CN113480537B - Quinazolinone [2,3-a ] carboline derivative and preparation method and application thereof - Google Patents

Quinazolinone [2,3-a ] carboline derivative and preparation method and application thereof Download PDF

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CN113480537B
CN113480537B CN202110677254.7A CN202110677254A CN113480537B CN 113480537 B CN113480537 B CN 113480537B CN 202110677254 A CN202110677254 A CN 202110677254A CN 113480537 B CN113480537 B CN 113480537B
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潘成学
王望
雷尧
陈南英
庞莉
莫冬亮
苏桂发
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Abstract

The invention mainly provides a method for synthesizing a novel quinazolino [2,3-a ]]Carboline compounds, their preparation and use, having the general formula (I) quinazolino [2,3-a]The carboline compound is
Figure DEST_PATH_IMAGE002
Or quinazolinono [2,3-a ] of the general formula (II)]The carboline compound is

Description

Quinazolinone [2,3-a ] carboline derivative and preparation method and application thereof
Technical Field
The invention relates to organic synthesis and medicinal chemistry, in particular to a novel quinazolino [2,3-a ] carboline derivative, a preparation method thereof and a potential application thereof in research and development of anti-inflammatory drugs.
Background
Quinazolinone and carboline are both important nitrogen-containing heterocyclic compounds, are one of the most important structural units in medicinal chemistry, and derivatives thereof have wide pharmacological activities, such as anti-inflammation, anti-tumor, anti-convulsion, sedation, anti-hypertension, vasodilation, antimicrobial and antibacterial properties. And thus has been a focus of research by organic synthesis and pharmaceutical chemists.
Recently, a novel quinazolino [2,3-a ] carboline derivative is synthesized, and the structure of the compound is not reported in any literature at present. We also carried out a preliminary screening on the anti-inflammatory activity of partial compounds, and the results show that the compounds show good effect of inhibiting NO release of RAW264.7 cells induced by LPS, have low toxicity on the RAW264.7 cells and have good potential of developing new anti-inflammatory drugs.
Disclosure of Invention
The invention mainly provides a novel quinazolino [2,3-a ] carboline compound, a preparation method and application thereof, and has an inhibiting effect on NO released by RAW264.7 cells induced by LPS.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a quinazolinone [2,3-a ] carboline compound with a general formula (I) or a general formula (II):
Figure GDA0003583632200000011
wherein R is1Selected from H, F, Cl, Br, I, OMe, Me or CF3；
R2Selected from H, F, Cl, Br, OMe or Me;
R3selected from H, Me, Ac, Boc, Ph, allyl or propyl;
R4selected from H, Me or Ph.
Preferably, in the quinazolino [2,3-a ] carboline compound of formula (I),
when R is2Is H, R3Is H, R4When is H, R1Selected from H, F, Cl, Br, I, OMe, Me, NO2Or CF3；
When R is1Is H, R3Is H, R4When is H, R2Selected from H, F, Cl, Br, OMe or Me;
when R is1Is H, R2Is H, R4When is H, R3Selected from Me, Ac, Boc, Ph, allyl or propyl;
when R is1Is H, R2Is H, R3When is H, R4Selected from Me or Ph;
in the quinazolinone [2,3-a ] carboline compound of the general formula (II),
R1is H, R2Is H, R3Is H.
The quinazolinone [2,3-a ] carboline compound provided by the invention has the following specific structure:
Figure GDA0003583632200000021
the invention also provides a preparation method of the quinazolino [2,3-a ] carboline compound with the general formula (I),
preparation of quinazolino [2,3-a ] of general formula (I)]Carboline compounds when R3When the compound is selected from Me, Ac, Boc, Ph, allyl or propyl, the following steps are included:
s1, isatoic anhydride derivative
Figure GDA0003583632200000031
As starting material with the corresponding alkynylamine
Figure GDA0003583632200000032
Reaction to give Compound 3
Figure GDA0003583632200000033
S2, reacting the compound 3 with corresponding N-protected indole-3-formaldehyde under the catalysis of p-toluenesulfonic acid
Figure GDA0003583632200000034
Reaction to give Compound 4
Figure GDA0003583632200000035
S3, carrying out cyclization reaction on the compound 4 under the catalysis of gold to obtain a compound containing R3A target compound of (a);
when R is3In the case of H, the compound has the structure,
in the step S2, in the above step,
Figure GDA0003583632200000036
is replaced by
Figure GDA0003583632200000037
Compound 4 corresponds to
Figure GDA0003583632200000038
The step S3 is replaced by: removing Boc protecting group to obtain compound 5
Figure GDA0003583632200000039
And carrying out cyclization reaction on the compound 5 under the catalysis of gold to obtain the target compound.
The present invention further provides a preferred process for the preparation of compounds of the general formula (I):
preparation of the Compound of formula (I) when R is3When the metal is selected from Me, Ac, Boc, Ph, allyl or propyl, the synthetic route is shown in Schme 1 as follows:
Figure GDA0003583632200000041
when R is3When selected from H, the synthetic route is shown as the following Schme 2:
Figure GDA0003583632200000042
further, during the reaction for removing the Boc protecting group, K is added2CO3And a methanol solution.
Furthermore, during the reaction process of cyclization reaction under the catalysis of gold, John PhosAuCl and AgNTf are added2And acetonitrile.
The invention further provides a preferred process for the preparation of compounds of the general formula (II):
preparation of quinazolino [2,3-a ] of general formula (II)]Carboline compounds when R1Is H, R2Is H, R3When the number is H, the method comprises the following steps:
A1. taking o-nitrobenzoyl chloride as a raw material, adding dichloromethane and o-aminophenylacetylene, and reacting to obtain a compound 2ad
Figure GDA0003583632200000051
A2. Addition of NH4Cl to form a concentrated state, then adding EtOH, iron powder and a compound 2ad to react to obtain a compound 3ad
Figure GDA0003583632200000052
A3. Adding a compound 3ad, p-toluenesulfonic acid, tetrahydrofuran, anhydrous magnesium sulfate and 1-Boc-indole-3-formaldehyde, and reacting to obtain a compound 4ad
Figure GDA0003583632200000053
A4. Removing Boc protecting group from compound 4ad to obtain compound 5ad
Figure GDA0003583632200000054
A5. And carrying out cyclization reaction on the compound 5ad under the catalysis of gold to obtain the target compound.
Further, in the step A4, in the reaction for removing the Boc protecting group, K is added2CO3And a methanol solution.
The invention further provides a pharmaceutical composition consisting of the quinazolinone [2,3-a ] carboline compound with the general formula (I) and pharmaceutically acceptable auxiliary materials.
The invention further provides application of the quinazolinone [2,3-a ] carboline compound with the general formula (I) or the pharmaceutical composition in preparing anti-inflammatory drugs.
The invention further provides application of the quinazolinone [2,3-a ] carboline compound with the general formula (I) or the pharmaceutical composition in preparation of an inhibitor for LPS-induced NO release of RAW264.7 cells.
Experiments show that the quinazolinone [2,3-a ] carboline compound with the general formula (I) or the general formula (II) shows good effect of inhibiting NO release of RAW264.7 cells induced by LPS, has low toxicity to the RAW264.7 cells, and has good potential of developing new anti-inflammatory drugs.
