CN117447468A - Bazedoxifene derivative and preparation method and application thereof - Google Patents

Bazedoxifene derivative and preparation method and application thereof Download PDF

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CN117447468A
CN117447468A CN202311407502.1A CN202311407502A CN117447468A CN 117447468 A CN117447468 A CN 117447468A CN 202311407502 A CN202311407502 A CN 202311407502A CN 117447468 A CN117447468 A CN 117447468A
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bazedoxifene
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余文颖
关洁
王进
胡宇轩
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China Pharmaceutical University
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to bazedoxifene, a preparation method and application thereof. The bazedoxifene derivative is used for a gp130 small molecule inhibitor, and the compound is a compound shown in a formula (I) or pharmaceutically acceptable salt or ester thereof, and relates to application in aspects of tumor-related activity and the like, in particular to application in preparing medicines for preventing and/or treating tumor-related diseases, in particular colorectal cancer.

Description

Bazedoxifene derivative and preparation method and application thereof
Technical Field
The invention relates to a novel GP130 small molecule inhibitor, in particular to a bazedoxifene derivative, a preparation method and application thereof, in particular to application in aspects of tumor-related activity and the like, and belongs to the technical field of pharmacy.
Background
The regulation of cell signals is closely related to the occurrence and development of tumors. Many studies have shown that glycoprotein 130 (GP 130, also known as IL-6ST or CD 130) is a highly conserved transmembrane glycoprotein, closely related to the development of cancer in vertebrates, and can act as a receptor for a variety of cytokines, including interleukin-6 (IL-6). GP130 protein is involved in many aspects of apoptosis, proliferation, angiogenesis, invasion and metastasis. The tumor microenvironment (tumor microenvironment, TME) plays a critical role in the pathogenesis of tumors. Cancer-associated fibroblasts (CAFs) are an important component of TME. Thus, inhibition of the IL-6/GP130 signaling pathway may provide important insight into the treatment of cancer.
The IL-6/GP130/STAT3 pathway is involved in a variety of tumor processes. IL-6 acts primarily through classical and trans signaling binding to the receptors IL-6Rα and gp130[5 ]. First, IL-6 binds to IL-6Rα or soluble sIL-6Rα on the surface of cell membrane to form a binary complex. The IL-6/IL-6Rα binary complex forms an IL-6/IL-6Rα/GP130 trimeric complex with the D2 and D3 domains of GP130 on the cell membrane.
IL-6/IL-6Rα/GP130 trimers homodimerize. IL-6 in one trimeric complex binds to the D1 domain of GP130 in another trimeric complex to form a hexamer receptor complex. Mediate activation of downstream MAKP, PI3K and JAK/STAT pathways, thereby producing a cascade effect. Studies have shown that abnormal expression of STAT3 plays an important role in neoplastic transformation. Overexpression or lack of negative regulators of IL-6, IL-6Rα and GP130 upstream signals can lead to aberrant STAT3 activation. Thus, modulation of the upstream target IL-6/IL-6Rα/GP130 of STAT3 may be important against tumors. STAT3 has been widely reported, while IL-6/GP130 signaling has been studied relatively rarely. Inhibiting the upstream IL-6/GP130 signal may provide a new anti-tumor regimen, and therefore it is of great importance to design new inhibitors against this target.
Bazedoxifene is an FDA-approved Selective Estrogen Receptor Modulator (SERM) useful in the prevention and treatment of postmenopausal osteoporosis using multi-ligand simultaneous docking (MLSD) and drug repositioning methods, which was found to be a novel GP130 small molecule inhibitor.
Disclosure of Invention
The invention aims to: a first object of the present invention is to provide a bazedoxifene derivative that enhances the effect of colorectal neoplasms; a second object is to provide a process for the preparation of said bazedoxifene derivative.
The technical scheme is as follows: the chemical structural formula of the bazedoxifene derivative is as follows:
wherein, the A group is a substituted or unsubstituted five-, six-, seven-membered saturated or unsaturated heterocycle, a substituted or unsubstituted aromatic ring; when the a group is a heterocycle, there are one to two heteroatoms in the ring, the heteroatoms being selected from: n, O, S; .
The B group is a ternary or quaternary condensed ring aromatic group.
Preferably, the A group is selected from furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, substituted phenyl, pyridyl.
Preferably, the B group is selected from fused ring saturated or unsaturated compounds, in particular
Wherein a, b, C are selected from C or N, R 3 Selected from the group consisting of aromatic ring combinations and aromatic heterocyclic ring substitutions.
Preferably, the a group is selected from:
preferably, the saidHas any one of the following structures:
preferably, the B group contains a specific structure of
Preferably, the bazedoxifene derivative has any one of the following structures:
in another aspect, the present invention provides a process for the preparation of bazedoxifene derivatives, when A isWhen the aliphatic heterocyclic compounds are used, the method comprises the following steps:
the p-hydroxybenzyl alcohol reacts with the hydrochloride of the corresponding halogeno compound under the action of a phase transfer catalyst to obtain a compound II.
(1) And (3) reacting the compound II overnight under the action of thionyl chloride to obtain a compound III.
(2) And obtaining the compound I from the compound III and the fragment B under the action of sodium hydride.
Preferably, in step (1), the reaction solvent is selected from one or more of acetone, water, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide or dioxane; the base is selected from potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine; the phase transfer catalyst selects tetrabutylammonium bromide; reaction temperatureThe progress of the reaction was monitored by TLC with ethyl acetate as developing reagent.
Preferably, in the step (2), the reaction solvent is selected from one or more of acetonitrile, ethylene glycol dimethyl ether, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; reaction temperatureThe reaction time is +.>TLC monitored the progress of the reaction, the developing reagent being dichloromethane: methanol=30:1.
Preferably, in the step (3), the reaction solvent is selected from one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, N-dimethylformamide, tertiary butanol, dimethyl sulfoxide or dioxane, and the base is selected from sodium hydride or tertiary butanol sodium, and the reaction is performed at room temperature or under reflux. Reaction progress TLC monitored the progress of the reaction with methylene chloride as developing reagent: methanol=15:1.
Specifically, when A isThe method comprises the following steps:
1) The 4- (hydroxymethyl) -phenol reacts with 1- (2-chloroethyl) pyrrolidine hydrochloride, 1- (2-chloroethyl) piperidine hydrochloride and 1- (2-chloroethyl) azacyclohexane hydrochloride respectively under the action of a phase transfer catalyst to generate (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) methanol, (4- (2- (piperidin-1-yl) ethoxy) phenyl) methanol and (4- (2- (aza-1-yl) ethoxy) phenyl) methanol respectively.
2) (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) methanol, (4- (2- (piperidin-1-yl) ethoxy) phenyl) methanol, (4- (2- (aza-1-yl) ethoxy) phenyl) methanol was reacted with thionyl chloride in tetrahydrofuran to give 1- (2- (4- (chloromethyl) phenoxy) ethyl) pyrrolidine hydrochloride, 1- (2- (4- (chloromethyl) phenoxy) ethyl) piperidine hydrochloride, 1- (2- (4- (chloromethyl) phenoxy) ethyl) azetidine hydrochloride, respectively.
