A 2-nitro-2-ene indole sugar C-glycoside compound, its synthesis method and application

Abstract

The present invention relates to the technical field of organic chemistry and medicinal chemistry, and specifically to a 2-nitro-2-ene indole sugar carbon glycoside compound and a synthesis method and application thereof. The specific technical scheme is: 2-nitro alkenyl sugar, substituted indole and molecular sieve are stirred in an organic solvent to form a 2-nitro-2-ene indole sugar carbon glycoside compound. The present invention solves the problems of a single type of indole sugar carbon glycoside, a large amount of catalyst must be used when synthesizing the corresponding sugar carbon glycoside, and poor stereoselectivity in the prior art.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemistry and medicinal chemistry, and in particular to a 2-nitro-2-ene indole sugar carbon glycoside compound and a synthesis method and application thereof. Background Art

[0002] Cancer is one of the leading causes of death in the world. Globally, the number of cancer patients diagnosed in 2020 reached 19.3 million, and the number of people who died from cancer reached 10 million. As a populous country in the world, cancer has now become the number one cause of death in China, and the number of diagnoses is increasing every year. Cancer has become one of the major public health issues in my country, seriously threatening people's health. Therefore, there is an urgent need to develop new, highly effective, and low-toxic anti-tumor drugs.

[0003] Indole is a very important raw material in organic synthesis. Indole is also widely present in various active natural products and drug molecules. Indole glycoside compounds have various biological activities, including anti-inflammatory activity, anti-tumor activity, antibacterial activity and inhibition of sodium-glucose cotransporter 2 inhibitor (SGLT2) activity. Therefore, indole glycoside compounds can be developed as potential drug precursors. The conventional indole carbon glycoside synthesis method uses halogenated sugars or olefin sugars as raw materials to form different indole glycosides under catalysts such as metals or thioureas. The conditions are harsh, the yield is low, the selectivity is poor, the functional group tolerance is low, and it is impossible to quickly carry out the construction of a compound library with diversity orientation, which limits the construction of its compound library and ultimately limits the development of drugs based on indole glycosides.

[0004] So far, there has been no report on the synthesis and activity evaluation of 2-nitro-2-ene indole sugar carbon glycoside compounds. 2-Nitro-2-ene indole sugar carbon glycoside compounds contain α, β-unsaturated nitroolefin structures in their structures, which can undergo more abundant derivatization reactions, greatly expand the types of indole glycoside compounds, and provide a material basis for subsequent drug discovery. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a 2-nitro-2-ene indole sugar carbon glycoside compound and its synthesis method and application, which solves the problems in the prior art of single indole sugar carbon glycoside type, the need to use a large amount of catalyst when synthesizing the corresponding sugar carbon glycoside and poor stereoselectivity.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0007] The present invention discloses a 2-nitro-2-ene indole sugar carbon glycoside compound, the structural formula of which is any one of the following formulas (I):

[0008]

[0009] Among them, Pg 1 is any one of a hydrogen atom, a methyl group, a formyl group, a benzoyl group, a phenyl group, a benzyl group, an allyl group, a propargyl group, a sulfonyl group, and a silicon group;

[0010] Pg 2 is any one of a hydrogen atom, a methyl group, a formyl group, a benzoyl group, a phenyl group, a benzyl group, an allyl group, a propargyl group, a sulfonyl group, and a silicon group;

[0011] or, Pg 1 O.Pg 2 O is substituted by any one of hydrogen, azido, substituted amino, thiol, alkyl sulfide, aryl sulfide, alkyl, alkenyl, and alkynyl;

[0012] R 1 is any one of a hydrogen atom, a methyl group, a phenyl group, a benzyl group, an allyl group, a propargyl group, an alkyl group, a cycloalkyl group, a sulfonyl group, an acyl group, and an alkoxycarbonyl group;

[0013] R 2 is any one or more of a hydrogen atom, a halogen, a methyl group, an alkyl group, a methoxy group, a benzyloxy group, an aromatic ring, an aromatic heterocycle, an allyloxy group, a propargyloxy group, a nitro group, an ester group, a carbonyl group, a cyano group, an alkyl thioether group, an aryl thioether group, and a substituted amino group;

[0014] R 3 , R 4 Any one of methyl, ethyl, n-butyl, tert-butyl and phenyl;

[0015] Z is a carbon atom or a silicon atom.

