H),1.59–1.46(m,2H),1.28(s,9H),1.15(d,J＝3.3Hz,1H),0.83(dd,J＝15.2,6.4Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.69,172.28,171.95,166.52,165.60,162.51,162.21,157.72,157.42,155.33,142.00,139.18,129.76(d,J＝16.5Hz),128.59,126.47,125.85,102.02,101.05,99.02,98.44,94.79,94.13,78.03,71.85,70.23–69.86(m),69.30,69.11,62.36,54.94,50.73,49.93,42.17,39.01,38.03,28.57,24.42,23.59,22.18。
EXAMPLE 29 preparation of xanthone derivative X1-4P-B5 (series 4, n=4)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.95(s,1H),11.84(s,1H),11.17(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.60(d,J＝9.0Hz,1H),7.28–7.17(m,5H),6.73(d,J＝2.2Hz,1H),6.48(d,J＝2.3Hz,1H),6.36(d,J＝2.1Hz,1H),6.24–6.15(m,2H),5.98(s,1H),5.29(s,2H),4.56(t,J＝5.1Hz,2H),4.34(td,J＝9.1,5.2Hz,1H),4.00–3.90(m,1H),3.86–3.79(m,3H),3.52(dd,J＝6.0,3.4Hz,2H),3.46(s,6H),3.41–3.33(m,6H),3.18(d,J＝4.9Hz,2H),2.78(dd,J＝13.3,7.2Hz,1H),2.66(dd,J＝13.3,7.7Hz,1H),1.57–1.46(m,2H),1.28(s,9H),1.15(s,1H),0.83(dd,J＝15.4,6.4Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,172.27,171.94,166.50,165.61,162.52,162.22,157.73,157.44,155.33,141.99,139.19,129.68,128.59,126.47,125.87,102.04,101.08,99.02,98.46,94.79,94.16,78.03,71.85,70.23–69.97(m),69.30,69.10,62.37,54.93,50.73,49.93,42.19,39.01,38.03,28.57,24.43,23.59,22.19。
EXAMPLE 30 preparation of xanthone derivative X1-5P-B5 (series 4, n=5)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.19(s,1H),8.26(s,1H),8.15–8.04(m,1H),7.60(d,J＝9.0Hz,1H),7.33–7.16(m,5H),6.73(d,J＝2.3Hz,1H),6.48(d,J＝2.2Hz,1H),6.37(d,J＝2.1Hz,1H),6.24–6.15(m,2H),5.99(s,1H),5.29(s,2H),4.56(t,J＝5.1Hz,2H),4.34(td,J＝9.0,5.3Hz,1H),4.00–3.93(m,1H),3.83(p,J＝4.9,3.9Hz,3H),3.52(dd,J＝6.1,3.5Hz,2H),3.48(s,6H),3.37(dd,J＝11.3,5.2Hz,8H),3.18(d,J＝5.8Hz,4H),2.78(dd,J＝13.3,7.2Hz,1H),2.66(dd,J＝13.3,7.7Hz,1H),1.56–1.44(m,2H),1.28(s,9H),1.15(s,1H),0.83(dd,J＝15.7,6.4Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,172.27,171.94,166.53,165.62,162.52,162.22,157.74,157.45,155.33,141.99,139.19,129.68,128.59,126.47,125.87,102.04,101.07,99.03,98.47,94.80,94.17,78.03,71.85,70.18(d,J＝4.3Hz),70.05,70.00,69.30,69.10,62.38,54.94,50.73,49.93,42.20,39.02,38.03,28.58,24.43,23.60,22.20。
Example 31 preparation of intermediate N3-2P-MDM2 (n=2)
200mg of MDM2 is added into a eggplant-shaped bottle, 5mL of DCM is added, 118.9mg of EDCI, 83.8mg of HoBt, 216 mu L of DIPEA and 59.2mg of azido-2 PEG-NH2 are sequentially added under ice bath stirring, 30mL of water and 30mL of dichloromethane are added for extraction, an organic layer is dried by anhydrous sodium sulfate, a crude product is obtained after concentration, and an organic layer is purified by open silica gel column chromatography (dichloromethane: methanol=25:1 elution) to obtain a white solid with the yield of 70%.