3) 1- (2- (4- (chloromethyl) phenoxy) ethyl) pyrrolidine hydrochloride, 1- (2- (4- (chloromethyl) phenoxy) ethyl) piperidine hydrochloride, and 1- (2- (4- (chloromethyl) phenoxy) ethyl) azacyclohexane hydrochloride are connected with a fragment B under the action of NaH to obtain the bazedoxifene derivative.
When A isWhen aromatic ring or aromatic heterocycle is used, the method comprises the following steps:
and (3) reacting the p-hydroxybenzaldehyde with 2-phenyl ethane-1-alcohol, 2- (3- (trifluoromethyl) phenyl) ethane-1-alcohol and 2- (pyridine-2-yl) ethane-1-alcohol under the condition of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound IV.
a. The compound IV is reduced to a compound V under the action of sodium borohydride.
b. The compound V is chlorinated into a compound VI under the action of thionyl chloride.
c. The compound VI and the fragment B are reacted with sodium hydride to obtain the compound I.
Preferably, in step a, the reaction solvent is selected from the group consisting of acetone, tetrahydrofuran, N-dimethylformamide, ethylene glycol dimethyl ether, dimethyl sulfoxide and dioxaneOne or more of (a) and (b); reaction temperatureThe reaction progress was monitored by TLC, and the developing agent was petroleum ether: ethyl acetate = 2:1.
preferably, in the step b, the reduction reaction solvent is selected from one or more of acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; reaction temperatureThe reaction time was 2h, tlc monitored the progress of the reaction and the developing solvent was ethyl acetate.
Preferably, in the step c, the reaction solvent is selected from one or more of acetonitrile, ethylene glycol dimethyl ether, dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide; reaction temperatureThe reaction time is +.>TLC monitored the progress of the reaction, the developing reagent being dichloromethane: methanol=30:1.
Preferably, in step d, the reaction solvent is selected from one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, N-dimethylformamide, tert-butanol, dimethyl sulfoxide or dioxane, and the base is selected from sodium hydride or tert-butanol sodium, and the reaction is performed at room temperature or under reflux. Reaction progress TLC monitored the progress of the reaction with methylene chloride as developing reagent: methanol=15:1.
Specifically, when A isThe method comprises the following steps:
(1) Reacting 4-hydroxybenzaldehyde with 2-phenylethane-1-ol, 2- (3- (trifluoromethyl) phenyl) ethan-1-ol, 2- (pyridin-2-yl) ethan-1-ol, respectively, to obtain 4-phenethoxybenzaldehyde, 4- (3- (trifluoromethyl) phenethoxy) benzaldehyde, 4- (2- (pyridin-2-yl) ethoxy) benzaldehyde, respectively
(2) The 4-phenethoxybenzaldehyde, 4- (3- (trifluoromethyl) phenethoxy) benzaldehyde and 4- (2- (pyridin-2-yl) ethoxy) benzaldehyde are respectively reduced under the action of sodium borohydride to obtain (4-phenethoxyphenyl) methanol, (4- (3- (trifluoromethyl) phenethoxy) phenyl) methanol and (4- (2- (pyridin-2-yl) ethoxy) phenyl) methanol.
(3) (4-Phenylethoxyphenyl) methanol, (4- (3- (trifluoromethyl) phenethyl) phenyl) methanol, (4- (2- (pyridin-2-yl) ethoxy) phenyl) methanol is reacted with thionyl chloride to form 1- (chloromethyl) -4-phenethoxybenzene, 1- (2- (4- (chloromethyl) phenoxy) ethyl) -3- (trifluoromethyl) benzene, 2- (2- (4- (chloromethyl) phenoxy) ethyl) pyridine, respectively.
(4) Further, 1- (chloromethyl) -4-phenethoxybenzene, 1- (2- (4- (chloromethyl) phenoxy) ethyl) -3- (trifluoromethyl) benzene and 2- (2- (4- (chloromethyl) phenoxy) ethyl) pyridine are respectively connected with the fragment B under the action of NaH to obtain the bazedoxifene derivative (I).
In another aspect, the invention provides an application of a bazedoxifene derivative in preparing a medicament for treating tumors. Preferably, the tumor is a colorectal tumor.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) By modifying the fragments of the derivatives, A and B parts, a series of new compounds are synthesized, a more effective GP130 inhibitor is explored, the inhibitor has obvious inhibition effect on colorectal tumor cells, acts on colorectal cancer cell line HT-29, and IC thereof 50 Minimum 2.048. Mu.M; (2) The preparation method designs and synthesizes a new bazedoxifene derivative, and the CCK-8 method is utilized to test the inhibition effect on cancer cells, so that the generation and development of various cancer cells such as colorectal cancer can be obviously inhibited.
Drawings
FIG. 1 is Compound I 6 Results of the HT29 cell Wounding Healing Assay test; (a) And (b) forming a quantity histogram for the colonies.
Detailed Description
The embodiment of the invention provides a bazedoxifene derivative, which has a structure shown as a formula (I):
wherein, the A group is a substituted or unsubstituted five-, six-, seven-membered saturated or unsaturated heterocycle, a substituted or unsubstituted aromatic ring; when the a group is a heterocycle, there are one to two heteroatoms in the ring, the heteroatoms being selected from: n, O, S;
the B group is a ternary or quaternary condensed ring aromatic group;
n is 1,2 or 3.
The embodiment of the invention provides a preparation method of bazedoxifene derivatives, when the group A is aliphatic heterocycle, the preparation method comprises the following steps:
(1) Reacting p-hydroxybenzyl alcohol with corresponding halogeno compound hydrochloride under the action of phase transfer catalyst to obtain a compound II;
(2) The compound II is reacted overnight under the action of thionyl chloride to obtain a compound III;
(3) And obtaining the compound I from the compound III and the fragment B under the action of sodium hydride.
When the group A is an aromatic ring or an aromatic heterocyclic ring, the method comprises the following steps:
the p-hydroxybenzaldehyde reacts with 2-phenyl ethane-1-alcohol, 2- (3- (trifluoromethyl) phenyl) ethane-1-alcohol and 2- (pyridine-2-yl) ethane-1-alcohol respectively under the condition of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound IV;
a. reducing the compound IV into a compound V under the action of sodium borohydride;
b. the compound V is chlorinated into a compound VI under the action of thionyl chloride;
c. the compound VI and the fragment B are reacted with sodium hydride to obtain the compound I.
The technical scheme of the invention is further described below by referring to examples.
Example 1
The chemical name of the bazedoxifene derivative is 9- (4- (2- (pyrrolidine-1-yl) ethoxy) benzyl) -9H-carbazole, and the synthetic route is shown as follows:
(1) Intermediate II 1 Is synthesized by (a)
To an aqueous solution (45 ml) of sodium hydroxide (88.61 mmol) was added p-hydroxybenzyl alcohol 40.28 (mmol), and the mixture was stirred for 20 minutes. Toluene (30 ml), the compound 1- (2-chloroethyl) pyrrolidine hydrochloride (48.33 mmol) and tetrabutylammonium bromide (2.42 mmol) were added sequentially. The solution was then heated to reflux (85-90 ℃) with vigorous stirring for 2h, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate and combined with the organic layer, washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain white solid II 1 The yield thereof was found to be 75%. 1 H NMR(300MHz,Chloroform-d)δ7.27–7.15(m,2H),6.92–6.72(m,2H),4.55(s,2H),3.99(t,J＝6.0Hz,2H),3.90(s,1H),2.84(t,J＝6.0Hz,2H),2.59(ddt,J＝6.8,4.4,2.4Hz,4H),1.78(p,J＝3.1Hz,4H).
