Indolo [3, 2-b] carbazole dimer derivative as well as preparation method and application thereof

Abstract

The invention discloses an indolo [3, 2-b] carbazole dimer derivative as well as a preparation method and application thereof, belongs to the technical field of medicines, the structural general formula of the indolo [3, 2-b] carbazole dimer derivative is one of the following structures, and provides an improvement on a method for oxidizing indolo [3, 2-b] carbazole dimer or deriving the indolo [3, 2-b] carbazole dimer after oxidation. The invention discloses a synthesis method of a bridged methylene modified indolo [3, 2-b] carbazole dimer derivative. Molecules of the indolo [3, 2-b] carbazole dimer derivative have fixed cavities and rich pi electron systems, so that drugs with large molecular sizes can be entrapped, the lipid-water partition coefficient of the drugs is improved, the indolo [3, 2-b] carbazole dimer derivative has good ultraviolet absorption and fluorescence color development performance, forms dimer compounds with strong fluorescence and fixed rigidity, has wide potential application, and has wide application prospects. The method can be applied to drug diagnostic reagents, ion fluorescence sensing, carriers of medical molecules, recognition of biomacromolecules and the like. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and relates to an indolo[3,2-b]carbazole dimer derivative and a preparation method thereof, and an application in drug molecule recognition, and specifically relates to an indolo[3,2-b]carbazole dimer derivative and a preparation method thereof, and an application in recognition and encapsulation of cytarabine. Background Art

[0002] Supramolecular strategies can improve drug solubility or the selectivity and stability of drug administration methods in biological treatment. It has broad application prospects, including encapsulation and protection of drugs, dissolution of insoluble drugs, photophysical reactions such as fluorescence and chiral detection, and drug molecule delivery and real-time detection. It has always been a research hotspot in the fields of life medicine, materials science and pharmacy.

[0003] Indolo[3,2-b]carbazole fused heterocycle has a large aromatic conjugated plane, with many sites for structural modification, and has excellent optical properties such as high molar extinction coefficient and fluorescence quantum yield. Its derivatives also have potential medicinal value. The synthesis of amphiphilic indolo[3,2-b]carbazole dimer derivatives based on indolo[3,2-b]carbazole has excellent optical properties, and can enhance its rigidity by regulating the steric hindrance formed by the ketal structure on the bridge and the two methoxy groups adjacent to the bridge to jointly restrict the free rotation of the molecule; the introduction of hydrophilic and lipophilic flexible side chains can improve its lipid-water partition coefficient. The dimer has the advantages of integrating drug recognition and sensing. Summary of the invention

[0004] The present invention uses p-phenylenedimethyl ether as a raw material, and successfully synthesizes indole [3,2-b] carbazole through iodination, boron tribromide demethylation, oxygen alkylation, Ullmann condensation, cardogen nitrogen cyclization and N-alkylation reactions; and uses it as a primitive, and synthesizes an amphiphilic indole [3,2-b] carbazole derivative dimer through Friedel-Crafts alkylation reaction, cross-methylene oxidation reaction and aminolysis reaction. As a supramolecular chemical subject, the molecule has a large cavity and a rich π electron system, which can not only encapsulate drugs with larger molecular size and enhance the fat solubility of water-soluble drugs, but also has good ultraviolet absorption and fluorescence coloration properties, and can use spectral means to study its drug encapsulation performance. The present invention explores and discovers the recognition and encapsulation performance of drugs such as cytarabine.

[0005] The present invention provides an indolo[3,2-b]carbazole dimer derivative having the following general structural formula:

[0006]

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

[0008] R2: C1~C8 carboxylic acid, C1~C8 carboxylic acid ester, C1~C8 amide, benzyl, benzyl substituted with at least one of N, O, S heteroatoms, C1~C8 straight-chain alkyl, C1~C8 branched-chain alkyl, C3~C8 cycloalkyl, C1~C8 straight-chain alkyl substituted with at least one of N, O, S heteroatoms, C1~C8 branched-chain alkyl substituted with at least one of N, O, S heteroatoms, C3~C8 cycloalkyl substituted with at least one of N, O, S heteroatoms.

[0009] R3: one of H, halogen, hydroxyl, and alkoxy.