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.5Hz,1H),7.03(d,J＝7.6Hz,4H),6.86(dd,J＝11.8,8.4Hz,4H),6.51(dd,J＝8.5,2.2Hz,1H),6.45(d,J＝2.1Hz,1H),6.27(t,J＝5.4Hz,1H),5.59(d,J＝9.9Hz,1H),5.45(d,J＝9.9Hz,1H),4.59(dt,J＝12.0,6.0Hz,1H),3.94–3.78(m,5H),3.75–3.68(m,2H),3.68–3.59(m,2H),3.57–3.39(m,6H),3.38–3.32(m,2H),3.31–3.22(m,1H),3.10(t,J＝5.2Hz,2H),1.37(dd,J＝16.5,6.0Hz,6H).
Other intermediates are fed simultaneously
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.5Hz,1H),7.06(dd,J＝20.9,8.5Hz,4H),6.91(dd,J＝26.3,8.4Hz,4H),6.55(dd,J＝8.5,2.2Hz,1H),6.51–6.40(m,2H),5.57(d,J＝9.7Hz,1H),5.48(d,J＝9.7Hz,1H),4.62(dt,J＝12.1,6.0Hz,1H),3.97–3.79(m,5H),3.78–3.57(m,9H),3.57–3.46(m,3H),3.41(dt,J＝10.1,4.4Hz,4H),3.32–3.19(m,1H),3.11(t,J＝5.2Hz,2H),1.36(dd,J＝14.8,6.0Hz,6H).
1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝8.5Hz,1H),7.10(d,J＝8.5Hz,2H),7.04(d,J＝8.6Hz,2H),6.95(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.56(dd,J＝8.5,2.2Hz,1H),6.48(d,J＝2.1Hz,1H),5.61(s,2H),4.69–4.52(m,1H),3.94(d,J＝15.7Hz,1H),3.86(s,3H),3.85–3.75(m,2H),3.68–3.57(m,16H),3.51(dd,J＝12.7,7.7Hz,5H),3.43–3.34(m,4H),3.29(dd,J＝13.1,6.2Hz,1H),3.13(s,2H),1.37(dd,J＝16.9,6.0Hz,6H)。
EXAMPLE 32 preparation of xanthone derivative X1-P-MDM2 (series 5, n=1)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.25(s,1H),7.93(t,J＝5.8Hz,1H),7.55(s,1H),7.13(dd,J＝13.5,7.9Hz,4H),7.04(s,2H),6.97(d,J＝8.0Hz,2H),6.73(s,1H),6.60(d,J＝7.3Hz,2H),6.49(d,J＝2.1Hz,1H),6.37(d,J＝2.1Hz,1H),6.22(d,J＝2.1Hz,1H),5.66(s,1H),5.29(s,1H),4.76–4.68(m,1H),4.54(t,J＝5.2Hz,2H),3.90–3.50(m,11H),3.40(t,J＝5.7Hz,3H),3.17(q,J＝6.1Hz,3H),2.99(d,J＝5.7Hz,2H),1.29–1.15(m,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.73,167.81,166.49,165.63,164.84,162.88,162.53,162.23,157.76,157.46,131.76,131.61,130.10,129.21,127.92,105.48,102.07,101.11,99.79,99.03,98.46,94.80,94.17,70.34,69.09,68.84,62.38,55.90,49.88,49.45,49.02,46.94,42.48,38.77,22.19,22.11。
EXAMPLE 33 preparation of xanthone derivative X1-2P-MDM2 (series 5, n=2)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.25(s,1H),7.94(t,J＝5.6Hz,1H),7.54(s,1H),7.13(dd,J＝14.5,8.1Hz,4H),7.05(s,2H),6.97(d,J＝8.1Hz,2H),6.73(d,J＝2.2Hz,1H),6.60(d,J＝6.9Hz,2H),6.49(d,J＝2.2Hz,1H),6.37(d,J＝2.1Hz,1H),6.22(d,J＝2.1Hz,1H),5.65(s,1H),5.29(s,1H),4.75–4.68(m,1H),4.55(t,J＝5.1Hz,2H),3.88–3.55(m,11H),3.48(ddd,J＝25.3,6.6,4.0Hz,6H),3.16(q,J＝6.0Hz,4H),2.99(s,2H),1.29–1.13(m,6H).
