CN108997341B - Amide-troger's base derivative and its synthesis method and use - Google Patents

Amide-troger's base derivative and its synthesis method and use Download PDF

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CN108997341B
CN108997341B CN201810680148.2A CN201810680148A CN108997341B CN 108997341 B CN108997341 B CN 108997341B CN 201810680148 A CN201810680148 A CN 201810680148A CN 108997341 B CN108997341 B CN 108997341B
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宛瑜
许江飙
张鹏
苑睿
吴翚
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Jiangsu Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/08—Bridged systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The amide-troger base derivative has a structural formula shown in one of the following formulas, and is synthesized by heating nitrogen heterocyclic amine, sodium hydride and an intermediate dissolved in anhydrous tetrahydrofuran or DMF in an inert atmosphere. The synthesis process of the invention has the advantages of mild reaction conditions, short reaction time, high yield and wide industrial/large-scale application prospect. The amide-troglibase derivatives of the present invention can be used as catalysts in the synthesis of naphthoquinopyran derivatives.

Description

Amide-troger's base derivative and its synthesis method and use
Technical Field
The invention belongs to the fields of chemical synthesis and biomedicine, and particularly relates to an amide-troger base derivative and a synthesis method and application thereof.
Background
Cancer, especially some malignant tumors, is a difficult point for scientists to attack for a long time, and chemotherapy is one of the main effective measures for treating cancer at present. However, the number of chemotherapeutic drugs available for clinical use is very limited, and finding new chemotherapeutic drugs that can be used clinically is a hot spot in cancer research at present. Among them, naphthoquinone pyran derivatives are the leading drug molecular skeleton with great potential.
Naphthoquinone derivatives have anticancer, antimalarial, antiplatelet, antiparasitic, antibacterial, antifungal, anti-inflammatory, etc. naphthoquinone skeleton is widely present in natural products, such as β -lapachone (a), dehydro- α -lapachone (B), proctosine (C), WS-5995a (d), streptonigrin (E), etc. pyran skeleton is widely present in natural products, such as vitamin E, alkaloids, anthocyanidins, flavonoids, etc. recently, many pyran derivatives are applied to medicinal chemistry and organic synthesis, some of which may be used as diuretics, anticonvulsants, anticancer drugs, etc.
Naphthoquinone benzopyran derivatives have recently received much attention from people due to their potential biological activities and wide application prospects, and thus a large number of synthetic methods have been reported. The catalyst mainly comprises triethylamine, DBU, potassium phthalimide and Fe3O4Nanoparticles, [ bmim]OH Ionic liquid, Zn (L-proline)2Lipase, urea, microwave, and the like. However, these methods still have limitations and disadvantages, such as large amount of catalyst, complicated synthesis steps, high catalyst toxicity, low yield, etc. Therefore, the development of a novel high-efficiency and low-toxicity synthesis method has certain research value and application prospect.
Disclosure of Invention
The inventor researches and develops a synthesis method of the amide-troglitazone derivative through a large amount of experimental researches, and designs and synthesizes a plurality of amide-troglitazone derivatives.
Specifically, the invention provides an amide-troglitazone derivative, which has a structural formula shown in one of the following formulas:
Figure BDA0001710166580000021
wherein the content of the first and second substances,
Figure BDA0001710166580000022
the invention also provides a synthesis method of the amide-troglibase derivative, wherein,
a method for synthesizing an amide-troglitazone derivative represented by formula 3a or 3b, comprising the steps of:
the method comprises the following steps:
1) adding nitrogen heterocyclic amine shown in the following formula 2a and sodium hydride into a container containing anhydrous tetrahydrofuran in inert atmosphere, and stirring for reaction at room temperature;
2) dissolving an intermediate shown in the following formula 1 in anhydrous tetrahydrofuran, and slowly dropping a mixed solution of the intermediate and the anhydrous tetrahydrofuran into the container;
3) heating and refluxing the container in inert atmosphere to obtain a target product
Figure BDA0001710166580000023
A method for synthesizing an amide-combretastatin derivative represented by formula 3c, 3d, 3e, or 3f, comprising the steps of:
the method 2 comprises the following steps:
1) the following formula 2aAdding the nitrogen heterocyclic amine and sodium hydride into a container containing anhydrous tetrahydrofuran in inert atmosphere, and stirring for reaction at room temperature;
2) dissolving an intermediate shown in the following formula 1 in anhydrous tetrahydrofuran, and slowly dropping a mixed solution of the intermediate and the anhydrous tetrahydrofuran into the container;
3) heating and refluxing the container in inert atmosphere to obtain a target product
Figure BDA0001710166580000031
Wherein the content of the first and second substances,
Figure BDA0001710166580000032
a method for synthesizing an amide-troglitazone derivative represented by formula 3g or 3h, comprising the steps of:
the method 3 comprises the following steps:
1) the following formula 2bAdding the nitrogen heterocyclic amine and sodium hydride into a container containing anhydrous DMF (dimethyl formamide) in an inert atmosphere, and stirring at room temperature for reaction;
2) dissolving an intermediate shown in the following formula 1 in anhydrous DMF, and slowly dropping a mixed solution of the intermediate and the anhydrous DMF into the container;
3) heating the container in inert atmosphere to obtain the target product
Figure BDA0001710166580000033
Wherein the content of the first and second substances,
Figure BDA0001710166580000034
the post-treatment process of method 1 and method 2 is as follows: after the reaction is finished, the solvent is evaporated to dryness under reduced pressure, water is added to adjust the pH value to be neutral, the organic solvent is extracted, the organic phases are combined, dried and dried in a spinning mode to obtain a crude product, and the crude product is purified through column chromatography to obtain a pure product.