Drawings
FIG. 1 is a graph showing the results of experiments in which compounds tested by Griess method inhibited NO release from RAW264.7 cells induced by LPS.
FIG. 2 is a diagram showing the results of an experiment for testing the cytotoxicity of a target compound on RAW264.7 cells by an MTT method.
Detailed Description
The present invention is further illustrated by the following specific examples, but the scope of the present invention is not limited to the following examples.
The present embodiment relates to compounds comprising:
Figure GDA0003583632200000061
example 1
Synthesis of compound 6 a:
Figure GDA0003583632200000071
to a 250mL round bottom flask, the compound isatoic anhydride 2a (5000mg, 30.6mmol), propiolic amine (2.10mL, 30.6mmol) and finally tetrahydrofuran (80mL) were added with magnetic stirring. The reaction was carried out at room temperature for 6h to precipitate a white solid. Suction filtration and drying gave 4794mg (90% yield) of compound 3a as a white solid.
Compound 3a (3000mg, 12.39mmol), p-toluenesulfonic acid (639mg, 3.72mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (4460mg, 37.17mmol), compound X1-Boc-indole-3-carbaldehyde (2160mg, 12.39mmol) were added sequentially to a 150mL round-bottomed flask with electromagnetic stirring, the mixture was reacted at room temperature for 10h, DDQ (3375mg, 14.87mmol) was added in an ice-water bath, reaction was carried out for 30 min, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)EA:VPE1:10, 1:4,1: 2) to yield 4105mg of compound 4a as a pale yellow solid (yield 83%).
To a 100mL round-bottomed flask, compound 4a (2000mg, 5.0mmol), K were added sequentially with magnetic stirring2CO3(1383mg, 10.0mmol) and methanol solution (30 mL). The reaction was stirred at ambient temperature for 1h (reaction monitored by TLC: V)EA:VPE1: 1); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)EA:VPE1:6, 1:4,1: 1) to obtain compound 5a1166mg (78%) of a white solid.
To a 20ml stoptube were added John PhosAuCl (7.1mg,0.014mmol), AgNTf in that order under electromagnetic stirring2(5.2mg,0.014mmol) and acetonitrile (2.0ml) were stirred at ambient temperature for 15min, then compound 5a (80mg,0.27mmol) was added and finally acetonitrile (2.0ml) was added; the reaction is continued to be stirred at normal temperature for 8 hours, and the reaction is finished (TLC monitoring reaction: V)EA:VPE1:2), the solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent: V)EA:VPE1:4,1:2,1:1) to give compound 6a as a white solid, 77mg (96% yield).
1H NMR(400MHz,DMSO-d6):δ12.22(s,1H),8.52(d,J＝7.7Hz,1H),8.11(dd,J＝7.9,0.9Hz,1H),7.80–7.73(m,1H),7.69(d,J＝7.8Hz,1H),7.49(d,J＝8.0Hz,1H),7.45–7.37(m,1H),7.35–7.28(m,1H),7.25(t,J＝7.1Hz,1H),5.87–5.85(m,1H),5.62–5.60(m,1H),5.08–5.06(m,2H).13C NMR(100MHz,DMSO–d6):δ160.9,148.8,148.5,138.6,138.6,134.7,129.2,127.2,126.6,125.8,125.1,124.7,122.6,121.9,120.1,112.4,112.2,107.1,46.9。
Example 2
Synthesis of compound 6 b:
Figure GDA0003583632200000081
6-Methoxyphenylisatoic anhydride was added to a 100mL round-bottomed flask with magnetic stirring
Figure GDA0003583632200000082
(1000mg, 5.2mmol), propynylamine (0.36mL, 5.18mmol) was added, and finally tetrahydrofuran (20mL) was added. The reaction was carried out at room temperature for 4h to precipitate a white solid. Suction filtration and drying gave 807mg (76% yield) of compound 3b as a white solid.
To a 100mL round-bottomed flask were added compound 3b (1020mg, 5.0mmol), p-toluenesulfonic acid (258mg, 1.5mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (1800mg, 15.0mmol), compound X1-Boc-indole-3-carbaldehyde (1225mg, 5.0mmol) in this order under electromagnetic stirring, and the mixture was stirredThe mixture was reacted at room temperature for 9h, DDQ (1362mg, 6.0mmol) was added under ice-water bath and reacted for 30 min, after the reaction was finished, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (eluent: V)EA:VPE1:10, 1:4,1: 2) to yield 1450mg of compound 4b as a pale yellow solid (67% yield).
To a 50mL round-bottomed flask, compound 4b (436mg, 1.0mmol), K were added sequentially with magnetic stirring2CO3(279mg, 2.0mmol) and methanol solution (15 mL). The reaction was stirred at ambient temperature for 1h (reaction monitored by TLC: V)EA:VPE1: 1); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)EA:VPE1:6, 1:4,1: 1) to give 269mg (81%) of compound 5b as a white solid.
To a 20ml stoptube were added sequentially John PhosAuCl (9.7mg,0.018mmol), AgNTf under electromagnetic stirring2(7.1mg,0.018mmol) and acetonitrile (2.0ml) were stirred at ambient temperature for 15min, then compound 5b (120mg,0.36mmol) was added and finally acetonitrile (2.0ml) was added again; the reaction is continued to be stirred at normal temperature for 8 hours, and the reaction is finished (TLC monitoring reaction: V)EA:VPE1:2), the solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent: V)EA:VPE1:4,1:2,1:1) to give compound 6b as a pale yellow solid, 97mg (yield 81%).
1H NMR(400MHz,DMSO-d6):δ12.22(s,1H),8.48(d,J＝7.8Hz,1H),7.65(t,J＝8.2Hz,1H),7.49(d,J＝8.0Hz,1H),7.33–7.28(m,1H),7.26–7.22(m,2H),6.92(d,J＝8.2Hz,1H),5.84(t,J＝1.9Hz,1H),5.58(t,J＝1.9Hz,1H),4.98–4.96(m,2H),3.87(s,3H).13C NMR(100MHz,DMSO-d6):δ160.1,158.8,150.9,149.2,138.7,138.6,134.9,129.5,125.3,124.7,122.5,121.9,119.3,112.4,112.1,109.8,107.7,106.9,56.4,46.6。
Example 3
Synthesis of compound 6 c:
the synthesis of compound 6c was performed in the same manner as in example 1 except that isatoic anhydride (2a) in example 1 was changed to 6-methylisatoic anhydride (2c), with a slightly different yield of intermediate products. Final transformationCompound 5c
Figure GDA0003583632200000091
Under gold catalysis, compound 6c was obtained as a pale yellow solid 76mg (95% yield).
1H NMR(400MHz,DMSO-d6):δ12.21(s,1H),8.45(d,J＝7.6Hz,1H),7.94(d,J＝7.7Hz,1H),7.62(d,J＝7.1Hz,1H),7.49(d,J＝7.9Hz,1H),7.35–7.21(m,3H),5.86–5.84(m,1H),5.60–5.58(m,1H),5.06–5.04(m,2H),2.65(s,3H).13CNMR(100MHz,DMSO-d6):δ161.2,147.8,146.9,138.6,138.5,134.9,134.8,129.2,125.3,125.1,124.7,124.3,122.4,122.0,119.9,112.5,112.2,107.5,46.9,17.8。
Example 4
Synthesis of compound 6 d: synthesis of Compound 6d the same procedure as in example 2 except that 6-methoxybenzeneisatoic anhydride from example 2 was used
Figure GDA0003583632200000092
To 5-methoxyisatoic anhydride
Figure GDA0003583632200000093
The yields of intermediate products differ slightly. Final Compound 5d
Figure GDA0003583632200000101
Under gold catalysis, compound 6d was obtained as a pale yellow solid 72mg (90% yield).