13 C NMR(101MHz,DMSO-d 6 )δ182.74,167.79,166.49,165.63,164.81,162.85,162.53,162.22,157.76,157.46,156.94,136.85,131.73,131.59,130.12,129.19,127.92(d,J＝3.2Hz),125.93,105.47,102.06,101.11,99.78,99.03,98.48,94.80,94.19,70.32,69.92,69.85,69.36,69.10,62.38,55.90,49.95,49.47,48.97,46.92,42.47,38.96,22.19,22.11。
EXAMPLE 34 preparation of xanthone derivative X1-3P-MDM2 (series 5, n=3)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.17(s,1H),8.26(s,1H),7.96(t,J＝5.6Hz,1H),7.55(s,1H),7.14(dd,J＝13.7,7.9Hz,4H),7.08–7.02(m,2H),6.97(d,J＝8.1Hz,2H),6.73(s,1H),6.62(s,2H),6.48(s,1H),6.37(s,1H),6.24–6.17(m,1H),5.68(s,1H),5.29(s,1H),4.73(p,J＝6.0Hz,1H),4.56(t,J＝5.1Hz,2H),3.91–3.50(m,14H),3.35(s,8H),3.24–3.15(m,3H),3.00(d,J＝5.5Hz,2H),1.27(d,J＝5.8Hz,3H),1.22(d,J＝5.8Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ182.72,170.81,167.79,166.49,165.62,164.78,162.93,162.53,162.22,157.74,157.45,156.96,136.78,132.37,131.79,131.65,130.12,129.22,127.93,105.51,102.06,101.10,99.81,99.02,98.47,94.80,94.17,70.37,70.13,70.05,69.99,69.38,69.10,62.41,60.22,55.90,49.95,49.46,48.96,46.89,42.47,38.98,22.18,22.11。
EXAMPLE 35 preparation of xanthone derivative X1-4P-MDM2 ((series 5, n=4)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.18(s,1H),8.27(s,1H),7.96(t,J＝5.5Hz,1H),7.56(s,1H),7.14(dd,J＝13.2,7.8Hz,4H),7.04(s,2H),6.97(d,J＝8.1Hz,2H),6.73(s,1H),6.62(d,J＝8.9Hz,2H),6.49(s,1H),6.37(s,1H),6.22(s,1H),5.69(s,1H),5.29(s,1H),4.80–4.69(m,1H),4.56(t,J＝5.1Hz,2H),3.92–3.49(m,18H),3.36(d,J＝4.5Hz,8H),3.18(q,J＝6.0Hz,3H),3.00(d,J＝5.9Hz,2H),1.28(d,J＝5.7Hz,3H),1.23(d,J＝5.4Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ182.72,170.81,167.78,166.48,165.62,164.77,162.96,162.52,162.22,157.74,157.45,156.93,136.73,131.82,131.67,130.10,129.23,127.93,105.53,102.05,101.09,99.82,99.02,98.47,94.79,94.17,70.40,70.23–69.95(m),69.38,69.09,62.44,60.22,55.91,49.96,49.46,48.97,46.89,42.48,38.99,22.18,22.11。
EXAMPLE 36 preparation of xanthone derivative X1-5P-MDM2 (series 5, n=5)
Preparation procedure and feed ratio reference example 10
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.85(s,1H),11.18(s,1H),8.27(s,1H),7.96(t,J＝5.5Hz,1H),7.57(s,1H),7.15(dd,J＝13.4,7.6Hz,4H),7.04(s,2H),6.97(d,J＝8.1Hz,2H),6.73(s,1H),6.64(s,2H),6.49(s,1H),6.37(s,1H),6.22(s,1H),5.71(s,1H),5.29(s,1H),4.75(d,J＝9.6Hz,1H),4.56(t,J＝5.1Hz,2H),3.92–3.47(m,22H),3.36(d,J＝6.2Hz,8H),3.18(q,J＝5.8Hz,3H),2.99(s,2H),1.29(d,J＝5.6Hz,3H),1.23(d,J＝5.3Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ182.72,167.78,166.49,165.62,164.76,162.98,162.52,162.22,157.74,157.45,156.91,131.84,131.68,130.09,129.23,127.94,105.55,102.05,101.09,99.84,99.02,98.47,94.79,94.17,70.42,70.16(d,J＝5.4Hz),70.02(d,J＝5.1Hz),69.38,69.08,62.46,60.22,55.92,49.97,49.45,48.97,46.88,42.48,38.99,22.18,22.11。
EXAMPLE 37 preparation of xanthone derivative X1-P-B5 (T) (series 6, n=1)
Dissolving the compound X1-P-B5 in ethyl acetate solution, adding excessive ethyl acetate solution of HCl, monitoring by thin layer, completely reacting, and evaporating to obtain the product.