The post-treatment process of method 3 is as follows: after the reaction is finished, the solvent is evaporated to dryness under reduced pressure, water is added to adjust the pH value to be neutral, a crude product is obtained by filtration, and the pure product is obtained by column chromatography purification.
The invention also provides application of the amide-troglitazone derivative shown in the formula 3h as a catalyst.
Compared with the prior art, the invention has the beneficial effects that: the synthesis process has the advantages of mild reaction conditions, short reaction time, high yield and wide industrial/large-scale application prospect; the amide-troglibase derivatives of the present invention can be used as catalysts in the synthesis of naphthoquinopyran derivatives.
The specific implementation mode is as follows:
example 1 Synthesis of amide-troglitazone derivatives 3a, 3b
Figure BDA0001710166580000041
Adding azacyclamine 2(2mmol), sodium hydride (60% paraffin mixture, 4mmol) into a dry double-neck bottle, adding anhydrous tetrahydrofuran (10mL) under the protection of argon, stirring at room temperature for reaction for 2h, dissolving the intermediate 1(1mmol) into 5mL of anhydrous tetrahydrofuran, slowly dropping the solution into the double-neck bottle, transferring to an oil bath pot after dropping, and heating under the protection of argon for reflux for 24h (TLC tracking). Evaporating the solvent under reduced pressure, adding waterWith 1M NaHSO4Adjusting pH of the solution to neutral, extracting with dichloromethane three times (each time 100mL), mixing organic phases, drying with anhydrous sodium sulfate, spin-drying solvent to obtain crude product, and purifying by column chromatography (V)Ethyl acetate:VMethanol1) to give pure product 3a or 3 b.
Example 2 Synthesis of amide-troglitazone derivatives 3c, 3d, 3e, 3f
Figure BDA0001710166580000042
Adding nitrogen heterocyclic amine 2 into a dry double-neck bottlea(2mmol), sodium hydride (60% paraffin mixture, 4mmol), anhydrous tetrahydrofuran (10mL) added under the protection of argon, stirred at room temperature for reaction for 2h, intermediate 1(1mmol) dissolved in 5mL anhydrous tetrahydrofuran, the solution slowly dropped into a two-necked flask, transferred to an oil bath, heated under the protection of argon for reflux for 24h (TLC follow-up). Evaporating the solvent under reduced pressure, adding water and using 1M NaHSO4Adjusting pH of the solution to neutral, extracting with dichloromethane three times (each time 100mL), mixing organic phases, drying with anhydrous sodium sulfate, spin-drying solvent to obtain crude product, and purifying by column chromatography (V)Ethyl acetate:VMethanol1) to give pure product 3c, 3d, 3e or 3 f.
EXAMPLE 3 Synthesis of amide-troglitazone derivative 3g, 3h
Figure BDA0001710166580000051
Adding nitrogen heterocyclic amine 2 into a dry double-neck bottleb(2mmol), sodium hydride (60% paraffin mixture, 4mmol), anhydrous DMF (10mL) added under argon protection, stirred at room temperature for 2h, intermediate 1(1mmol) dissolved in 5mL anhydrous DMF, the solution slowly dropped into a two-necked flask, transferred to the oil bath, heated at 100 ℃ under argon protection for 24h (TLC follow-up). Evaporating the solvent under reduced pressure, adding water and using 1M NaHSO4Adjusting pH of the solution to neutral, filtering to obtain crude product, and purifying by column chromatography (V)Ethyl acetate:VMethanol1) to give pure product 3g or 3 h.
