A chiral tetrahydro-beta-carboline derivative, and a preparation method and application thereof

Abstract

This invention belongs to the field of pharmaceutical chemistry, specifically relating to a chiral tetrahydro-β-carboline derivative, its preparation method, and its applications. This invention discloses a chiral tetrahydro-β-carboline derivative (see the structural formula below), which exhibits good antitumor activity, particularly against breast cancer, ductal carcinoma of the breast, and colon cancer cells, demonstrating significant application value in antitumor therapy. Furthermore, this invention uses compounds 1, 2, and 3 or 7 as raw materials to prepare the basic skeleton of the chiral tetrahydro-β-carboline derivative through a one-step reaction. Further cyclization and removal of the protecting group yield the target product. Compared to other methods, the preparation method of this invention is simple, mild, involves few steps, and has a fast reaction rate.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a chiral tetrahydro-β-carboline derivative, its preparation method, and its application. Background Technology

[0002] Heterocyclic drugs exhibit significant activity in numerous clinical applications, such as as anticancer drugs, analgesics, antibacterial drugs, anti-HIV drugs, antimalarial drugs, hypnotics, and antidepressants. Simultaneously, a large number of heterocyclic compounds have wide applications in pesticides, herbicides, rodenticides, and insecticides. Furthermore, many heterocyclic compounds are essential dietary components for humans, such as thiamine, riboflavin, pyridoxine, nicotinic acid, and ascorbic acid. Therefore, heterocyclic compounds form the core framework for drug discovery and design.

[0003] Nitrogen-containing heterocyclic compounds occupy a unique position in the pharmaceutical field as a valuable source of drugs. Among them, nitrogen-containing heterocyclic molecules have become highly attractive synthetic backbones in recent years due to their structural diversity and biological significance. Moreover, nitrogen-containing heterocycles can establish various weak interactions, such as hydrogen bonds, hydrophobic interactions, and van der Waals forces. These advantages enable them to bind to a variety of enzymes or receptors. Therefore, the development of nitrogen-containing drugs plays a crucial role in contemporary chemical research. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a chiral tetrahydro-β-carboline derivative, which has a certain inhibitory effect on breast cancer, ductal carcinoma of the breast, and colon cancer cells, and is expected to play an important role in the field of anti-tumor therapy.

[0005] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0006] The first aspect of this invention provides a chiral tetrahydro-β-carbaline derivative having the structure shown in formula (I) or formula (II):

[0007]

[0008] Among them, R 1 Selected from hydrogen, alkyl, alkoxy, or benzyl; R 2 Selected from alkyl or alkoxy; Ar 1 Selected from aryl or substituted aryl; Ar 2 Selected from aryl or substituted aryl; Ar 3 Selected from aryl or substituted aryl; said aryl is C 6-10 The aryl group; the substituent group in the substituted aryl group is selected from alkyl, haloalkyl or halogen.

[0009] Preferably, R 1 Selected from alkyl or benzyl; R 2 Selected from alkyl groups; Ar 1 Selected from phenyl or methyl, trifluoromethyl or halogen-substituted aryl groups; Ar 2 Selected from phenyl or methyl, trifluoromethyl or halogen-substituted aryl groups; Ar 3 It is selected from methyl, trifluoromethyl or halogen-substituted aryl groups.

[0010] More preferably, the R 1 Methyl; R 2 Methyl; Ar 1 It is phenyl; Ar 2 It is phenyl; Ar 3 It is a methyl, trifluoromethyl or halogen-substituted aryl group.

[0011] More preferably, the R 1 Methyl; R 2 Methyl; Ar 1 It is phenyl; Ar 2 It is phenyl; Ar 3 It is a halogen-substituted aryl group.

[0012] Preferably, the derivative is selected from at least one of the following structural formulas:

[0013]

[0014]

[0015] The second aspect of this invention provides a method for preparing the chiral tetrahydro-β-carboline derivative described in the first aspect, as shown in the following reaction equation. The method for preparing the derivative shown in formula (I) includes the following steps:

[0016] S1. First, mix compound 1, compound 2, rhodium dimer acetate, chiral PA and water absorbent (molecular sieve) in an organic solvent to prepare solution A. Then, under argon protection, dissolve compound 3 in an organic solvent to prepare solution B. Then, add solution B dropwise to solution A to react until the diazo compound is completely consumed. Stop the reaction, concentrate under reduced pressure, and directly separate by column chromatography to prepare compound 4.

[0017] Compound 4 was dissolved in an appropriate amount of toluene, and then DDQ was added. The reaction was carried out at 50°C for 3 hours. After the reaction was completed by thin-layer chromatography, the mixture was concentrated under reduced pressure and directly column-chromatographically oxidized to obtain product 5. The product was then dissolved in MeOH, and formaldehyde solution and 12N HCl were added sequentially at 0°C. The mixture was left to stand overnight at room temperature. After the reaction was completed, the target product 6 was separated by column chromatography.

[0018]

[0019] In the formula, R 1 R 2 Ar 1 Ar 2 Ar 3 The value is the same as in claim 1;

[0020] As shown in the following reaction equation, the preparation method of the derivative represented by formula (II) includes the following steps:

[0021] S1. First, mix compound 1, compound 2, rhodium dimer acetate, chiral PA and water absorbent (molecular sieve) in an organic solvent to prepare solution A. Then, under argon protection, dissolve compound 7 in an organic solvent to prepare solution B. Then, add solution B dropwise to solution A to react until the diazo compound is completely consumed. Stop the reaction, concentrate under reduced pressure, and directly separate by column chromatography to prepare compound 8.

[0022] S2. Compound 8 was then dissolved in an appropriate amount of DCM, formaldehyde solution was added at 0°C, followed by acetic acid. After reacting at room temperature for 2 hours, the reaction was monitored. Once the reaction was complete, the cyclized product 9 was separated by column chromatography. MeOH was then added, followed by Pd / C. After purging with H2, the mixture was stirred at room temperature until the reaction was complete. The product 10 was then separated by column chromatography.