[0016] Preferably, when Pg 1 and / or Pg 2 When Pg is any one of methyl, formyl, acetyl, benzoyl, benzyl, allyl, sulfonyl and silyl, 1 and / or Pg 2 Can be represented by one or more independent R X Substituents are substituted;

[0017] Or, when Pg 1 O and / or Pg 2 When O is any one of substituted amino, mercapto, alkyl sulfide, aryl sulfide, alkyl, alkenyl, and alkynyl, Pg 1 O and / or Pg 2 O can be represented by one or more independent R X Substituents are substituted;

[0018] When R 1When R is any one of methyl, phenyl, benzyl, allyl, propargyl, alkyl, cycloalkyl, sulfonyl, acyl, and alkoxycarbonyl, 1 Can be represented by one or more independent R X replace;

[0019] When R 2 When R is any one of a methyl group, an alkyl group, a methoxy group, a benzyloxy group, an aromatic ring, an aromatic heterocyclic ring, an allyloxy group, a propargyloxy group, a nitro group, an ester group, a carbonyl group, a cyano group, an alkyl thioether group, an aryl thioether group, and a substituted amino group, 2 Can be represented by one or more independent R X Substituents are substituted;

[0020] When R 3 and / or R 4 When R is any one of methyl, ethyl, n-butyl, tert-butyl, and phenyl, 3 and / or R 4 Can be represented by one or more independent R X replace;

[0021] The R X It is any one of a hydrogen atom, a halogen, an alkyl group, a fluoroalkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, an aryl group, an amino group, an alkoxy group, a substituted amino group, an amide group, a hydroxyl group and a sulfonamide group.

[0022] Preferably, when R X When R is any one of a hydrogen atom, a halogen, an alkyl group, a fluoroalkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, an aryl group, an amino group, an alkoxy group, a substituted amino group, an amide group, a hydroxyl group and a sulfonamide group, X They may be substituted with one or more hydrogen atoms, halogen, alkyl, fluoroalkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, aryl, amino, alkoxy, substituted amino, amide, hydroxyl and sulfonamide groups, respectively.

[0023] Correspondingly, a method for preparing 2-nitro-2-eneindole sugar carbon glycoside compounds is provided, wherein 2-nitroalanose, substituted indole, and molecular sieve are stirred in an organic solvent for 1 to 72 hours to form 2-nitro-2-eneindole sugar carbon glycoside compounds.

[0024] Preferably, the equivalent ratio of the 2-nitro glycan to the substituted indole is 1:1-100, the reaction concentration is 0.001-100 mol / L, the reaction temperature is -100-200° C., and the concentration of the molecular sieve is 0-500 g / mol.

[0025] Preferably, the organic solvent is any one of 2,2,2-trifluoroethanol, 2,2,2-trichloroethanol, 1,1,1,3,3,3-hexafluoro-2-2propanol, chloroethanol, 2,2-dichloroethanol, dichloromethane, chloroform, acetonitrile, methanol, ethanol, n-butanol, tert-butanol, isopropanol, benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, 2-methyltetrahydrofuran, ether, and methyl tert-butyl ether, or a mixture of any proportions of several solvents.

[0026] Preferably, the molecular sieve is Any one of .

[0027] Preferably, a catalyst is added to the reaction system of nitroglycoside and substituted indole, the amount of the catalyst is 0.001 to 10.0 equivalents, and the catalyst includes any one of BF3·Et2O, TMSOTf, TBSOTf, TESOTf, metal halides, metal sulfonates, perchloric acid and its metal salts, triarylborone, organic phosphoric acid, organic thiourea, and organic carbonyl acid.

[0028] Correspondingly, a pharmaceutical composition comprises the above-mentioned compound or the compound synthesized by the above-mentioned preparation method, or its stereoisomer, tautomer or salt, or its prodrug molecule, or a medically acceptable carrier.

[0029] Correspondingly, the use of the above-mentioned compound or the compound synthesized by the above-mentioned preparation method, or its stereoisomer, tautomer or salt, or its prodrug molecule, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating cancer or tumors.

[0030] The present invention has the following beneficial effects:

[0031] 1. The present invention uses 2-nitroalanose and substituted indole as raw materials to efficiently and highly selectively synthesize a series of 2-nitro-2-ene indole sugar carbon glycoside compounds, and the entire synthesis process has the advantages of mild conditions, high yield, good selectivity, simple operation, etc.