Example 4 Synthesis of naphthoquinopyran derivative 7
Figure BDA0001710166580000052
2-hydroxy-1, 4-naphthoquinone 4(1.0mmol), arylaldehyde 5(1mmol), benzothiazole-2-acetonitrile 6(1.0mmol), catalyst 3h (10 mol%) from example 3 and ethanol (5mL) were added to a dry round bottom flask, heated to reflux with stirring, the reaction was complete (TLC trace), cooled to room temperature, and the excess solvent was spun off to give the crude product as VPetroleum ether:VEthyl acetateAnd (3) carrying out column chromatography purification on the developing solvent with the ratio of 1:2 to obtain the target compound 7.
Example 5 Synthesis of naphthoquinopyran derivative 9
Figure BDA0001710166580000061
Wherein the content of the first and second substances,
Figure BDA0001710166580000062
2-hydroxy-1, 4-naphthoquinone 4(1.0mmol), substituted isatin 8(1mmol), benzothiazole-2-acetonitrile 6(1.0mmol), catalyst from example 3 for 3h (10 mol%) and ethanol (5mL) were added to a dry round bottom flask, heated with stirring under reflux, reaction ended (TLC track), cooled to room temperature, excess solvent was spun off to give crude product as VPetroleum ether:VEthyl acetateAnd (3) carrying out column chromatography purification on the developing solvent with the ratio of 1:2 to obtain the target compound 9.
Example 6 product Structure characterization
3a
8- (pyridin-2-ylcarbamoyl) -6H,12H-5, 11-methylenedibenzo [ b, f ] [1,5] diazocine-2-carboxylic acid ethyl ester
Figure BDA0001710166580000063
Hz,1H),7.81(t,J＝8.2Hz,2H),7.76-7.65(m,2H),7.61(s,1H),7.30-7.18(m,2H),7.17-7.08(m,1H),4.80-4.65(m,2H),4.37-4.18(m,6H),1.26(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ166.45,166.02,152.66,149.17,148.62,147.79,136.94,130.79,129.54,129.32,129.20,129.13,127.32,125.55,120.85,119.08,115.69,114.86,113.91,67.99,60.92,60.22,57.66,14.68.HRMS(ESI)m/z:calcd for C24H22N4O3[M+H]+:415.1770；found:415.1781.
3b
N2,N8Bis (pyridin-2-yl) -6H,12H-5, 11-methylenedibenzo [ b, f][1,5]Diazocine-2, 8-dicarboxamides
Figure BDA0001710166580000071
8.3Hz,2H),7.81(t,J＝9.7Hz,4H),7.71(s,2H),7.26(d,J＝8.4Hz,2H),7.18-7.07(m,2H),4.75(d,J＝16.7Hz,2H),4.29(d,J＝18.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.39,152.21,151.56,147.86,138.00,128.93,127.76,127.23,126.84,124.50,119.58,114.44,65.87,58.08.HRMS(ESI)m/z:calcd for C24H22N4O3[M+H]+:463.1882；found:463.1888.
3c
N2,N8-bis (3-methylisoxazol-5-yl) -6H,12H-5, 11-methylenedibenzo [ b, f)][1,5]Diazocine-2, 8-dicarboxamides
Figure BDA0001710166580000072
7.29(d,J＝8.5Hz,2H),6.25(s,2H),4.75(d,J＝16.3Hz,2H),4.31(d,J＝19.2Hz,4H),2.19(s,6H).13C NMR(100MHz,DMSO-d6)δ162.95,161.55,160.59,152.07,128.03,127.38,127.33,126.92,124.74,112.71,89.35,58.05,11.33.HRMS(ESI)m/z:calcd for C25H22N6O4[M+H]+:471.1781；found:471.1796.
3d
N2,N8-bis (1-methyl-1H-pyrazol-5-yl) -2, 8-dicarboxamide-6H, 12H-5, 11-methylenedibenzo [ b, f [ ]][1,5]Diazocine
Figure BDA0001710166580000073
Hz,2H),4.32(d,J＝22.5Hz,4H),3.63(s,6H).13C NMR(100MHz,DMSO-d6)δ165.04,151.62,137.29,136.25,128.27,127.98,127.05,126.72,124.68,100.32,65.89,58.20,35.56.HRMS(ESI)m/z:calcd for C25H24N8O2[M+H]+:469.2100；found:469.2108.