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

[0011] As a preference:

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

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

[0014] R3: -OCH3.

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

[0016]

[0017]

[0018]

[0019]

[0020]

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

[0022] According to the different structures represented by R1 and R2 in the indolo[3,2-b]carbazole dimer derivative, the indolo[3,2-b]carbazole derivative moiety is first synthesized using the following synthetic route:

[0023] According to R1, the structural formula of the reaction raw material A is determined as follows:

[0024]

[0025] The reaction raw material A and the reaction raw material B are subjected to Ullmann coupling reaction to obtain intermediate C;

[0026] Intermediate C is subjected to cardogen cyclization to obtain intermediate D;

[0027] The intermediate D is N-alkylated according to the structure of R2 to obtain the indole[3,2-b]carbazole moiety.

[0028] The specific synthetic route is:

[0029]

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

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

[0032] The indolecarbazole moiety is dissolved in an organic solvent, Lewis acid and polyformaldehyde are added, and the mixture is stirred at room temperature. After the reaction is completed, the mixture is quenched with alkaline solution, and then the indole[3,2-b]carbazole dimer derivative is obtained through extraction, concentration, and silica gel column chromatography.

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

[0034] In the preparation method of the indolo[3,2-b]carbazole dimer derivative, the organic solvent is selected from one or more of dichloromethane, chloroform 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 preparation method of the indole[3,2-b]carbazole dimer derivative, the molar ratio of Lewis acid to indole[3,2-b]carbazole moiety is (0.4-1.2):1, preferably (0.6-0.7):1.

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

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

[0038] The "bridge" methylene group is oxidized to form a "bridge ketal" structure with ethylene glycol or butanediol; the "bridge" methylene group is oxidized to derive a "bridge ketal" structure, and then aminolysis is performed on R3 to form an amide structure.

[0039] When the indolo[3,2-b]carbazole dimer derivative is subjected to cross-methylene oxidation, the solvent used is anhydrous tetrahydrofuran, the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), the indolo[3,2-b]carbazole dimer derivative: ethylene glycol = 1 g: 0.5-5 mL, or the indolo[3,2-b]carbazole dimer derivative: 1,4-butanediol = 1 g: 0.5-5 mL; in a molar ratio, the indolo[3,2-b]carbazole dimer derivative: DDQ = 1:2, and the reaction time is 1 to 5 hours.

[0040] The aminolysis is specifically performed as follows: according to the solid-liquid ratio, indole [3,2-b] carbazole dimer derivative: amine compound = 100 mg: (1-10) mL, DIEA 3 to 10 drops, the amine compound is selected from butylamine, benzylamine, diglycolamine, ethanolamine, preferably ethanolamine, and heated at 60 to 120° C. for 72 to 120 hours.

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

[0042] The recognition drug is preferably a recognition cytarabine compound as a prodrug carrier.

[0043] The invention discloses an application of the indole[3,2-b]carbazole dimer derivative in drug molecule recognition, wherein the drug molecule is cytarabine.

[0044] The beneficial effects of the present invention are:

[0045] The present invention specifically relates to the oxidation of the bridge methylene group of an indole[3,2-b]carbazole dimer to generate a ketal structure and an epoxy structure and further substitution products and their synthesis methods, thereby forming a strongly fluorescent and rigidly fixed dimer compound, which has a wide range of potential uses, such as drug diagnostic reagents, ion fluorescence sensors, carriers of medical molecules, and recognition of biomacromolecules.

[0046] The molecules of indole[3,2-b]carbazole dimer derivatives have fixed cavities and rich π-electron systems, which can not only encapsulate drugs with larger molecular sizes and improve the lipid-water partition coefficient of the drugs, but also have good ultraviolet absorption and fluorescence coloration properties, and can be used to detect drug molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 It is the UV titration spectrum of cytarabine and compound 27;

[0048] Figure 2 is the SEM image of cytarabine;

[0049] Figure 3 This is the SEM image of compound 27 and cytarabine encapsulation. DETAILED DESCRIPTION

[0050] The present invention is further described in detail below in conjunction with embodiments.