(1) Intermediate III 1 Is synthesized by (a)
Intermediate II 1 A solution of (27.11 mmol) in tetrahydrofuran was cooled to 0℃and sulfoxide chloride (30.35 mmol) was slowly added dropwise thereto, followed by stirring at room temperature overnight. When TLC showed the reaction was complete, the precipitated product was filtered with cyclohexane: tetrahydrofuran=1: 1 washing the filter cake, and drying in an oven at 80 ℃ to obtain white solid III 1 . The yield was 67%, 1 H NMR(300MHz,DMSO-d 6 )δ11.05(s,1H),7.44–7.36(m,2H),7.06–6.97(m,2H),4.74(s,2H),4.37(t,J＝5.1Hz,2H),3.56(q,J＝5.0Hz,4H),3.10(d,J＝9.0Hz,2H),2.04–1.82(m,4H)。
(2) Target product I 1 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide under argon to obtain carbazole (1.2 mmol solution, adding sodium hydride (3.55 mmol) solution, stirring at 0deg.C for 1 hr, adding compound III 1 (1.32 mmol) was stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 1 . The yield thereof was found to be 78%. 1 H NMR(300MHz,DMSO-d 6 )δ8.17(d,J＝7.7Hz,2H),7.65(d,J＝8.2Hz,2H),7.49–7.37(m,2H),7.24–7.16(m,2H),7.12(d,J＝8.6Hz,2H),6.81(d,J＝8.7Hz,2H),5.57(s,2H),3.95(t,J＝5.9Hz,2H),2.70(t,J＝5.9Hz,2H),2.48–2.38(m,4H),1.64(h,J＝3.1Hz,4H)。 13 C NMR(75MHz,DMSO-d 6 )δ158.18,140.52,130.16,128.62,126.24,122.66,120.78,119.39,114.90,110.04,67.05,54.72,54.40,45.46,23.56。
Example 2
The chemical name of the bazedoxifene derivative is 9- (4- (2- (piperidine-1-yl) ethoxy) benzyl) -9H-carbazole, and the synthetic route is shown as follows:
(1) Intermediate II 2 Is synthesized by (a)
To an aqueous solution (45 ml) of sodium hydroxide (53.17 mmol) was added p-hydroxybenzyl alcohol (24.17 mmol), and the mixture was stirred for 20 minutes. Toluene (30 ml), the compound 1- (2-chloroethyl) piperidinoalkane hydrochloride (29 mmol) and tetrabutylammonium bromide (14.5 mmol) were added sequentially. The solution was then heated to reflux (85-90 ℃) with vigorous stirring for 2h, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate and combined with the organic layer, washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. Purifying by silica gel column chromatographyDissolving the residue to obtain white solid II 2 . The yield was 70%, 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J＝6.6Hz,2H),6.91–6.85(m,2H),4.61(s,2H),4.09(t,J＝6.1Hz,2H),2.77(t,J＝6.1Hz,2H),2.51(t,J＝5.5Hz,4H),1.62(p,J＝5.6Hz,4H),1.45(q,J＝6.2Hz,2H)。
(2) Intermediate III 2 Is synthesized by (a)
Intermediate II 2 A solution of (23.16 mmol) in tetrahydrofuran was cooled to 0℃and sulfoxide chloride (46.32 mmol) was slowly added dropwise thereto, followed by stirring at room temperature overnight. When TLC showed the reaction was complete, the precipitated product was filtered with cyclohexane: tetrahydrofuran=1: 1 washing the filter cake, and drying in an oven at 80 ℃ to obtain white solid III 2 . The yield was 67%, 1 H NMR(300MHz,Chloroform-d)δ12.49(s,1H),7.33(d,J＝8.0Hz,2H),6.88(d,J＝8.1Hz,2H),4.57(d,J＝8.2Hz,4H),3.64(d,J＝12.0Hz,2H),3.48–3.33(m,2H),2.83(q,J＝11.4Hz,2H),2.28(q,J＝13.9Hz,2H),1.88(d,J＝13.8Hz,2H)。
(3) Target product I 2 Is synthesized by (a)
A solution of carbazole (598.05. Mu. Mol) was obtained by stirring in anhydrous N, N-dimethylformamide under argon, and sodium hydride (1.79 mmol) was added. After stirring the solution at 0℃for 1h, the compound III is added 1 (777.46. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 2 The yield thereof was found to be 85%. 1 H NMR(300MHz,DMSO-d 6 )δ8.17(dt,J＝7.8,0.9Hz,2H),7.68–7.58(m,2H),7.43(ddd,J＝8.3,7.1,1.2Hz,2H),7.20(td,J＝7.5,0.9Hz,2H),7.16–7.05(m,2H),6.86–6.76(m,2H),5.57(s,2H),3.95(t,J＝5.9Hz,2H),2.57(t,J＝5.9Hz,2H),2.36(t,J＝5.2Hz,4H),1.45(p,J＝5.4Hz,4H),1.39–1.28(m,2H)。 13 C NMR(75MHz,DMSO-d 6 )δ158.19,140.52,130.15,128.60,126.24,122.66,120.78,119.38,114.94,110.03,65.91,57.80,54.84,45.46,26.01,24.38。
Example 3
The chemical name of the bazedoxifene derivative is 9- (4- (2- (azepan-1-yl) ethoxy) benzyl) -9H-carbazole, and the synthetic route is shown as follows:
(1) Intermediate II 3 Is synthesized by (a)
To an aqueous solution (45 ml) of sodium hydroxide (53.17 mmol) was added p-hydroxybenzyl alcohol (24.17 mmol), and the mixture was stirred for 20 minutes. Toluene (30 ml), 1- (2-chloroethyl) azacyclohexane hydrochloride (29 mmol) and tetrabutylammonium bromide (14.5 mmol) were added sequentially. The solution was then heated to reflux (85-90 ℃) with vigorous stirring for 2h, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate and combined with the organic layer, washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain white solid II 3 . The yield thereof was found to be 67%. 1 H NMR(400MHz,Chloroform-d)δ7.27(d,J＝8.6Hz,2H),6.91–6.83(m,2H),4.60(s,2H),4.05(t,J＝6.2Hz,2H),2.94(t,J＝6.2Hz,2H),2.81–2.74(m,4H),2.32(s,1H),1.71–1.56(m,8H)。
(2) Intermediate III 3 Is synthesized by (a)
Intermediate II 2 A solution of (18.16 mmol) in tetrahydrofuran was cooled to 0℃and after slow dropwise addition of sulfoxide chloride (36.32 mmol), the mixture was stirred at room temperature overnight. When TLC showed the reaction was complete, the precipitated product was filtered with cyclohexane: tetrahydrofuran=1: 1 washing the filter cake, and drying in an oven at 80 ℃ to obtain white solid III 3 .61 percent of Kailu, 1 H NMR(300MHz,Chloroform-d)δ12.52(s,1H),7.39–7.29(m,2H),6.96–6.81(m,2H),4.56(s,4H),3.63(q,J＝9.5,8.6Hz,2H),3.48(s,2H),3.23–3.04(m,2H),2.19(q,J＝9.7Hz,2H),1.95–1.82(m,4H),1.66(dq,J＝16.5,8.8,7.2Hz,2H)。
(3) Target product I 3 Is synthesized by (a)