3e
N2,N8Bis (4H-1,2, 4-triazol-4-yl) -6H,12H-5, 11-methylenedibenzo [ b, f)][1,5]Diazocine-2, 8-dicarboxamides
Figure BDA0001710166580000081
7.34(d,J＝8.4Hz,2H),4.77(d,J＝16.8Hz,2H),4.40-4.26(m,4H).13C NMR(100MHz,DMSO-d6)δ170.31,152.27,143.83,128.29,127.11,126.55,125.62,124.90,65.81,58.19.HRMS(ESI)m/z:calcd for C21H18N10O2[M+H]+:443.1692；found:443.1685.
3f
N2,N8Bis (4-methylpyrimidin-2-yl) -2, 8-dicarboxamide-6H, 12H-5, 11-methylenedibenzo [ b, f)][1,5]Diazocine
Figure BDA0001710166580000082
2H),4.74(d,J＝16.6Hz,2H),4.29(d,J＝18.9Hz,4H),2.41(s,6H).13C NMR(100MHz,DMSO-d6)δ168.04,164.74,157.90,157.76,151.64,129.13,127.73,127.43,127.03,124.47,116.50,65.83,58.04,23.47.HRMS(ESI)m/z:calcd for C27H24N8O2[M+H]+:493.2100；found:493.2110.
3g
N2,N8-bis (4-oxo-4, 5-dihydro-1, 3, 5-triazin-2-yl) -6H,12H-5, 11-methylenedibenzo [ b, f)][1,5]Diazocine-2, 8-dicarboxamides
Figure BDA0001710166580000083
7.59(d,J＝9.2Hz,2H),7.42-7.16(m,4H),4.80-4.64(m,2H),4.29-4.20(m,4H).13C NMR(100MHz,DMSO-d6)δ166.09,158.22,128.49,128.17,128.10,127.91,127.50,126.90,124.88,124.71,65.71,58.02.HRMS(ESI)m/z:calcd for C23H18N10O4[M+H]+:499.1591；found:499.1609.
3h
N2,N8Bis (1H-tetrazol-5-yl) -6H,12H-5, 11-methylenedibenzo [ b, f)][1,5]Diazocine-2, 8-dicarboxamides
Figure BDA0001710166580000084
2H),7.58(s,2H),7.36-7.18(m,2H),4.74(t,J＝17.1Hz,2H),4.30(d,J＝13.8Hz,4H),2.41(s,6H).13C NMR(100MHz,DMSO-d6)δ164.78,152.28,151.31,128.53,128.00,127.61,127.12,124.74,65.73,58.01.HRMS(ESI)m/z:calcd for C19H16N12O2[M+H]+:445.1597；found:445.1584
7l
2-amino-5, 10-dioxo-4- (p-tolyl) -5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000091
135.52,134.47,134.07,131.04,130.52,128.63,128.00,125.99,125.79,125.22,76.57,59.03,34.00,20.54,14.22.HRMS(ESI)m/z:calcd for C23H19NO5[M+H]+:390.1341；found:358.1350.
7m
2-amino-4- (3-chlorophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000092
182.77,176.89,167.49,158.84,148.83,147.31,134.42,134.09,132.44,130.99,130.68,129.91,128.22,126.97,126.43,126.01,125.81,123.83,75.93,59.10,34.58,14.13.HRMS(ESI)m/z:calcd for C22H16ClNO5[M+H]+:410.0795；found:410.0786.
7n
2-amino-4- (3-nitrophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000093
182.75,176.87,167.36,158.86,148.98,147.36,147.08,135.13,134.42,134.10,130.96,130.68,129.52,125.99,125.79,123.27,123.07,121.53,75.61,59.18,34.88,14.05.HRMS(ESI)m/z:calcd for C22H16N2O7[M+H]+:421.1036；found:421.1042.
7o
2-amino-4- (4-cyanophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000094
148.91,134.46,134.13,131.98,130.93,130.63,129.45,126.02,125.79,123.52,118.79,109.19,75.51,59.15,35.09,14.15.HRMS(ESI)m/z:calcd for C23H16N2O5[M+H]+:401.1137；found:401.1145.
7p
2-amino-4- (4-bromophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000101
125.68,121.19,119.97,119.19,75.49,56.91,36.00.HRMS(ESI)m/z:calcd forC21H14BrNO5[M+H]+:440.0134；found:440.0141.
7q
2-amino-4- (3-chlorophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000102
167.79,159.02,148.82,147.20,134.40,134.08,132.65,130.97,130.67,129.99,127.84,126.88,126.54,125.99,125.82,124.00,75.75,50.76,34.40.HRMS(ESI)m/z:calcd forC21H14ClNO5[M+H]+:396.0639；found:396.0650.