[0051] Example 1

[0052] Synthesis of Compound ac

[0053]

[0054] 1,4-diiodo-2,5-dimethyl ether and 4-bromo-3-nitrobenzene were subjected to Ullmann coupling, Cadogan cyclization and N-alkylation to obtain compound a; 1,4-bis(octyloxy)-2,5-diiodobenzene and 4-bromo-3-nitrobenzene were subjected to Ullmann coupling, Cadogan cyclization and N-alkylation to obtain compound b; 1,4-bis(isooctyloxy)-2,5-diiodobenzene and 4-bromo-3-nitrobenzene were subjected to Ullmann coupling, Cadogan cyclization and N-alkylation to obtain compound c; the above compounds were detected by nuclear magnetic hydrogen spectrum, which proved that the corresponding structures were synthesized.

[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 an indole and carbazole moiety in compound ac and add it into the flask, add 0.58-1L of dichloromethane, slowly add 135-592mg of ferric chloride hexahydrate, and then add 45-175mg of paraformaldehyde, stir, stir at room temperature for 0.5-5h, and after the reaction is complete, add ammonia water to quench the reaction. After silica gel chromatography, the product is obtained; nuclear magnetic hydrogen spectrum detection, 1 H NMR (600 MHz, 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] Take a 25mL round-bottom flask, weigh 0.5-2g of one of the indolecarbazole dimers of compound 1, compound 5, and compound 7, add it into the flask, add 5mL of ethanolamine, slowly add 5-10 drops of DIEA, stir, stir at 65℃ for 72-120h, the reaction is complete, extract with ethyl acetate and water. After silica gel chromatography, the product is obtained; nuclear magnetic hydrogen spectrum detection, 1 H NMR (600 MHz, 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 compound 1, compound 2, compound 5, compound 6, compound 7, and compound 8, 2 mL of anhydrous ethylene glycol, 10 mL of anhydrous tetrahydrofuran, nitrogen protection, 0.16-0.32 g of 2,3-dichloro-5,6-dinitrile benzoquinone, stir in an ice bath for 2 h, and after the reaction is completed, extract with dichloromethane, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain the product; detect by hydrogen nuclear magnetic spectrum, 1 H NMR (600 MHz, 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] The same method as in Example 3 was used except that the corresponding raw materials were used, and the results were detected by H NMR. 1 H NMR (600 MHz, 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] The same method as in Example 4 was used except that the corresponding raw materials were used. The results were detected by H NMR. 1 H NMR (600 MHz, 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 (600 MHz, 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 (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), 5.56 (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] The same method as in Example 3 was used except that the corresponding raw materials were used, and the results were detected by H NMR. 1 H NMR (600 MHz, 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 Indolo[3,2-b]carbazole Dimer Derivatives

[0141] The present invention uses ultraviolet-visible and fluorescence spectroscopy for testing, selects water and acetonitrile in a ratio of 3:1 as solvent, sets the excitation wavelength to 375nm, sets the slit width to 3nm (Ex), 5nm (Em), fixes the concentration of compound 27, and performs ultraviolet titration experiments in sequence by changing the amount of cytarabine. The test results are as follows ( Figure 1 ) as shown.

[0142] From the UV spectrum ( Figure 1 ) It can be seen that with the addition of compound 27, a group of "iso-extinction points" appeared at 300nm in the UV absorption spectrum. The above state indicates that there is a specific binding between cytarabine and compound 27, and the binding constant is calculated to be 1.4×108M -2 .

[0143] At the same time, field scanning electron microscopy experiments of compound 27 and cytarabine were also conducted. From the SEM diagram, it can be seen that cytarabine is prismatic under the scanning electron microscope ( Figure 2 ), while after combining with indole[3,2-b]carbazole dimer derivatives ( Figure 3 ), which is spherical, indicating good binding effect.

Claims

1. Indolo[3,2-b]carbazole dimer derivatives as shown in general structural formulas I and II; R1: one of H, halogen, hydroxyl, C1-C8 ester, C1-C8 alkyl, alkoxy or alkylamino; R2: one of C1-C8 carboxylic acid, C1-C8 carboxylic acid ester, C1-C8 amide, benzyl, benzyl substituted with at least one of N, O, and S heteroatoms, C1-C8 straight-chain alkyl, C1-C8 branched-chain alkyl, C3-C8 cycloalkyl, C1-C8 straight-chain alkyl substituted with at least one of N, O, and S heteroatoms, C1-C8 branched-chain alkyl substituted with at least one of N, O, and S heteroatoms, and C3-C8 cycloalkyl substituted with at least one of N, O, and S heteroatoms; R3: one of H, halogen, hydroxyl, and alkoxy; n: an integer from 1 to 3.