[0023]

[0024] In the formula, R 1 R 2 Ar 1 Ar 2 Ar 3 The value of is the same as in claim 1.

[0025] The method of this invention uses compounds 1, 2, and 3 or 7 as raw materials to prepare the basic skeleton of the chiral tetrahydro-β-carbamoline derivative in a single reaction step. After further cyclization and removal of the protecting group, the target product is obtained. Compared with the existing reported synthetic methods, the reaction of this invention has the advantages of simple operation, mild conditions, fewer steps, and fast reaction speed.

[0026] Preferably, the molar ratio of compound 1, compound 2, compound 3 or compound 7, chiral PA and rhodium dimer acetate is 1.0-1.5:0.5-1.2:0.5-1.2:0.02-0.05:0.02-0.05.

[0027] Preferably, based on the amount of compound 3 or compound 7, the dosage of the desiccant is 10.0–50.0 mg / mmol; and the dosage of the organic solvent is 0.5–1.0 mL / mmol. More preferably, based on the amount of compound 3 or compound 7, the dosage of the desiccant is 10.0 mg / mmol; and the dosage of the organic solvent is 1.0 mL / mmol.

[0028] Preferably, the reaction temperature is -40℃ to 40℃, and the reaction time is 0.5h to 6h. More preferably, the reaction temperature is 0℃, and the reaction time is 2.0h. When the reaction temperature is 25℃, the yield of the target product is higher, heating is not required, and the operation is simple and energy consumption is low.

[0029] Preferably, the organic solvent is toluene or xylene; the molecular sieve is... Molecular sieve.

[0030] The third aspect of this invention provides the use of the chiral tetrahydro-β-carboline derivatives described in the first aspect in the preparation of anti-breast cancer drugs or drugs that inhibit the proliferation of breast cancer cells.

[0031] The fourth aspect of this invention provides the use of the chiral tetrahydro-β-carboline derivatives described in the first aspect in the preparation of drugs for treating breast ductal carcinoma or for inhibiting the proliferation of breast ductal carcinoma cells.

[0032] The fifth aspect of this invention provides the use of the chiral tetrahydro-β-carboline derivatives described in the first aspect in the preparation of anti-colon cancer drugs or drugs that inhibit the proliferation of colon cancer cells.

[0033] Preferably, the breast cancer cells include SKBR3 cells, MDA-MB-231 cells, and MCF-7 cells, and the derivative that inhibits SKBR3 cells is selected from at least one of the following structural formulas:

[0034]

[0035] The derivative that inhibits MDA-MB-231 cells is selected from at least one of the following structural formulas:

[0036]

[0037] The derivatives that inhibit MCF-7 cells are selected from at least one of the following structural formulas:

[0038]

[0039] Preferably, the breast ductal carcinoma cells are HCC1954 cells, and the derivative is selected from at least one of the following structural formulas:

[0040]

[0041] Preferably, the colon cancer cells are HCT116 cells, and the derivative is selected from at least one of the following structural formulas:

[0042]

[0043]

[0044] Studies have shown that the chiral tetrahydro-β-carboline derivatives of this invention exhibit certain inhibitory effects on breast cancer cells, mammary ductal carcinoma cells, and colon cancer cells. They can be prepared into anti-tumor drugs, especially anti-breast cancer drugs, anti-mammary ductal carcinoma drugs, and anti-colon cancer drugs, and have great application potential.

[0045] The sixth aspect of the present invention provides an antitumor drug, wherein the drug uses the chiral tetrahydro-β-carboline derivatives described in the first aspect as the main active ingredient.

[0046] Preferably, the aforementioned antitumor drugs further include pharmaceutically acceptable carriers and / or excipients, and are prepared into clinically acceptable dosage forms. The dosage forms refer to commonly used clinical formulations such as injections, tablets, and capsules. The drug formulation can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally). If certain drugs are unstable under gastric conditions, they can be prepared as enteric-coated tablets.

[0047] Compared with the prior art, the beneficial effects of the present invention are:

[0048] This invention discloses a chiral tetrahydro-β-carboline derivative, which exhibits good antitumor activity, particularly against breast cancer, ductal carcinoma of the breast, and colon cancer cells, demonstrating significant application value in antitumor therapy. Furthermore, this invention uses compounds 1, 2, and 3 or 7 as raw materials to prepare the basic skeleton of the chiral tetrahydro-β-carboline derivative via a one-step reaction. Further cyclization and removal of the protecting group yield the target product. Compared to other methods, the preparation method of this invention is simple, uses mild conditions, involves fewer steps, and has a faster reaction rate. Detailed Implementation

[0049] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0050] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0051] This invention provides a method for preparing chiral tetrahydro-β-carboline derivatives.

[0052] One of the reaction processes for preparing chiral tetrahydro-β-carboline derivatives is shown below:

[0053]

[0054] Among them, R 1 It is an alkyl or benzyl group; R 2 It is an alkyl group; Ar 1 Ar is a phenyl or methyl, trifluoromethyl, or halogen-substituted aryl group. 2 Ar is a phenyl or methyl, trifluoromethyl, or halogen-substituted aryl group. 3 It is a methyl, trifluoromethyl or halogen-substituted aryl group.

[0055] More preferably, the R 1 Methyl; R 2 Methyl; Ar 1 It is phenyl; Ar 2 It is phenyl; Ar 3 It is a methyl, trifluoromethyl or halogen-substituted aryl group.

[0056] More preferably, the R 1 Methyl; R 2 Methyl; Ar 1 It is phenyl; Ar 2 It is phenyl; Ar 3 It is a halogen-substituted aryl group.

