An indole compound, a preparation method and application thereof

Abstract

The application discloses an indole compound, a preparation method and application thereof, and the indole compound has the structure shown in formula (I). The indole compound has anti-inflammatory activity and bioactivity of promoting angiogenesis. Meanwhile, raw materials used in a synthesis method of preparing the indole compound by using a rhodium / copper bimetal catalyst are cheap and easy to obtain, and the preparation process is simple and easy to operate.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, and in particular to an indole compound, its preparation method, and its application. Background Technology

[0002] Indole compounds play a crucial role in modulating the bioactivity and photophysical properties of natural products, drugs, and materials. However, existing methods for synthesizing indole compounds are cumbersome and require harsh reaction conditions. Pyridine is one of the simplest aza-aromatic hydrocarbons, and functionalizing the C-H bonds of the pyridine group is a simple and atomically efficient method for obtaining complex aza-indole compounds.

[0003] Currently, significant progress has been made in carbon-carbon coupling of pyridine with alkenes, ketones, and alkyl halides via transition metals and photocatalysis. In contrast, research on the carbamatization of pyridine is limited. Meanwhile, 1,2,3-triazole is a simple and readily available azirethylene carbene precursor, sharing many characteristics with diazo-derived carbenes in carbon-carbon coupling reactions. Its vinylamine group can also be further amination. In 2019, a cobalt(II)-catalyzed reaction of the Csp2-H bond of pyridine with α-diazo ester compounds was reported, synthesizing valuable compounds containing ester and methylpyridine groups via long-range directing of the 2-amino group to the C3 position of pyridine.

[0004] Cardiovascular disease (CVD) is a serious threat to human health, with high morbidity and mortality rates. Endothelial dysfunction (ED) is an early marker of CVD, mainly manifested as impaired vasodilation, altered angiogenesis and barrier function, and enhanced oxidative stress and inflammation, including atherosclerosis, hypertension, and coronary heart disease. To date, there are few existing bioactive molecules for treating cardiovascular disease, and their bioactivity is limited. Therefore, it is essential to synthesize bioactive molecules with high bioactivity for treating cardiovascular disease (CVD). Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention provides a synthetic method for preparing indole compounds using rhodium / copper bimetallic catalysis. These indole compounds possess anti-inflammatory activity and angiogenesis-promoting bioactivity. Furthermore, the raw materials used in this method are inexpensive and readily available, and the preparation process is simple and easy to operate.

[0006] The purpose of this invention is to provide an indole compound having the structure shown in formula (I):

[0007]

[0008] Among them, R 1 R2 Independently Me, Bn, or MeO-Ph;

[0009] Or, R 1 R 2 The N atoms respectively bonded to them form a ring, wherein the ring is pyrrolidinyl or morpholinyl;

[0010] R 3 It can be H, Me, OMe, halogen, CF3, Ph, CN, ethynylbenzene or vinylbenzene;

[0011] Or, R 1 For methyl, R 2 R 3 and R 2 The connected nitrogen atoms form a ring, which is a pyrrolidinyl ring;

[0012] R 4 For H or Me;

[0013] Or, R 3 R 4 Cyclonification, wherein the ring is cyclohexyl or phenylcycloyl;

[0014] R 6 When it is H, R 5 It is n-pentyl, estrone, phenyl, or a substituted phenyl group, wherein the substituent of the substituted phenyl group is Me, OMe, CF3, halogen, COO-L-menthol, COO-stigmasterol, or COOMe;

[0015] Or, R 5 R 6 Cyclic formation, wherein the ring is naphthyl or substituted naphthyl, and the substituent of the substituted naphthyl is n-butyl, OMe, halogen, CF3 or OMe-Ph;

[0016] R 7 It is Me, naphthyl, phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is Me, OMe, halogen or CF3.