[0032] 2. Since the protecting group in the product can be removed under mild conditions, and the nitroolefin in the product can be further converted into indole sugar carbon glycoside compounds substituted with other C3-substituted analogs (such as alcohol, thiol, phenol, thiophenol, azide, amino, hydroxyl, alkyl, aryl, etc.) through addition reaction, the nitro group can also be further converted into an amino group and further undergo other reactions to form a variety of sugar derivatives. The azide group in some products can also react with other various alkynyl-substituted small molecule compounds, natural products, and active drug molecules through Click reaction (click chemistry). Therefore, the present invention also provides an irreplaceable route for the diverse synthesis and modification of indole-substituted sugar derivatives.

[0033] 3. Some of the 2-nitro-2-ene indole sugar carbon glycoside compounds obtained by the present invention exhibit a wide range of anti-tumor cell or cancer cell activities and extremely low toxicity to normal liver cells, and have the characteristics of high efficiency and low toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The cytotoxic activity of each compound on the following tumor cells and cancer cells (A549 human lung cancer cells; MKN-45 human gastric cancer cells; L-02 human normal liver cells; MCF7 human breast cancer cells; HCT 116 human colon cancer cells; 5637 human bladder cancer cells; DU145 human prostate cancer cells; CAL-62 human thyroid cancer cells; PATU8988T human pancreatic cancer cells; A-673 human rhabdomyosarcoma cells);

[0035] Figure 2 is the half inhibitory concentration IC of compound W5 and positive drug doxorubicin hydrochloride (Dox) on 5637 human bladder cancer cells 50 value. DETAILED DESCRIPTION

[0036] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0038] 1. The present invention discloses a 2-nitro-2-ene indole sugar carbon glycoside compound, the structural formula of which is any one of the following formulas (I):

[0039]

[0040] Among them, Pg 1 is any one of a hydrogen atom, a methyl group, a formyl group, a benzoyl group, a phenyl group, a benzyl group, an allyl group, a propargyl group, a sulfonyl group, and a silicon group;

[0041] Pg 2 is any one of a hydrogen atom, a methyl group, a formyl group, a benzoyl group, a phenyl group, a benzyl group, an allyl group, a propargyl group, a sulfonyl group, and a silicon group;

[0042] or, Pg 1 O.Pg 2O is substituted by any one of hydrogen, azido, substituted amino, thiol, alkyl sulfide, aryl sulfide, alkyl, alkenyl, and alkynyl;

[0043] R 1 is any one of a hydrogen atom, a methyl group, a phenyl group, a benzyl group, an allyl group, a propargyl group, an alkyl group, a cycloalkyl group, a sulfonyl group, an acyl group, and an alkoxycarbonyl group;

[0044] R 2 is any one or more of a hydrogen atom, a halogen, a methyl group, an alkyl group, a methoxy group, a benzyloxy group, an aromatic ring, an aromatic heterocycle, an allyloxy group, a propargyloxy group, a nitro group, an ester group, a carbonyl group, a cyano group, an alkyl thioether group, an aryl thioether group, and a substituted amino group;

[0045] R 3 , R 4 They are any one of the protecting groups commonly used in sugar chemistry to form a six-membered ring structure with sugar rings 4 and 6, such as methyl, ethyl, n-butyl, tert-butyl, and phenyl;

[0046] Z is a carbon atom or a silicon atom.

[0047] Furthermore, when Pg 1 and / or Pg 2 When Pg is any one of methyl, formyl, acetyl, benzoyl, benzyl, allyl, sulfonyl and silyl, 1 and / or Pg 2 Can be represented by one or more independent R X Substituents are substituted;

[0048] Or, when Pg 1 O and / or Pg 2 When O is any one of substituted amino, mercapto, alkyl sulfide, aryl sulfide, alkyl, alkenyl, and alkynyl, Pg 1 O and / or Pg 2 O can be represented by one or more independent R X Substituents are substituted;

[0049] When R 1 When R is any one of methyl, phenyl, benzyl, allyl, propargyl, alkyl, cycloalkyl, sulfonyl, acyl, and alkoxycarbonyl, 1 Can be represented by one or more independent R X replace;

[0050] When R 2 When R is any one of a methyl group, an alkyl group, a methoxy group, a benzyloxy group, an aromatic ring, an aromatic heterocyclic ring, an allyloxy group, a propargyloxy group, a nitro group, an ester group, a carbonyl group, a cyano group, an alkyl thioether group, an aryl thioether group, and a substituted amino group, 2 Can be represented by one or more independent RX Substituents are substituted;

[0051] When R 3 and / or R 4 When R is any one of methyl, ethyl, n-butyl, tert-butyl, and phenyl, 3 and / or R 4 Can be represented by one or more independent R X replace;

[0052] The R X It is any one of a hydrogen atom, a halogen, an alkyl group, a fluoroalkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, an aryl group, an amino group, an alkoxy group, a substituted amino group, an amide group, a hydroxyl group and a sulfonamide group.

