Indeno[3,2-b]carbazole dimer derivatives, processes for their preparation and use

Abstract

Indol[3,2-b]carbazole dimer derivative and preparation method and application thereof, belong to medical technology field, the structural general formula of indol[3,2-b]carbazole dimer derivative is one of following structures, the present application provides a kind of method for improving the oxidation or the method of derivative after oxidation to indol[3,2-b]carbazole dimer, obtain the synthesis method of methylene bridge modified indol[3,2-b]carbazole dimer derivative.Indol[3,2-b]carbazole dimer derivative has fixed cavity and rich π electron system, not only can be loaded with the drug of larger molecular size, improve the lipophilic partition coefficient of drug, and it has good ultraviolet absorption and fluorescence color performance, form strong fluorescence and rigid fixed dimer compound, widely potential use, such as drug diagnostic reagent, ion fluorescence sensing, drug molecule carrier and biological macromolecule recognition etc.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to indo[3,2-b]carbazole dimer derivatives, their preparation methods, and their applications in drug molecule recognition. Specifically, it relates to indo[3,2-b]carbazole dimer derivatives, their preparation methods, and their applications in the recognition and encapsulation of cytarabine. Background Technology

[0002] Supramolecular strategies can improve drug solubility and the selectivity and stability of drug delivery methods in biotherapy. They have broad application prospects, including drug encapsulation and protection, dissolving insoluble drugs, photophysical reactions such as fluorescence and chiral detection, and drug molecule delivery and real-time detection. This has consistently been a research hotspot in the fields of life sciences, materials science, and pharmacy.

[0003] Indo[3,2-b]carbazole fused heterocycles possess a large aromatic conjugated plane, providing numerous sites for structural modification. Furthermore, it exhibits excellent optical properties such as high molar extinction coefficient and fluorescence quantum yield, and its derivatives also hold potential pharmaceutical value. The synthesis of amphiphilic indo[3,2-b]carbazole dimer derivatives based on indo[3,2-b]carbazole as the building block reveals excellent optical properties. Furthermore, the rigidity of the molecule can be enhanced by adjusting the steric hindrance formed by the ketal structure on the bridge and the two adjacent methoxy groups. Introducing hydrophilic and lipophilic flexible side chains can improve its lipid-water partition coefficient. This dimer possesses the advantage of integrating drug recognition and sensing. Summary of the Invention

[0004] This invention successfully synthesized indobro[3,2-b]carbazole from dimethyl terephthalate via iodination, boron tribromide demethylation, oxyalkylation, Ullmann condensation, cardo nitrogen cyclization, and N-alkylation. Using this as a building block, amphiphilic indobro[3,2-b]carbazole derivative dimers were synthesized through Friedel-Crafts alkylation, bridged methylene oxidation, and ammonolysis. This molecule, as a supramolecular chemical host, possesses a large cavity and abundant π-electron system, enabling it not only to encapsulate drugs with larger molecular sizes and enhance the lipophilicity of water-soluble drugs, but also exhibits excellent UV absorption and fluorescence properties, allowing for spectroscopic studies of its drug encapsulation performance. This invention explored and discovered its recognition and encapsulation performance for drugs such as cytarabine.

[0005] This invention provides indolo[3,2-b]carbazole dimer derivatives having the following general structural formula:

[0006]

[0007] In the above general structural formula, R1 represents one of H, halogen, hydroxyl, C1-C8 ester group, C1-C8 alkyl, alkoxy or alkylamine group.

[0008] R2: One of the following: C1-C8 carboxylic acids, C1-C8 carboxylic acid esters, C1-C8 amides, benzyl, benzyl containing at least one substituted N, O, or S heteroatom, C1-C8 straight-chain alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, C1-C8 straight-chain alkyl containing at least one substituted N, O, or S heteroatom, C1-C8 branched alkyl containing at least one substituted N, O, or S heteroatom, and C3-C8 cycloalkyl containing at least one substituted N, O, or S heteroatom.

[0009] R3: One of H, halogen, hydroxyl, or alkoxy.

[0010] n: an integer from 1 to 3.

[0011] As a preferred option:

[0012] R1: One of H, methoxy, n-octyloxy, and isooctyloxy.

[0013] R2: One of -CH2COO(C2H4O)2CH3, -CH2COO(C2H4O)3CH3, -CH2CONH(CH2)2OH, and -CH2COO(C2H4O)2C3H7.

[0014] R3: -OCH3.

[0015] More preferably, the structure of the indolo[3,2-b]carbazole dimer derivative of the present invention is as follows:

[0016]

[0017]

[0018]

[0019]

[0020]

[0021] Of the compounds with the above structures, compound 27 is preferred.

[0022] Based on the different structures represented by R1 and R2 in the indo[3,2-b]carbazole dimer derivative, the following synthetic route is used to first synthesize the indo[3,2-b]carbazole derivative motif:

[0023] Based on R1, the structural formula of reactant A is determined as follows:

[0024]

[0025] Reactant A and reactant B were subjected to a Ullmann coupling reaction to obtain intermediate C;

[0026] Intermediate C is cyclically modified to obtain intermediate D;

[0027] Based on the structure of R2, intermediate D was N-alkylated to obtain the indodo[3,2-b]carbazole moiety.

[0028] The specific synthesis route is as follows:

[0029]

[0030] Using the above-mentioned indolo[3,2-b]carbazole moiety, an indolo[3,2-b]carbazole dimer was synthesized, and its "bridge" methylene group was oxidized or derivatized.