A solution of carbazole (299.02. Mu. Mol) was obtained by stirring in anhydrous N, N-dimethylformamide under argon, and sodium hydride (1.35 mmol) was added thereto. After stirring the solution at 0℃for 1h, the compound III is added 3 (328.993. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 3 The yield thereof was found to be 83%. 1 H NMR(300MHz,DMSO-d 6 )δ8.17(d,J＝7.7Hz,2H),7.65(d,J＝8.2Hz,2H),7.48–7.37(m,2H),7.20(t,J＝7.4Hz,2H),7.12(d,J＝8.5Hz,2H),6.85–6.76(m,2H),5.57(s,2H),3.92(t,J＝6.1Hz,2H),2.76(t,J＝6.0Hz,2H),2.62(t,J＝5.1Hz,4H),1.54–1.46(m,8H)。 13 C NMR(75MHz,DMSO-d 6 )δ158.26,140.52,130.14,128.61,126.24,122.67,120.77,119.38,114.96,110.03,66.60,56.44,55.57,45.47,28.31,27.00。
Example 4
The chemical name of the bazedoxifene derivative is 5- (4- (2- (pyrrolidine-1-yl) ethoxy) benzyl) -5H-pyrido [4,3-b ] indole, and the synthetic route is shown as follows:
(1) Target product I 4 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 5H-pyrido [4,3-b ]]A solution of indole (297.27. Mu. Mol) was added with sodium hydride (1.34 mmol). After stirring the solution at 0℃for 1h, the compound III is added 1 (356.72. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 4 . The yield thereof was found to be 68%. 1 H NMR(300MHz,Chloroform-d)δ9.34(s,1H),8.53(d,J＝5.8Hz,1H),8.18(dt,J＝7.7,1.0Hz,1H),7.50(ddd,J＝8.2,7.0,1.2Hz,1H),7.42(dt,J＝8.3,1.1Hz,1H),7.37–7.27(m,2H),7.10–7.02(m,2H),6.86–6.74(m,2H),5.44(s,2H),4.13(t,J＝5.7Hz,2H),2.99(t,J＝5.7Hz,2H),2.85–2.67(m,4H),1.93–1.78(m,4H)。 13 C NMR(75MHz,Chloroform-d)δ158.09,145.15,144.74,140.48,128.49,127.82,126.95,121.58,120.81,120.81,114.97,109.59,104.43,66.14,54.71,54.61,46.19,23.39。
Example 5
The chemical name of the bazedoxifene derivative is 5- (4- (2- (piperidine-1-yl) ethoxy) benzyl) -5H-pyrido [4,3-b ] indole, and the synthetic route is shown as follows:
(1) Target product I 5 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 5H-pyrido [4,3-b ]]A solution of indole (297.27. Mu. Mol) was added with sodium hydride (1.34 mmol). After stirring the solution at 0℃for 1h, the compound III is added 2 (356.72. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 5 The yield thereof was found to be 61%. 1 H NMR(400MHz,Chloroform-d)δ9.35(d,J＝0.9Hz,1H),8.52(s,1H),8.19(dt,J＝7.8,1.0Hz,1H),7.51(ddd,J＝8.3,7.1,1.2Hz,1H),7.43(dt,J＝8.3,1.0Hz,1H),7.39–7.29(m,2H),7.11–7.01(m,2H),6.84–6.74(m,2H),5.45(s,2H),4.18(t,J＝5.4Hz,2H),2.99(t,J＝5.5Hz,2H),2.75(t,J＝5.6Hz,4H),1.72(p,J＝5.7Hz,4H),1.50(t,J＝6.0Hz,2H)。 13 C NMR(101MHz,Chloroform-d)δ158.15,144.77,142.53,140.55,128.35,127.81,127.02,121.57,120.89,120.84,119.89,114.99,109.61,104.44,65.22,57.22,54.54,46.23,25.06,23.61。
Example 6
The chemical name of the bazedoxifene derivative is 5- (4- (2- (azepine-1-yl) ethoxy) benzyl) -5H-pyrido [4,3-b ] indole, and the synthetic route is shown as follows:
(1) Target product I 6 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 5H-pyrido [4,3-b ]]A solution of indole (297.27. Mu. Mol) was added with sodium hydride (1.34 mmol). After stirring the solution at 0℃for 1h, the compound III is added 3 (356.72. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 5 . The yield thereof was found to be 63%. 1 H NMR(400MHz,Chloroform-d)δ9.36(s,1H),8.55(d,J＝5.8Hz,1H),8.20(d,J＝7.8Hz,1H),7.56–7.46(m,1H),7.43(d,J＝8.1Hz,1H),7.35(t,J＝7.5Hz,1H),7.30(d,J＝11.0Hz,1H),7.08(d,J＝8.4Hz,2H),6.90–6.75(m,2H),5.45(s,2H),4.07(t,J＝6.0Hz,2H),2.98(t,J＝6.0Hz,2H),2.90–2.74(m,4H),1.77–1.54(m,8H)。 13 C NMR(101MHz,Chloroform-d)δ158.32,145.01,144.78,142.75,140.53,128.28,127.79,126.95,121.60,120.82,120.81,119.88,114.99,109.59,104.42,65.95,56.13,55.66,46.23,27.08,27.03。
Example 7
The chemical name of the bazedoxifene derivative is 7- (6-fluoropyridine-3-yl) -5- (4- (2- (pyrrolidine-1-yl) ethoxy) -5H-pyrido [4,3-b ] indole, and the synthetic route is shown as follows:
(1) Target product I 7 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain the compound 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ]]A solution of indole (189.92. Mu. Mol) was added with sodium hydride (854.62. Mu. Mol). After stirring the solution at 0℃for 1h, the compound III is added 1 (189.92. Mu. Mol), room temperatureStirring for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 7 . The yield thereof was found to be 53%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.56(d,J＝5.7Hz,1H),8.46(s,1H),8.25(d,J＝8.0Hz,1H),8.02(t,J＝8.1Hz,1H),7.50(d,J＝9.8Hz,2H),7.33(d,J＝5.9Hz,1H),7.12–6.98(m,3H),6.84(d,J＝7.6Hz,2H),5.49(s,2H),4.08(t,J＝5.9Hz,2H),2.91(t,J＝5.8Hz,2H),2.66(d,J＝5.9Hz,4H),1.81(t,J＝4.5Hz,4H)。 13 C NMR(75MHz,Chloroform-d)δ158.50,146.25,146.06,145.58,145.37,143.13,141.06,140.20,140.09,135.68,127.86,127.71,121.50,120.18,119.43,115.08,109.80,109.30,108.04,104.56,66.80,54.91,54.68,46.32,23.44。
Example 8
The bazedoxifene derivative of the invention has the chemical name as shown in the following synthetic route:
(1) Target product I 8 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain the compound 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ]]A solution of indole (189.92. Mu. Mol) was added with sodium hydride (854.62. Mu. Mol). After stirring the solution at 0℃for 1h, the compound III is added 2 (227.90. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 8 . The yield thereof was found to be 48%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.57(d,J＝5.8Hz,1H),8.46(s,1H),8.26(d,J＝8.0Hz,1H),8.02(t,J＝7.9Hz,1H),7.50(d,J＝9.9Hz,2H),7.33(d,J＝5.8Hz,1H),7.12–6.99(m,3H),6.82(d,J＝7.4Hz,2H),5.49(s,2H),4.07(t,J＝6.0Hz,2H),2.77(t,J＝6.1Hz,2H),2.51(t,J＝5.1Hz,4H),1.61(t,J＝5.8Hz,4H),1.44(q,J＝5.9Hz,2H)。 13 C NMR(75MHz,Chloroform-d)δ158.50,146.26,146.06,145.60,143.14,141.06,140.19,140.09,135.67,127.82,127.71,121.50,120.18,119.43,115.08,109.80,109.30,108.03,104.55,65.81,57.75,54.99,46.32,25.70,24.01。