[0057] According to the above reaction formula, the preparation method is as follows: First, compound 1, compound 2 catalyst (rhodium dimer acetate, PA, etc.) and water-absorbing agent (molecular sieve) are mixed and dissolved in an organic solvent to prepare solution A. Compound 7 is dissolved in an organic solvent under argon protection to prepare solution B. Then, solution B is added dropwise to solution A to react until the diazo compound is completely consumed. The reaction is then stopped, concentrated under reduced pressure, and directly separated by column chromatography to prepare compound 8. Subsequently, compound 8 is dissolved in an appropriate amount of DCM, formaldehyde solution is added at 0°C, followed by acetic acid. After reacting at room temperature for 2 hours, the reaction is monitored. After the reaction is complete, the cyclized product 9 is separated by column chromatography. Then, MeOH and Pd / C are added, and after purging with H2, the mixture is stirred at room temperature until the reaction is complete. The resulting product 10 is then separated by column chromatography.

[0058] To more clearly illustrate the first preparation method containing chiral tetrahydro-β-carboline derivatives, further details are provided below through Examples 1 and 2.

[0059] Another reaction process for preparing chiral tetrahydro-β-carboline derivatives is shown below:

[0060]

[0061] Among them, R 1 It is an alkyl or benzyl group; R 2 It is an alkyl group; Ar 1 Ar is a phenyl or methyl, trifluoromethyl, or halogen-substituted aryl group. 2 Ar is a phenyl or methyl, trifluoromethyl, or halogen-substituted aryl group. 3 It is a methyl, trifluoromethyl or halogen-substituted aryl group.

[0062] More preferably, the R 1 Methyl; R 2 Methyl; Ar 1 It is phenyl; Ar 2 It is phenyl; Ar 3 It is a methyl, trifluoromethyl or halogen-substituted aryl group.

[0063] More preferably, the R 1 Methyl; R 2 Methyl; Ar 1 It is phenyl; Ar 2 It is phenyl; Ar 3 It is a halogen-substituted aryl group.

[0064] According to the above reaction formula, the preparation method is as follows: First, compound 1, compound 2 catalyst (rhodium dimer acetate, PA), and desiccant (molecular sieve) are mixed and dissolved in an organic solvent to prepare solution A. Then, compound 3 is dissolved in an organic solvent under argon protection to prepare solution B. Solution B is then added dropwise to solution A to react until the diazo compound is completely consumed. The reaction is then stopped, concentrated under reduced pressure, and separated by direct column chromatography to prepare compound 4. Compound 4 is dissolved in an appropriate amount of toluene, and then DDQ is added. The reaction is carried out at 50°C for 3 hours. After the reaction is completed by thin-layer chromatography, the mixture is concentrated under reduced pressure and separated by direct column chromatography to obtain oxidation product 5. This product is then dissolved in MeOH, and formaldehyde solution and 12N HCl are added sequentially at 0°C. The mixture is left to stand overnight at room temperature. After the reaction is completed, the target product 6 is obtained by column chromatography.

[0065] To more clearly illustrate the second preparation method containing chiral tetrahydro-β-carboline derivatives, further details are provided below through Examples 3-12:

[0066] Example 1: Preparation of compound syn-a

[0067] The structure of compound syn-a is shown below:

[0068]

[0069] The preparation process of compound syn-a is as follows:

[0070] Using N-methylindole, methyl 2-diazo-2-phenylacetate, and N-benzylmethylene-4-trifluoromethylaniline as raw materials, molecular sieves as desiccant, and chiral PA and rhodium dimer acetate as catalysts, rhodium dimer acetate (2 mol% Equiv), chiral PA (2 mol% Equiv), and N-benzylmethylene-4-trifluoromethylaniline (1 Equiv) were added to a clean reaction tube equipped with a stir bar. The activated... Molecular sieve (1 Equiv / 100 mg) was used to replace air in the system with argon. N-methylindole (1.2 Equiv) was dissolved in anhydrous xylene (1 mL) and added to the reaction system. Then, methyl 2-diazo-2-phenylacetate (1.2 Equiv) was dissolved in anhydrous xylene (1 mL) and slowly added dropwise to the reaction tube at room temperature using a peristaltic pump. After the addition was complete, stirring continued at room temperature until the diazo compound was completely consumed. After the reaction was stopped, the mixture was concentrated under reduced pressure, and the product was directly separated by column chromatography using 200-300 mesh silica gel. The product was then dissolved in DCM (1 mL), and formaldehyde solution (5 Equiv) was added at 0 °C, followed by acetic acid (10 Equiv). The reaction was allowed to proceed for 2 hours at room temperature, and the reaction was monitored. After the reaction was complete, the cyclized product was separated by column chromatography using 200-300 mesh silica gel. Then, add MeOH (1 mL) and Pd / C (10 mol% Equiv), purge with H2, stir at room temperature until the reaction is complete, and then separate the target product by column chromatography with 200-300 mesh silica gel powder to prepare compound syn-a.

[0071] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 64%, dr: 90:10, ee: 95% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 254 nm: t r (minor) = 6.71 min,t r (major) = 16.65 min). 1H NMR (500MHz, CDCl3) δ7.39–7.32(m,3H),7.28–7.24(m,1H),7.21–7.14(m,3H),6.98–6.89(m ,4H),6.82(d,J=7.2Hz,2H),4.39–4.34(m,2H),4.04–3.99(m,1H),3.73(s,3H),3.58(s,3H). 13 C NMR (125MHz, CDCl3) δ174.0,142.8,139.6,137.4,137.3,130.0,129.4,129.0(q,J=32.2Hz),127.5,127.1,125 .6,124.3(q,J=271.9Hz),123.8(q,J=3.7Hz),121.6,121.2,119.3,110.2,108.7,70.3,57.7,51.7,43.4,29.6. 19 F NMR(471MHz,CDCl3)δ-62.38.HRMS(ESI + ) calculated for C 27 H 24 F3N2O2[M+H] + :465.1784,found465.1780.