[0031] The present invention discloses a method for preparing an indole[3,2-b]carbazole dimer derivative, comprising the following steps:

[0032] The indo-[3,2-b]carbazole dimer derivative was prepared by dissolving the indo-[3,2-b]carbazole moiety in an organic solvent, adding Lewis acid and paraformaldehyde, stirring at room temperature, quenching the reaction with alkali solution after completion, extracting, concentrating, and silica gel column chromatography.

[0033] In the method for preparing the indo[3,2-b]carbazole dimer derivative, the concentration of the indo[3,2-b]carbazole moiety in the organic solvent is 0.5 g / L to 4.0 g / L, preferably 2.0 g / L.

[0034] In the method for preparing the indolo[3,2-b]carbazole dimer derivative, the organic solvent is selected from one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane, preferably dichloromethane; the Lewis acid is selected from one or more of ferric chloride hexahydrate, anhydrous ferric chloride, aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, and p-toluenesulfonic acid, preferably ferric chloride hexahydrate.

[0035] In the method for preparing the indo[3,2-b]carbazole dimer derivative, the molar ratio is Lewis acid:indo[3,2-b]carbazole moiety = (0.4-1.2):1, preferably (0.6-0.7):1.

[0036] In the method for preparing the indo[3,2-b]carbazole dimer derivative, the molar ratio of paraformaldehyde to indo[3,2-b]carbazole moiety is (0.5-2.0):1, preferably (1.6-1.7):1.

[0037] In the preparation method of the indo[3,2-b]carbazole dimer derivative, stirring is carried out at room temperature, preferably at 25-30°C; the reaction time is 0.5-12 h, preferably 0.5-2 h.

[0038] The process involves oxidizing the "bridge" methylene group to form a "bridged ketal" structure with ethylene glycol or butanediol; oxidizing the "bridge" methylene group to derive a "bridged ketal" structure, followed by ammonolysis at R3 to form an amide structure.

[0039] When bridging methylene derivatives of indo[3,2-b]carbazole dimer is performed, anhydrous tetrahydrofuran is used as the solvent, and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is used as the oxidant. The ratio of indo[3,2-b]carbazole dimer derivative to ethylene glycol is 1 g: 0.5-5 mL, or the ratio of indo[3,2-b]carbazole dimer derivative to 1,4-butanediol is 1 g: 0.5-5 mL. The molar ratio of indo[3,2-b]carbazole dimer derivative to DDQ is 1:2, and the reaction time is 1-5 h.

[0040] The ammonolysis is specifically performed as follows: the solid-liquid ratio is indo[3,2-b]carbazole dimer derivative: amine compound = 100 mg: (1-10) mL, DIEA 3-10 drops are added, the amine compound is selected from butylamine, benzylamine, diethylene glycolamine, ethanolamine, preferably ethanolamine, and the mixture is heated to 60-120°C for 72-120 h.

[0041] The indo[3,2-b]carbazole dimer derivative of the present invention has the functions of recognizing drugs, encapsulating drugs, and increasing the lipid solubility of drugs, thus it can be well used as a prodrug carrier and drug delivery material.

[0042] The preferred identification drug is a cytarabine compound used as a prodrug carrier.

[0043] The present invention relates to the application of the indo[3,2-b]carbazole dimer derivative in drug molecule recognition, wherein the drug molecule is cytarabine.

[0044] The beneficial effects of this invention are as follows:

[0045] Specifically, this invention relates to the oxidation of the bridged methylene group containing indo[3,2-b]carbazole dimer to generate ketal and epoxy structures, as well as further substitution products and their synthetic methods, forming strongly fluorescent and rigidly fixed dimer compounds with wide potential applications, such as drug diagnostic reagents, ion fluorescence sensing, carriers of pharmaceutical molecules, and recognition of biomacromolecules.

[0046] Indodo[3,2-b]carbazole dimer derivatives have fixed cavities and abundant π-electron systems, which can not only encapsulate drugs with large molecular sizes and improve the lipid-water partition coefficient of drugs, but also have good ultraviolet absorption and fluorescence color development properties, which can be used to detect drug molecules. Attached Figure Description

[0047] Figure 1 The UV titration spectra of cytarabine and compound 27 are shown.

[0048] Figure 2 SEM image of cytarabine;

[0049] Figure 3 This is a SEM image of compound 27 encapsulated with cytarabine. Detailed Implementation

[0050] The present invention will be further described in detail below with reference to the embodiments.

[0051] Example 1

[0052] Synthesis of compound ac

[0053]

[0054] 1,4-Diiodo-2,5-dimethyl ether was coupled with 4-bromo-3-nitrobenzene via Ullmann coupling, Cadogan cyclization, and N-alkylation to give compound a; 1,4-bis(octoxy)-2,5-diiodobenzene was coupled with 4-bromo-3-nitrobenzene via Ullmann coupling, Cadogan cyclization, and N-alkylation to give compound b; 1,4-bis(isooctoxy)-2,5-diiodobenzene was coupled with 4-bromo-3-nitrobenzene via Ullmann coupling, Cadogan cyclization, and N-alkylation to give compound c; 1H NMR spectroscopy confirmed the synthesis of the corresponding structures.