1 H NMR(400MHz,DMSO-d 6 )δ11.97(s,1H),11.84(s,1H),11.30(s,1H),8.27(s,1H),8.19(t,J＝5.7Hz,1H),8.03(s,1H),7.30(ddd,J＝18.7,11.4,7.1Hz,5H),6.72(dd,J＝12.8,4.0Hz,2H),6.48(d,J＝2.2Hz,1H),6.42(d,J＝2.1Hz,1H),6.25(d,J＝2.1Hz,1H),5.28(s,2H),4.53(t,J＝5.1Hz,2H),4.26(td,J＝8.3,5.8Hz,1H),4.01(q,J＝4.0,3.5Hz,1H),3.78(t,J＝5.1Hz,2H),3.55(s,1H),3.41(d,J＝5.9Hz,4H),3.24–3.09(m,2H),2.90(qd,J＝13.8,7.1Hz,2H),1.57(dt,J＝13.6,7.5Hz,1H),1.51–1.43(m,2H),0.86(dd,J＝9.2,4.9Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.72,172.24,171.04,166.62,165.61,162.49,162.22,157.72,157.47,142.04,136.76,129.89,129.09,127.38,125.89,102.06,101.07,99.07,98.45,94.84,94.17,69.05,68.88,68.72,62.36,54.70,51.72,49.87,41.44,38.86,35.13,24.68,23.29,22.42。
EXAMPLE 38 preparation of xanthone derivative X1-2P-B5 (T) (series 6, n=2)
Specific operation example 37
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.84(s,1H),11.34(s,1H),8.27(s,1H),8.19(t,J＝5.5Hz,1H),8.00(s,1H),7.30(h,J＝7.1,6.6Hz,5H),6.73(s,2H),6.47(s,1H),6.42(d,J＝1.9Hz,1H),6.25(d,J＝1.9Hz,1H),5.29(s,2H),4.55(t,J＝5.1Hz,2H),4.26(q,J＝7.7Hz,1H),4.00(q,J＝4.3,3.7Hz,1H),3.81(t,J＝5.0Hz,2H),3.60–3.46(m,4H),3.45–3.41(m,2H),3.33(d,J＝5.7Hz,3H),3.15(dt,J＝12.5,5.9Hz,2H),2.92(dq,J＝15.1,7.8Hz,2H),1.57(dd,J＝13.1,6.7Hz,1H),1.48(tt,J＝13.5,5.9Hz,2H),0.85(t,J＝7.0Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.70,172.20,170.99,166.65,165.59,162.46,162.20,157.69,157.45,142.00,136.81,129.90,129.07,127.36,125.88,102.04,101.03,99.08,98.46,94.84,94.16,69.92,69.84,69.26,69.11,68.70,62.36,54.71,51.72,49.93,41.49,39.01,35.10,24.65,23.29,22.45。
EXAMPLE 39 preparation of xanthone derivative X1-3P-B5 (T) (series 6, n=3)
Specific operation example 37
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.83(s,1H),11.34(s,1H),8.27(s,1H),8.19(t,J＝5.6Hz,1H),8.00(s,1H),7.39–7.20(m,5H),6.72(t,J＝4.4Hz,2H),6.47(d,J＝2.2Hz,1H),6.42(d,J＝2.1Hz,1H),6.25(d,J＝2.1Hz,1H),5.29(s,2H),4.56(t,J＝5.1Hz,2H),4.26(td,J＝8.3,5.9Hz,1H),4.01(q,J＝3.6Hz,1H),3.82(t,J＝5.1Hz,2H),3.55(s,1H),3.51(dd,J＝6.1,3.5Hz,2H),3.47–3.44(m,2H),3.41–3.32(m,8H),3.17(tt,J＝13.4,6.5Hz,2H),2.91(qd,J＝13.7,7.1Hz,2H),1.59(dt,J＝13.5,7.0Hz,1H),1.48(ddd,J＝13.4,9.8,5.5Hz,2H),0.86(t,J＝6.9Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.69,172.20,170.98,166.65,165.58,162.47,162.20,157.69,157.45,142.00,136.81,129.91,129.08,127.36,125.86,102.04,101.03,99.07,98.45,94.84,94.15,70.13,70.05,69.98,69.27,69.12,68.68,62.36,54.71,51.70,49.94,41.51,39.03,35.11,24.65,23.29,22.46。
EXAMPLE 40 preparation of xanthone derivative X1-4P-B5 (T) (series 6, n=4)
Specific operation example 37