[0017] In some embodiments of the present invention, the R 1 R 2 Independently Me, Bn, or 4-MeO-Ph;

[0018] Or, R 1 R 2 The N atoms respectively bonded to them form a ring, wherein the ring is pyrrolidinyl or morpholinyl;

[0019] R 3 The components are H, Me, OMe, Cl, Br, CF3, Ph, CN, ethynylbenzene, or vinylbenzene;

[0020] Or, R 1 For methyl, R 2 R 3 and R 2 The connected nitrogen atoms form a ring, which is a pyrrolidinyl ring;

[0021] R 4 For H or Me;

[0022] Or, R 3 R 4 Cyclonification, wherein the ring is cyclohexyl or phenylcycloyl;

[0023] R 6 When it is H, R 5 It is n-pentyl, estrone, phenyl, or a substituted phenyl group, wherein the substituent of the substituted phenyl group is Me, OMe, CF3, halogen, 4-COO-L-menthol, 4-COO-stigmasterol, or COOMe;

[0024] Or, R 5 R 6 Cyclic formation, wherein the ring is naphthyl or substituted naphthyl, and the substituent of the substituted naphthyl is n-butyl, OMe, Br, CF3 or 4-OMePh;

[0025] R 7 It is Me, naphthyl, phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is Me, OMe, F, Cl, Br or CF3.

[0026] In a second aspect, the present invention provides a method for preparing the aforementioned indole compounds, comprising the following steps:

[0027] Replaced pyridine With substituted triazoles The reaction yields indole compounds.

[0028] In some embodiments of the present invention, the molar ratio of the substituted pyridine to the substituted triazole is 1:1 to 4.

[0029] In some embodiments of the present invention, the molar ratio of the substituted pyridine to the substituted triazole is 1:1.5 to 4.

[0030] In some embodiments of the present invention, the catalyst for the reaction is a composite catalyst of a rhodium metal catalyst and a copper metal catalyst.

[0031] In some embodiments of the present invention, the rhodium metal catalyst includes at least one of RhCl3, Rh2(OAc)4, Rh2(oct)4, Rh2(OPiv)4, Rh2(esp)2, and Rh2(CF3COO)4.

[0032] In some embodiments of the present invention, the rhodium metal catalyst is selected from Rh2(esp)2.

[0033] In some embodiments of the present invention, the molar ratio of the substituted pyridine to the rhodium metal catalyst is 100:1 to 10.

[0034] In some embodiments of the present invention, the molar ratio of the substituted pyridine to the rhodium metal catalyst is 100:5.

[0035] In some embodiments of the present invention, the copper metal catalyst includes at least one of Cu(OAc)2, CuOAc, CuBr, CuF2, and Cu(OH)Cl.

[0036] In some embodiments of the present invention, the copper metal catalyst is selected from Cu(OH)Cl.

[0037] In some embodiments of the present invention, the molar ratio of the substituted pyridine to the copper metal catalyst is 1:1 to 3.

[0038] In some embodiments of the present invention, the molar ratio of the substituted pyridine to the copper metal catalyst is 1:2.

[0039] In some embodiments of the present invention, the reaction temperature is 80–100°C.

[0040] In some embodiments of the present invention, the reaction time is 12 to 48 hours.

[0041] In some embodiments of the present invention, the reaction time is 24 hours.

[0042] In some embodiments of the present invention, the solvent for the reaction includes at least one selected from dichloromethane, 1,2-dichloroethane, trichloromethane, tetrachloroethane, trifluorotoluene, tetrahydrofuran, and 1,4-dioxane.

[0043] In a third aspect, the present invention proposes the use of the aforementioned indole compounds in the preparation of pharmaceutical compositions.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] (1) The indole compounds obtained in this invention have anti-inflammatory activity and bioactivity that promotes angiogenesis in vivo.

[0046] (2) The present invention uses substituted pyridine and substituted triazole as raw materials and rhodium / copper metal as catalyst to prepare indole compounds at 80-100℃. The preparation method of the present invention has the advantages of simple operation, high atomic efficiency, easy purification of products, low toxicity and environmental friendliness. Attached Figure Description

[0047] Figure 1 The photon spectrum of indole compound 3a prepared in Example 1 is shown.