7r
2-amino-4- (3-nitrophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000103
148.95,147.57,146.94,135.02,134.42,134.10,130.95,130.68,129.56,125.99,125.81,123.41,122.75,121.61,75.47,50.79,34.73.HRMS(ESI)m/z:calcd for C21H14N2O7[M+H]+:407.0879；found:407.0885.
7s
2-amino-4- (4-cyanophenyl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000104
DMSO-d6)δ182.68,176.81,167.70,158.98,150.31,148.97,134.46,134.14,132.10,130.93,130.64,129.24,126.02,125.81,123.61,118.76,109.27,75.40,50.76,34.94.HRMS(ESI)m/z:calcd for C22H14N2O5[M+H]+:387.0981；found:387.0992.
7t
2-amino-5, 10-dioxo-4- (p-tolyl) -5, 10-dihydro-4H-benzo [ g ] benzopyran-3-carboxylic acid ethyl ester
Figure BDA0001710166580000111
δ182.77,177.01,168.02,159.04,148.37,141.82,135.61,134.49,134.11,131.02,130.51,128.78,127.81,126.01,125.81,125.32,76.38,50.72,33.84,20.53.HRMS(ESI)m/z:calcd for C22H17NO5[M+H]+:376.1185；found:376.1193.
7u
2-amino-3- (benzo [ d ] thiazol-2-yl) -4-phenyl-4H-benzo [ g ] benzopyran-5, 10-dione
Figure BDA0001710166580000112
142.76,134.57,134.14,131.45,128.71,128.32,127.70,127.10,126.80,126.12,125.88,125.71,123.96,123.05,121.42,120.21,79.97,37.85.HRMS(ESI)m/z:calcd forC26H16N2O3S[M+H]+:437.0960；found:437.0967.
7v
2-amino-3- (benzo [ d ] thiazol-2-yl) -4- (3-chlorophenyl) -4H-benzo [ g ] benzopyran-5, 10-dione
Figure BDA0001710166580000113
DMSO-d6)δ182.72,176.94,167.47,153.91,152.65,148.11,145.14,134.53,134.16,132.85,131.40,131.01,130.65,130.17,128.47,127.61,127.20,126.19,126.06,125.91,123.13,122.92,121.49,120.27,79.38,37.71.HRMS(ESI)m/z:calcd for C26H15ClN2O3S[M+H]+:471.0570；found:471.0581.
7w
2-amino-3- (benzo [ d ] thiazol-2-yl) -4- (3-bromophenyl) -4H-benzo [ g ] benzopyran-5, 10-dione
Figure BDA0001710166580000114
13C NMR(100MHz,DMSO-d6)δ182.70,173.93,172.93,167.50,153.86,153.66,152.66,147.91,142.11,134.58,134.17,131.90,131.40,131.19,130.98,130.56,126.17,126.07,125.88,123.21,123.11,121.45,120.26,112.70,79.46,37.44.HRMS(ESI)m/z:calcd forC26H15BrN2O3S[M+H]+:515.0065；found:5115.0074.
7x
2-amino-3- (benzo [ d ] thiazol-2-yl) -4- (3-nitrophenyl) -4H-benzo [ g ] benzopyran-5, 10-dione
Figure BDA0001710166580000121
MHz,DMSO-d6)δ182.70,176.92,167.28,153.98,152.64,148.26,147.66,144.82,135.77,135.60,134.52,134.16,131.35,130.98,130.65,129.74,126.22,126.04,125.91,123.22,122.41,122.28,121.50,120.31,79.10,37.84.HRMS(ESI)m/z:calcd for C26H15N3O5S[M+H]+:482.0811；found:482.0803.
7y
4- (2-amino-3- (benzo [ d ] thiazol-2-yl) -5, 10-dioxo-5, 10-dihydro-4H-benzo [ g ] chromen-4-yl) benzonitrile
Figure BDA0001710166580000122
148.23,134.55,134.19,132.89,132.23,131.34,130.94,130.48,129.88,126.21,126.07,125.89,123.37,123.15,122.59,121.43,120.29,109.90,79.09,38.15.HRMS(ESI)m/z:calcd for C27H15N3O3S[M+H]+:462.0912；found:462.0921.
9e
2-amino-5 ' -methoxy-2 ', 5, 10-trioxo-5, 10-dihydrospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -3-carbonitrile
Figure BDA0001710166580000123
DMSO-d6)δ177.36,165.86,160.06,155.27,139.92,139.14,135.01,134.81,127.56,125.71,124.06,122.21,121.48,120.30,118.06,117.35,114.06,110.77,110.49,60.63,55.30,48.80.