1 H NMR(400MHz,DMSO-d 6 )δ11.96(s,1H),11.84(s,1H),11.33(s,1H),8.27(s,1H),8.20(t,J＝5.7Hz,1H),8.00(s,1H),7.30(tq,J＝13.8,7.2Hz,5H),6.72(dd,J＝12.1,4.0Hz,2H),6.48(d,J＝2.2Hz,1H),6.42(d,J＝2.0Hz,1H),6.25(d,J＝2.1Hz,1H),5.29(s,2H),4.56(t,J＝5.1Hz,2H),4.27(td,J＝8.3,5.9Hz,1H),4.08–3.98(m,1H),3.83(t,J＝5.0Hz,2H),3.52(dd,J＝6.1,3.4Hz,5H),3.37(s,12H),3.17(dtt,J＝19.6,13.5,6.2Hz,2H),2.91(qd,J＝13.8,7.1Hz,2H),1.59(dt,J＝13.4,6.9Hz,1H),1.53–1.43(m,2H),0.86(t,J＝7.0Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,172.19,170.98,166.64,165.60,162.48,162.21,157.70,157.46,141.99,136.79,129.91,129.08,127.37,125.88,102.05,101.04,99.08,98.46,94.84,94.17,70.19,70.06,70.00,69.28,69.11,68.69,62.37,54.72,51.70,49.94,41.53,39.03,35.12,24.66,23.29,22.46。
EXAMPLE 41 preparation of xanthone derivative X1-5P-B5 (T) (series 6, n=5)
1 H NMR(400MHz,DMSO-d 6 )δ11.97(s,1H),11.84(s,1H),11.33(s,1H),8.27(s,1H),8.20(t,J＝5.6Hz,1H),8.00(s,1H),7.31(ddd,J＝18.9,11.5,7.0Hz,5H),6.72(dd,J＝15.8,4.0Hz,2H),6.48(d,J＝2.2Hz,1H),6.42(d,J＝2.1Hz,1H),6.25(d,J＝2.1Hz,1H),5.29(s,2H),4.56(t,J＝5.1Hz,2H),4.27(td,J＝8.3,6.1Hz,1H),4.00(dd,J＝5.8,3.3Hz,1H),3.83(t,J＝5.0Hz,2H),3.52(dd,J＝6.1,3.5Hz,5H),3.46(d,J＝3.3Hz,16H),3.17(dtq,J＝19.4,12.3,5.9Hz,2H),2.91(qd,J＝13.7,7.1Hz,2H),1.59(dt,J＝13.6,7.0Hz,1H),1.52–1.43(m,2H),0.87(t,J＝7.1Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ182.71,172.20,170.97,166.64,165.61,162.48,162.22,157.71,157.46,141.99,136.79,129.91,129.09,127.37,125.88,102.05,101.05,99.08,98.47,94.84,94.18,70.18,70.06,70.00,69.28,69.10,68.69,62.38,54.72,51.70,49.94,41.53,39.04,35.12,24.66,23.29,22.46。
EXAMPLE 43 drug screening based on inhibition of DYRK1A enzymatic Activity
Inhibition of DYRK1A enzyme activity and a series of compounds was detected by measuring NADH consumption. After 30. Mu.L of an enzyme reaction solution (containing 0.70. Mu.m DYRK1A 28.5. Mu.L, 1.5. Mu.L of a test compound of different gradient concentration or 100% DMSO 1.5. Mu.L) was incubated at room temperature for 30min, it was added to a mixture (containing 250mM HEPES PH7.5 10. Mu.L; 1.5M NaCl 10. Mu.L; 0.5M MgCl) to which 70. Mu.L of the mixture had been added in advance 2 1 μl;50mM ATP 4. Mu.L; 250mM NADH 0.2. Mu.L; 100mM potassium phosphoenolpyruvate 5. Mu.L; 12.5mM RARPGTPALRE 4. Mu.L; 2.5KU/mL lactate dehydrogenase 1.5. Mu.L; 5KU/mL M2 pyruvate kinase 1. Mu.L; 33.3 μl of water) was immediately read at 340nm of uv absorbance using a BioTEK Synergy H1 multifunctional microplate reader every 1min, continuously monitored for 20min, and the absorbance change was recorded. IC was calculated using standard dose response curve fitting with GraphPad Prism version 6 50 Values. The experimental results are shown in Table 1.