[0048] Figure 2 The carbon spectrum of indole compound 3a prepared in Example 1 is shown.

[0049] Figure 3 The photon spectrum of the indole compound 3s prepared in Example 2 is shown.

[0050] Figure 4 The image shows the carbon spectrum of the indole compound 3s prepared in Example 2.

[0051] Figure 5 The photon spectrum of the indole compound 4m prepared in Example 3 is shown.

[0052] Figure 6 The image shows the carbon spectrum of the indole compound 4m prepared in Example 3.

[0053] Figure 7 The photon spectrum of indole compound 6d prepared in Example 4 is shown.

[0054] Figure 8 The carbon spectrum of the indole compound 6d prepared in Example 4 is shown.

[0055] Figure 9 The photon spectrum of 6g of the indole compound prepared in Example 5 is shown.

[0056] Figure 10 The carbon spectrum of 6g of the indole compound prepared in Example 5 is shown.

[0057] Figure 11 The results of anti-inflammatory tests on indole compounds 3m, 3s, 4e, 4g, 4m, 4q, 4s, 6a, and 6i are presented.

[0058] Figure 12 Results of tests showing that indole compounds 4d, 4k, 4m, 4o, 4q, 6d, 6g, and 6h promote angiogenesis in zebrafish. Detailed Implementation

[0059] The following will describe the concept and technical effects of the present invention clearly and completely with reference to the embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available.

[0060] In the description of this invention, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0061] COO-L-menthol represents

[0062] estrone represents

[0063] COO-stigmasterol represents

[0064] Example 1

[0065] This embodiment provides indole compound 3a, and the specific process is as follows:

[0066]

[0067] 2-Pyrrolidinylpyridine 1a (0.1 mmol), 4-phenyl-1-toluenesulfonyl-1H-1,2,3-triazole 1b (0.15 mmol), Rh2(esp)2 (0.005 mmol), Cu(OH)Cl (0.2 mmol), and dichloromethane (1.5 mL) were added to a sealed tube. The mixture was stirred at 100 °C and reacted for 24 h. Heating was then stopped, and the mixture was cooled to room temperature and evaporated to dryness. The solution was purified by column chromatography using petroleum ether as the eluent to obtain indole compound 3a in 72% yield.

[0068] 1H NMR (400MHz, CDCl3) δ8.13(d,J=8.4Hz,1H),7.79(d,J=8.7Hz,1H),7.59-7.51(m,2H),7.42(t,J=7.6 Hz,1H),7.34-7.22(m,2H),6.28(d,J=8.7Hz,1H),3.63-3.47(m,2H),2.36(s,2H),2.09-1.97(m,2H).

[0069] 13 C NMR (100MHz, CDCl3) δ154.8,147.4,144.7,135.7,133.9,130.0,129.3,128.9,128.6,127.2,127.1,120.4,117.1,110.7,103.7,47.1,25.6,21.7.

[0070] HR-MS(ESI)m / z:[M+H] + Calculated for; C 24 H 24 N3O2S 418.1584; found 418.1583.

[0071] Example 2

[0072] This embodiment provides an indole compound 3s, the specific process of which is as follows:

[0073]

[0074] 1-Pyrrolidine-5,6,7,8-tetrahydroisoquinoline 1b (0.1 mmol), 4-phenyl-1-toluenesulfonyl-1H-1,2,3-triazole 2b (0.15 mmol), Rh2(esp)2 (0.005 mmol), Cu(OH)Cl (0.2 mmol), and dichloromethane (1.5 mL) were added to a sealed tube. The mixture was stirred at 100 °C and reacted for 24 h. Heating was then stopped, and the mixture was cooled to room temperature and evaporated to dryness. The solution was purified by column chromatography using petroleum ether as the eluent to obtain indole compound 3s, with a yield of 49%.