[0055] Example 2

[0056] Synthesis of Compound 1

[0057]

[0058] Synthesis of Compound 2

[0059]

[0060] Synthesis of Compound 5

[0061] Synthesis of Compound 6

[0062] Synthesis of Compound 7

[0063] Synthesis of Compound 8

[0064] Take a 1L round-bottom flask, weigh 0.58–2g of one of the indole-carbazole units of compound ac, add it to the flask, add 0.58–1L of dichloromethane, slowly add 135–592mg of ferric chloride hexahydrate, then add 45–175mg of paraformaldehyde, stir, and stir at room temperature for 0.5–5 hours. After the reaction is complete, quench the reaction with ammonia. Obtain the product by silica gel column chromatography; detect the result with 1H NMR. 1 H NMR (600MHz, DMSO-d6);

[0065] Compound 1: 780 mg, yield 85%. 1 H NMR(600MHz,Methylene Chloride-d2)δ7.85(d,J=8.6Hz,1H),7.50(s,1H),7.10(s,1H),6.95(s,1H),6.60(d,J=8.6Hz,1H),5.35-5.00( dd,2H),4.18(s,1H),4.14(d,2H),3.92(s,3H),3.66(s,3H),3.47(t,2H),3.30(t,2H),3.22(t,2H),3.11(s,3H).

[0066] Compound 2: 680 mg, yield 75%. 1 H NMR (600MHz, DMSO-d6) δ7.92(d,J=8.6Hz,1H),7.72(s,1H),7.26(s,1H),7.06(s,1H),6.82(d,J=8.6Hz,1H),5.35-5.00(dd,2H),4 .18(s,1H),4.16(d,2H),3.92(s,3H),3.66(s,3H),3.50(t,2H),3.39(t,2H),3.32(t,2H),3.27(t,2H),3.22(t,2H),3.10(s,3H).

[0067] Compound 5: 700 mg, yield 82%. 11H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 8.6 Hz, 2H), 7.72 (s, 2H), 7.26 (s, 2H), 7.06 (s, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.51 (s, 4H), 5.36 (s, 4H), 4.24 (t, J = 4.7 Hz, 4H), 4.14 (s, 2H), 4.09 (t, J = 6.8 Hz, 4H), 4.02 (t, J = 6.8 Hz, 4H), 3.92 (s, 6H), 3.84 (s, 6H), 3.80 (t, J = 6.2 Hz, 4H), 3.64 (t, J = 4.8 Hz, 4H), 3.53–3.42 (m, 18H), 3.42–3.32 (m, 14H), 3.22 (s, 6H), 3.18 (s, 6H), 2.03 (q, J = 6.2 Hz, 4H), 1.54 (t, J = 7.6 Hz, 4H), 1.41 - 1.30 (m, 6.9 Hz, 24H), 1.06 - 1.01 (m, 8H), 0.94 - 0.86 (m, 14H), 0.68 (t, J = 7.2 Hz, 6H).

[0068] Compound 6: 730 mg, yield 76%. 1 1H NMR (600 MHz, DMSO-d6) δ 7.90 (d, J = 8.6 Hz, 2H), 7.71 (s, 2H), 7.30 (s, 2H), 7.06 (s, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.51 (s, 4H), 5.36 (s, 4H), 4.44 (t, J = 4.7 Hz, 4H), 4.14 (s, 2H), 4.09 (t, J = 6.8 Hz, 4H), 4.02 (t, J = 6.8 Hz, 4H), 3.92 (s, 6H), 3.84 (s, 6H), 3.80 (t, J = 6.2 Hz, 4H), 3.64 (t, J = 4.8 Hz, 4H), 3.53–3.42 (m, 10H), 3.42–3.32 (m, 6H), 3.22 (s, 6H), 3.18 (s, 6H), 2.03 (q, J = 6.2 Hz, 4H), 1.54 (t, J = 7.6 Hz, 4H), 1.41 - 1.30 (m, 6.9 Hz, 24H), 1.06 - 1.01 (m, 8H), 0.94 - 0.86 (m, 14H), 0.68 (t, J = 7.2 Hz, 6H).

[0069] Compound 7: 730 mg, yield 83%. 1H NMR (600MHz, DMSO-d6) δ7.97(d,J=8.6Hz,2H),7.77(s,2H),7.24(s,2H),7.00(s,2H),6.83(d,J=8.6Hz,2H),5.53 (s,3H),5.40(s,3H),4.22(t,J=6.0Hz,4H),4.15(s,2H),4.10(d,J=4.7Hz,4H),3.92(s,6H),3.90(s,4H),3.83(s ,6H),3.68(s,4H),3.62(t,J=4.8Hz,4H),3.50(t,J=5.8Hz,4H),3.46(t,J=5.8Hz,4H),3.28(t,J=4.7Hz,4H),3.2 0(s,6H),3.13(s,6H),2.17–2.08(m,2H),1.73-1.65(m,2H),1.58–1.28(m,20H),1.23(m,6H),1.08–0.78(m,30H).

[0070] Compound 8: 750 mg, yield 79%. 1 H NMR (600MHz, DMSO-d6) δ7.97(d,J=8.6Hz,2H),7.80(s,2H),7.24(s,2H),7.11(s,2H),6.83(d,J=8.6Hz ,2H),5.53(s,3H),5.40(s,3H),4.22(t,J=6.0Hz,4H),4.15(s,2H),4.10(d,J=4.7Hz,4H),3.92(s,6H), 3.90(s,4H),3.83(s,6H),3.68–3.62(m,16H),3.50–3.46(m,16H),3.28(t,J=4.7Hz,4H),3.20(s,6H),3 .13(s,6H),2.17–2.08(m,2H),1.73-1.65(m,2H),1.58–1.28(m,20H),1.23(m,6H),1.08–0.78(m,30H).