EXAMPLE 44 micro thermophoresis experiment
With Monolith NT TM Protein Labeling Kit RED (Cat#L001) DYRK1A protein was labeled and samples were diluted with 20mM HEPES (pH 7.5) and 0.5 (v/v)% Tween-20. The test compound powder was dissolved in 10% dmso solution,1:1, after gradient dilution, the protein and the compound are mixed according to the volume ratio of 1:1 after incubation for 15min at room temperature, the complexes were loaded into a Monolith (TM) standard treated capillary and thermophoresis was measured at 20℃on a Monolith NT.115 instrument (NanoTemper Technologies, munchen, germany). The power of the LED was set to 100%. The dissociation constant Kd values were fitted by using NTAnalysis software (NanoTemper Technologies, munchen, germany).
The experimental results showed that compounds 1, X1-CH2-V2, 2 and 4 had equilibrium dissociation constants Kd of 265.00.+ -. 41.30. Mu.M, 14.80.+ -. 1.56. Mu.M, 17.00.+ -. 2.16. Mu.M and 6.26.+ -. 0.65. Mu.M, respectively.
EXAMPLE 45 PROTAC mediates degradation of DYRK1A protein in INS-1 cells
Preparing INS-1 cells in logarithmic phase into cell suspension with concentration of 50000/mL with fresh culture medium, mixing, and adding into 6-well plate with concentration of 2mL per well; after the cells are attached, adding compounds to be tested (containing 0.5% DMSO) with different concentrations, and centrifuging to collect the cells after 24 hours of treatment; the collected cells were subjected to Western Blot detection and DYRK1A protein degradation was detected using DYRK1A antibody. The results show that PROTAC (X1-P-T, X1-3P-T, X1-4P-T, X1-5P-T, X1-2P-MDM2, X1-3P-MDM2, X1-5P-B (T), X1-CH2-B4, X1-CH2-V2, X1-7CH 2-V2) is capable of inducing degradation of DYRK1A protein in INS-1 cells at 1.25. Mu.M. The experimental results are shown in FIG. 2.
EXAMPLE 46 determination of Compounds X1-CH2-V2 to promote proliferation of INS-1 cells
INS-1 cells are derived from rat insulinoma cell lines, and since INS-1 cells have many important characteristics of pancreatic beta cells, they are widely used as model cells of beta cells to evaluate the function of beta cells. Therefore, we used INS-1 cells to further investigate the effect of the compound X1-CH2-V2 on beta cell proliferation. CCK-8 assays showed that compound X1-CH2-V2 was concentration dependent on INS-1 cell proliferation. At 75 μm, the proliferation rate reached 31.46±14.38% (×p < 0.01), significantly higher than the control (-0.57±5.06%). Insulin levels in the culture supernatant also increased after treatment with compounds at concentrations of 9.375 μm or higher. This indicates that the proliferated INS-1 cells have insulin-secreting function, and that the compound X1-CH2-V2 is effective in inducing INS-1 cells to secrete insulin. After treatment with compound X1-CH2-V2, the number of EdU positive INS-1 cells was significantly increased. In addition, we also examined the proliferation of the compound X1-CH2-V2 on STZ-damaged INS-1 cells. The results showed that STZ-damaged INS-1 cells proliferated more after 24 hours of action of compound X1-CH 2-V2. The experimental results are shown in fig. 3 and 4.
EXAMPLE 46 Compounds X1-CH2-V2 promote beta cell proliferation by the NFAT pathway, upregulating cell proliferation-related proteins
Immunofluorescence method detects distribution of NFATc1 protein in INS-1 cells after compound treatment; compound X1-CH2-V2 treatment induced a dose-dependent increase in NFATc1 protein relative to cytoplasmic NFATc1 protein in INS-1 cells (FIG. 5 a). This suggests that compound X1-CH2-V2 may stimulate translocation of NFATc1 protein from the cytoplasm to the nucleus.