[0072] Example 2: Preparation of compound syn-b

[0073] The structure of compound syn-b is shown below:

[0074]

[0075] The preparation process is the same as in Example 1, except that ethyl 2-diazo-2-phenylacetate is used instead of methyl 2-diazo-2-phenylacetate, which allows the R of compound syn-a to be expressed. 2 The R of methyl group transforming into compound b 2 Ethyl groups can be used to prepare the compound syn-b.

[0076] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 60%, dr: 95:5, ee: 93% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 254 nm:t r (minor) = 5.94min,t r (major) = 16.73 min). 1H NMR (400MHz, CDCl3) δ7.38(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,1H),7.29–7.24(m,1H),7.21–7.15(m,3H),7.00(d,J=7.9Hz,1H),6.9 7–6.90(m,3H),6.84(d,J=7.3Hz,2H),4.38–4.35(m,2H),4.14–4.06(m,1H),4.03–3.96(m,2H),3.73(s,3H),1.06(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ173.5,142.9,139.8,137.5,137.3,130.0,129.5,128.9(q,J=32.2Hz),127.5,127.0,125.7, 124.4(q,J=272.0Hz),123.8(q,J=3.5Hz),121.9,121.2,119.1,110.4,108.7,70.4,60.8,57.6,43.4,29.6,13.9. 19 F NMR(376MHz, CDCl3)δ-62.34.HRMS(ESI + ) calculated for C 28 H 26 F3N2O2[M+H] + :479.1941,found479.1924.

[0077] Example 3: Preparation of compound anti-c

[0078] The structure of the compound anti-c is shown below:

[0079]

[0080] The preparation process is as follows:

[0081] Using N-methylindole, methyl 2-diazonyl-2-phenylacetate, and bisphenylmethylene-4-trifluoromethylaniline as raw materials, molecular sieves as desiccant, and chiral PA and rhodium dimer acetate as catalysts, rhodium dimer acetate (2 mol% Equiv), chiral PA (2 mol% Equiv), and bisphenylmethylene-4-trifluoromethylaniline (1 Equiv) were added to a clean reaction tube equipped with a stir bar. The activated... Molecular sieve (1 Equiv / 100 mg) was used to replace the air in the system with argon. N-methylindole (1.5 Equiv) was dissolved in anhydrous xylene (1 mL) and added to the reaction system. Then, methyl 2-diazo-2-phenylacetate (2 Equiv) was dissolved in anhydrous xylene (1 mL) and slowly added dropwise to the reaction tube at room temperature using a peristaltic pump. After the addition was complete, stirring was continued at room temperature until the diazo compound was completely consumed. After the reaction was stopped, the mixture was concentrated under reduced pressure, and the product was obtained by column chromatography using 200-300 mesh silica gel powder.

[0082] The product was dissolved in an appropriate amount of toluene (1 mL), and then DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) (1.5 Equiv) was added. The reaction was carried out at 50 °C for 3 hours. After the reaction was completed by thin-layer chromatography, the solution was concentrated under reduced pressure, and the oxidation product was obtained by direct column chromatography. The product was then dissolved in MeOH (1 mL), and formaldehyde solution (10 Equiv) and 12N HCl (1.5 Equiv) were added sequentially at 0 °C. The reaction was carried out overnight at room temperature. After the reaction was completed, the target product was obtained by column chromatography, thus preparing the compound anti-c.

[0083] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 51%, dr: 7:93, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 254 nm: t r (minor) = 9.11 min,t r (major) = 31.06 min). 1 H NMR (500MHz, CDC) l3 )δ7.37(d,J=8.2Hz,2H),7.33(d,J=8.3Hz,1H),7.26(d,J=8.0Hz,1H),7.21–7.16(m,1H),7.13–7.08(m,1H),7.02–6.96(m,3H),6.95–6.90(m ,2H),6.59(d,J=7.5Hz,2H),5.31–5.27(m,1H),4.30(d,J=16.5Hz,1H),4.23(d,J=16.5Hz,1H),3.73(s,3H),3.70(s,3H),2.05–1.98(m,1H). 13 C NMR (125MHz, CDC) l3)δ174.5,144.2,137.4,136.8,136.0,130.4,129.4(q,J=32.3Hz),128.7,127.0,126.8,125.7,124.5 (q, J=3.6Hz), 124.2 (q, J=272.0Hz), 121.5, 120.3, 119.6, 108.9, 108.7, 64.8, 58.7, 52.3, 42.6, 29.6. 19 F NMR (471MHz, CDC) l3 )δ-62.39.HRMS(ESI+)calculated forC 27 H 24 F3N2O2[M+H]+:465.1784, found 465.1769.

[0084] Example 4: Preparation of compound anti-d

[0085] The structure of compound anti-d is shown below:

[0086]

[0087] The preparation process is the same as in Example 3, except that bisphenylmethylene-4-bromoaniline is used instead of bisphenylmethylene-4-trifluoromethylaniline, which can remove the anti-c Ar of the compound. 3 Ar for the conversion of trifluoromethylphenyl to the compound anti-d 3 p-Bromophenyl can be used to prepare the compound anti-d.

[0088] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 71%, dr: 5:95, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 220 nm: t r (minor) = 11.01 min,t r (major) = 36.33 min). 1H NMR(500MHz, CDCl3)δ7.31(d,J=8.2Hz,1H),7.25–7.19(m,3H),7.19–7.14 (m,1H),7.12–7.07(m,1H),7.03–6.97(m,2H),6.96–6.90(m,1H),6.67(d, J=8.3Hz,2H),6.61(d,J=7.6Hz,2H),5.19–5.14(m,1H),4.26(d,J=16.4Hz ,1H),4.18(d,J=16.4Hz,1H),3.70(s,3H),3.66(s,3H),2.05–1.98(m,1H). 13 C NMR (125MHz, CDCl3) δ174.5,139.1,137.4,136.9,136.0,130.8,130.6,130.1,127.0,1 26.8,125.7,121.4,121.2,120.2,119.6,108.9,64.6,58.7,52.2,42.7,29.6.HRMS(ESI + )calculated for C 26 H 24 BrN2O2[M+H] + :475.1016,found475.1005.