[0053] Furthermore, when R X When R is any one of a hydrogen atom, a halogen, an alkyl group, a fluoroalkyl group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, an aryl group, an amino group, an alkoxy group, a substituted amino group, an amide group, a hydroxyl group and a sulfonamide group, X They may be substituted with one or more hydrogen atoms, halogen, alkyl, fluoroalkyl, alkenyl, alkynyl, nitro, cyano, cycloalkyl, aryl, amino, alkoxy, substituted amino, amide, hydroxyl and sulfonamide groups, respectively.

[0054] 2. The present invention discloses a method for preparing 2-nitro-2-ene indole sugar carbon glycoside compounds, wherein 2-nitro ene sugar, substituted indole and molecular sieve are stirred in an organic solvent to form 2-nitro-2-ene indole sugar carbon glycoside compounds. The stirring time can be 1 to 72 hours, but is certainly not limited to this time period.

[0055] The equivalent ratio of the 2-nitro glycan to the substituted indole is 1:1-100, the reaction concentration is 0.001-100 mol / L, the reaction temperature is -100-200°C, and the concentration of the molecular sieve is 0-500 g / mol. The reaction concentration refers to the amount of the substance of the reaction substrate in a unit volume of solvent (i.e., the amount of the substance of the reaction substrate in 1 L of solvent is 0.001-100 mol).

[0056] Furthermore, the 2-nitrosalen includes, but is not limited to, fully acetylated 2-nitrosalen prepared from oligosaccharides such as fully acetylated glucose 2-nitrosalen, fully acetylated galactose 2-nitrosalen, fully acetylated arabinose 2-nitrosalen, and fully acetylated rhamnose 2-nitrosalen.

[0057] The corresponding 2-nitrosalen formed after the 6-position of monosaccharide is functionalized, the disaccharide fully acetylated 2-nitrosalen, and the 2-nitrosalen with different substitutions at the 4 and 6 positions. 1is any one of the protecting groups commonly used in sugar chemistry, such as a hydrogen atom, a methyl group, a formyl group, an acetyl group, a benzoyl group, a benzyl group, an allyl group, a sulfonyl group, and a silicon group; in particular, Pg 1 O can also be substituted by other functional groups, such as hydrogen, azido, substituted amino, thiol, alkyl sulfide, aryl sulfide, alkyl, alkenyl, alkynyl, etc. 2 is any one of the protecting groups commonly used in sugar chemistry, such as a hydrogen atom, a methyl group, a formyl group, an acetyl group, a benzoyl group, a benzyl group, an allyl group, a sulfonyl group, and a silicon group; in particular, Pg 2 O can also be substituted by other functional groups, such as a hydrogen atom, an azido group, a substituted amino group, a thiol group, an alkyl sulfide, an aryl sulfide, an alkyl group, an alkenyl group, an alkynyl group, etc.

[0058] Further, the organic solvent is any one of 2,2,2-trifluoroethanol, 2,2,2-trichloroethanol, 1,1,1,3,3,3-hexafluoro-2-2propanol, chloroethanol, 2,2-dichloroethanol, dichloromethane, chloroform, acetonitrile, methanol, ethanol, n-butanol, tert-butanol, isopropanol, benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, 2-methyltetrahydrofuran, ether, and methyl tert-butyl ether, or a mixture of several solvents in any proportion.

[0059] Furthermore, the molecular sieve is (Sodium A type), (Potassium Type A), (Calcium type A).

[0060] The general reaction formula is as follows:

[0061]

[0062] Furthermore, a catalyst is added to the reaction system of nitroglycoside and substituted indole, wherein the amount of the catalyst is 0.001 to 10.0 equivalents, and the catalyst includes any one of BF3·Et2O, TMSOTf, TBSOTf, TESOTf, metal halides, metal sulfonates, perchloric acid and its metal salts, triarylborone, organic phosphoric acid, organic thiourea, and organic carbonyl acid.

[0063] 3. The present invention discloses a pharmaceutical composition, comprising the above-mentioned compound or the compound synthesized by the above-mentioned preparation method, or its stereoisomer, tautomer or salt, or its prodrug molecule, or a medically acceptable carrier.

[0064] 4. The present invention also discloses the use of the above-mentioned compound or the compound synthesized by the above-mentioned preparation method, or its stereoisomer, tautomer or salt, or its prodrug molecule, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating cancer or tumors.