Example 9
The chemical name of the bazedoxifene derivative is 5- (2- (azepan-1-yl) ethoxy) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole, and the synthetic route is shown as follows:
(1) Target product I 9 Is synthesized by (a)
Stirring in anhydrous dimethylformamide protected by argon to obtain the compound 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b]A solution of indole (189.92. Mu. Mol) was added with sodium hydride (854.62. Mu. Mol). After stirring the solution at 0℃for 1h, the compound III is added 3 (227.90. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 9 . The yield thereof was found to be 51%. 1 H NMR(300MHz,Chloroform-d)δ9.37(d,J＝1.0Hz,1H),8.57(d,J＝5.8Hz,1H),8.46(q,J＝1.1Hz,1H),8.26(dd,J＝7.8,0.9Hz,1H),8.02(ddd,J＝8.4,7.6,2.6Hz,1H),7.50(dd,J＝9.1,1.2Hz,2H),7.33(dd,J＝5.9,1.0Hz,1H),7.13–7.00(m,3H),6.87–6.78(m,2H),5.50(s,2H),4.08(t,J＝6.0Hz,2H),2.99(t,J＝6.0Hz,2H),2.83(s,4H),1.72–1.59(m,8H)。 13 C NMR(75MHz,Chloroform-d)δ158.52,146.26,146.06,145.56,145.38,143.11,141.07,140.09,135.68,128.63,127.83,127.72,121.50,120.19,119.44,115.08,109.31,108.04,104.57,66.16,56.16,55.76,46.33,27.38,27.02。
Example 10
The chemical name of the bazedoxifene derivative is 5- (2- (azepan-1-yl) ethoxy) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole, and the synthetic route is shown as follows:
(1) Target product I 10 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 6H-indolo [2,3-b ]]A solution of quinoxaline (228.05. Mu. Mol) was added with sodium hydride (912.21. Mu. Mol). After stirring the solution at 0℃for 1h, the compound III is added 3 (273.66. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 10 . The yield thereof was found to be 64%. 1 H NMR(300MHz,Chloroform-d)δ8.48(dt,J＝7.7,1.1Hz,1H),8.35–8.28(m,1H),8.20–8.11(m,1H),7.77(ddd,J＝8.4,6.9,1.7Hz,1H),7.70(ddd,J＝8.3,6.9,1.6Hz,1H),7.62(ddd,J＝8.3,7.2,1.3Hz,1H),7.43–7.32(m,2H),7.32–7.26(m,2H),6.87–6.77(m,2H),5.65(s,2H),4.10(t,J＝5.8Hz,2H),2.93(t,J＝5.8Hz,2H),2.68(d,J＝6.3Hz,4H),1.83(p,J＝3.3Hz,4H)。 13 C NMR(75MHz,Chloroform-d)δ158.23,144.25,140.67,139.50,131.00,129.36,128.82,128.78,128.65,127.90,126.10,122.69,121.10,119.65,114.82,110.20,66.64,54.91,54.68,44.50,23.42。
Example 11
The chemical name of the bazedoxifene derivative is 6- (4- (2- (piperidine-1-yl) ethoxy) -6H-indolo [2,3-b ] quinoxaline, and the synthetic route is shown as follows:
(1) Target product I 11 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide under the protection of argonMixing to obtain the compound 6H-indolo [2,3-b ]]A solution of quinoxaline (228.05. Mu. Mol) was added with sodium hydride (912.21. Mu. Mol). After stirring the solution at 0℃for 1h, the compound III is added 3 (273.66. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 11 . The yield thereof was found to be 60%. 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J＝7.7Hz,1H),8.32(dd,J＝8.4,1.5Hz,1H),8.16(dd,J＝8.4,1.5Hz,1H),7.78(ddd,J＝8.4,6.9,1.6Hz,1H),7.70(ddd,J＝8.3,6.8,1.5Hz,1H),7.62(ddd,J＝8.4,7.3,1.3Hz,1H),7.43–7.33(m,2H),7.33–7.26(m,2H),6.86–6.73(m,2H),5.65(s,2H),4.07(t,J＝6.0Hz,2H),2.77(t,J＝6.0Hz,2H),2.51(s,4H),1.61(p,J＝5.5Hz,4H),1.43(d,J＝3.4Hz,2H)。 13 C NMR(101MHz,Chloroform-d)δ158.29,145.76,144.26,140.68,139.50,130.97,129.35,128.80,128.71,128.64,127.90,126.08,122.69,121.08,119.67,114.83,110.18,65.75,57.77,54.95,44.51,25.72,24.03。
Example 12
The chemical name of the bazedoxifene derivative is 6- (4- (2- (azepine-1-yl) ethoxy) -6H-indolo [2,3-b ] quinoxaline, and the synthetic route is shown as follows:
(1) Target product I 12 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 6H-indolo [2,3-b ]]A solution of quinoxaline (228.05. Mu. Mol) was added with sodium hydride (912.21. Mu. Mol). After stirring the solution at 0℃for 1h, the compound III is added 3 (273.66. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain yellow solid of the target compoundⅠ 11 . The yield thereof was found to be 58%. 1 H NMR(300MHz,Chloroform-d)δ8.48(dt,J＝7.6,1.0Hz,1H),8.32(dd,J＝8.1,1.6Hz,1H),8.21–8.08(m,1H),7.77(ddd,J＝8.4,6.8,1.6Hz,1H),7.70(ddd,J＝8.3,6.9,1.6Hz,1H),7.62(ddd,J＝8.3,7.2,1.3Hz,1H),7.44–7.33(m,2H),7.32–7.26(m,2H),6.88–6.74(m,2H),5.65(s,2H),4.06(t,J＝6.1Hz,2H),2.96(t,J＝6.0Hz,2H),2.81(s,4H),1.67(s,4H),1.59(dd,J＝6.1,3.2Hz,4H)。 13 C NMR(75MHz,Chloroform-d)δ158.36,145.77,144.26,140.68,140.09,139.50,130.99,129.36,128.82,128.64,127.90,126.09,122.69,121.09,114.82,110.20,66.21,56.24,55.78,44.52,27.60,27.03。
Example 13
The chemical name of the bazedoxifene derivative is 8-chloro-11- (1- (4- (2- (pyrrolidine-1-yl) ethoxy) piperidine-4-subunit) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine, and the synthetic route is shown as follows:
(1) Target product I 13 Is synthesized by (a)
The compound 6H-indolo [2,3-b]Quinoxaline (160.86. Mu. Mol), anhydrous potassium carbonate (402.16. Mu. Mol) and III 1 (209.12. Mu. Mol) was added to N, N-dimethylformamide and stirred with heating at 70 ℃. After 4 hours of reaction, the plates were monitored and ethyl acetate was added for extraction when TLC indicated the reaction was complete. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 13 . The yield thereof was found to be 82%. 1 H NMR(300MHz,Chloroform-d)δ8.38(dd,J＝4.8,1.7Hz,1H),7.42(dd,J＝7.7,1.7Hz,1H),7.24–7.16(m,2H),7.16–7.09(m,3H),7.07(dd,J＝7.7,4.8Hz,1H),6.89–6.80(m,2H),4.13(t,J＝5.8Hz,2H),3.52–3.28(m,4H),2.94(t,J＝5.9Hz,2H),2.89–2.76(m,2H),2.76–2.64(m,6H),2.51(ddd,J＝13.8,9.7,4.1Hz,1H),2.44–2.24(m,3H),2.13(d,J＝9.4Hz,2H),1.84(h,J＝3.2Hz,4H)。 13 C NMR(75MHz,Chloroform-d)δ157.89,146.66,139.52,139.20,137.20,132.59,132.50,130.92,130.36,130.30,128.95,125.98,122.05,114.22,66.85,62.27,55.07,54.72,54.67,54.62,31.87,31.45,30.98,30.74,23.48。