Ccdns promote cell proliferation by promoting the transition from the G1-S phase in the cell cycle. The Ccdns and CDK4 mRNA levels were detected using real-time PCR. Gene expression analysis showed that mRNA levels of Ccnd1, ccnd2 and Ccnd3 in INS-1 cells after compound X1-CH2-V2 treatment were upregulated in a dose-dependent manner, whereas mRNA levels of CDK4 were not significantly affected (FIG. 5 b). The above results suggest that compound X1-CH2-V2 regulates the NFAT pathway by inhibiting DYRK1A, promoting nuclear localization of NFATc1, up-regulating the expression level of cell proliferation-related proteins, and the like, thereby promoting INS-1 cell proliferation. The experimental results are shown in FIG. 5.
EXAMPLE 47 Compound X1-CH2-V2 restores islet function in db/db mice and effects on the expression levels of the islet tissue FOXO1, PDX1, injulin proteins
The compound X1-CH 2-V2-induced repair of damaged islets was evaluated by immunofluorescence counterstaining for insulin (green) and glucagon (red) expression levels. Normal groups of mice have intact islets, clear boundaries and high insulin content, but only small amounts of glucagon at the outer periphery of the pancreas. Diabetic mice had irregular islet morphology, reduced insulin content, and a chaotic distribution of insulin and glucagon. Compared with the diabetes group, after 6 weeks of treatment with Harmine and compound X1-CH2-V2, the morphology of islet tissues of the diabetes mice is recovered, and insulin and glucagon expression is normalized. The improvement of islet function of the mice in the group with high doses of compound X1-CH2-V2 is most evident, already approaching the normal group level. The results show that the compound X1-CH2-V2 can protect and repair islets and improve the functions of islets. In addition, protein expression levels of PDX1, insulin were decreased in islet tissue of diabetic mice. After 6 weeks of compound, harmine, metformin treatment, protein expression levels of PDX1, insulin were significantly elevated in the four animals compared to the diabetic group. Of these, the high dose group of compound X1-CH2-V2 showed the most significant increase in expression level. FOXO1 protein expression was significantly elevated in islet tissue of diabetic mice. FOXO1 protein expression levels in islet tissue of diabetic mice were reduced compared to the diabetic group after 6 weeks of compound, harmine, metformin treatment. Of these, the high dose group of compound X1-CH2-V2 showed the most significant decrease in expression level. The experimental results are shown in FIG. 6.
EXAMPLE 48 Effect of Compounds X1-CH2-V2 on diabetic mice body weight, food intake, blood glucose levels, serum insulin levels, oral glucose tolerance test and blood lipid levels
6 weeks after dosing, the db/db mice treated with compound, harmine and metformin had an average decrease in 6 hours of abdominal blood glucose levels compared to the control group. The weight and food intake of diabetic mice were significantly increased compared to normal mice, and no significant differences between the treatment groups were observed for these parameters. Wherein, harmine treatment group showed a slower blood glucose lowering rate compared to the compound and metformin treatment group, and the compound significantly reduced fasting blood glucose levels in diabetic mice and was dose dependent. The fasting blood glucose levels in diabetic mice were maintained at higher levels throughout the administration period. An oral glucose tolerance test was performed at week 6 post-dosing to assess the glucose homeostasis of the mice. The results show that oral glucose tolerance of diabetic mice is impaired. Blood glucose levels in all drug treated mice steadily decreased from 30 minutes post-administration. The compound can obviously improve the oral glucose tolerance of the diabetic mice. These experimental results indicate that compound treatment results in a significant increase in β cell mass in diabetic mice, which may explain the glycemic control effect of the compounds. The serum content of insulin in the mice of the administration group is obviously increased. The experimental results are shown in FIG. 7.
IC for inhibition of DYRK1A enzymatic Activity by Compounds of Table 1 50 Value of
As can be seen from the above table, compounds 1,4,7,9, 10 and X1-CH2-VHL2 have a better effect in inhibiting DYRK1A enzyme activity.

Claims (10)

1. Xanthone of formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof:
wherein: r is R 1 、R 2 Independently represents hydrogen, deuterium, hydroxy, alkoxy, benzoyloxy, benzyloxy, p-toluenesulfonyloxy, methanesulfonyloxy, acetoxy, propynyloxy or one of the following structural formulae (III):
in the structural formula (III), T is selected from one of phenyl, piperazinyl, piperidinyl, heterocyclic groups and hydrocarbyl;
b is selected from one of O, S, C, H;
y is selected from one of-alkyl, -cycloalkyl, -Cl, -F, -H and Br;
R 3 one selected from H, D.