1H NMR(400MHz,DMSO-d6):δ12.16(s,1H),8.49(d,J＝7.8Hz,1H),7.65(d,J＝8.9Hz,1H),7.49–7.47(m,2H),7.38(dd,J＝8.9,2.9Hz,1H),7.30(t,J＝7.1Hz,1H),7.23(t,J＝7.4Hz,1H),5.85–5.83(m,1H),5.61–5.59(m,1H),5.08–5.06(m,2H),3.86(s,3H).13C NMR(100MHz,DMSO-d6):δ160.7,157.4,146.9,143.0,138.5,138.0,129.3,128.9,125.0,124.6,124.3,122.5,121.8,120.7,112.3,111.8,107.2,106.6,56.0,47.0。
Example 5
Synthesis of compound 6 e:
synthesis of Compound 6e and procedure in example 2The same was followed except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 5-methylbenzeneisatoic anhydride 2e, in which the yield of the intermediate product was slightly different. Final Compound 5e
Figure GDA0003583632200000102
Under gold catalysis, compound 6e was obtained as a pale yellow solid, 75mg (94% yield).
1H NMR(400MHz,DMSO-d6):δ12.20(s,1H),8.50(d,J＝7.8Hz,1H),7.90(s,1H),7.60–7.56(m,2H),7.49(d,J＝8.0Hz,1H),7.35–7.29(m,1H),7.27–7.19(m,1H),5.86–5.84(m,1H),5.60–5.58(m,1H),5.06–5.04(m,2H),2.42(s,3H).13C NMR(100MHz,DMSO-d6):δ160.9,148.1,146.4,138.5,138.3,136.0,135.4,129.3,127.1,126.0,125.0,124.6,122.6,121.8,119.8,112.4,112.0,107.2,46.9,21.3。
Example 6
Synthesis of compound 6 f:
the synthesis of compound 6f was performed in the same manner as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 5-chlorobenzeneisatoic anhydride 2f, in which the yield of intermediate product was slightly different. Final Compound 5f
Figure GDA0003583632200000111
Under gold catalysis, compound 6f was obtained as a pale yellow solid, 75mg (94% yield).
1H NMR(400MHz,DMSO-d6):δ12.26(s,1H),8.43(d,J＝7.8Hz,1H),7.96(d,J＝2.4Hz,1H),7.72(dd,J＝8.7,2.5Hz,1H),7.64(d,J＝8.7Hz,1H),7.46(d,J＝8.0Hz,1H),7.31–7.27(m,1H),7.21(t,J＝7.2Hz,1H),5.85–5.83(m,1H),5.58–5.56(m,1H),5.01–4.99(m,2H).13C NMR(100MHz,DMSO-d6):δ159.9,149.2,147.2,138.7,138.5,134.7,129.7,129.3,128.9,125.5,125.0,124.7,122.5,121.9,121.0,112.4,106.8,47.0。
Example 7
Synthesis of Compound 6 g:
synthesis of 6g Compound the same procedure as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 5-iodobenzeneIsatoic anhydride 2g, with slightly different yields of intermediate products. Final Compound 5g
Figure GDA0003583632200000112
Under the catalysis of gold, compound 6g is obtained as a white solid 68mg (yield 85%).
1H NMR(400MHz,DMSO-d6):δ12.28(s,1H),8.47(d,J＝7.7Hz,1H),8.35(s,1H),8.02(d,J＝8.4Hz,1H),7.50–7.47(m,2H),7.31(t,J＝7.4Hz,1H),7.24(t,J＝7.4Hz,1H),5.86(s,1H),5.61(s,1H),5.04(s,2H).13C NMR(100MHz,DMSO-d6):δ159.7,149.4,147.8,143.0,138.9,138.6,134.8,129.4,129.0,125.0,124.8,122.5,122.0,121.9,112.6,112.5,106.9,90.1,47.0。
Example 8
Synthesis of compound 6 h:
the synthesis of compound 6h was the same procedure as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 4-methoxybenzeneisatoic anhydride 2h, with a slightly different yield of intermediate product. Final Compound 5h
Figure GDA0003583632200000113
Under the catalysis of gold, compound 6h is obtained as a pale yellow solid 67mg (yield 84%).
1H NMR(400MHz,DMSO-d6):δ12.22(s,1H),8.53(d,J＝7.8Hz,1H),7.99(d,J＝8.8Hz,1H),7.49(d,J＝8.0Hz,1H),7.31(t,J＝7.2Hz,1H),7.24(t,J＝7.4Hz,1H),7.13(d,J＝2.3Hz,1H),6.96(dd,J＝8.8,2.3Hz,1H),5.85–5.83(m,1H),5.60–5.58(m,1H),5.04–5.02(m,2H),3.92(s,3H).13C NMR(100MHz,DMSO-d6):δ164.4,160.5,150.7,149.4,138.6,138.5,129.3,128.2,125.1,124.7,122.8,121.8,115.7,113.6,112.4,112.1,108.0,107.1,56.1,46.7。
Example 9
Synthesis of compound 6 i:
the synthesis of compound 6i was performed in the same manner as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 4-methylbenzeneisatoic anhydride 2i, in which the yield of the intermediate product was slightly different. Final Compound 5i
Figure GDA0003583632200000121
Under gold catalysis, compound 6i was obtained as a pale yellow solid 72mg (90% yield).
1H NMR(400MHz,DMSO-d6):δ12.23(s,1H),8.52(d,J＝7.7Hz,1H),7.99(d,J＝8.0Hz,1H),7.51–7.49(m,2H),7.32(t,J＝7.4Hz,1H),7.27–7.22(m,2H),5.86–5.84(m,1H),5.61–5.59(m,1H),5.06–5.04(m,2H),2.46(s,3H).13C NMR(100MHz,DMSO-d6):δ160.8,148.9,148.5,145.1,138.6,138.5,129.3,127.3,126.8,126.5,125.1,124.7,122.6,121.8,117.7,112.4,112.1,107.2,46.8,21.8。
Example 10
Synthesis of compound 6 j:
the synthesis of compound 6j was the same procedure as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 4-bromobenzeneisatoic anhydride 2j, with a slightly different yield of intermediate product. Final Compound 5j
Figure GDA0003583632200000122
Under the catalysis of gold, compound 6j was obtained as a pale yellow solid 72mg (yield 90%).