Example 14
The chemical name of the bazedoxifene derivative is 8-chloro-11- (1- (4- (2- (piperidine-1-yl) ethoxy) benzyl) piperidine-4-subunit) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine, and the synthetic route is shown as follows:
(1) Target product I 14 Is synthesized by (a)
The compound 6H-indolo [2,3-b]Quinoxaline (160.86. Mu. Mol), anhydrous potassium carbonate (402.16. Mu. Mol) and III 1 (209.12. Mu. Mol) was added to N, N-dimethylformamide and stirred with heating at 70 ℃. After 4 hours of reaction, the plates were monitored and ethyl acetate was added for extraction when TLC indicated the reaction was complete. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 13 . The yield thereof was found to be 85%. 1 H NMR(300MHz,Chloroform-d)δ8.38(dd,J＝4.8,1.7Hz,1H),7.42(dd,J＝7.6,1.7Hz,1H),7.23–7.16(m,2H),7.15–7.02(m,4H),6.88–6.79(m,2H),4.10(t,J＝6.1Hz,2H),3.52–3.29(m,4H),2.88–2.69(m,6H),2.51(tt,J＝9.9,4.0Hz,5H),2.35(tdd,J＝14.1,9.6,4.0Hz,3H),2.12(td,J＝10.8,5.4Hz,2H),1.71–1.54(m,4H),1.45(d,J＝5.8Hz,2H)。 13 C NMR(75MHz,Chloroform-d)δ157.80,146.66,139.53,137.84,137.24,133.41,132.63,130.87,130.46,130.46,128.97,126.00,122.08,114.26,65.51,62.18,57.76,54.93,54.61,54.55,31.85,31.45,30.85,30.61,25.54,23.90。
Example 15
The chemical name of the bazedoxifene derivative is 11- (1- (4- (2- (azepan-1-yl) ethoxy) benzyl) piperidine-4-subunit) -8-chloro-6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine, and the synthetic route is shown as follows:
(1) Target product I 15 Is synthesized by (a)
The compound 6H-indolo [2,3-b]Quinoxaline (160.86. Mu. Mol), anhydrous potassium carbonate (402.16. Mu. Mol) and III 3 (209.12. Mu. Mol) was added to N, N-dimethylformamide and stirred with heating at 70 ℃. After 4 hours of reaction, the plates were monitored and ethyl acetate was added for extraction when TLC indicated the reaction was complete. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as yellow solid I 15 . The yield thereof was found to be 82%. 1 H NMR(400MHz,Chloroform-d)δ8.38(dd,J＝4.9,1.6Hz,1H),7.42(dd,J＝7.7,1.7Hz,1H),7.21(d,J＝8.2Hz,2H),7.16–7.10(m,3H),7.07(dd,J＝7.7,4.8Hz,1H),6.87–6.81(m,2H),4.13(s,2H),3.49–3.31(m,4H),3.03(s,2H),2.97–2.66(m,8H),2.52(t,J＝11.9Hz,1H),2.46–2.28(m,3H),2.13(s,2H),1.72(s,4H),1.63(s,4H)。 13 C NMR(75MHz,Chloroform-d)δ157.93,146.64,139.51,139.21,137.21,133.41,132.59,132.48,130.92,130.36,130.27,128.96,125.98,122.06,114.22,66.23,62.28,56.36,55.83,54.68,54.63,31.87,31.44,30.98,30.75,27.68,27.05。
Example 16
The chemical name of the bazedoxifene derivative is 9- (4-phenethoxybenzyl) -9H-pyrido [2,3-b ] indole, and the synthetic route is shown as follows:
(1) Intermediate IV 1 Is synthesized by (a)
Phenethyl alcohol (1.85 mmol), 4-hydroxybenzaldehyde (1.85 mmol) and PPh3 (2.22 mmol) were stirred in dry THF (20 mL) at 0 ℃ under nitrogen atmosphere. DIAD (2.22 mmol) was added dropwise to this mixture for 5min and the reaction was monitored by thin layer chromatography. After complete disappearance of the starting material (1 h),the solvent was evaporated under reduced pressure and the resulting oil was purified by column chromatography on silica gel (hexane/AcOEt, 8/2). After precipitation, 4-phenethoxybenzaldehyde was obtained as a white powder in 76% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H),7.90–7.80(m,2H),7.38–7.28(m,4H),7.26–7.19(m,1H),7.16–7.07(m,2H),4.31(t,J＝6.9Hz,2H),3.07(t,J＝6.8Hz,2H)。
(2) Intermediate V 1 Is synthesized by (a)
Intermediate IV 1 (3.97 mmol) is added into methanol solution, sodium borohydride (11.91 mmol) is added, stirring is carried out at room temperature for 2 hours, when TLC shows that the reaction is finished, 1mol/L hydrochloric acid is added to quench until no gas is discharged, saturated sodium bicarbonate solution is used for adjusting the alkalinity, methanol in the system is spun out, dichloromethane extraction, saturated sodium chloride washing, anhydrous sodium sulfate drying and filtration and spin drying are carried out, thus obtaining white solid V 1 The yield thereof was found to be 100%. 1 H NMR(300MHz,DMSO-d 6 )δ7.35–7.26(m,4H),7.26–7.15(m,3H),6.93–
6.83(m,2H),5.04(t,J＝5.7Hz,1H),4.40(d,J＝5.7Hz,2H),4.16(t,J＝6.9Hz,2H),3.02(t,J＝6.9Hz,2H)。
(3) Intermediate VI 1 Is synthesized by (a)
Intermediate V 1 A solution of (27.11 mmol) in tetrahydrofuran was cooled to 0℃and sulfoxide chloride (30.35 mmol) was slowly added dropwise thereto, followed by stirring at room temperature overnight. When TLC showed that the reaction was complete, directly spin-dried, without further purification, to give intermediate III 1 。
(4) Target product I 16 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 9H-pyrido [2,3-b ]]A solution of indole (416.17. Mu. Mol) was added with sodium hydride (1.87 mmol). After stirring the solution at 0 ℃ for 1h, adding the compound IV 3 (457.79. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 16 . The yield thereof was found to be 82%. 1 H NMR(300MHz,DMSO-d 6 )δ8.61–8.47(m,2H),8.21(dd,J＝7.7,1.2Hz,1H),7.64(d,J＝8.2Hz,1H),7.48(ddd,J＝8.3,7.2,1.2Hz,1H),7.31–7.18(m,9H),6.87–6.77(m,2H),5.63(s,2H),4.09(t,J＝6.9Hz,2H),2.96(t,J＝6.8Hz,2H)。
13 C NMR(75MHz,Chloroform-d)δ158.13,145.94,139.54,138.19,129.46,129.00,128.49,128.38,126.82,126.50,121.03,120.60,120.03,115.26,114.68,109.97,68.64,44.54,35.75。
Example 17
The chemical name of the bazedoxifene derivative is 9- (4- (3-trifluoromethyl) phenethyl) benzyl-9H-pyrido [2,3-b ] indole, and the synthetic route is shown as follows:
(1) Intermediate IV 2 Is synthesized by (a)