2. The indolo[3,2-b]carbazole dimer derivative according to claim 1, characterized in that: In the general formulas I and II: R1: one of H, methoxy, n-octyloxy, and isooctyloxy; R2: one of -CH2COO(C2H4O)2CH3, -CH2COO(C2H4O)3CH3, -CH2CONH(CH2)2OH, -CH2COO(C2H4O)2C3H7; R3: -OCH3.

3. The indolo[3,2-b]carbazole dimer derivative according to claim 2, characterized in that: The structure of the indole[3,2-b]carbazole dimer derivative is as follows:

4. The method for preparing the indolo[3,2-b]carbazole dimer derivative according to claim 1, characterized in that: First, synthesize the indolo[3,2-b]carbazole derivative moiety: According to R1, the structural formula of the reaction raw material A is determined as follows: The reaction raw material A and the reaction raw material B are subjected to Ullmann coupling reaction to obtain intermediate C; Intermediate C is subjected to cardogen cyclization to obtain intermediate D; According to the structure of R2, the intermediate D is N-alkylated to obtain the indole[3,2-b]carbazole moiety; The specific synthetic route is: Indolo[3,2-b]carbazole dimer is synthesized by using indolo[3,2-b]carbazole moiety, and its "bridge" methylene is oxidized or derivatized after oxidation.

5. The method for preparing the indolo[3,2-b]carbazole dimer derivative according to claim 4, characterized in that: The following steps are involved: The indolecarbazole moiety is dissolved in an organic solvent, Lewis acid and polyformaldehyde are added, and the mixture is stirred. After the reaction is completed, the mixture is quenched with an alkali solution, and then the mixture is extracted, concentrated, and subjected to silica gel column chromatography to obtain an indole[3,2-b]carbazole dimer derivative.

6. The method for preparing the indolo[3,2-b]carbazole dimer derivative according to claim 5, characterized in that: The concentration of indolo[3,2-b]carbazole moiety in the organic solvent is 0.5 g / L-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.

7. The method for preparing the indolo[3,2-b]carbazole dimer derivative according to claim 5, characterized in that: The molar ratio of Lewis acid: indole [3,2-b] carbazole moiety is (0.4-1.2): 1; the molar ratio of polyformaldehyde: indole [3,2-b] carbazole moiety is (0.5-2.0): 1; stirring at room temperature, the reaction time is 0.5-12 hours; the "bridge" methylene is oxidized to form a "bridge ketal" structure with ethylene glycol or butanediol; the "bridge" methylene is oxidized and then derived to form a "bridge ketal" structure, and then aminolysis is performed on R3 to form an amide structure; When the cross-methylene group is oxidized, the solvent used is anhydrous tetrahydrofuran, the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone, indolo[3,2-b]carbazole dimer derivative: ethylene glycol = 1 g: 0.5-5 mL, or indolo[3,2-b]carbazole dimer derivative: 1,4-butanediol = 1 g: 0.5-5 mL; in a molar ratio, indolo[3,2-b]carbazole dimer derivative: 2,3-dichloro-5,6-dicyanobenzoquinone = 1:2, and the reaction time is 1 to 5 hours.

8. The method for preparing the indolo[3,2-b]carbazole dimer derivative according to claim 7, characterized in that: The aminolysis is carried out according to the solid-liquid ratio of indole [3,2-b] carbazole dimer derivative: amine compound = 100 mg: (1-10) mL, DIEA 3-10 drops, the amine compound is selected from butylamine, benzylamine, diglycolamine, ethanolamine, and heated at 60-120° C. for 72-120 hours.

9. Use of the indolo[3,2-b]carbazole dimer derivative according to claim 1 as a drug recognition and drug carrier.

10. The use according to claim 9, characterized in that The drug is a cytarabine compound.

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