1H NMR(400MHz,DMSO-d6):δ8.48(d,J＝7.8Hz,1H),7.97(d,J＝8.5Hz,1H),7.86(d,J＝1.6Hz,1H),7.56–7.44(m,2H),7.31(t,J＝7.3Hz,1H),7.23(t,J＝7.4Hz,1H),5.86–5.84(m,1H),5.60–5.58(m,1H),5.02–5.00(m,2H).13C NMR(100MHz,DMSO-d6):δ160.5,150.0,149.7,139.0,138.5,129.2,128.9,128.6,128.5,128.2,125.0,124.8,122.6,122.0,119.0,112.5,112.4,106.8,46.9。
Example 11
Synthesis of compound 6 k:
the synthesis of compound 6k was performed in the same manner as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 4-trifluoromethylbenzeneisatoic anhydride 2k, in which the yield of the intermediate product was slightly different. Final Compound 5k
Figure GDA0003583632200000131
Under the catalysis of gold, compound 6k was obtained as a pale yellow solid 71mg (89% yield).
1H NMR(400MHz,DMSO-d6):δ12.25(s,1H),8.48(d,J＝7.8Hz,1H),8.22(d,J＝8.2Hz,1H),7.95(s,1H),7.62(dd,J＝8.3,1.4Hz,1H),7.46(d,J＝8.0Hz,1H),7.31–7.27(m,1H),7.24–7.18(m,1H),5.85–5.83(m,1H),5.59–5.57(m,1H),5.02–5.00(m,2H).13C NMR(100MHz,DMSO-d6):δ160.2,150.2,148.5,139.0,138.5,134.3(J＝63.5Hz),128.8,128.3,125.0,124.2(J＝271.4Hz),124.8,124.2(J＝8.1Hz),122.6,122.6,122.0,121.1(J＝6.6Hz),112.6,112.4,106.7,47.0。
Example 12
Synthesis of Compound 6 l:
the synthesis of compound 6l was the same as the procedure of example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 3-methoxybenzeneisatoic anhydride 2l, with a slightly different yield of intermediate product. Final Compound 5l
Figure GDA0003583632200000132
Under gold catalysis, 64mg (yield 80%) of compound 6l was obtained as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ12.22(s,1H),8.56(d,J＝7.7Hz,1H),7.70–7.68(m,1H),7.50(d,J＝8.0Hz,1H),7.38–7.34(m,2H),7.33–7.29(m,1H),7.26(t,J＝7.4Hz,1H),5.86–5.84(m,1H),5.62–5.60(m,1H),5.09–5.07(m,2H),4.00(s,3H).13C NMR(100MHz,DMSO-d6):δ160.9,154.6,147.6,139.3,138.6,138.3,129.2,126.0,125.1,124.7,122.7,121.9,121.0,117.8,115.3,112.4,112.1,107.6,56.8,47.0。
Example 13
Synthesis of compound 6 m:
the synthesis of compound 6m was performed in the same manner as in example 1 except that isatoic anhydride (2a) in example 1 was changed to 3-methylisatoic anhydride (2m), and the yield of intermediate products was slightly different. Final Compound 5m
Figure GDA0003583632200000141
Under gold catalysis, 34mg (yield 42%) of compound 6m was obtained as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ12.20(s,1H),8.49(d,J＝7.8Hz,1H),7.59(t,J＝7.7Hz,1H),7.53–7.48(m,2H),7.31(t,J＝7.1Hz,1H),7.24(t,J＝7.3Hz,1H),7.15(d,J＝7.1Hz,1H),5.85–5.83(m,1H),5.58–5.56(m,1H),5.01–4.99(m,2H),2.78(s,3H).13C NMR(101MHz,DMSO-d6):δ161.5,149.9,148.5,140.3,138.6,138.6,133.7,129.4,128.34,125.5,125.0,124.6,122.5,121.8,118.5,112.4,112.0,107.0,46.8,23.3。
Example 14
Synthesis of compound 6 n:
the synthesis of compound 6n was performed in the same manner as in example 2 except that 6-methoxybenzeneisatoic anhydride 2b in example 2 was changed to 3-chlorobenzeneisatoic anhydride 2n, in which the yield of intermediate product was slightly different. Final Compound 5n
Figure GDA0003583632200000142
Under gold catalysis, 67mg (84% yield) of compound 6n was obtained as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ12.24(s,1H),8.55(d,J＝7.6Hz,1H),8.01(d,J＝7.7Hz,1H),7.87(d,J＝7.5Hz,1H),7.46(d,J＝7.8Hz,1H),7.34–7.22(m,3H),5.84(s,1H),5.58(s,1H),5.01(s,2H).13C NMR(100MHz,DMSO-d6):δ160.4,149.3,145.0,138.9,138.6,134.5,130.3,128.9,125.7,125.1,124.8,122.6,122.1,121.5,112.4,112.4,107.1,47.0。
Example 15
Synthesis of compound 6 o:
the synthesis of compound 6o was the same procedure as in example 1 except that 1-Boc-indole-3-carbaldehyde in example 1 was changed to 1-Boc-5-methoxy-indole-3-carbaldehyde, with slightly different yields of intermediate products. Final Compound 5o
Figure GDA0003583632200000143
Under gold catalysis, compound 6o was obtained as a pale yellow solid 51mg (64% yield).
1H NMR(400MHz,DMSO-d6):δ12.09(s,1H),8.09(d,J＝7.6Hz,1H),8.02(d,J＝2.2Hz,1H),7.76(t,J＝7.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.41–7.36(m,2H),6.94(dd,J＝8.8,2.4Hz,1H),5.80–5.78(m,1H),5.56–5.54(m,1H),5.04–5.02(m,2H),3.87(s,3H).13C NMR(100MHz,DMSO-d6):δ160.9,155.4,148.9,148.5,138.7,134.6,133.4,129.2,127.2,126.6,125.8,125.7,119.9,114.3,113.1,111.7,106.8,104.4,55.8,46.9。
Example 16
Synthesis of compound 6 p:
the synthesis of compound 6p was the same procedure as in example 1 except that 1-Boc-indole-3-carbaldehyde in example 1 was changed to 1-Boc-5-fluoro-indole-3-carbaldehyde, with slightly different yields of intermediate products. Final Compound 5p
Figure GDA0003583632200000151
Under the catalysis of gold, compound 6p was obtained as a pale yellow solid, 55mg (yield 69%).
1H NMR(400MHz,DMSO-d6):δ12.33(s,1H),8.16(dd,J＝9.7,2.5Hz,1H),8.12–8.07(m,1H),7.80–7.74(m,1H),7.71(d,J＝7.6Hz,1H),7.50–7.46(m,1H),7.43–7.37(m,1H),7.15(td,J＝9.2,2.6Hz,1H),5.86–5.84(m,1H),5.63–5.61(m,1H),5.06–5.04(m,2H).13C NMR(100MHz,DMSO-d6):δ160.9,158.6(J＝233.0Hz),148.5,148.4,140.0,134.9(J＝42.1Hz),129.0,127.2,126.6,125.9,125.5(J＝11.3Hz),120.0,113.6(J＝9.6Hz),112.8,112.7(J＝25.9Hz),107.4,107.2,107.1(J＝4.6Hz),46.8。
Example 17
Synthesis of compound 6 q:
the synthesis of compound 6q was the same procedure as in example 1 except that 1-Boc-indole-3-carbaldehyde in example 1 was changed to 1-Boc-5-chloro-indole-3-carbaldehyde, with slightly different yields of intermediate products. Final Compound 5q
Figure GDA0003583632200000152
Under the catalysis of gold, 56mg (yield 6%) of compound 6q was obtained as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ12.34(s,1H),8.41(d,J＝1.6Hz,1H),8.07(d,J＝7.7Hz,1H),7.73(d,J＝7.1Hz,1H),7.67(d,J＝8.0Hz,1H),7.44(d,J＝8.6Hz,1H),7.39(t,J＝7.4Hz,1H),7.27(dd,J＝8.6,1.9Hz,1H),5.84–5.82(m,1H),5.61–5.59(m,1H),5.01–4.99(m,2H).13C NMR(100MHz,DMSO-d6):δ160.8,148.4,148.3,139.7,137.0,134.7,128.8,127.2,126.6,126.4,126.1,126.0,124.6,121.4,120.1,114.0,113.1,106.6,46.8。
Example 18
Synthesis of compound 6 r:
the synthesis of compound 6r was the same procedure as in example 1 except that 1-Boc-indole-3-carbaldehyde in example 1 was changed to 1-Boc-6-methoxy-indole-3-carbaldehyde, and the yield of the intermediate product was slightly different. Final Compound 5r
Figure GDA0003583632200000161
Under gold catalysis, compound 6r was obtained as a pale yellow solid 56mg (93% yield).