[0071] Example 3

[0072] Synthesis of Compound 3

[0073]

[0074] Synthesis of Compound 4

[0075]

[0076] Synthesis of Compound 9

[0077]

[0078] Weigh 0.5–2 g of one of the following indole-carbazole dimers (compounds 1, 5, and 7) into a 25 mL round-bottom flask. Add 5 mL of ethanolamine, then slowly add 5–10 drops of DIEA. Stir and incubate at 65 °C for 72–120 h. After the reaction is complete, extract with ethyl acetate and water. Analyze the product using a silica gel column chromatography; detect the result using 1H NMR. 1 H NMR (600MHz, DMSO-d6);

[0079] Compound 3: 750 mg, yield 85%. 1 H NMR (600MHz, DMSO-d6) δ8.30(t,J=5.6Hz,2H),8.17(t,J=4.9Hz,2H),7.94(d,J=8.6H z,2H),7.74(s,2H),6.90(s,2H),6.80(d,J=8.2Hz,2H),6.79(s,2H),5.29(s,4H),5. 15(s,4H),4.10(s,2H),4.05(t,J=7.5Hz,4H),3.90(s,6H),3.84(s,4H),3.83(s,6H) ,3.50(s,6H),3.47–3.44(m,6H),3.29(s,6H),3.26–3.20(m,8H),3.14–3.11(m,6H).

[0080] Compound 4: 600 mg, yield 76%. 11H NMR (600 MHz, DMSO-d6) δ 8.22 (t, J = 5.6 Hz, 2H), 8.15 (t, J = 4.9 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.74 (s, 2H), 6.98 (s, 2H), 6.82 (d, J = 8.2 Hz, 2H), 6.79 (s, 2H), 5.29 (s, 4H), 5.15 (s, 4H), 4.13 (s, 2H), 4.05 (t, J = 7.5 Hz, 4H), 3.90 (s, 6H), 3.84 (s, 4H), 3.83 (s, 6H), 3.50 (s, 6H), 3.47–3.44 (m, 4H), 3.29 (s, 6H), 3.26–3.20 (m, 8H), 3.14–3.11 (m, 4H), 1.98 (d, J = 7.2 Hz, 4H), 1.48 (d, J = 6.9 Hz, 4H), 1.41–1.34 (m, 16H), 1.05–0.97 (m, 12H), 0.89 (d, J = 6.3 Hz, 10H), 0.85 (d, J = 6.6 Hz, 8H), 0.67 (d, J = 7.3 Hz, 6H).

[0081] Compound 9: 500 mg, yield 57%. 1 1H NMR (600 MHz, DMSO-d6) δ 8.27 (t, J = 5.2 Hz, 2H), 8.18 (t, J = 5.9 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 7.81 (s, 2H), 6.93 (s, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.72 (s, 2H), 5.30 (s, 4H), 5.16 (s, 4H), 4.73 (t, J = 5.4 Hz, 2H), 4.66 (t, J = 5.4 Hz, 2H), 4.14 (s, 2H), 3.95 (d, J = 6.6 Hz, 4H), 3.90 (s, 6H), 3.83 (s, 6H), 3.77 (d, J = 5.6 Hz, 4H), 3.46 (q, J = 5.9 Hz, 4H), 3.40–3.35 (m, 4H), 3.22 (q, J = 5.5 Hz, 4H), 3.13 (q, J = 6.7 Hz, 4H), 2.14–2.07 (m, 2H), 1.69–1.62 (m, 2H), 1.48 (dd, J = 14.1, 7.7 Hz, 8H), 1.37–1.30 (m, 8H), 1.24 (d, J = 10.5 Hz, 6H), 1.13 (s, 3H), 0.96 (t, J = 7.3 Hz, 12H), 0.91 (t, J = 6.8 Hz, 8H), 0.60 (dt, J = 20.7, 6.9 Hz, 12H). 13C NMR (151MHz, DMSO-d6) δ168.5,168.4,158.7,157.0,143.4,142.1,134.4,128.6,128.5,123.1,117.3,115.4,114.7,107.2,93. 5,91.7,77.2,76.9,60.2,56.0,55.7,41.9,41.8,40.3,39.4,30.0,28.7,28.4,23.5,23.1,23.0,22.9,14.3,14.0,11.3,10.9.

[0082] Example 4 Synthesis of Compound 10

[0083] Synthesis of Compound 11

[0084] Synthesis of Compound 13

[0085] Synthesis of Compound 14

[0086] Synthesis of Compound 16

[0087]

[0088] Synthesis of Compound 17

[0089]

[0090] In a 50 mL round-bottom flask, add 0.5-1 g of one of compounds 1, 2, 5, 6, 7, and 8 sequentially, along with 2 mL of anhydrous ethylene glycol and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 0.16-0.32 g of 2,3-dichloro-5,6-diacetonicyanoquinone. Stir in an ice bath for 2 h. After the reaction is complete, extract with dichloromethane, dry to anhydrous sodium sulfate, and purify by column chromatography to obtain the product. Detect by 1H NMR. 1 H NMR (600MHz, DMSO-d6);

[0091] Compound 10: 500 mg, yield 49%. 1H NMR (600MHz, DMSO-d6) δ8.60(s,2H),7.95(d,J=8.1Hz,2H),7.30(d,J=13.7Hz,2H),7.21(s,2H),6.86(d,J=8.0Hz,2H),5.52(m,8H),4.27(s,4H) ,4.19(s,4H),4.11(s,2H),4.00(s,12H),3.96(s,2H),3.90(s,6H),3.7 0–3.50(m,10H),3.48–3.39(m,22H),3.22(s,6H),3.15(d,J=6.8Hz,6H).