9f
2-amino-2 ', 5, 10-trioxo-5, 10-dihydrospiro [ benzo [ g ] benzopyran-4, 3' -indoline ] -3-carboxylic acid ethyl ester
Figure BDA0001710166580000124
10.47(s,1H),8.11(s,2H),8.03(d,J＝4.4Hz,1H),7.81(s,3H),7.17-7.01(m,2H),6.79(d,J＝7.3Hz,2H),3.32(s,3H).13C NMR(100MHz,DMSO-d6)δ181.63,179.34,176.56,167.34,158.73,149.26,143.46,135.69,134.76,134.14,130.84,129.94,128.01,126.04,125.91,123.51,121.65,120.82,108.51,75.71,50.34,47.95.HRMS(ESI)m/z:calcd for C22H14N2O6[M+H]+:403.0930；found:403.0921.
9g
2-amino-5 ' -fluoro-2 ', 5, 10-trioxo-5, 10-dihydrospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -3-carboxylic acid ethyl ester
Figure BDA0001710166580000131
(100MHz,DMSO-d6)δ181.69,179.34,176.54,167.24,158.75,156.45,149.45,139.83,137.32,134.76,134.16,130.83,129.95,126.06,125.90,120.97,114.07,111.67,108.79,75.37,50.38,48.44.HRMS(ESI)m/z:calcd for C22H13FN2O6[M+H]+:421.0836；found:421.0844.
9h
2-amino-5 ' -bromo-2 ', 5, 10-trioxo-5, 10-dihydrospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -3-carboxylic acid ethyl ester
Figure BDA0001710166580000132
DMSO-d6)δ181.78,179.02,176.49,167.16,158.76,149.59,142.94,138.02,134.72,134.17,130.81,130.64,130.03,126.49,126.07,125.90,120.74,112.37,110.33,75.29,50.43,48.13.HRMS(ESI)m/z:calcd for C22H13BrN2O6[M+H]+:481.0035；found:481.0029.
9i
2-amino-5 ' -methyl-2 ', 5, 10-trioxo-5, 10-dihydrospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -3-carboxylic acid ethyl ester
Figure BDA0001710166580000133
NMR(100MHz,DMSO-d6)δ182.38,181.65,177.15,176.26,149.78,140.82,134.89,134.47,133.76,130.78,130.17,130.08,130.00,129.37,126.17,126.15,125.58,120.57,108.90,87.77,51.05,47.31,20.49.HRMS(ESI)m/z:calcd for C23H16N2O6[M+H]+:417.1087；found:417.1093.
9j
2-amino-5 ' -nitro-2 ', 5, 10-trioxo-5, 10-dihydrospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -3-carboxylic acid ethyl ester
Figure BDA0001710166580000141
DMSO-d6)δ182.00,180.00,176.41,166.93,158.89,150.27,150.00,141.69,136.54,134.67,134.23,130.73,130.10,126.06,125.94,125.69,120.06,119.49,108.43,74.86,56.00,50.53.HRMS(ESI)m/z:calcd for C22H13N3O8[M+H]+:448.0781；found:448.0792.
9k
2-amino-3- (benzo [ d ] thiazol-2-yl) spiro [ benzo [ g ] benzopyran-4, 3 '-indoline ] -2', 5, 10-trione
Figure BDA0001710166580000142
(m,1H).13C NMR(100MHz,DMSO-d6)δ181.74,177.46,165.39,153.95,150.64,149.33,149.02,144.28,134.83,134.14,132.35,132.12,130.99,129.98,129.56,126.17,126.11,125.93,125.02,123.45,121.96,120.74,120.23,112.70,109.84,79.17,49.80.HRMS(ESI)m/z:calcd for C27H15N3O4S[M+H]+:478.0862；found:478.0856.
9l
2-amino-3- (benzo [ d ] thiazol-2-yl) -5 ' -chlorospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -2 ', 5, 10-trione
Figure BDA0001710166580000143
DMSO-d6)δ184.67,176.39,173.04,170.02,158.94,157.54,151.77,142.39,136.02,135.22,134.98,134.78,132.77,132.43,130.56,129.53,128.54,127.84,126.36,126.30,126.04,124.03,123.49,123.18,107.71,95.63,59.62.HRMS(ESI)m/z:calcd forC27H14ClN3O4S[M+H]+:512.0472；found:512.0481.