[0075] 1H NMR(500MHz, CDCl3)δ8.10(d,J=8.3Hz,2H),7.35(s,5H),7.31(s,1H),7.26(d,J=8.9Hz,2H),3.58-3.49 (m,4H),2.59(d,J=5.0Hz,2H),2.48(d,J=5.4Hz,2H),2.38(s,3H),2.00-1.89(m,4H),1.61-1.56(m,4H). 13 C NMR (125MHz, CDCl3) δ157.6,144.6,143.4,141.5,136.0,135.6,130.1,129.3,128.4 ,127.8,127.2,121.8,119.4,117.4,113.5,50.6,28.1,27.5,25.7,23.0,22.1,21.6.

[0076] HR-MS(ESI)m / z:[M+H] + Calculated for; C 28 H 30 N3O2S 472.2053; found 472.2054.

[0077] Example 3

[0078] This embodiment provides an indole compound 4m, and the specific process is as follows:

[0079]

[0080] 2-pyrrolylpyridine 1c (0.1 mmol), 1-((4-methoxyphenyl)sulfonyl)-4-phenyl-1H-1,2,3-triazole 2c (0.15 mmol), Rh2(esp)2 (0.005 mmol), Cu(OH)Cl (0.2 mmol), and dichloromethane (1.5 mL) were added to a sealed tube. The mixture was stirred at 100 °C and reacted for 24 h. Heating was then stopped, and the mixture was cooled to room temperature and evaporated to dryness. The solution was purified by column chromatography using petroleum ether as the eluent to obtain indole compound 4m, with a yield of 58%.

[0081] 1H NMR (500MHz, CDCl3) δ8.19(d,J=8.7Hz,2H),7.80(d,J=8.7Hz,1H),7.60-7.54(m,3H),7.43(t,J=7.6Hz,2H),7.31(t ,J=7.4Hz,1H),6.92(d,J=8.7Hz,2H),6.33(d,J=8.7Hz,1H),3.81(s,3H),3.55(t,J=6.3Hz,4H),2.07-1.99(m,5H).

[0082] 113 C NMR (125MHz, CDCl3) δ163.8,155.0,147.3,133.9,130.9,130.1,129.9,128.9,127.2,127.1,120.2,117.2,113.9,110.8,103.9,55.7,47.4,25.5.

[0083] HR-MS(ESI)m / z:[M+H] + Calculated for; C 24 H 24 N3O3S 434.1533; found 434.1525.

[0084] Example 4

[0085] This embodiment provides indole compound 6d, and the specific process is as follows:

[0086]

[0087] N,N-dibenzylisoquinoline-1-amine 1d (0.1 mmol), 8-methoxy-3-toluenesulfonyl-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazole 2d (0.15 mmol), Rh2(esp)2 (0.005 mmol), Cu(OH)Cl (0.2 mmol), and dichloromethane (1.5 mL) were added to a sealed tube. The mixture was stirred at 100 °C and reacted for 24 h. Heating was then stopped, and the mixture was cooled to room temperature and evaporated to dryness. The solution was purified by column chromatography using petroleum ether as the eluent to obtain indole compound 6d, with a yield of 60%.

[0088] 1H NMR (400MHz, CDCl3) δ8.93(d,J=8.5Hz,1H),8.64(d,J=9.0Hz,1H),8.44(d,J=8.3Hz,1H),8.18(s,1H),7.96(d,J=9.0Hz,1H),7.88(d,J=8.6Hz,3H) ,7.74(t,J=7.6Hz,1H),7.54(t,J=7.2Hz,1H),7.33-7.29(m,6H),7.29-7 .22(m,5H),7.00(d,J=8.2Hz,2H),4.87(s,4H),4.00(s,3H),2.31(s,3H).

[0089] 13 C NMR (100MHz, CDCl3) δ159.5,157.5,144.9,144.3,138.3,136.5,134.6,134.4,130.5,129.5,129.2,128.6,128.5,1 28.1,127.5,127.4,127.1,126.3,126.2,125.4,124.6,119.0,118.9,116.9,112.1,106.4,105.3,55.5,54.9,21.6.