2- (3- (trifluoromethyl) phenyl) ethan-1-ol (1.85 mmol), 4-hydroxybenzaldehyde (1.85 mmol) and PPh3 (2.22 mmol) were stirred in dry THF (20 mL) at 0deg.C under nitrogen. DIAD (2.22 mmol) was added dropwise to this mixture for 5min and the reaction was monitored by thin layer chromatography. After complete disappearance of starting material (1 h), the solvent was evaporated under reduced pressure and the resulting oil was purified by silica gel column chromatography (hexane/AcOEt, 8/2). After precipitation, 4-phenethoxybenzaldehyde was obtained as a white powder in 76% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H),7.89–7.81(m,2H),7.73(s,1H),7.70–7.64(m,1H),7.62–7.52(m,2H),7.18–7.09(m,2H),4.37(t,J＝6.7Hz,2H),3.19(t,J＝6.7Hz,2H)。
(2) Intermediate V 2 Is synthesized by (a)
Intermediate IV 1 (3.97 mmol) is added into the solution A, sodium borohydride (11.91 mmol) is added, stirring is carried out for 2 hours at room temperature, when TLC shows that the reaction is finished, 1mol/L hydrochloric acid is added to quench until no gas is discharged, saturated sodium bicarbonate solution is used for adjusting the alkalinity, methanol in the system is spun out, dichloromethane extraction, saturated sodium chloride washing, anhydrous sodium sulfate drying and filtration and spin drying are carried out, thus obtaining the whiteColor solids V 2 The yield thereof was found to be 100%. 1 H NMR(400MHz,DMSO-d 6 )δ7.70(d,J＝1.8Hz,1H),7.67–7.63(m,1H),7.61–7.51(m,2H),7.25–7.16(m,2H),6.91–6.83(m,2H),5.03(t,J＝5.7Hz,1H),4.40(d,J＝5.7Hz,2H),4.21(t,J＝6.7Hz,2H),3.13(t,J＝6.7Hz,2H)。
(3) Intermediate VI 3 Is synthesized by (a)
Intermediate V 1 A solution of (27.11 mmol) in tetrahydrofuran was cooled to 0℃and sulfoxide chloride (30.35 mmol) was slowly added dropwise thereto, followed by stirring at room temperature overnight. When TLC showed that the reaction was complete, directly spin-dried, without further purification, to give intermediate VI 1 。
(4) Target compound I 17 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 9H-pyrido [2,3-b ]]A solution of indole (416.17. Mu. Mol) was added with sodium hydride (1.87 mmol). After stirring the solution at 0 ℃ for 1h, adding the compound IV 3 (457.79. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 17 . The yield thereof was found to be 83%. 1 H NMR(300MHz,DMSO-d 6 )δ8.56(dd,J＝7.6,1.6Hz,1H),8.50(dd,J＝4.9,1.6Hz,1H),8.21(dt,J＝7.8,1.0Hz,1H),7.65–7.44(m,6H),7.30–7.19(m,4H),6.86–6.78(m,2H),5.62(s,2H),4.13(t,J＝6.6Hz,2H),3.07(t,J＝6.6Hz,2H)。 13 C NMR(75MHz,Chloroform-d)δ157.92,139.52,139.31,132.41,132.40,129.70,128.86,128.41,128.36,126.82,125.81,125.76,123.36,121.04,120.05,116.02,115.27,114.67,109.94,68.05,44.51,35.51。
Example 18
The chemical name of the bazedoxifene derivative is 9- (4- (2- (pyridin-2-yl) ethoxy) benzyl) -9H-pyrido [2,3-b ] indole, and the synthetic route is shown as follows:
(1) Intermediate IV 3 Is synthesized by (a)
2- (pyridin-2-yl) ethan-1-ol (1.85 mmol), 4-hydroxybenzaldehyde (1.85 mmol) and PPh3 (2.22 mmol) were stirred in dry THF (20 mL) at 0deg.C under nitrogen. DIAD (2.22 mmol) was added dropwise to this mixture for 5min and the reaction was monitored by thin layer chromatography. After complete disappearance of starting material (1 h), the solvent was evaporated under reduced pressure and the resulting oil was purified by silica gel column chromatography (hexane/AcOEt, 8/2). After precipitation, 4-phenethoxybenzaldehyde was obtained as a white powder in 76% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.86(s,1H),8.51(ddd,J＝4.9,1.9,1.0Hz,1H),7.91–7.80(m,2H),7.73(td,J＝7.7,1.9Hz,1H),7.37(dt,J＝7.9,1.1Hz,1H),7.24(ddd,J＝7.5,4.8,1.2Hz,1H),7.18–7.02(m,2H),4.49(t,J＝6.6Hz,2H),3.22(t,J＝6.6Hz,2H)。
(2) Intermediate V 3 Is synthesized by (a)
Intermediate IV 3 (3.97 mmol) is added into the solution A, sodium borohydride (11.91 mmol) is added, stirring is carried out for 2 hours at room temperature, when TLC shows that the reaction is finished, 1mol/L hydrochloric acid is added to quench until no gas is discharged, saturated sodium bicarbonate solution is used for adjusting the reaction to be alkaline, methanol in the system is spun out, dichloromethane extraction, saturated sodium chloride washing, anhydrous sodium sulfate drying and filtration and spin drying are carried out, thus obtaining white solid V 3 The yield thereof was found to be 100%. 1 H NMR(400MHz,DMSO-d 6 )δ8.51(ddd,J＝4.9,1.9,0.9Hz,1H),7.72(td,J＝7.6,1.9Hz,1H),7.36(dt,J＝7.9,1.1Hz,1H),7.27–7.16(m,3H),6.92–6.82(m,2H),5.03(t,J＝5.7Hz,1H),4.40(d,J＝5.7Hz,2H),4.33(t,J＝6.7Hz,2H),3.17(t,J＝6.7Hz,2H)。
(3) Intermediate VI 3 Is synthesized by (a)
Intermediate V 3 A solution of (27.11 mmol) in tetrahydrofuran was cooled to 0℃and sulfoxide chloride (30.35 mmol) was slowly added dropwise thereto, followed by stirring at room temperature overnight. When TLC showed that the reaction was complete, directly spin-dried, without further purification, to give intermediate VI 3 。
(4) Target compound I 18 Is synthesized by (a)
Stirring in anhydrous N, N-dimethylformamide protected by argon to obtain a compound 9H-pyrido [2,3-b ]]A solution of indole (416.17. Mu. Mol) was added with sodium hydride (1.87 mmol). After stirring the solution at 0℃for 1h, the compound VI is added 3 (457.79. Mu. Mol) and stirred at room temperature for 4h. When TLC showed the reaction was complete, ice water was added and washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purifying the residue by silica gel column chromatography to obtain the target compound as white solid I 18 . The yield thereof was found to be 83%.