[0065] In order to further illustrate the synthesis of 2-nitro-2-ene indole sugar carbon glycoside compounds in the present invention, the present invention selectively synthesized the following substances, and described the synthesis process of each compound in combination with specific examples.

[0066]

[0067] Example 1

[0068] At room temperature, (3R,4S,5R)-2-nitro-3,4-diacetyloxy-5-azidomethylenepyranose-1-ene (60.0 mg, 0.2 mmol), indole (28.1 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W1 (37.1 mg, yield 52%).

[0069] The reaction equation is:

[0070]

[0071] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0072] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),7.53(d,J=7.6Hz,1H),7.47(s,1H),7.38(d,J=8.0Hz,1H),7.26(s,1H),7.10(t,J=7.5Hz,1H),7.02(t ,J=7.5Hz,1H),6.18(s,1H),5.66(d,J=8.7Hz,1H),4.10(t,J=7.5Hz,1H),3.63(d,J=13.5Hz,1H),3.49(dd,J=13.7,6.2Hz,1H),2.13(s,3H). 13C NMR(101MHz,DMSO-d6)δ170.2,151.9,136.7,131.0,126.6,125.8,121.9,119.8,119.1,112.3,110.0,74.7,70.0,65.1,50.7,21.2.HRMS(ESI)calcd for C 16 H 15 N5NaO5[M+Na] + 380.0965, found 380.0962.

[0073] Example 2

[0074] At room temperature, (3S,4S,5S)-2-nitro-3,4-diacetoxy-5-methylpyranose-1-ene (51.8 mg, 0.2 mmol), indole (28.1 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W2 (33.1 mg, yield 42%).

[0075] The reaction equation is:

[0076]

[0077] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0078] 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),7.51(d,J=7.9Hz,1H),7.46(d,J=2.5Hz,1H),7.37(d,J=8.1Hz,1H),7.22(s,1H),7. 02(q,J=7.0Hz,1H),6.11–6.06(m,1H),5.45–5.39(m,1H),3.92(dd,J=8.5,6.2Hz,1H),2.15(s,3H),1.27(d,J=6.1Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ170.4,152.2,136.6,131.3,126.6,125.8,121.9,119.7,119.1,112.3,110.4,71.9,69.8,69.5,21.2,18.0.HRMS(ESI)calcd for C 16 H17 N2O5[M+H] + 317.1132, found 317.1133.

[0079] Example 3

[0080] At room temperature, (3S,4S)-2-nitro-3,4-diacetyloxypyranose-1-ene (49.0 mg, 0.2 mmol), indole (28.1 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W3 (44.2 mg, yield 59%).

[0081] The reaction equation is:

[0082]

[0083] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0084] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),7.65(d,J=7.8Hz,1H),7.38(d,J=8.9Hz,3H),7.32(d,J=4.4Hz,1H),7.12(d,J=7.4Hz,1H),7 .03(t,J=7.4Hz,1H),6.03(s,1H),5.52(d,J=4.1Hz,2H),3.90(dd,J=12.2,4.0Hz,1H),3.76(dd,J=12.2,4.6Hz,1H),2.15(s,3H). 13 CNMR(101 MHz,DMSO-d6)δ170.4,153.6,136.8,128.6,126.4,126.2,122.1,119.7,119.2,112.3,109.8,67.9,64.7,62.9,21.2.HRMS(ESI)calcd for C 15 H 14 N2NaO5[M+Na] + 325.0795, found 352.0802.

[0085] Example 4

[0086] At room temperature, (3S,4S,5R)-2-nitro-3,4-diacetyloxy-5-acetyloxymethylenepyranose-1-ene (63.4 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 12 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W4 (48.9 mg, yield 63%).

[0087] The reaction equation is:

[0088]

[0089] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0090] 1 H NMR (400 MHz, DMSO-d6) δ7.54(d,J=7.9 Hz,1H),7.48(s,1H),7.42(d,J=8.2Hz,1H),7.27(t,J=1.9 Hz,1H),7.17(t,J=7.6 Hz,1H),7.06(t,J=7.2 Hz,1H),6.18–6.13(m,1H),5.72–5.64(m,1H),4.29–4.21(m,1H),4.19–4.10(m,2H),3.75(s,3H),2.13(s,3H),1.99(s,3H). 13 C NMR(101 MHz, DMSO-d6)δ170.6,170.2,151.8,137.1,131.0,130.7,126.2,122.0,119.9,11 9.4,110.6,109.2,73.5,69.6,64.6,62.9,32.9,21.20,21.0.HRMS(ESI)calcdfor C 19 H 20 N2NaO7[M+Na] + 411.1163, found 411.1163.