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.36(d,J＝8.7Hz,1H),8.11(dd,J＝7.9,0.9Hz,1H),7.81–7.72(m,1H),7.67(d,J＝8.0Hz,1H),7.47–7.33(m,1H),6.93(d,J＝2.0Hz,1H),6.88(dd,J＝8.7,2.2Hz,1H),5.76–5.75(m,1H),5.52–5.50(m,1H),5.05–5.03(m,2H),3.84(s,3H).13C NMR(100MHz,DMSO-d6):δ160.9,157.9,148.7,148.5,139.7,137.7,134.6,129.2,127.1,126.6,125.7,123.2,120.0,119.1,111.7,110.7,107.3,95.3,55.7,47.0。
Example 19
Synthesis of compound 6 s:
synthesis of Compound 6s was performed in the same manner as in example 1 except that 1-Boc-indole-3-carbaldehyde in example 1 was changed to 1-Boc-6-bromo-indole-3-carbaldehyde, and the yield of the intermediate product was slightly different. Finally, the compound 5s is catalyzed by gold to obtain a compound 6s
Figure GDA0003583632200000162
Pale yellow solid 71mg (yield 89%).
1H NMR(400MHz,DMSO-d6):δ12.41(s,1H),8.44(d,J＝8.5Hz,1H),8.12(dd,J＝7.9,1.2Hz,1H),7.82–7.76(m,1H),7.71(d,J＝7.6Hz,1H),7.66(d,J＝1.6Hz,1H),7.46–7.43(m,1H),7.43–7.38(m,1H),5.89–5.87(m,1H),5.68–5.66(m,1H),5.10–5.08(m,2H).13C NMR(100MHz,DMSO-d6):δ160.9,148.5,148.3,139.4,139.3,134.8,128.9,127.2,126.7,126.1,124.9,124.1,120.2,117.3,115.0,113.1,107.1,46.9。
Example 20
Synthesis of compound 6 t:
the synthesis of compound 6t was the same procedure as in example 1 except that 1-Boc-indole-3-carbaldehyde in example 1 was changed to 1-Boc-7-methyl-indole-3-carbaldehyde, with a slightly different yield of intermediate product. Final Compound 5t
Figure GDA0003583632200000171
Under gold catalysis, 53mg (66% yield) of compound 6t was obtained as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ11.79(s,1H),8.35(d,J＝7.7Hz,1H),8.10(d,J＝7.7Hz,1H),7.76(t,J＝7.1Hz,1H),7.67(d,J＝8.0Hz,1H),7.40(t,J＝7.2Hz,1H),7.16–7.03(m,2H),6.03(s,1H),5.60(s,1H),5.04(s,2H),2.54(s,3H).13C NMR(100MHz,DMSO-d6):δ160.9,148.9,148.5,138.5,138.0,134.6,129.1,127.1,126.6,125.7,125.3,124.8,122.0,121.8,120.1,120.0,112.7,107.5,47.0,17.5。
Example 21
Synthesis of compound 6 u:
Figure GDA0003583632200000172
to a 250mL round bottom flask, under magnetic stirring, was added the compound 2u isatoic anhydride (5000mg, 30.6mmol), followed by propynylamine (2.10mL, 30.6mmol) and finally tetrahydrofuran (80 mL). The reaction was carried out at room temperature for 6h to precipitate a white solid. Suction filtration and drying gave 4794mg (yield: 90%) of compound 3u as a white solid.
Under electromagnetic stirring, to a 150mL round bottomThe compound 3u (500mg, 2.87mmol), p-toluenesulfonic acid (148mg, 0.86mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (1033mg, 8.61mmol), and the compound Y N-methyl-indole-3-carbaldehyde (457mg, 2.87mmol) were sequentially added to a flask, the mixture was reacted at room temperature for 12 hours, DDQ (782mg, 3.44mmol) was added to an ice-water bath, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)EA:VPE1:10, 1:4,1: 2) to give 300mg of compound 4u as a pale yellow solid (yield 33%).
To a 20ml stoptube were added sequentially John PhosAuCl (5.1mg,0.009mmol), AgNTf under electromagnetic stirring2(3.7mg,0.009mmol) and acetonitrile (2.0ml), stirred at ambient temperature for 15min, then added compound 4u (60mg,0.19mmol), and finally supplemented with acetonitrile (2.0 ml); the reaction was continued for 12h with stirring at room temperature and ended (reaction monitored by TLC: V)EA:VPE1:2), the solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent: V)EA:VPE1:4,1:2,1:1) to give compound 6u as a pale yellow solid 57mg (yield 65%).
1H NMR(400MHz,DMSO-d6):δ8.57(d,J＝7.7Hz,1H),8.10(dd,J＝7.9,1.1Hz,1H),7.82–7.73(m,1H),7.70–7.64(m,2H),7.46–7.35(m,2H),7.33–7.29(m,1H),5.86–5.84(m,1H),5.83–5.81(m,1H),5.03–5.01(m,2H),3.96(s,3H).13C NMR(100MHz,DMSO-d6):δ160.7,148.8,148.6,140.1,139.0,134.7,129.0,127.2,126.7,125.8,124.6,124.1,122.5,122.4,120.0,117.3,111.2,107.4,48.3,32.3。
Example 22
Synthesis of compound 6 v:
the synthesis of compound 6v was the same procedure as in example 21 except that N-methyl-indole-3-carbaldehyde in example 21 was changed to N-propyne-indole-3-carbaldehyde in a slightly different yield from the intermediate product. Final Compound 4v
Figure GDA0003583632200000181
Under gold catalysis, compound 6v was obtained as a pale yellow solid 91mg (91% yield).
1H NMR(400MHz,DMSO-d6):δ8.60(d,J＝7.7Hz,1H),8.11(dd,J＝7.9,1.1Hz,1H),7.83–7.75(m,1H),7.74–7.70(m,2H),7.44–7.41(m,2H),7.35(t,J＝7.2Hz,1H),5.92–5.90(m,1H),5.90–5.88(m,1H),5.29(d,J＝2.3Hz,2H),5.04–5.02(m,2H),3.53(t,J＝2.3Hz,1H).13C NMR(100MHz,DMSO-d6):δ160.7,148.5,148.4,139.2,138.3,134.8,128.6,127.3,126.7,126.1,125.0,124.18,122.9,122.7,120.1,117.4,111.3,108.4,79.0,76.6,48.3,34.5。
Example 23
Synthesis of compound 6 w:
the synthesis of compound 6w was the same procedure as in example 21 except that N-methyl-indole-3-carbaldehyde in example 21 was changed to N-propylene-indole-3-carbaldehyde in a slightly different yield from the intermediate product. Final Compound 4w
Figure GDA0003583632200000191
Under the catalysis of gold, compound 6w is obtained as a pale yellow solid 74mg (yield 93%).