2. The xanthone of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, wherein R 1 Is one of the following structural formulas:
3. the xanthone of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, wherein when R 1 Or R is 2 In the case of formyloxy or benzoyloxy, xanthone having an ester group is formed; when R is 1 Or R is 2 The sulfonyl group and the p-toluenesulfonyloxy group are sulfonate, the formed xanthone with a sulfonic acid group forms a prodrug of xanthone, wherein the xanthone with an ester group and the xanthone with a sulfonic acid group form the xanthone, and the ester group or the sulfonic acid group is hydrolyzed into a hydroxyl group in a body.
4. A xanthone derivative, or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, having the structural formula (IV) or (V):
wherein R is 1 、R 2 、R 3 The xanthone determination of claim 1;
E 3 is one of CRBN, VHL, MDM, CIAP, UBR7, RNF114, CBLB and KEAP1 in the E3 ligase ligand;
l is a linking arm selected from one of a fatty chain, an aromatic chain, an ether chain, and an amide chain.
5. The xanthone derivative of claim 4, or a pharmaceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, wherein when E 3 Is CRBN ligaseIs selected from the group consisting of thalidomide and its derivatives, lenalidomide and its derivatives, pomalidomide and its derivatives.
6. The xanthone derivative of claim 4, or a pharmaceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, wherein E 3 The structure is any one of the structures shown in the following structural formula (VI):
wherein: in the structural formula (IV), W is selected from CH 2 、C＝O、SO 2 One of NH, N-alkyl;
x is selected from one of O, S;
z is selected from one of-alkyl, -cycloalkyl, -Cl, -F and H;
G. g' is independently selected from the group consisting of-H, alkyl, -OH, -CH 2 -one of the heterocycles;
R 1 selected from the group consisting of-H, -D, -F, -Cl, -Br, -I, -NO 2 、-CN、-NH 2 、-OH、-CH 3 、-CH 2 F、-CHF 2 、-CF 3 、-CH 2 D、-CHD 2 、-CD 3 、-CH 2 CH 3 One of the following;
q is selected from CH 2 、C＝O、-NH-C＝O、-NH 2 -one of NHBoc;
m is selected from one of amide group, ester group, carboxyl group and acyl chloride;
a is selected from piperazinyl, piperidinyl, heterocyclic groups or one of the linking groups shown in the following structural formula (V);
wherein: the heterocyclic group is one of piperazinonyl, pyrrolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
the structural formula of the structural formula (VII) is as follows, wherein n is an integer of 0 to 3:
7. the xanthone derivative of claim 4, or a pharmaceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, wherein the structure of L is any one of the structures shown in structural formula (VIII):
wherein, m is more than or equal to 1 and less than or equal to 10.
8. A pharmaceutical composition comprising at least one of the following: a xanthone according to any one of claims 1 to 3, a stereoisomer of a xanthone, a pharmaceutically acceptable salt of a xanthone, a hydrate of a xanthone, a prodrug of a xanthone, a xanthone derivative according to any one of claims 4 to 7, a stereoisomer of a xanthone derivative, a pharmaceutically acceptable salt of a xanthone, a hydrate of a xanthone, a prodrug of a xanthone; also included are pharmaceutically acceptable carriers, diluents, adjuvants, vehicles, or combinations thereof.
9. A method of preparing the xanthone of claim 1 or the xanthone derivative of claim 4 comprising the steps of:
the reaction route using 2,4, 6-trihydroxybenzoic acid as the starting material is as follows:
10. use of a xanthone of formula (I) or (II) as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, or a xanthone derivative as claimed in any one of claims 4 to 7, or a pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, or a pharmaceutical composition as claimed in claim 9, in the manufacture of a medicament for the treatment or prophylaxis of diabetes, cancer and neurodegenerative diseases.
CN202210137962.6A 2022-02-15 2022-02-15 Xanthone and derivative, and preparation method and application thereof Pending CN116640125A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116640123A (en) * 2022-02-15 2023-08-25 沈阳药科大学 Bifunctional molecule compound for inducing degradation of HK2 protein and synthesis and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116640123A (en) * 2022-02-15 2023-08-25 沈阳药科大学 Bifunctional molecule compound for inducing degradation of HK2 protein and synthesis and application thereof
CN116640123B (en) * 2022-02-15 2024-06-18 沈阳药科大学 Bifunctional molecule compound for inducing degradation of HK2 protein and synthesis and application thereof

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