[0091] Example 5

[0092] At room temperature, (3R,4S,5R)-2-nitro-3,4-diacetyloxy-5-p-toluenesulfonyloxymethylenepyranose-1-ene (85.8 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 12 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W5 (66.3 mg, yield 66%).

[0093] The reaction equation is:

[0094]

[0095] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0096] 1 H NMR (400MHz, DMSO-d6) δ7.67(d,J=8.2Hz,2H),7.49(d,J=7.9Hz,1H),7.44(d,J=7.3Hz,2H),7.25–7.17(m,4H),7.07(t,J=7.5Hz,1H), 6.09(t,J=2.7Hz,1H),5.58(dt,J=8.5,2.7Hz,1H),4.24(d,J=10.0Hz,1H),4.20–4.09(m,2H),3.76(s,3H),2.29(s,3H),2.04(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.0,151.6,145.4,137.07,132.2,130.8,130.6,130.4,128.1,126.2 ,122.0,112.0,119.2,110.6,109.0,73.1,69.7,68.8,64.0,33.0,21.5,21.1.HRMS(ESI)calcd for C 24 H 24 N2NaO8S[M+Na] + 523.1146, found 523.1145.

[0097] Example 6

[0098] At room temperature, (3R,4S,5R)-2-nitro-3,4-diacetoxy-5-azidomethylenepyranose-1-ene (60.0 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W6 (50.4 mg, yield 68%).

[0099] The reaction equation is:

[0100]

[0101] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0102] 1 H NMR (400MHz, DMSO-d6) δ7.56(d,J=7.8Hz,0H),7.48(s,1H),7.42(d,J=8.2Hz,1 H),7.28(s,0H),7.18(t,J=7.6Hz,1H),7.07(t,J=7.5Hz,1H),6.19(dd,J=3.4, 1.8Hz,1H),5.68-5.64(m,1H),4.13-4.09(m,1H),3.75(s,3H),3.62(dd,J=13. 7,2.6Hz,1H),3.49(dd,J=13.6,6.2Hz,1H),3.35(d,J=1.7Hz,1H),2.13(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.2,151.2,137.1,131.2,130.6,126.2,122.0,120 .0,119.3,110.6,109.2,74.7,69.7,65.1,50.7,32.9,21.2.HRMS(ESI)calcd for C 17 H 17 N5NaO5[M+Na] + 394.1122, found 394.1119.

[0103] Example 7

[0104] At room temperature, (3S,4S,5S)-2-nitro-3,4-diacetoxy-5-methylpyranose-1-ene (51.8 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W7 (37.9 mg, yield 58%).

[0105] The reaction equation is:

[0106]

[0107] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0108] 1 H NMR(400MHz, CDCl3)δ7.60(d,J=7.9Hz,1H),7.27(d,J=5.0Hz 1H),7.22(t,J=7.5Hz,1H),7.14–7.11(m,2H),7.07(s,1H),6.02(s,1H),5.49(d, J=8.5Hz,1H),3.86–3.80(m,2H),3.74(s,3H),2.18(s,3H),1.36(d,J=6.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.08,155.80,151.90,137.20,130.14,129.15,125.94,122.22,12 0.02,119.31,109.67,109.39,72.59,70.04,69.67,32.90,20.90,17.92.HRMS(ESI)calcd for C 17 H 19 N2NaO5[M+H] + 331.1288, found 331.1279.

[0109] Example 8

[0110] At room temperature, (3S,4S)-2-nitro-3,4-diacetyloxypyranose-1-ene (49.0 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W8 (42.2 mg, yield 66%).

[0111] The reaction equation is:

[0112]

[0113] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0114] 1 H NMR (400MHz, DMSO-d6) δ7.67(d,J=7.9Hz,1H),7.43(d,J=8.2Hz,1H),7.39(s,1H),7.34(d,J=4.4Hz,1H),7.19(t,J=7.6Hz,1H),7.08( t,J=7.5Hz,1H),6.04(s,1H),5.59–5.39(m,1H),3.90(dd,J=12.3,4.2Hz,1H),3.76(s,3H),3.74(dd,J=12.3,4.2Hz,1H),2.15(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.36,153.37,137.28,130.30,128.91,126.61,122.20,1 19.89,119.39,110.57,109.05,67.51,64.67,62.72,32.96,21.16.HRMS(ESI)calcd for C 16 H 16 N2NaO5[M+Na] + 339.0951, found 339.0950.