[0089] Example 5: Preparation of compound anti-e

[0090] The structure of the compound anti-e is shown below:

[0091]

[0092] The preparation process is the same as in Example 3, except that bisphenylmethylene-2-fluoroaniline is used instead of bisphenylmethylene-4-trifluoromethylaniline, which can remove the anti-c Ar of the compound. 3 Ar for the conversion of trifluoromethylphenyl to the compound anti-e 3 o-Fluorophenyl compounds can be prepared to yield anti-e compounds.

[0093] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 44%, dr: 17:83, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 230 nm: t r (minor) = 11.22min,t r (major) = 19.87 min).1 H NMR (500MHz, CDC) l3 )δ7.35(d,J=8.2Hz,1H),7.24–7.17(m,2H),7.14–7.09(m,2H),7.04–7.00(m,2H),6.99–6.94(m,1H),6.88–6.84(m,2H),6. 84–6.78(m,3H),5.46–5.43(m,1H),4.28(d,J=16.8Hz,1H),4.22(d,J=16.8Hz,1H),3.73(s,3H),3.67(s,3H),2.16(br,1H). 13 C NMR (125MHz, CDC) l3 )δ174.6,160.9(d,J=246.2Hz),137.2(d,J=11.2Hz),136.1,130.3(d,J=4.4Hz),130.1,128.9(d,J=8.8Hz),126.9,126.5 ,126.4,126.0,123.3(d,J=3.1Hz),121.4,120.5,119.5,115.5(d,J=23.6Hz),108.8,108.6,57.6,52.3,41.7,29.7,29.6. 19 F NMR (471MHz, CDC) l3 )δ-115.36.HRMS(ESI+)calculatedfor C 26 H 24 FN2O2[M+H]+:415.1816,found 415.1807.

[0094] Example 6: Preparation of compound anti-f

[0095] The structure of compound anti-f is shown below:

[0096]

[0097] The preparation process is the same as in Example 3, except that: bisphenylmethylene-4-bromoaniline is used instead of bisphenylmethylene-4-trifluoromethylaniline, and methyl 2-(4-bromophenyl)-2-diazoacetic acid is used instead of methyl 2-diazo-2-phenylacetic acid, thus removing anti-c Ar 2 The conversion of phenyl into the anti-f compound Ar 2 p-Bromophenyl, Ar of the anti-c of the compound 3 Ar for the conversion of trifluoromethylphenyl to compound anti-f 3p-Bromophenyl can be used to prepare the compound anti-f.

[0098] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 70%, dr: 10:90, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 220 nm: t r (minor) = 10.87min,t r (major) = 28.85 min). 1 H NMR (500MHz, CDC) l3 )δ7.33(d,J=8.3Hz,1H),7.29(d,J=8.5Hz,2H),7.21–7.16(m,2H),7.15–7.11(m,2H),6.98–6.93(m,1H),6.70(d,J=8.4Hz,2H),6.47 (d,J=8.6Hz,2H),5.17–5.14(m,1H),4.31(d,J=16.2Hz,1H),4.22(d,J=16.2Hz,1H),3.72(s,3H),3.70(s,3H),1.87–1.82(m,1H).13C NMR (125MHz, CDCl3) δ174.0,138.8,137.4,136.0,135.8,132.5,131.0,129.9,129.7,125.4,1 21.6,121.5,121.3,119.8,108.9,108.6,64.5,58.4,52.3,42.8,29.6.HRMS(ESI+)calculated for C26H23Br2N2O2[M+H]+:553.0121, found553.0115.

[0099] Example 7 Preparation of compound anti-g

[0100] The structure of the compound anti-g is shown below:

[0101]

[0102] The preparation process is the same as in Example 3, except that: diphenylmethylene-4-bromoaniline is used instead of p-diphenylmethylene-4-trifluoromethylaniline, and methyl 2-(4-methylphenyl)-2-diazoacetic acid is used instead of methyl 2-diazo-2-phenylacetic acid, thus removing anti-c Ar 2 The conversion of phenyl into the anti-g compound Ar 2 p-Methylphenyl, Ar of the anti-c compound3 Ar for the conversion of trifluoromethylphenyl to compound anti-g 3 p-Bromophenyl can be used to prepare the compound anti-g.

[0103] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 77%, dr: 7:93, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 230 nm: t r (minor) = 10.22min,t r (major) = 49.85 min). 1 H NMR (400MHz, CDC) l3 )δ7.36(d,J=8.2Hz,1H),7.31–7.27(m,3H),7.24–7.18(m,1H),7.02–6.96(m,1H),6.86(d,J=8.0Hz,2H),6.74(d,J=8.4Hz,2H),6.52(d,J =8.2Hz,2H),5.20–5.17(m,1H),4.32(d,J=16.5Hz,1H),4.23(d,J=16.5Hz,1H),3.75(s,3H),3.72(s,3H),2.27(s,3H),2.03–1.99(m,1H). 13 C NMR (100MHz, CDC) l3 )δ174.7,139.2,137.3,136.6,135.8,133.7,130.7,130.5,130.1,127.6,125.7,121.4,121. 2,120.1,119.6,109.2,108.8,64.6,58.4,52.2,42.7,29.6,21.1.HRMS(ESI+)calculatedfor C 27 H 26 BrN2O2[M+H]+:489.1172,found489.1159.