1H NMR(400MHz,DMSO-d6):δ8.63–8.55(m,1H),8.11(dd,J＝7.9,1.1Hz,1H),7.80–7.75(m,1H),7.73–7.68(m,1H),7.55(d,J＝7.9Hz,1H),7.44–7.29(m,3H),6.16–6.07(m,1H),5.81–5.79(m,1H),5.64–5.62(m,1H),5.20(dd,J＝10.5,1.2Hz,1H),5.08–5.03(m,2H),5.02–5.00(m,2H),4.84(dd,J＝17.2,1.2Hz,1H).13C NMR(100MHz,DMSO-d6):δ160.7,148.7,148.5,139.7,138.7,134.8,133.6,128.7,127.2,126.7,125.9,124.8,124.2,122.6,120.1,116.8,116.7,111.4,108.0,48.3,46.7。
Example 24
Synthesis of compound 6 x:
the synthesis of compound 6x was the same procedure as in example 21 except that N-methyl-indole-3-carbaldehyde in example 21 was changed to N-phenyl-indole-3-carbaldehyde in a slightly different yield from the intermediate product. Final Compound 4X
Figure GDA0003583632200000192
Under the catalysis of gold, compound 6x was obtained as a white solid 76mg (yield 95%).
1H NMR(400MHz,DMSO-d6):δ8.71(d,J＝7.1Hz,1H),8.16(d,J＝7.8Hz,1H),7.91–7.78(m,2H),7.72–7.60(m,5H),7.51–7.44(m,1H),7.44–7.31(m,2H),7.13(d,J＝7.3Hz,1H),5.53–5.51(m,1H),5.10–5.08(m,2H),4.57–4.55(m,1H).13C NMR(100MHz,DMSO-d6):δ160.7,148.6,148.5,140.8,138.2,136.8,134.9,130.7,129.8,128.7,128.4,127.4,126.8,126.2,125.5,124.3,123.1,122.9,120.2,116.2,111.2,109.2,47.9。
Example 25
Synthesis of compound 6 y:
the synthesis of compound 6y was the same procedure as in example 21 except that N-methyl-indole-3-carbaldehyde in example 21 was changed to N-Boc-indole-3-carbaldehyde in a slightly different yield from the intermediate product. Final Compound 4y
Figure GDA0003583632200000193
Under gold catalysis, compound 6y was obtained as a white solid 33mg (41% yield).
1H NMR(400MHz,DMSO-d6):δ8.74(d,J＝7.5Hz,1H),8.17(d,J＝7.8Hz,1H),8.07(d,J＝8.1Hz,1H),7.86(t,J＝7.4Hz,1H),7.79(d,J＝7.9Hz,1H),7.57–7.42(m,3H),5.95(s,1H),5.62(s,1H),5.02(s,2H),1.69(s,9H).13C NMR(100MHz,DMSO-d6):δ160.4,149.1,147.9,147.5,139.1,138.5,134.9,127.8,127.7,126.9,126.65,125.2,124.7,123.3,120.6,120.5,115.0,113.9,86.1,47.9,27.9。
Example 26
Synthesis of compound 6 z:
the synthesis of compound 6z was the same procedure as in example 21 except that N-methyl-indole-3-carbaldehyde in example 21 was changed to N-acetyl-indole-3-carbaldehyde in a slightly different yield from the intermediate product. Final Compound 4z
Figure GDA0003583632200000201
Under the catalysis of gold, compound 6z was obtained as a white solid, 40mg (yield 50%).
1H NMR(400MHz,DMSO-d6):δ12.19(s,1H),8.49(d,J＝7.8Hz,1H),7.61–7.55(m,1H),7.52–7.47(m,2H),7.34–7.27(m,1H),7.26–7.20(m,1H),7.14(d,J＝7.1Hz,1H),5.84–5.82(m,1H),5.57–5.59(m,1H),5.00–4.98(m,2H),2.78(s,3H).13C NMR(100MHz,DMSO-d6):δ161.5,149.9,148.5,140.3,138.6,138.5,133.7,129.4,128.3,125.5,125.0,124.6,122.5,121.8,118.5,112.4,111.9,107.0,46.8,23.3。
Example 27
Synthesis of compound 6 aa:
the synthesis of compound 6aa was the same procedure as in example 2 except that 2-amino-6-methoxybenzoic acid (1b) in example 2 was changed to 2-amino-3-chlorobenzoic acid (1aa), and the yield of intermediate product was slightly different. Final Compound 5aa
Figure GDA0003583632200000202
Under gold catalysis, compound 6aa was obtained as a pale yellow solid 71mg (89% yield).
1H NMR(400MHz,DMSO-d6):δ12.16(s,1H),8.54(d,J＝7.8Hz,1H),7.49(d,J＝8.0Hz,1H),7.43(s,1H),7.31(t,J＝7.1Hz,1H),7.24(t,J＝7.4Hz,1H),7.18(s,1H),5.84–5.82(m,1H),5.60–5.58(m,1H),5.07–5.05(m,2H),3.96(s,3H),3.87(s,3H).13C NMR(100MHz,DMSO-d6):δ160.3,155.1,148.3,147.6,144.6,138.5,138.0,129.4,125.0,124.6,122.6,121.7,112.9,112.3,111.8,108.0,107.3,105.8,56.4,56.1,46.9。
Example 28
Synthesis of compound 6 ab:
the synthesis of compound 6ab was performed in the same manner as in example 1 except that propynylamine in example 1 was changed to 2-alkynylbutylamine, which was slightly different in the yield of intermediate product. Final Compound 5ab
Figure GDA0003583632200000211
Under the catalysis of gold, compound 6ab was obtained as a white solid (83 mg, 83%).