[0115] Example 9

[0116] At room temperature, (3S,4S,5R)-2-nitro-3,4-diacetoxy-5-acetoxymethylenepyranose-1-ene (63.4 mg, 0.2 mmol), 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline (37.6 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 12 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W9 (58.0 mg, yield 70%).

[0117] The reaction equation is:

[0118]

[0119] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0120] 1 H NMR (400MHz, DMSO-d6) δ7.46(s,1H),7.29(d,J=7.9Hz,1H),7.26(s,1H),6.93(t,J=7.5Hz,1H),6.85(d,J=7.0Hz,1H),6.12(t,J=4.0Hz 1H),5.69–5.63(m,1H),4.28–4.19(m,1H),4.13(p,J=6.1Hz,4H),2.89(t,J=5.7Hz,2H),2.12(s,3H),2.08–2.02(m,2H),1.99(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.6,170.2,151.9,134.3,130.9,128.0,123.8,122.7,120.3,1 19.0,116.9,109.2,73.5,69.9,64.6,62.9,44.0,24.4,22.7,21.2,21.0.HRMS(ESI)calcd for C 21 H 22 N2NaO7[M+Na] + 437.1319, found 437.1318.

[0121] Example 10

[0122] At room temperature, (3R,4S,5R)-2-nitro-lactose-1-ene (121.1 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), Molecular sieves (100 mg) and 2,2,2-trifluoroethanol (0.4 mL, 0.5 mol / L) were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W10 (37.1 mg, yield 52%).

[0123] The reaction equation is:

[0124]

[0125] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were:

[0126] 1H NMR (400MHz, DMSO-d6) δ7.56(d,J=7.9Hz,1H),7.47(d,J=4.4Hz,1H),7.42(d,J=8.2Hz,1H),7.26(s,1H),7.1 7(t,J=7.6Hz,1H),7.06(t,J=7.2Hz,1H),6.14(s,1H),5.67,(d,J=8.0Hz,1H),5.06–5.02(m,1H),4.87(d,J=7 .9Hz,1H),4.69–4.68(m,1H),4.45(t,J=11.2Hz,1H),4.19–4.12(m,2H),4.00–3.94(m,2H),3.77(s,3H),3.3 9(dd,J=6.9Hz,1H),3.18(dd,J=6.9Hz,1H),1.97(s,3H),1.89(s,3H),1.83(s,3H),1.57(s,3H),1.50(s,3H). 13 C NMR (101MHz, DMSO-d6) δ170.6,170.2,170.1,170.0,169.4,151.8,137.0,129.4,128.1,122.4,120.1,119.1,118.9,110. 4,105.6,98.0,109.8,88.5,70.9,70.7,69.5,68.9,67.3,63.4,60.7,33.0,21.0,20.8,20.7,20.2,20.0.HRMS(ESI)calcd forC 31 H 36 N2NaO 15 [M+Na] + 699.2008, found 699.2008.

[0127] Embodiment 11

[0128] At room temperature, (3S,4S,5R)-2-nitro-3,4-diacetyloxy-5-acetyloxymethylenepyranose-1-ene (63.4 mg, 0.2 mmol), N-methylindole (31.2 mg, 0.24 mmol), catalyst (CAT, 20 mg, 0.01 mmol), After adding molecular sieves (100 mg) and chloroform (0.4 mL, 0.5 mol / L), the mixture was stirred at 65°C for 72 h. The reaction solution was purified by silica gel column chromatography (eluent: n-hexane / acetone = 6:1) to obtain compound W4 (25.1 mg, yield 32%).

[0129] The reaction equation is:

[0130]

[0131] The obtained product was measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data were the same as those in Example 4.

[0132] Example 12 Activity Test

[0133] The concentration of doxorubicin hydrochloride (Dox) was 10 μM, and the concentration of the other compounds (W1-W10) was 20 μM. The cytotoxic activity of the following cancer cells or tumor cells (A549 human lung cancer cells; MKN-45 human gastric cancer cells; L-02 human normal liver cells; MCF7 human breast cancer cells; HCT 116 human colon cancer cells; 5637 human bladder cancer cells; DU145 human prostate cancer cells; CAL-62 human thyroid cancer cells; PATU8988T human pancreatic cancer cells; A-673 human rhabdomyosarcoma cells) was tested by CCK-8 method.