[0092] Compound 11: 510 mg, yield 47%. 1 H NMR (600MHz, DMSO-d6) δ8.57(s,2H),7.91(d,J=8.1Hz,2H),7.20(d,J=13.7Hz,2H),7.04(s,2H),6.80(d,J=8.0Hz,2H),5.49(m,8H),4.40(s,4H) ,4.22(s,4H),4.17(s,2H),4.04(s,12H),3.92(s,2H),3.89(s,6H),3.7 2–3.51(m,18H),3.48–3.39(m,30H),3.30(s,6H),3.12(d,J=6.8Hz,6H).

[0093] Compound 13: 420 mg, yield 40%. 1 H NMR (600MHz, DMSO-d6) δ8.51(s,2H),8.00(d,J=8.1Hz,2H),7.20(d,J=13.7Hz,2H),7.15(s,2H),6.86(d ,J=8.0Hz,2H),5.50(m,8H),4.25(s,4H),4.22(s,4H),4.11(s,2H),4.01(s,8H),3.96(s,2H),3.89(s,6H ),3.72–3.50(m,10H),3.48–3.39(m,22H),3.22(s,6H),3.19(d,J=6.8Hz,6H),2.12(s,2H),1.97(s,4H), 1.51(s,10H),1.39–1.29(m,20H),1.23(s,4H),0.99(s,6H),0.90(dd,J=13.2,6.6Hz,10H),0.80(s,4H).

[0094] Compound 14: 400 mg, yield 38%.1 H NMR (600MHz, DMSO-d6) δ8.51(s,2H),7.97(d,J=8.1Hz,2H),7.13(d,J=13.7Hz,2H),7.04(s,2H),6.86(d ,J=8.0Hz,2H),5.49(m,8H),4.25(s,4H),4.22(s,4H),4.11(s,2H),4.04(s,8H),3.92(s,2H),3.89(s,6H ),3.72–3.51(m,18H),3.48–3.39(m,30H),3.22(s,6H),3.19(d,J=6.8Hz,6H),2.12(s,2H),1.97(s,4H), 1.51(s,10H),1.39–1.29(m,20H),1.23(s,4H),0.99(s,6H),0.90(dd,J=13.2,6.6Hz,10H),0.80(s,4H).

[0095] Compound 16: 380 mg, yield 36%. 1 H NMR(600MHz,DMSO-d6)δ8.49(s,2H),7.97(d,J=8.3Hz,2H),7.12(s,2H),7.04(d,J=26.0Hz,2H), 6.85(d,J=8.2Hz,2H),5.49(m,8H),4.25–4.18(m,8H),4.10(s,2H),4.04(s,8H),3.94–3.90(m,2 H),3.87(s,6H),3.64(s,6H),3.60(s,6H),3.36(s,34H),3.20(s,6H),3.17(s,6H),2.09(s,2H), 1.97(s,4H),1.39–1.31(m,20H),1.25–1.20(m,16H),0.99–0.84(m,22H),0.78(q,J=6.2Hz,6H).

[0096] Compound 17: 350 mg, yield 33%. 1H NMR(600MHz,DMSO-d6)δ8.49(s,2H),7.97(d,J=8.3Hz,2H),7.12(s,2H),7.04(d,J=26.0Hz,2H),6 .85(d,J=8.2Hz,2H),5.49(m,8H),4.30–4.25(m,8H),4.13(s,2H),4.02(s,8H),3.94–3.90(m,2H) ,3.87(s,6H),3.64(s,6H),3.59(s,6H),3.50-3.30(m,42H),3.20(s,6H),3.17(s,6H),2.09(s,2H ),1.97(s,4H),1.39–1.31(m,20H),1.25–1.20(m,16H),0.99–0.84(m,22H),0.78(q,J=6.2Hz,6H).

[0097] Example 5

[0098] Synthesis of Compound 12

[0099]

[0100] Synthesis of Compound 15

[0101]

[0102] Synthesis of Compound 18

[0103]

[0104] Except for the use of appropriate raw materials, it was prepared using the same method as in Example 3, and detected by 1H NMR spectroscopy. 1 H NMR (600MHz, DMSO-d6);

[0105] Compound 12: 650 mg, yield 79%. 1 H NMR (600MHz, DMSO-d6) δ8.55(s,2H),8.13(s,4H),7.98(s,2H),6.55(s,6H),5.26(d,J=13.9Hz,8H),4.56(t,J=5.4Hz,2H),4.67( t,J=5.4Hz,2H),4.30(s,4H),3.85(s,6H),3.61(s,6H),3.50(s,12H),3.43(dd,J=10.4,4.9Hz,8H),3.11(dd,J=11.9,5.9Hz,8H).