[0104] Example 8: Preparation of compound anti-h

[0105] The structure of compound anti-h is shown below:

[0106]

[0107] The preparation process is the same as in Example 3, except that: diphenylmethylene-4-bromoaniline is used instead of p-diphenylmethylene-4-trifluoromethylaniline, and methyl 2-(3-bromophenyl)-2-diazoacetic acid is used instead of methyl 2-diazo-2-phenylacetic acid, thus removing the anti-c Ar... 2 The conversion of phenyl into the Ar of compound anti-h 2 m-Bromophenyl, Ar of the anti-c compound 3 Ar for the conversion of trifluoromethylphenyl to compound anti-h 3 p-Bromophenyl can be used to prepare the compound anti-h.

[0108] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 70%, dr: 10:90, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 230 nm: t r (minor) = 11.79min,t r (major) = 43.43 min). 1 H NMR (500MHz, CDC) l3 )δ7.37-7.31(m,3H),7.30–7.27(m,1H),7.27–7.24(m,1H),7.24–7.20(m,1H),7.02–6.98(m,1H),6.93–6.88(m,1H),6.72–6.68(m,3H) ,6.59(d,J=7.9Hz,1H),5.21–5.18(m,1H),4.32(d,J=16.3Hz,1H),4.25(d,J=16.3Hz,1H),3.76(s,3H),3.71(s,3H),1.96–1.91(m,1H). 13 C NMR (125MHz, CDC) l3 )δ173.8,139.5,138.8,137.4,135.9,133.7,131.0,130.0,129.8,129.3,128.2,125.4,121.63,121 .56,120.9,119.78,119.75,109.0,108.2,64.7,58.8,52.4,42.8,29.6.HRMS(ESI+)calculatedfor C 26 H 23 Br2N2O2[M+H]+:553.0121, found 553.0117.

[0109] Example 9: Preparation of compound anti-i

[0110] The structure of compound anti-i is shown below:

[0111]

[0112] The preparation process is the same as in Example 3, except that: diphenylmethylene-4-bromoaniline is used instead of p-diphenylmethylene-4-trifluoromethylaniline, and methyl 2-(3-trifluoromethylphenyl)-2-diazoacetic acid is used instead of methyl 2-diazo-2-phenylacetic acid, thus removing anti-c Ar 2 The conversion of phenyl into the anti-i Ar compound 2 m-Trifluoromethylphenyl, Ar of the anti-c compound 3 Ar for the conversion of trifluoromethylphenyl into compound anti-i 3 p-Bromophenyl can be used to prepare the compound anti-i.

[0113] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 82%, dr: 15:85, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 220 nm: t r (minor) = 10.09min,t r (major) = 33.54 min). 1 H NMR (500MHz, CDC) l3 )δ7.40(d,J=7.7Hz,1H),7.36(d,J=8.2Hz,1H),7.30(d,J=8.6Hz,2H),7.2 4–7.18(m,2H),7.18–7.13(m,1H),7.01–6.96(m,1H),6.88(d,J=8.0Hz,1H) ,6.76(s,1H),6.66(d,J=8.4Hz,2H),5.23–5.21(m,1H),4.35(d,J=16.1Hz ,1H),4.28(d,J=16.1Hz,1H),3.76(s,3H),3.74(s,3H),1.91–1.87(m,1H). 13 C NMR (125MHz, CDC) l3)δ173.8,138.6,138.1,137.4,135.9,133.7,131.1,129.5,128.7(q,J=31.9Hz),127.8(q,J=3.8Hz),127.2,124.1( q, J=272.6Hz), 125.4, 123.7 (q, J=3.7Hz), 121.7, 121.6, 119.8, 119.6, 109.0, 108.1, 64.7, 58.8, 52.4, 42.9, 29.6. 19 F NMR (471MHz, CDC) l3 )δ-62.53.HRMS(ESI+)calculated for C 27 H 23 BrF3N2O2[M+H]+:543.0890,found543.0882.

[0114] Example 10 Preparation of compound anti-j

[0115] The structure of compound anti-j is shown below:

[0116]

[0117] The preparation process is the same as in Example 3, except that: diphenylmethylene-4-bromoaniline is used instead of p-diphenylmethylene-4-trifluoromethylaniline, and 5-iodo-N-methylindole is used instead of N-methylindole, thus removing anti-c Ar 1 The phenyl group is converted into the Ar of the compound anti-j. 1 Iodophenyl, the anti-c Ar of the compound 3 Ar for the conversion of trifluoromethylphenyl to compound anti-j 3 p-Bromophenyl can be used to prepare the compound anti-j.

[0118] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 77%, dr: 3:97, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 220 nm: t r (minor) = 11.77min,t r (major) = 46.65 min). 1 H NMR (500MHz, CDC) l3)δ7.58(d,J=1.4Hz,1H),7.44(dd,J=8.6,1.4Hz,1H),7.25(d,J=8.4Hz,2 H),7.18–7.14(m,1H),7.11(d,J=8.6Hz,1H),7.08–7.01(m,2H),6.65(d,J =8.3Hz,2H),6.57(d,J=7.7Hz,2H),5.17–5.13(m,1H),4.30(d,J=16.5Hz, 1H), 4.22 (d, J = 16.5Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 1.83–1.73 (m, 1H). 13 C NMR (125MHz, CDC) l3 )δ174.2,138.8,136.9,136.53,136.52,130.7,130.4,130.1,129.9,128.8,128.0,127.1,12 6.9,121.3,110.8,108.4,83.4,64.5,58.6,52.2,42.7,29.72,29.65.HRMS(ESI+)calculated for C 26 H 23 BrIN2O2[M+H]+:600.9982, found 600.9975.

[0119] Example 11 Preparation of compound anti-k

[0120] The structure of compound anti-k is shown below:

[0121]

[0122] The preparation process is the same as in Example 3, except that: diphenylmethylene-4-bromoaniline is used instead of p-diphenylmethylene-4-trifluoromethylaniline, and 1,6-dimethylindole is used instead of N-methylindole, thus removing anti-c Ar 1 The conversion of phenyl into the Ar of compound anti-k 1 Methylphenyl, the anti-c Ar of the compound 3 Ar for the conversion of trifluoromethylphenyl to compound anti-k 3 p-Bromophenyl can be used to prepare the compound anti-k.