[0090] HR-MS(ESI)m / z:[M+H] + Calculated for; C 41 H 34 N3O3S 648.2315; found 648.2318.

[0091] Example 5

[0092] This embodiment provides 6g of an indole compound, and the specific process is as follows:

[0093]

[0094] N,N-dibenzylisoquinoline-1-amine 1e (0.1 mmol), 7-(4-methoxyphenyl)-3-toluenesulfonyl-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazole 2e (0.15 mmol), Rh2(esp)2 (0.005 mmol), Cu(OH)Cl (0.2 mmol), and dichloromethane (1.5 mL) were added to a sealed tube. The mixture was stirred at 100 °C and reacted for 24 h. Heating was then stopped, and the mixture was cooled to room temperature and evaporated to dryness. The solution was purified by column chromatography using petroleum ether as the eluent to obtain 6 g of indole compounds, with a yield of 62%.

[0095] 1 H NMR (500MHz, CDCl3) δ8.90(d,J=8.6Hz,2H),8.74(d,J=9.1Hz,1H),8.37(dd,J=8.4 ,1.3Hz,1H),8.15(d,J=2.0Hz,1H),7.92(d,J=9.1Hz,1H),7.88-7.81(m,3H),7.74- 7.68(m,3H),7.50-7.45(m,1H),7.26(dt,J=5.9,2.5Hz,6H),7.24-7.20(m,4H),7. 02(d,J=8.7Hz,2H),6.95(d,J=8.3Hz,2H),4.83(s,4H),3.84(s,3H),2.25(s,3H)..

[0096] 13 C NMR (125MHz, CDCl3) δ159.6,159.3,145.0,144.4,138.3,136.9,136.5,134.5,133.8,133.4,131.6,129.8,129.5,128.5,128.3,1 28.2,127.5,127.3,127.1,126.6,126.3,126.1,126.0,125.2,124.8,124.7,119.7,118.9,114.9,114.5,106.6,55.4,54.9,21.6.

[0097] HR-MS(ESI)m / z:[M+H] + Calculated for; C 47 H 38 N3O3S 724.2628; found 724.2630.

[0098] Examples 6-47

[0099] This embodiment provides indole compounds 3b-3r, 4a-4l, 4n-4s, 6a-6c, 6e-6f, and 6h-6j, whose structural formulas are shown below, and whose preparation methods are the same as in Example 1.

[0100]

[0101]

[0102] Performance testing:

[0103] The care of zebra fish is as follows:

[0104] Wild-type AB and transgenic lines Tg(Fli1:GFP) and Tg(corolla:GFP; lyz:Dsred) were provided by Professor Wenqing Zhang (South China University of Technology). Zebrafish were kept in a 14-hour light / 10-hour dark cycle in 0.03%–0.04% circulating water. All embryos were cultured in E3 medium (5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2, 0.33 mM MgSO4, and 0.1% methylene blue, equilibrated to pH 7.0).

[0105] The zebrafish toxicity test results are shown below:

[0106] Zebrafish larvae at 3 days post-fertilization (3 dpf) and 4 hours post-fertilization (4 hpf) were randomly assigned to 6-well plates, with 20 embryos per well in each group. Indole compounds were diluted in 0.1% dimethyl sulfoxide and 0.1% Tween-80. Except for the control group, all groups received different concentrations of indole compounds (18, 30, and 50 μM). After 24 hours, malformations and mortality of the zebrafish embryos were observed and recorded under an SZX7 stereomicroscope (Olympus, Japan).

[0107] The non-toxic concentrations (μM) of compounds 3a-6i in zebrafish for their anti-inflammatory and angiogenesis effects are shown in Table 1 below.

[0108] Table 1. Non-toxic concentrations of indole compounds in zebrafish for their anti-inflammatory and angiogenesis effects.

[0109]

[0110]

[0111] The statistical analysis of data from zebrafish anti-inflammatory tests and tests promoting in vivo angiogenesis is shown below:

[0112] All data are expressed as mean ± standard deviation. Comparisons of means among multiple groups were performed using one-way ANOVA. Tukey's test and Dunnett's test were used for comparisons among multiple groups. A p-value <0.05 was considered statistically significant.