[0106] Compound 15: 600 mg, yield 75%.1 H NMR(600MHz,DMSO-d6)δ8.45(s,2H),8.22(s,4H),7.98(s,2H),6.82(s,6H),5.26(d,J=13.9Hz,8H ),4.70(t,J=5.4Hz,2H),4.67(t,J=5.4Hz,2H),4.11(s,4H),4.04(s,8H),3.86(s,6H),3.61(s,6H ),3.43(dd,J=10.4,4.9Hz,8H),3.20(dd,J=11.9,5.9Hz,8H),2.00–1.95(m,4H),1.91(s,4H),1.4 9(d,J=2.9Hz,8H),1.36(s,8H),1.29–1.18(m,24H),0.88(t,J=6.9Hz,6H),0.79(t,J=6.8Hz,6H).

[0107] Compound 18: 500 mg, yield 57%. 1 H NMR (600MHz, DMSO-d6) δ8.55(s,2H),8.23(d,J=7.4Hz,2H),8.02(d,J=8.4Hz,2H),6.91–6.80(m,4H),6.74(s,2 H),5.28(d,J=20.4Hz,8H),4.05(d,J=14.0Hz,8H),3.97(s,4H),3.86(s,6H),3.56(s,6H),3.51(s,4H),3.45(d ,J=6.3Hz,4H),3.41(d,J=5.6Hz,4H),3.20(dd,J=19.0,2.8Hz,8H),2.11–2.03(m,4H),1.68–1.61(m,4H),1.52 –1.44(m,8H),1.39–1.27(m,21H),0.95(dd,J=12.5,5.1Hz,12H),0.90(d,J=6.4Hz,6H),0.86(d,J=5.9Hz,6H).

[0108] Example 6

[0109] Synthesis of Compound 19

[0110]

[0111] Synthesis of Compound 20

[0112]

[0113] Synthesis of Compound 22

[0114]

[0115] Synthesis of Compound 23

[0116]

[0117] Synthesis of Compound 25

[0118]

[0119] Synthesis of Compound 26

[0120]

[0121] Except for the use of the corresponding raw materials, it was prepared using the same method as in Example 4, and detected by 1H NMR spectroscopy. 1 H NMR (600MHz, DMSO-d6);

[0122] Compound 19: 480 mg, yield 44%. 1 H NMR (600MHz, DMSO-d6) δ8.55(s,2H),8.10(d,J=8.5Hz,2H),7.50(s,2H),7.22(s,2H),6.76(d,J=8 .5Hz,2H),5.51(s,4H),5.33(s,4H),4.27–4.24(m,4H),4.18(s,4H),4.04(t,J=6.2Hz,4H),3.89( t,J=7.4Hz,4H),3.85(s,6H),3.79(s,6H),3.60(s,4H),3.56–3.49(m,6H),3.49–3.45(m,12H),3. 40(dd,J=4.9,3.1Hz,12H),3.37(s,12H),3.28(s,6H),3.15(s,6H),2.02(dt,J=15.3,7.4Hz,4H).

[0123] Compound 20: 500 mg, yield 43%. 11H NMR(600MHz, DMSO-d6) δ 8.45 (s, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.45 (s, 2H), 7.40 (s, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.56 (s, 4H), 5.44 (s, 4H), 4.28–4.24 (m, 4H), 4.13 (s, 4H), 4.04 (t, J = 6.2 Hz, 4H), 3.90 (t, J = 7.4 Hz, 4H), 3.85 (s, 6H), 3.79 (s, 6H), 3.66 (s, 4H), 3.52–3.49 (m, 6H), 3.49–3.45 (m, 12H), 3.39 (dd, J = 4.9, 3.1 Hz, 12H), 3.37 (s, 12H), 3.21 (s, 6H), 3.15 (s, 6H), 2.02 (dt, J = 15.3, 7.4 Hz, 4H).

[0124] Compound 22: 390 mg, yield 33%. 1 1H NMR(600MHz, DMSO-d6) δ 8.16 (s, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.34 (s, 2H), 7.13 (s, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.56 (s, 4H), 5.40 (s, 4H), 4.28–4.24 (m, 4H), 4.13 (s, 4H), 4.08 (t, J = 6.2 Hz, 4H), 3.90 (t, J = 7.4 Hz, 4H), 3.85 (s, 6H), 3.80 (s, 6H), 3.66 (s, 4H), 3.52–3.49 (m, 6H), 3.49–3.45 (m, 4H), 3.40 (dd, J = 4.9, 3.1 Hz, 4H), 3.37 (s, 12H), 3.21 (s, 6H), 3.17 (s, 6H), 2.02 (dt, J = 15.3, 7.4 Hz, 4H), 1.56–1.46 (m, 10H), 1.40 (s, 8H), 1.31 (s, 8H), 1.26–1.22 (m, 6H), 1.17–1.13 (m, 4H), 1.01 (s, 8H), 0.91 (s, 6H), 0.67 (t, J = 7.2 Hz, 6H).