1 H NMR(300MHz,Chloroform-d)δ8.51(dt,J＝4.9,1.4Hz,2H),8.33(dd,J＝7.7,1.6Hz,1H),8.07(dt,J＝7.8,1.0Hz,1H),7.57(td,J＝7.7,1.9Hz,1H),7.49–7.38(m,1H),7.38–7.32(m,1H),7.30–7.14(m,5H),7.11(ddd,J＝7.6,4.9,1.2Hz,1H),6.86–6.72(m,2H),5.62(s,2H),4.28(t,J＝6.6Hz,2H),3.20(t,J＝6.6Hz,2H)。
13 C NMR(75MHz,Chloroform-d)δ158.45,158.09,149.27,146.15,139.51,136.48,129.54,128.34,128.19,126.74,123.79,121.61,121.01,120.61,119.95,115.87,115.26,114.72,109.92,67.08,44.45,37.97。
Application of
The cck-8 assay detects the inhibitory effect of Compound I on colorectal cancer cell lines
Taking bazedoxifene as a positive control, preparing a concentration of 20 mu M for primary screening, and calculating the cell inhibition rate of HT29 at 20 mu M; compound I was formulated at the same concentration and then subjected to a primary screening and compound with lower inhibition than bazedoxifene was subjected to a secondary screening. The concentration gradients of bazedoxifene and compound I were set at 0.94, 1.88, 3.75, 7.50, 15.00, 30.00 μm at the secondary screening. Both rounds of screening were performed on colorectal cancer cell line HT29, with an initial cell number of 4000 per well, and the cell viability at 48h was directly determined, and the IC of the compound was finally determined 50 。
Cell viability = [ (experimental group reading-blank group reading)/(control group reading-blank group reading) ]x100%.
TABLE 1 inhibition of HT29 by Compound I
2. Compound I 6 Growth inhibitory effect on HT29 cells
HT29 cells were seeded 1000 per well into six well plates and given different concentrations of I of 1. Mu.M, 2. Mu.M, 4. Mu.M, 8. Mu.M and 12. Mu.M 6 The administration group and the 0.1% DMSO control group are washed by precooled PBS after 48 hours of action, and are further cultured for 10-14 days, so that cells are fixed by 4% paraformaldehyde after forming colonies, and are dyed by 1% crystal violet dye solution, and the following results are obtained by counting Image J:
in summary, based on the effect of bazedoxifene on GP130, we designed and synthesized a series of compounds I. In vitro research and test on colorectal cancer cells HT29 show that the HT29 can significantly inhibit occurrence and development of colorectal cancer cells; provides possibility for the preparation of small-molecule antitumor drugs for colorectal cancer, and has good application prospect.

Claims (10)

1. A bazedoxifene derivative, characterized in that it has a structure represented by formula (I):
wherein, the A group is a substituted or unsubstituted five-, six-, seven-membered saturated or unsaturated heterocycle, a substituted or unsubstituted aromatic ring; when the a group is a heterocycle, there are one to two heteroatoms in the ring, the heteroatoms being selected from: n, O, S;
the B group is a ternary or quaternary condensed ring aromatic group;
n is 1,2 or 3.
2. A bazedoxifene derivative according to claim 1 wherein the a group is selected from furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, substituted phenyl or pyridyl;
the B group being
Wherein a, b, C are each independently selected from C or N.
3. Bazedoxifene derivative according to claim 2, wherein the a group is specifically selected from any of the following compounds:
4. bazedoxifene derivative according to claim 2, wherein said
Has any one of the following structures:
5. a bazedoxifene derivative according to claim 2, wherein the B group comprises the following structure:
6. a bazedoxifene derivative according to claim 1, wherein said bazedoxifene derivative has any one of the following compound structures:
7. a process for the preparation of a bazedoxifene derivative according to claim 1, characterized in that when said group a is an aliphatic heterocycle, it comprises the following steps:
(1) Reacting p-hydroxybenzyl alcohol with corresponding halogeno compound hydrochloride under the action of phase transfer catalyst to obtain a compound II;
(2) The compound II is reacted overnight under the action of thionyl chloride to obtain a compound III;
(3) And obtaining the compound I from the compound III and the fragment B under the action of sodium hydride.
8. The method for preparing bazedoxifene derivative according to claim 6, wherein in step (2), a reaction solvent is added to the hydrochloride of p-hydroxybenzyl alcohol and the corresponding halide to participate in the reaction, wherein the reaction solvent is one or more selected from the group consisting of acetone, diethyl ether, ethylene glycol dimethyl ether, and toluene; and or; in the step (3), the reaction solvent is selected from one or more of tetrahydrofuran, N dimethylformamide, diethyl ether, ethylene glycol dimethyl ether, N-methylpyrrolidone and tert-butyl alcohol.
9. A process for the preparation of a bazedoxifene derivative according to claim 1, wherein when the group a is an aromatic or heteroaromatic ring, comprising the steps of:
the p-hydroxybenzaldehyde reacts with 2-phenyl ethane-1-alcohol, 2- (3- (trifluoromethyl) phenyl) ethane-1-alcohol and 2- (pyridine-2-yl) ethane-1-alcohol respectively under the condition of diisopropyl azodicarboxylate and triphenylphosphine to obtain a compound IV;
a. reducing the compound IV into a compound V under the action of sodium borohydride;
b. the compound V is chlorinated into a compound VI under the action of thionyl chloride;
c. the compound VI and the fragment B are reacted with sodium hydride to obtain the compound I.
10. Use of a bazedoxifene derivative according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a tumour.
CN202311407502.1A 2023-10-27 2023-10-27 Bazedoxifene derivative and preparation method and application thereof Pending CN117447468A (en)

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