[0123] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 78%, dr: 2:98, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 230 nm: t r (minor) = 11.57min,t r (major) = 36.62 min). 1 H NMR (500MHz, CDC) l3 )δ7.27–7.21(m,2H),7.16–7.07(m,3H),7.05–6.96(m,2H),6.80(d,J=8.4Hz,1H),6.67(d,J=8.2Hz,2H),6.62(d,J=7.7Hz,2H) ,5.20–5.13(m,1H),4.28(d,J=16.4Hz,1H),4.20(d,J=16.4Hz,1H),3.72(s,3H),3.68(s,3H),2.47(s,3H),2.10–2.02(m,1H). 13 CNMR (125MHz, CDC) l3 )δ174.6,139.1,137.8,137.0,135.3,131.2,130.7,130.5,130.1,126.9,126.8,123.5,121. 20,121.17,119.9,109.0,108.6,64.5,58.6,52.2,42.5,29.5,21.8.HRMS(ESI+)calculated for C 27 H 26 BrN2O2[M+H]+:489.1172, found 489.1175.

[0124] Example 12 Preparation of compound anti-l

[0125] The structure of compound anti-l is shown below:

[0126]

[0127] The preparation process is the same as in Example 3, except that: diphenylmethylene-4-bromoaniline is used instead of p-diphenylmethylene-4-trifluoromethylaniline, and N-benzylindole is used instead of N-methylindole, thus enabling the anti-c R... 1 The methyl group is converted into the R of the compound anti-l. 1 benzyl, which will enhance the anti-c Ar group of the compound. 3Ar for the conversion of trifluoromethylphenyl to compound anti-l 3 p-Bromophenyl can be used to prepare the compound anti-l.

[0128] The physicochemical properties and 1H NMR spectrum of the product are as follows: White solid, yield: 78%, dr: 1:99, ee: >99% (Chiralcel IA, hexanes / i-PrOH = 80 / 20, 1.0 mL / min, 254 nm: t r (minor) = 16.20 min, t r (major) = 65.53 min). 1 H NMR (500MHz, CDC) l3 )δ7.36–7.27(m,5H),7.24–7.19(m,2H),7.16–7.07(m,4H),7.06–7.01(m,2H),6.99–6.94(m,1H),6.67-6.62(m,4H),5.35(d,J=16. 8Hz,1H),5.27(d,J=16.8Hz,1H),5.19–5.16(m,1H),4.21(d,J=16.4Hz,1H),4.09(d,J=16.4Hz,1H),3.74(s,3H),2.07–2.00(m,1H). 13 C NMR (125MHz, CDC) l3 )δ174.5,139.0,137.22,137.20,136.9,136.0,130.7,130.5,130.1,129.1,127.8,127.0,126.8,126.2 ,125.9,121.7,121.2,120.5,119.8,109.6,109.3,64.6,58.7,52.3,46.9,42.6.HRMS(ESI+)calculated for C 32 H 28 BrN2O2[M+H]+:551.1329, found 551.1325.

[0129] Experimental Example 1: Cytotoxicity test of tumor cells containing chiral tetrahydro-β-carboline derivatives

[0130] 1. The tumor cells used in the test were: human breast cancer cells (SKBR3) (purchased from ATCC Shanghai Cell Bank), human breast ductal carcinoma cells (HCC1954) (purchased from Wuhan Pronosai Biotechnology Co., Ltd.), human breast cancer cells (MDA-MB-231) (purchased from Wuhan Pronosai Biotechnology Co., Ltd.), human breast cancer cells (MCF-7) (purchased from Wuhan Pronosai Life Science Technology Co., Ltd.), and human colon cancer cells (HCT116) (purchased from Guangzhou Saiku Biotechnology Co., Ltd.).

[0131] 2. Test Methods: The CCK-8 assay was used to determine the inhibitory effects of chiral tetrahydro-β-carboline derivatives (anti-a to anti-l) on the proliferation of human breast cancer cells (SKBR3), human breast ductal carcinoma cells (HCC1954), human breast cancer cells (MCF7), human breast cancer cells (MDA-MB-231), and human colon cancer cells (HCT116). The specific test procedure is as follows:

[0132] (1) The above-mentioned tumor cell lines were prepared into single-cell suspensions using the corresponding complete culture medium. The concentration of the single-cell suspension was 50,000 cells / mL. 100 μL of the cell suspension was seeded into a 96-well culture plate and cultured in a CO2 incubator (37℃, 5% CO2, 95% air) for 24 h. Human breast cancer cells (SKBR3), human breast ductal carcinoma cells (HCC1954), human breast cancer cells (MDA-MB-231), and human breast cancer cells (MCF-7) were cultured in DMEM medium (containing 10% newborn calf serum and 1% penicillin antibody). Human colon cancer cells (HCT116) were cultured in 1640 medium (containing 10% newborn calf serum and 1% penicillin antibody).

[0133] (2) Dissolve the compound in DMSO to prepare a 10 mM stock solution, and dilute the compound syn-a to anti-l with the corresponding complete cell culture medium. After incubating the cells in 96-well plates overnight, remove the culture medium and add 100 μL of complete culture medium containing the compound (final concentration of 10 μM or 20 μM) to each well. Set up two parallel wells for each concentration of the compound. Add 100 μL of complete culture medium without the compound to the negative control group and blank control group. Incubate in a CO2 incubator for 48 hours.

[0134] (3) After culturing for 48 hours, the culture medium was removed, and then 100 μL of basal culture medium containing 10% CCK-8 (Cell Counting Kits-8) reagent was added to each well of cells. After incubation at 37°C for 1-2 hours, the absorbance A at 450 nm was measured using a Biotek multi-mode microplate reader, and the inhibition rate of the compound on tumor cell growth was calculated. The inhibition rate was calculated as follows: [1-(A 药物处理组 -A空白对照 ) / (A 阴性对照组 -A 空白对照 )]×100%, where A is absorbance.