1H NMR(400MHz,DMSO-d6):δ12.13(br,1H),8.49(d,J＝7.5Hz,1H),8.11(d,J＝7.3Hz,1H),7.79–7.76(m,1H),7.69(d,J＝8.0Hz,1H),7.50–7.36(m,2H),7.29–7.20(m,2H),6.46(q,J＝6.9Hz,1H),5.02(s,2H),1.93(d,J＝7.1Hz,3H).13C NMR(101MHz,DMSO-d6):δ161.2,149.0,148.6,139.6,138.5,134.7,127.1,126.6,125.6,125.2,124.2,122.8,122.3,121.9,121.7,119.9,112.2,105.3,43.6,13.8。
Example 29
Synthesis of compound 6 ac:
the synthesis of compound 6ac was the same procedure as in example 1 except that propargylamine in example 1 was changed to 3-phenyl-2-alkynylpropylamine, with a slightly different yield of intermediate product. Final Compound 5ac
Figure GDA0003583632200000212
Under gold catalysis, 47mg (59% yield) of compound 6ac was obtained as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ11.79(s,1H),8.50–8.38(m,1H),8.20(dd,J＝8.0,1.1Hz,1H),7.83(ddd,J＝8.4,7.0,1.5Hz,1H),7.74(d,J＝7.7Hz,1H),7.54–7.42(m,7H),7.38–7.26(m,2H),6.61(t,J＝7.3Hz,1H),5.77(s,2H).13C NMR(100MHz,DMSO-d6):δ161.0,151.2,148.5,139.8,138.1,137.7,136.8,134.8,129.3,129.3,128.7,127.4,126.9,126.8,126.4,125.9,124.2,122.6,121.4,120.6,113.3,112.6,55.4。
Example 30
Synthesis of compound 6 ad:
Figure GDA0003583632200000221
under the protection of electromagnetic stirring and nitrogen, adding o-nitrobenzoyl chloride 1ad (1000mg, 5.39mmol) into a 150mL two-neck flask, then adding dichloromethane (25mL), stirring for 5 minutes in ice bath, then slowly adding o-aminophenylacetylene (631mg,5.39mmol), continuing to stir for reaction for 10 minutes, then raising the temperature to room temperature, continuing to react for 10 hours, ending the reaction, removing the solvent under reduced pressure, and purifying the crude product by column chromatography (eluent: V)EA:VPE1:10, 1:4,1: 2) to give 1098mg of compound 2ad as a yellow solid (yield 77%).
Under electromagnetic stirringTo a 150mL round bottom flask, NH was added4Cl(1245mg,23.48mmol)、H2O (8mL), NH was stirred in an oil bath at 55 ℃ for 20 minutes4Cl was concentrated, EtOH (20mL), iron powder (693mg,12.38mmol), and compound 2ad (1098mg,4.12mmol) were added in that order and the reaction was continued for 8 h. After the reaction has ended, the reaction mixture is cooled to room temperature, the iron powder is filtered off with suction, extracted with ethyl acetate (4X 20mL), the organic phases are combined, the solvent is removed under reduced pressure, and the crude product is purified by column chromatography on silica gel (eluent: V)EA:VPE1:6, 1:4,1: 1) to give compound 3ad as a pale yellow solid 700mg (72%).
To a 150mL round-bottomed flask were added 3ad (700mg, 2.97mmol), p-toluenesulfonic acid (139mg, 0.89mmol), tetrahydrofuran (20.0mL), anhydrous magnesium sulfate (1068mg, 8.91mmol) and 1-Boc-indole-3-carbaldehyde (726mg, 2.97mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 10 hours, DDQ (809mg, 3.56mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)EA:VPE1:10, 1:4,1: 2) to yield 800mg of compound 4ad as a pale yellow solid (58% yield).
To a 100mL round-bottomed flask, compound 4ad (800mg, 1.73mmol), K were added sequentially with magnetic stirring2CO3(479mg, 3.47mmol) and methanol solution (20mL), the reaction was stirred at room temperature for 4h (TLC monitor reaction: V)EA:VPE1: 1); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)EA:VPE1:6, 1:4,1: 1) to give compound 5ad as a white solid 510mg (82%).
To a 20ml stoptube were added sequentially John PhosAuCl (6.0mg,0.011mmol), AgNTf under electromagnetic stirring2(4.3mg,0.011mmol) and acetonitrile (2.0ml), stirring at room temperature for 15min, adding compound 5ad (80mg,0.22mmol), and adding acetonitrile (2.0 ml); the reaction is continued to be stirred at normal temperature for 8 hours, and the reaction is finished (TLC monitoring reaction: V)EA:VPE1:2), the solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent: V)EA:VPE1:4,1:2,1:1) to obtain compound 6ad, white solid 50mg (63% yield).
1H NMR(400MHz,DMSO-d6):δ11.49(s,1H),8.62–8.57(m,1H),8.15(dd,J＝7.9,1.1Hz,1H),7.91–7.84(m,1H),7.81(d,J＝7.6Hz,1H),7.68–7.59(m,3H),7.53–7.47(m,1H),7.38–7.33(m,1H),7.22–7.16(m,2H),5.98(d,J＝3.1Hz,1H),5.40(d,J＝1.9Hz,1H),5.07(d,J＝1.9Hz,1H).13C NMR(100MHz,DMSO-d6):δ162.4,150.9,148.6,137.0,136.5,135.8,135.4,134.8,131.6,131.0,130.7,130.3,129.1,127.5,127.5,126.9,126.5,123.1,123.0,121.3,119.8,118.6,112.1,109.4.
Effect verification examples
An MTT method is adopted to test cytotoxicity of a target compound on RAW264.7 cells, a Griess method is adopted to test the experiment that the compound inhibits LPS-induced RAW264.7 cells to release NO, and the test results are respectively shown in figure 1 and figure 2.
The cell culture method comprises culturing RAW264.7 macrophage in 10% fetal calf serum and 3% double antibody DMEM culture solution at 37 deg.C and 5% CO2Cells in logarithmic growth phase were taken for experiment.
Example 31
Detecting the cell viability by an MTT method:
a log-phase RAW264.7 (cell density adjusted to 105/mL) macrophage suspension is inoculated in a 96-well plate, 180 mu L of the macrophage suspension is inoculated in each well, and a blank control group (cells + culture medium) and a drug experimental group (cells + drug) are arranged. Blank wells (plus medium) and drug wells (20. mu.L of drug per well to give a final concentration of 100. mu.M) were provided for each 96-well plate. And (3) lightly tapping the 96-well plate to uniformly mix the medicines in each group of 5 multiple wells, putting the mixture into an incubator for culture, regularly observing the cell state, sucking the supernatant after 24 hours, adding 10 mu L of MTT solution into each well, continuing to culture for 4 hours, slightly sucking and removing the supernatant, adding 100 mu L of DMSO into each well, placing the mixture on a shaker, vibrating the mixture at a low speed for 10 minutes to fully dissolve crystals, and measuring the absorbance value (A) of each well by using an enzyme linked immunosorbent assay (ELISA) detector, wherein the result is shown in figure 2.
Example 32
The Griess method is used for measuring the NO release amount:
1. cell culture supernatant harvesting
Inoculating logarithmic phase RAW264.7 macrophage suspension in 24-well plate with cell density of 5 × 105Each well is 400 mu L, a control group, an LPS stress model group, an LPS + drug experimental group and an LPS + positive drug group are arranged, 100 mu L of culture medium is added into the control group and the LPS stress model group, the experimental group is firstly added with 100 mu L of drug solution for treatment for 1h, then added with LPS with the final concentration of 1 mu g/mL for joint treatment for 24h, and then cell supernatant is collected and centrifuged at 1200rpm for 10 min.
Determination of NO Release amount by Griess method
The operation steps are carried out according to the kit instructions, and the specific steps are as follows:
a. the diluted serial concentrations of standard reagents and test cell culture supernatants were transferred to a 96-well plate at 50 μ L per well.
b. Adding Griess reagent I into each well at room temperature, standing for 10min, wherein each well is 50 mu L.
c. Add under Griess reagent II at room temperature, 50 μ L per well, and let stand for 10 min.
d. And (3) measuring the light absorption value at 540nm by using an enzyme-linked immunosorbent assay detector to obtain a standard curve, and determining the NO release amount of the sample to be measured.