[0125] Compound 23: 410 mg, yield 31%. 11H NMR (600 MHz, DMSO-d6) δ 8.17 (s, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.34 (s, 2H), 7.13 (s, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.56 (s, 4H), 5.40 (s, 4H), 4.28–4.24 (m, 4H), 4.13 (s, 4H), 4.04 (t, J = 6.2 Hz, 4H), 3.90 (t, J = 7.4 Hz, 4H), 3.85 (s, 6H), 3.79 (s, 6H), 3.66 (s, 4H), 3.52–3.49 (m, 6H), 3.49–3.45 (m, 12H), 3.40 (dd, J = 4.9, 3.1 Hz, 12H), 3.37 (s, 12H), 3.21 (s, 6H), 3.17 (s, 6H), 2.02 (dt, J = 15.3, 7.4 Hz, 4H), 1.56–1.46 (m, 10H), 1.40 (s, 8H), 1.31 (s, 8H), 1.26–1.22 (m, 6H), 1.17–1.13 (m, 4H), 1.01 (s, 8H), 0.91 (s, 6H), 0.67 (t, J = 7.2 Hz, 6H).

[0126] Compound 25: 290 mg, yield 25%. 1 1H NMR (600 MHz, DMSO-d6) δ 8.16 (s, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.34 (s, 2H), 7.13 (s, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.50 (s, 4H), 5.40 (s, 4H), 4.27–4.24 (m, 4H), 4.13 (s, 4H), 4.05 (t, J = 6.2 Hz, 4H), 3.90 (t, J = 7.4 Hz, 4H), 3.85 (s, 6H), 3.80 (s, 6H), 3.66 (s, 4H), 3.52–3.49 (m, 6H), 3.49–3.45 (m, 4H), 3.40 (dd, J = 4.9, 3.1 Hz, 4H), 3.37 (s, 12H), 3.20 (s, 6H), 3.17 (s, 6H), 2.02 (dt, J = 15.3, 7.4 Hz, 4H), 1.56–1.46 (m, 10H), 1.40 (s, 8H), 1.31 (s, 8H), 1.26–1.22 (m, 6H), 1.17–1.13 (m, 4H), 1.01 (s, 8H), 0.91 (s, 6H), 0.67 (t, J = 7.2 Hz, 6H).

[0127] Compound 26: 310 mg, yield 23%. 1H NMR (600MHz, DMSO-d6) δ8.15(s,2H),7.94(d,J=8.5Hz,2H),7.34(s,2H),7.13(s,2H),6.85(d,J=8.5Hz,2H),5.56(s,4H),5.40(s,4 H),4.28–4.24(m,4H),4.13(s,4H),4.04(t,J=6.2Hz,4H),3.95(t,J=7.4Hz,4H),3.85(s,6H),3.79(s,6H),3.66(s,4H),3.52–3.49 (m,6H),3.49–3.45(m,12H),3.40(dd,J=4.9,3.1Hz,12H),3.37(s,12H),3.25(s,6H),3.17(s,6H),2.02(dt,J=15.3,7.4Hz,4H),1. 56–1.46(m,10H),1.40(s,8H),1.31(s,8H),1.26–1.22(m,6H),1.17–1.13(m,4H),1.01(s,8H),0.91(s,6H),0.67(t,J=7.2Hz,6H).

[0128] Example 7

[0129] Synthesis of Compound 21

[0130]

[0131] Synthesis of Compound 24

[0132]

[0133] Synthesis of Compound 27

[0134]

[0135] Except for the use of appropriate raw materials, it was prepared using the same method as in Example 3, and detected by 1H NMR spectroscopy. 1 H NMR (600MHz, DMSO-d6);

[0136] Compound 21: 600 mg, yield 77%. 1H NMR(600MHz,DMSO-d6)δ8.88(s,1H),8.26–8.24(m,2H),7.95(d,J=8.5Hz,1H ),6.90(s,1H),6.80(d,J=9.5Hz,1H),6.72(s,1H),5.31(s,2H),5.22(s,2H) ,4.21(s,2H),4.06(s,2H),3.85(s,3H),3.62(s,2H),3.47(t,J=6.0Hz,2H), 3.40(s,6H),3.24(d,J=5.6Hz,2H),3.15(d,J=5.4Hz,2H),2.17–2.13(m,4H).

[0137] Compound 24: 470 mg, yield 57%. 1 H NMR(600MHz,DMSO-d6)δ8.78(s,1H),8.30–8.20(m,2H),7.95(d,J=8.5Hz,1H),6.90(s,1H),6.85(d,J=9.5Hz ,1H),6.72(s,1H),5.31(s,2H),5.22(s,2H),4.21(s,2H),4.06(s,2H),3.68(s,3H),3.62(s,2H),3.42(t,J= 6.0Hz,2H),3.40(s,5H),3.24(d,J=5.6Hz,2H),3.18(d,J=5.4Hz,2H),2.13–2.10(m,2H),2.00–1.96(m,2H), 1.77(s,2H),1.63(s,2H),1.48–1.45(m,2H),1.45–1.41(m,2H),1.36(s,6H),1.33(s,6H),0.89-0.84(m,6H).

[0138] Compound 27: 500 mg, yield 62%. 1H NMR(600MHz,DMSO-d6)δ8.80(s,1H),8.26–8.20(m,2H),7.97(d,J=8.5Hz,1H),6.90(s,1H),6.85(d,J=9.5Hz ,1H),6.72(s,1H),5.31(s,2H),5.22(s,2H),4.21(s,2H),4.06(s,2H),3.87(s,3H),3.62(s,2H),3.47(t,J= 6.0Hz,2H),3.40(s,5H),3.24(d,J=5.6Hz,2H),3.18(d,J=5.4Hz,2H),2.17–2.10(m,2H),2.00–1.96(m,2H), 1.70(s,2H),1.63(s,2H),1.48–1.45(m,2H),1.45–1.41(m,2H),1.36(s,6H),1.28(s,6H),0.89-0.84(m,6H).