[0135] 3. Test Results: As shown in Table 1, the compounds syn-b, anti-c, anti-d, anti-, and anti-k of this invention exhibited certain inhibitory effects on individual tumor cells, while compound anti-h showed strong inhibitory effects on a variety of tumor cells. Specifically, for HCC1954 cells, compound anti-d showed a high IC50 value. 50 The IC50 of the compound anti-h was 9.90 ± 1.29 μM. 50 The concentration was 1.08 ± 0.21 μM; the IC50 of compound syn-b against HCT116 cells was 1.08 ± 0.21 μM. 50 The IC50 of the compound anti-c was 9.66 ± 0.37 μM. 50 The concentration was 15.84 ± 1.87 μM; the IC50 of the compound anti-h was 15.84 ± 1.87 μM. 50 The IC50 of the compound anti-k was 10.06 ± 1.23 μM. 50 The concentration was 15.18 ± 1.03 μM. Overall, the chiral tetrahydro-β-carboline derivatives of this invention exhibited certain inhibitory effects on breast cancer cells, mammary ductal carcinoma cells, and colon cancer cells, and can be prepared as anti-tumor drugs, especially anti-breast cancer drugs, anti-mammary ductal carcinoma drugs, and anti-colon cancer drugs, showing great application potential.

[0136] Table 1. Cytotoxic effects of chiral tetrahydro-β-carboline derivatives on various cancer cell lines.

[0137]

[0138]

[0139] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.

Claims

1. A chiral tetrahydro-β-carboline derivative comprising, characterized by, The derivative has the structure shown in formula (I) or formula (II): or ; Wherein, the compound represented by formula (Ⅰ) is selected from anti-c, anti-d, anti-e, anti-f, anti-g, anti-h, anti-i, anti-j, anti-k, and anti-l, and the compound represented by formula (Ⅱ) is selected from syn-a and syn-b: 、 、 、 、 、 、 、 、 、 、 、 。 2. The process for the preparation of chiral tetrahydro-β-carboline derivatives containing according to claim 1, characterized in that, As shown in the following reaction equation, the preparation method of the derivative represented by formula (Ⅰ) includes the following steps: S1. First, mix compound 1, compound 2, rhodium dimer acetate, chiral PA and molecular sieve in an organic solvent to prepare solution A. Then, under argon protection, dissolve compound 3 in an organic solvent to prepare solution B. Then, add solution B dropwise to solution A to react until the diazo compound is completely consumed. Stop the reaction, concentrate under reduced pressure, and directly separate by column chromatography to prepare compound 4. Compound 4 was dissolved in an appropriate amount of toluene, then DDQ was added, and the reaction was carried out at 50°C for 3 hours. After the reaction was completed by thin-layer chromatography, the mixture was concentrated under reduced pressure and directly column-chromatographically oxidized to product 5. The product was then dissolved in MeOH, and formaldehyde solution and 12NHCl were added sequentially at 0°C. The mixture was left to stand overnight at room temperature. After the reaction was completed, the target product 6 was separated by column chromatography. ； wherein R 1 , R 2 , Ar 1 , Ar 2 , Ar 3 have the same meanings as in claim 1 ; As shown in the following reaction equation, the preparation method of the derivative represented by formula (II) includes the following steps: S1. First, mix compound 1, compound 2, dirhodium acetate, chiral PA and molecular sieve in an organic solvent to prepare solution A. Then, under argon protection, dissolve compound 7 in an organic solvent to prepare solution B. Then, add solution B dropwise to solution A to react until the diazo compound is completely consumed. Stop the reaction, concentrate under reduced pressure, and directly separate by column chromatography to prepare compound 8. S2. Then, compound 8 was dissolved in an appropriate amount of dichloromethane, formaldehyde solution was added at 0°C, followed by acetic acid. After reacting at room temperature for 2 hours, the reaction was monitored. After the reaction was completed, the cyclized product 9 was separated by column chromatography. Then, MeOH was added, Pd / C was added, H2 was used for purging, and the mixture was stirred at room temperature until the reaction was completed. The target product 10 was then separated by column chromatography. ； wherein R 1 , R 2 , Ar 1 , Ar 2 , Ar 3 have the same meanings as in claim 1.

3. The use of the chiral tetrahydro-β-carboline derivative as described in claim 1 in the preparation of anti-breast cancer drugs or drugs that inhibit the proliferation of breast cancer cells.

4. The use of the chiral tetrahydro-β-carboline derivative of claim 1 in the preparation of drugs for treating breast ductal carcinoma or drugs for inhibiting the proliferation of breast ductal carcinoma cells.

5. The use of the chiral tetrahydro-β-carboline derivative of claim 1 in the preparation of anti-colon cancer drugs or drugs that inhibit the proliferation of colon cancer cells.

6. Use according to claim 3, characterized in that, The breast cancer cells include SKBR3 cells, MDA-MB-231 cells, and MCF-7 cells, and the derivatives that inhibit SKBR3 cells are selected from at least one of the following structural formulas: 、 、 、 、 、 ； The derivative that inhibits MDA-MB-231 cells is selected from at least one of the following structural formulas: 、 、 、 、 、 、 、 、 ； The derivatives that inhibit MCF-7 cells are selected from at least one of the following structural formulas: 、 、 、 、 、 、 。 7. Use according to claim 4, characterized in that, The breast ductal carcinoma cells are HCC1954 cells, and the derivative is selected from at least one of the following structural formulas: 、 、 。 8. Use according to claim 5, characterized in that, The colon cancer cells are HCT116 cells, and the derivative is selected from at least one of the following structural formulas: 、 、 、 、 、 、 、 、 。 9. An antitumor agent, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The drug uses the chiral tetrahydro-β-carboline derivative as described in claim 1 as its main active ingredient.

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