3. Effect of Compounds on LPS-induced RAW264.7 macrophage NO
Inoculating the logarithmic phase RAW264.7 macrophage suspension to a 24-pore plate, wherein the cell density is 5 multiplied by 105400 mu L of the compound per mL of the cell, culturing in a 5% CO2 incubator at 37 ℃ and 4 duplicate wells per 24-well plate, setting a control group, an LPS stress model group, an LPS + drug experimental group and an LPS + positive drug group on each 24-well plate, adding 100 mu L of different compounds (the final concentration is 50 mu M) when the cell growth reaches 70%, stimulating for 24h under the condition of adding or not adding LPS (the final concentration is 1 mu g/mL), and detecting the release amount of NO in the supernatant by a Griess method.
4. Effect of different concentrations of Compound 6 on the amount of NO released from RAW264.7 macrophages stimulated by LPS
Inoculating the logarithmic phase RAW264.7 macrophage suspension to a 24-pore plate, wherein the cell density is 5 multiplied by 105Each well is 400 μ L, culturing at 37 deg.C in 5% CO2 incubator, and setting 4 multiple wells for each group including control group, LPS stress model group, LPS + drug experimental group, and LPS + positive drug groupWhen the cells grew to 70%, 6100. mu.L of the compound (final concentration 25, 50. mu. μ. mu.M) was added at various concentrations, and then stimulated with or without LPS (1. mu.g/mL) for 24 hours, and the amount of NO released from the supernatant was measured by the Griess method.
Result analysis, the cytotoxicity test of the target compound on RAW264.7 cells by an MTT method shows that most of the compounds basically show low toxicity on RAW264.7 cells. In particular, compounds 6b, 6c, 6e, 6f, 6i, 6j, 6k, 6l, 6q, 6t, 6u, 6w, 6aa, 6ad, at a concentration of 100. mu.M, were found to be comparable in toxicity to RAW264.7 cells as the positive control drug indomethacin, and some of the compounds 6b, 6c, 6i, 6j, 6k, 6l, 6t, 6u, 6aa, 6ad were found to be even less toxic than indomethacin. The experimental result of the Griess method for determining the NO release amount shows that: compared with a control drug indometacin, most of the tested compounds have good inhibition effect on NO release, particularly the compounds 6t, 6w and 6ad show stronger NO release inhibition activity than that of the positive control drug indometacin, and the compounds have good application prospect as lead compounds for research and development of new anti-inflammatory drugs.

Claims (10)

1. Quinazolino [2,3-a ] carboline compounds having the general formula (i) or (ii):
Figure 339211DEST_PATH_IMAGE001
(I) or
Figure 920366DEST_PATH_IMAGE002
（Ⅱ）
Wherein R is1Selected from H, F, Cl, Br, I, OMe, Me or CF3；
R2Selected from H, F, Cl, Br, OMe or Me;
R3selected from H, Me, Ac, Boc, Ph, allyl or propyl;
R4selected from H, Me or Ph.
2. The compound of claim 1, wherein:
in the quinazolinone [2,3-a ] carboline compound with the general formula (I),
when R is2Is H, R3Is H, R4When is H, R1Selected from H, F, Cl, Br, I, OMe, Me or CF3；
When R is1Is H, R3Is H, R4When is H, R2Selected from H, F, Cl, Br, OMe or Me;
when R is1Is H, R2Is H, R4When is H, R3Selected from Me, Ac, Boc, Ph, allyl or propyl;
when R is1Is H, R2Is H, R3When is H, R4Selected from Me or Ph;
in the quinazolinone [2,3-a ] carboline compound of the general formula (II),
R1is H, R2Is H, R3Is H.
3. A process for the preparation of a compound according to claim 1, characterized in that:
preparation of quinazolino [2,3-a ] of general formula (I)]Carboline compounds of formula (I) when R3When selected from Me, Ac, Boc, Ph, allyl or propyl, comprising the steps of:
s1, isatoic anhydride derivative
Figure 786690DEST_PATH_IMAGE003
As starting material with the corresponding alkynylamine
Figure 951830DEST_PATH_IMAGE004
Reaction to give Compound 3
Figure 437169DEST_PATH_IMAGE005
；
S2 reaction of compound 3 with corresponding N-protected indole-3-carbaldehyde under catalysis of p-toluenesulfonic acid
Figure 872830DEST_PATH_IMAGE006
Reaction to give Compound 4
Figure 582160DEST_PATH_IMAGE007
；
S3, carrying out cyclization reaction on the compound 4 under the catalysis of gold to obtain a compound containing R3A target compound of (a);
when R is3In the case of H, the compound has the structure,
in the step S2, in the above step,
Figure 63957DEST_PATH_IMAGE006
is replaced by
Figure 851522DEST_PATH_IMAGE008
Compound 4 corresponds to
Figure 735164DEST_PATH_IMAGE009
；
The step S3 is replaced by: removing Boc protecting group to obtain compound 5
Figure 84237DEST_PATH_IMAGE010
And carrying out cyclization reaction on the compound 5 under the catalysis of gold to obtain the target compound.
4. The production method according to claim 3, characterized in that:
in the reaction for removing the Boc protecting group, K is added2CO3And a methanol solution.
5. The production method according to claim 3, characterized in that:
in the reaction process of cyclization reaction under the catalysis of gold, John PhosAuCl and AgNTf are added2And acetonitrile.
6. A process for the preparation of a compound according to claim 1, characterized in that:
preparation of quinazolines of general formula (II)Keto [2,3-a ]]Carboline compounds when R1Is H, R2Is H, R3When the number is H, the method comprises the following steps:
A1. taking o-nitrobenzoyl chloride as a raw material, adding dichloromethane and o-aminophenylacetylene, and reacting to obtain a compound 2ad
Figure 53330DEST_PATH_IMAGE011
；
A2. Addition of NH4Cl to form a concentrated state, then adding EtOH, iron powder and a compound 2ad to react to obtain a compound 3ad
Figure 411630DEST_PATH_IMAGE012
；
A3. Adding a compound 3ad, p-toluenesulfonic acid, tetrahydrofuran, anhydrous magnesium sulfate and 1-Boc-indole-3-formaldehyde, and reacting to obtain a compound 4ad
Figure 290725DEST_PATH_IMAGE013
；
A4. Removing Boc protecting group from compound 4ad to obtain compound 5ad
Figure 935333DEST_PATH_IMAGE014
；
A5. And carrying out cyclization reaction on the compound 5ad under the catalysis of gold to obtain the target compound.
7. The method of claim 6, wherein:
in the step A4, in the reaction for removing the Boc protecting group, K is added2CO3And a methanol solution.
8. The quinazolinone [2,3-a ] carboline compound of the general formula (i) or the general formula (ii) according to claim 1 or 2, and pharmaceutically acceptable excipients.
9. Use of a quinazolinone o [2,3-a ] carboline compound of general formula (i) or general formula (ii) according to claim 1 or 2 or a pharmaceutical composition according to claim 8 for the preparation of an anti-inflammatory medicament.
10. Use of a quinazolinone o [2,3-a ] carboline compound of general formula (i) according to claim 1 or 2 or a pharmaceutical composition according to claim 8 for the preparation of an inhibitor of NO release from RAW264.7 cells induced by LPS.
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