[0139] Example 8

[0140] Recognition of cytarabine by indo[3,2-b]carbazole dimer derivatives

[0141] This invention employs ultraviolet-visible and fluorescence spectroscopy for testing. A 3:1 ratio of water to acetonitrile is used as the solvent. The excitation wavelength is set to 375 nm, and the slit width is set to 3 nm (Ex) and 5 nm (Em). The concentration of compound 27 is fixed. Ultraviolet titration experiments are performed sequentially by varying the dosage of cytarabine. The test results are shown below. Figure 1 As shown in the figure.

[0142] From the ultraviolet spectrum ( Figure 1 As can be seen in the image, with the addition of compound 27, a set of "isoextinction points" appeared in the ultraviolet absorption spectrum at 300 nm. This state indicates that cytarabine and compound 27 have undergone specific binding, and its binding constant was calculated to be 1.4 × 10⁸ M. -2 .

[0143] Simultaneously, field scanning electron microscopy (SEM) experiments were also conducted on compound 27 and cytarabine. The SEM images show that cytarabine appears as a prismatic structure under the SEM. Figure 2 ), and after binding with indolo[3,2-b]carbazole dimer derivatives ( Figure 3 The spherical shape indicates a good binding effect.

Claims

1. Indodo[3,2-] as shown in general structural formula II b Carbazole dimer derivatives; R1: n-octyloxy or isooctyloxy; R2: -CH2CONH(CH2)2OH; R3: -OCH3; n: an integer from 1 to 3.

2. The indodo[3,2-] as described in claim 1 b Carbazole dimer derivative, characterized in that, The indodo[3,2-] b The structure of the carbazole dimer derivative is as follows: 。 3. The indodo[3,2-] according to claim 1 b A method for preparing carbazole dimer derivatives, characterized in that, First, indole[3,2-] was synthesized. b Carbazole derivative basic units: Based on R1, the structural formula of reactant A is determined as follows: Reactant A and reactant B were subjected to a Ullmann coupling reaction to obtain intermediate C; Intermediate C is cyclically modified to obtain intermediate D; Based on the structure of R2, intermediate D was N-alkylated to obtain indodo[3,2-] b Carbazole moiety; The specific synthesis route is as follows: With indole[3,2- b Synthesis of indole[3,2-]carbazole moiety from indole[3,2-] b Carbazole dimer, and its "bridge" methylene group, or derivatized by oxidation. R1 and R2 are as described in claim 1.

4. The indodo[3,2-] as described in claim 3 b A method for preparing carbazole dimer derivatives, characterized in that, Includes the following steps: Indodo[3,2-]carbazole moiety was dissolved in an organic solvent, Lewis acid and paraformaldehyde were added, and the mixture was stirred. After the reaction was completed, the mixture was quenched with an alkaline solution, extracted, concentrated, and purified by silica gel column chromatography to obtain indodo[3,2-]carbazole moiety. b Carbazole dimer derivatives.

5. The indodo[3,2-] as described in claim 4 b A method for preparing carbazole dimer derivatives, characterized in that, Indodo[3,2-] b The concentration of the carbazole moiety in the organic solvent is 0.5 g / L to 4.0 g / L; the organic solvent is selected from one or more of dichloromethane, chloroform, and 1,2-dichloroethane; the Lewis acid is selected from one or more of ferric chloride hexahydrate, anhydrous ferric chloride, aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride, and p-toluenesulfonic acid.

6. The indodo[3,2-] as described in claim 4 b A method for preparing carbazole dimer derivatives, characterized in that, molar ratio, Lewis acid: indo[3,2- b Carbazole moiety = (0.4-1.2):1; molar ratio, paraformaldehyde: indo[3,2- b Carbazole moiety = (0.5-2.0):1; stirring at room temperature for 0.5-12 h; oxidation of the "bridge" methylene group to form a "bridged ketal" structure with ethylene glycol or butanediol; oxidation of the "bridge" methylene group to form a "bridged ketal" structure, followed by ammonolysis on R3 to form an amide structure; the solvent used for bridging methylene group oxidation is anhydrous tetrahydrofuran, and the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone, indo[3,2- b Carbazole dimer derivative: ethylene glycol = 1g: 0.5-5 mL, or indole[3,2- b Carbazole dimer derivative: 1,4-butanediol = 1g: 0.5-5 mL; molar ratio, indo[3,2- b Carbazole dimer derivative: 2,3-dichloro-5,6-dicyanobenzoquinone = 1:2, reaction time 1-5 h.

7. The indodo[3,2-] as described in claim 6 b A method for preparing carbazole dimer derivatives, characterized in that, The ammonolysis, according to the solid-liquid ratio, involves indodo[3,2-] b Carbazole dimer derivative: amine compound = 100 mg: (1-10) mL, DIEA 3-10 drops, wherein the amine compound is selected from one of butylamine, benzylamine, diethylene glycolamine, and ethanolamine, and heated to 60-120°C for 72-120 h.

8. The indodo[3,2-] according to claim 1 b Applications of carbazole dimer derivatives as drug recognition and drug carriers.

9. The application as described in claim 8, characterized in that, The drug is cytarabine.

Images