9m
2-amino-3- (benzo [ d ] thiazol-2-yl) -5 ' -bromospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -2 ', 5, 10-trione
Figure BDA0001710166580000144
11.11(s,1H),9.04(s,2H),8.01(d,J＝6.5Hz,1H),7.89-7.73(m,4H),7.37(d,J＝6.3Hz,1H),7.37-7.21(m,3H),6.97(d,J＝7.1Hz,1H),6.98-6.86(m,1H).13C NMR(100MHz,DMSO-d6)δ181.65,177.79,165.41,152.97,151.36,149.41,149.14,142.36,135.79,134.31,133.32,132.09,130.86,129.87,129.43,127.37,126.21,125.83,125.01,122.98,121.87,120.54,119.93,112.70,108.99,78.67,50.02.HRMS(ESI)m/z:calcd for C27H14BrN3O4S[M+H]+:555.9967；found:555.9960.
9n
2-amino-3- (benzo [ d ] thiazol-2-yl) -5 ' -methylspiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -2 ', 5, 10-trione
Figure BDA0001710166580000151
(m,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ181.63,179.67,176.21,165.84,161.08,154.01,152.99,140.18,139.13,135.80,134.86,134.26,130.66,130.01,127.70,127.20,126.14,123.36,122.46,120.14,116.69,112.84,111.15,106.27,97.24,69.42,55.20,14.01.HRMS(ESI)m/z:calcd for C28H17N3O4S[M+H]+:492.1018；found:492.1027.
9o
2-amino-3- (benzo [ d ] thiazol-2-yl) -5 ' -nitrospiro [ benzo [ g ] benzopyran-4, 3 ' -indoline ] -2 ', 5, 10-trione
Figure BDA0001710166580000152
13C NMR(100MHz,DMSO-d6)δ184.67,176.39,173.04,170.02,158.94,157.54,151.77,149.80,136.27,136.02,135.22,134.78,132.77,132.43,130.56,128.54,127.84,126.30,126.04,124.87,123.49,123.18,123.06,120.20,107.62,95.63,59.62.HRMS(ESI)m/z:calcd for C27H14N4O6S[M+H]+:523.0712；found:523.0724.
Example 7 antitumor Activity assay
MTT assay was used to test the inhibitory effect of compounds 7a to 7y of example 4, and compounds 9a to 9o of example 5 on human lung cancer cells (A549), human triple positive breast cancer cells (MCF-7), human triple negative breast cancer cells (MDA-MB-231), and normal human bronchial epithelial cells (HBE), respectively.
The test procedure was as follows:
1. inoculating the thawed and revived tumor cell strain to be tested into a DMEM medium containing 10% newborn bovine serum, and placing the DMEM medium at 37 ℃ and 5% CO2Subculturing in a saturated humidity incubator, and taking cells in logarithmic growth phase for experiment;
2. the logarithmic growth expectation tumor cell is prepared into 1 × 104The single cell suspension/mL was inoculated into a 96-well plate at 100 uL/well and placed at 37 ℃ with 5% CO2Culturing for 24h under the condition, and allowing the cells to adhere to the wall;
3. removing the original culture solution, adding culture medium of compound to be detected with concentration of 5ug/mL to treat cells, and arranging blank control group; the plates were placed at 37 ℃ in 5% CO2Conventionally culturing for 24h in a cell culture box;
4. before 4h after termination of the experiment, 20uL of 5mg/mL MTT solution was added to each well, prepared in PBS, sterilized by 0.22um filter, pH 7.4, and the culture was terminated, and the culture supernatant in the wells was aspirated. Adding DCM 100 uL/hole into each hole, and oscillating for 10min at room temperature;
5. measuring absorbance value of each well on an enzyme linked immunosorbent assay monitor, selecting the wavelength of 490nm, and repeating for 3 times;
6. calculating the inhibition rate of each compound on tumor cells, wherein the calculation formula of the inhibition rate is as follows:
the inhibition rate [1- (medicated cell OD-blank OD)/(control cell OD-blank OD) ] × 100%.
The results of testing compounds 7 a-7 y are shown in table 1:
TABLE 1 inhibition of tumor and Normal cell lines by Compound 7a(IC50Unit μ g/mL)
Figure BDA0001710166580000161
aIC5050. mu.g/mL or more is marked "-"
As can be seen from Table 1, the products 7c, 7j, 7k, 7n, 7r and 7t have good inhibitory effect on one or two of the three tumor cells, but at the same time, the products show cytotoxicity to human bronchial epithelial cells (HBE). The products 7f, 7g, 7l, 7m and 7o have inhibitory effects on three tumor cells, and may have universal applicability to tumor cells, but the products also show cytotoxicity to human bronchial epithelial cells (HBE). Therefore, it is necessary to modify the structure thereof to prepare antitumor drugs.
The product 7u only shows good inhibition effect on human three positive breast cancer cells (MCF-7), has high specificity, and has no toxicity on normal human bronchial epithelial cells (HBE).