[0113] Anti-inflammatory test in zebrafish:

[0114] 3dpf-Tg (corolla:GFP; lyz:Dsred) zebrafish larvae were randomly placed in 12-well plates, with 20 larvae per well per group. CuSO4 (20 μM) was used to induce inflammation in the zebrafish. The larvae were treated with different indole compounds (3a-6i) at the maximum safe concentration. After 2 hours of stimulation, neutrophil migration behavior was observed and recorded under an MVX10 fluorescence microscope (Olympus, Japan). Preliminary bioactivity tests showed that compounds 3m, 3s, 4e, 4g, 4m, 4q, 4s, 6a, and 6i had a good inhibitory effect on cellular inflammation. Results are shown below. Figure 11 .

[0115] Tests to promote angiogenesis in zebrafish;

[0116] 12 hpf-Tg(Fli1:GFP) zebrafish embryos were randomly assigned to 12-well plates, with 15 embryos per well per group. The embryos were treated with indole compounds (3a-6i) for 12 hours, followed by membrane rupture. Finally, the formation of intersegmental vessels (ISVs) in the zebrafish was observed and recorded under a fluorescence microscope (Olympus, Japan), and the ISV index was calculated. Preliminary bioactivity tests showed that compounds 4d, 4k, 4m, 4o, 4q, 6d, 6g, and 6h promoted ISV formation (×3.2). Results are shown below. Figure 12 .

[0117] This invention provides an indole compound with anti-inflammatory activity and promoting angiogenesis, and a method for synthesizing indole compounds using rhodium / copper bimetallic catalysis. This discovery of indole compounds and their applications has significant research and development potential.

[0118] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An indole compound, characterized in that, Its structural formula is shown in formulas 3s, 6a, 6d, 6h or 6i:

2. The method for preparing the indole compound according to claim 1, characterized in that, Includes the following steps: In the presence of a catalyst, the substituted pyridine With substituted triazoles The reaction yields indole compounds as shown in formula (Ⅰ). Equation (Ⅰ); Among them, the substituent R in the indole compound shown in formula (Ⅰ) 1 R 2 R 3 R 4 R 5 R 6 R 7 The substituents at the corresponding positions of the compound as described in claim 1; the catalyst is a composite catalyst of a rhodium metal catalyst and a copper metal catalyst.

3. The method for preparing indole compounds according to claim 2, characterized in that, The molar ratio of the substituted pyridine to the substituted triazole is 1:1 to 4.

4. The method for preparing indole compounds according to claim 2, characterized in that, The rhodium metal catalyst is selected from at least one of RhCl3, Rh2(OAc)4, Rh2(oct)4, Rh2(OPiv)4, Rh2(esp)2, and Rh2(CF3COO)4, and the molar ratio of the substituted pyridine to the rhodium metal catalyst is 100:1 to 10.

5. The method for preparing indole compounds according to claim 2, characterized in that, The copper metal catalyst is selected from at least one of Cu(OAc)2, CuOAc, CuBr, CuF2, and Cu(OH)Cl, and the molar ratio of the substituted pyridine to the copper metal catalyst is 1:1 to 3.

6. The method for preparing indole compounds according to claim 2, characterized in that, The reaction temperature is 80~100℃, and the reaction time is 12~48h.

7. The method for preparing indole compounds according to claim 2, characterized in that, The solvent used in the reaction is selected from at least one of dichloromethane, 1,2-dichloroethane, trichloromethane, tetrachloroethane, trifluorotoluene, tetrahydrofuran, and 1,4-dioxane.

8. The use of the indole compounds 3S, 6A, and 6I according to claim 1 in the preparation of anti-inflammatory pharmaceutical compositions.

9. The use of the indole compounds 6d and 6h according to claim 1 in the preparation of pharmaceutical compositions that promote in vivo angiogenesis.

Images