[0134] The results are as follows Figure 1 As shown, compounds W1-W10 have good activity against different tumor cells or cancer cells, and show significantly lower toxicity than the positive control drug. Among them, compounds W1, W3, W4, W5, W7, W8, W9, and W10 have an inhibition rate of less than 50% on normal liver cells at 20 μM (the inhibition rate of positive control drug doxorubicin hydrochloride (Dox) on normal liver cells at 10 μM is higher than 97%). It should be noted that due to slight differences in structure, some compounds show good selectivity for individual cancer cells, such as compound W6, which shows very good activity against MCF7 human breast cancer cells, but the activity of other analogs is lower. Figure 2 IC of W5 and positive control doxorubicin hydrochloride (Dox) against 5673 human bladder cancer cells 50 Value, IC of compound W5 50 =5.0606±0.4114μM, IC of positive control doxorubicin hydrochloride (Dox) 50 =0.0706±0.0021μM.

[0135] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A 2-nitro-2-ene indole sugar carbon glycoside compound, characterized in that: is any one of the following compounds, 。 2. A method for preparing the 2-nitro-2-ene indole sugar carbon glycoside compound according to claim 1, characterized in that: The preparation process of compound W1 is as follows: at room temperature, add (3 R ,4 S ,5 R )-2-nitro-3,4-diacetoxy-5-azidomethylenepyranose-1-ene 60.0 mg, 0.2 mmol, indole 28.1 mg, 0.24 mmol, MS4Å molecular sieve 100 mg and 2,2,2-trifluoroethanol 0.4 mL, 0.5 mol / L, stirred at -15°C for 48 h, and the reaction solution was purified by silica gel column chromatography with n-hexane / acetone = 6:1 as the eluent to obtain compound W1; The preparation process of compound W6 is as follows: at room temperature, add (3 R ,4 S, 5 R )-2-nitro-3,4-diacetoxy-5-azidomethylenepyranose-1-ene 60.0 mg, 0.2 mmol, N-methylindole 31.2 mg, 0.24 mmol, MS4Å molecular sieve 100 mg and 2,2,2-trifluoroethanol 0.4 mL, 0.5 mol / L, stirred at -15°C for 48 h, and the reaction solution was purified by silica gel column chromatography with n-hexane / acetone = 6:1 as the eluent to obtain compound W6; The preparation process of compound W9 is as follows: at room temperature, add (3 S ,4 S, 5 R )-2-nitro-3,4-diacetoxy-5-acetoxymethylenepyranose-1-ene 63.4 mg, 0.2 mmol, 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline 37.6 mg, 0.24 mmol, MS4Å molecular sieves 100 mg and 2,2,2-trifluoroethanol 0.4 mL, 0.5 mol / L, stirred at -15°C for 12 h, and the reaction solution was purified by silica gel column chromatography with n-hexane / acetone = 6:1 as the eluent to obtain compound W9; The preparation process of compound W10 is as follows: at room temperature, add (3 R ,4 S ,5 R )-2-nitro-lactose-1-ene 121.1 mg, 0.2 mmol, N-methylindole 31.2 mg, 0.24 mmol, MS4Å molecular sieves 100 mg and 2,2,2-trifluoroethanol 0.4 mL, 0.5 mol / L were added, and the mixture was stirred at -15°C for 48 h. The reaction solution was purified by silica gel column chromatography with n-hexane / acetone = 6:1 as the eluent to obtain compound W10.

3. A pharmaceutical composition, characterized in that: The invention comprises the compound according to claim 1 or the compound synthesized by the preparation method according to claim 2 or its stereoisomer or salt, and a medically acceptable carrier.

4. Use of the compound according to claim 1 or the compound synthesized by the preparation method according to claim 2 or its stereoisomer or salt or the pharmaceutical composition according to claim 3 in the preparation of drugs for treating cancer or tumors, characterized in that: Use of compound W1 in the preparation of drugs for treating lung cancer, gastric cancer, colon cancer, bladder cancer, prostate cancer, thyroid cancer, and rhabdomyosarcoma; Use of compound W6 in the preparation of drugs for treating lung cancer, gastric cancer, breast cancer, colon cancer, bladder cancer, prostate cancer, thyroid cancer, pancreatic cancer, and rhabdomyosarcoma; Application of compound W9 in the preparation of drugs for treating lung cancer, gastric cancer, colon cancer and bladder cancer; The invention discloses a compound W10 for preparing medicines for treating lung cancer, gastric cancer, colon cancer, bladder cancer, prostate cancer and rhabdomyosarcoma.

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