Triple positive breast cancer is a breast cancer that is positive for all of the Estrogen Receptor (ER), the Progesterone Receptor (PR), and the human epidermal growth factor receptor (HER-2), and has been investigated: although the proportion of the breast cancer is small, the three-positive breast cancer has the pathological characteristics of large lump, poor biological behavior, more grade III pathology, axillary lymph node metastasis, frequent neural or vascular infiltration, high tumor load, high proliferation index and the like. And the three-positive breast cancer has earlier recurrence and metastasis compared with the negative breast cancer, and the overall survival rate and disease-free survival rate are lower. Therefore, the development of the targeting drug for treating the three-positive breast cancer has important significance in reducing the recurrence and metastasis rate of the three-positive breast cancer.
The product 7u has no substitution on the 4-position aromatic ring and the 3-position is a product substituted by benzothiazolyl, which indicates that the receptor in MCF-7 cells has high requirements on steric hindrance, and the substituent on the 4-position can damage the combination of the product and the receptor due to steric hindrance. Meanwhile, the steric hindrance, the position of a binding site, the electronic effect and the like of the unsubstituted benzothiazole just meet the requirements of the receptor. Through further space combination mode simulation and detailed structure-activity relationship research, and by combining professional means, the receptor of the compound in MCF-7 is expected to be found, the mechanism of the compound for inhibiting MCF-7 is clear, and the compound has wide application prospect in the aspect of preparing high-efficiency and low-toxicity medicines for treating the triple-positive breast cancer.
The product 7u only shows good inhibition effect on human three positive breast cancer cells (MCF-7), has high specificity, and has no toxicity on normal human bronchial epithelial cells (HBE). It is shown that the receptor in MCF-7 cells has high requirements for steric hindrance, and the substituent at position 4 may disrupt the binding of the product to the receptor due to steric hindrance. Meanwhile, the steric hindrance, the position of a binding site, the electronic effect and the like of the unsubstituted benzothiazole just meet the requirements of the receptor. Through further space combination mode simulation and detailed structure-activity relationship research, and by combining professional means, the receptor of the compound in MCF-7 is expected to be found, the mechanism of the compound for inhibiting MCF-7 is clear, and the compound has a good application prospect in the aspect of preparing a high-efficiency low-toxicity medicament for treating the triple-positive breast cancer.
The results of the testing of compounds 9a to 9o are shown in table 2:
TABLE 2 inhibition of three cancer and normal cells by Compound 9a(IC50,μg/mL)
Figure BDA0001710166580000171
Figure BDA0001710166580000181
aIC50Values above 50 are marked "-".
Table 2 the test results show that: the product 9c shows an inhibiting effect on human lung cancer cells (A549), but shows cytotoxicity on normal human bronchial epithelial cells (HBE); the products 9a, 9b, 9d, 9f, 9g, 9h, 9i, 9j, 9l, 9m, 9n and 9o have good inhibitory effect on three tumor cells, and the deficiency in the beauty is that the products also show toxicity to normal cells. Most of the products show good inhibition effect on tumor cells, so that the structure of the products needs to be modified to prepare the antitumor drugs.
The product 9k is used as naphthoquinopyran derivative, the 3-position substituent is benzothiazolyl, and the 4-position is isatin without substitution on benzene ring, and its structure characteristic is very similar to that of 7 u. This result indicates that benzothiazole and suitable steric hindrance are the necessary conditions for both types of products to possess antitumor activity. The product 9k shows good anti-tumor activity on three tumor cells, has no toxicity on normal cells, and has wide application prospect in the aspect of preparing anti-cancer drugs.

Claims (3)

1. An amide-combretastatin derivative characterized by the structural formula:
Figure FDA0002300133950000011
2. a process for the synthesis of an amide-troglibase derivative of formula 3h as claimed in claim 1, characterized in that it comprises the steps of:
1) the following formula 2bAdding the nitrogen heterocyclic amine and sodium hydride into a container containing anhydrous DMF (dimethyl formamide) in an inert atmosphere, and stirring at room temperature for reaction;
2) dissolving an intermediate shown in the following formula 1 in anhydrous DMF, and slowly dropping a mixed solution of the intermediate and the anhydrous DMF into the container;
3) heating the container in inert atmosphere to obtain the target product
Figure FDA0002300133950000012
Wherein the content of the first and second substances,
Figure FDA0002300133950000013
3. the synthesis method according to claim 2, characterized in that the post-treatment process comprises the following steps: after the reaction is finished, the solvent is evaporated to dryness under reduced pressure, water is added to adjust the pH value to be neutral, a crude product is obtained by filtration, and the pure product is obtained by column chromatography purification.
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