Imidazole quinoline small-molecule derivative as well as preparation method and application thereof

Abstract

The invention discloses an imidazole quinoline small-molecule derivative and a preparation method and application thereof, the small-molecule derivative has a structure as shown in a formula I, in the formula I, R1 is selected from C1-C4 alkyl or C1-C4 ether; r2 is selected from alkylene and / or phenylene of C1-C3; r3 is selected from alkylene of C1-C3; r4 and R5 are respectively selected from hydrogen or methyl. The imidazole quinoline small-molecule derivative can be converted into IMDQ under an ultrasonic condition; the compound can be used as an ultrasonic activation prodrug, almost has no harmful effect on a human body, and can improve the enrichment of the drug at a tumor site. Formula I

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to an imidazoquinoline small molecule derivative, its preparation method and application, including a novel IMDQ small molecule derivative, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Tumor immunotherapy is an innovative therapy that identifies and eliminates cancer cells by activating or enhancing the body's own immune system. It does not directly attack cancer cells but rather helps the immune system fight tumors more effectively, resulting in long-lasting efficacy and a high cure rate. IMDQ belongs to the imidazoquinoline class of compounds, and its chemical structure is shown below. It is commonly used as an immunotherapy drug in tumor immunotherapy. .

[0003] IMDQ is a small-molecule TLR7 / 8 agonist whose core mechanism of action is to trigger an immune response by activating the Toll-like receptor 7 / 8 (TLR7 / 8) pathway. Simply put, it acts like a "start switch" for the immune system, helping the body more effectively recognize and fight viruses or tumor cells. However, overactivation can lead to a massive release of inflammatory factors, triggering a systemic reaction that may cause fever, headache, fatigue, hypotension, and multiple organ dysfunction, potentially life-threatening in severe cases. Furthermore, free IMDQ is widely distributed in the body, making precise targeting difficult and increasing the risk of side effects. Therefore, improving the precise distribution of IMDQ is a pressing issue that needs to be addressed.

[0004] Existing technologies primarily utilize nanodelivery techniques to optimize the targeted distribution of IMDQ. For example, the team led by Huai-Min Wang at Westlake University utilized peptide self-assembly technology to construct GrB-responsive peptide hydrogel adjuvants, enabling personalized adjuvant immunotherapy (J.Am. Chem. Soc. 2024, 146, 12, 8585-8597). The pH / enzyme-responsive nanovaccine (TNV) designed by Yi-Guang Wang's team at Peking University can also reduce systemic drug distribution and improve safety (Nano Lett. 2022, 22, 7, 2978-2987). Another example is the single-oxygen atom engineered radiotherapy-responsive small molecule prodrug (SAE-RAP) developed by the teams of Fu Yangxin and Liu Zhibo at Tsinghua University. By introducing oxygen atoms into the active group of an IMDQ analog to "lock" them, a prodrug (such as O-R848) is formed. When the tumor receives local radiotherapy, the active drug is released (Angew 2020, JACS 2022, Angew 2022, Nat. Chem.2024, Nat. Biomed. Eng. 2024, ACS Cent. Sci. 2024, Sci. Bull. 2024).

[0005] Compared to direct application of small-molecule drugs, existing nanodelivery technologies, while showing certain advantages, still have some limitations. These include insufficient drug loading in hydrogel applications, and the release rate of the drug from the hydrogel affecting efficacy. Other vaccines or carriers still exhibit some systemic toxicity; and prodrug-based radiotherapy has significant side effects. Summary of the Invention

[0006] In view of this, the present invention provides an imidazoquinoline small molecule derivative, its preparation method and application. The provided novel small molecule compound can be used as a prodrug for ultrasound activation, has almost no harmful effects on the human body, and can improve the accumulation of drugs at tumor sites.

[0007] This invention provides an imidazoquinoline intermediate having the structure of Formula 1: Formula 1; Wherein, R0 is selected from primary amino or nitro, preferably primary amino; R1 is selected from C1-C4 alkyl or C1-C4 ether groups, preferably C1-C4 straight-chain alkyl groups, including methyl, ethyl, n-butyl, etc.; R2 is selected from C1~C3 alkylene and / or phenylene, for example, methylene or benzylidene; R3 is selected from C1~C3 alkylene groups, preferably methylene; R4 and R5 are selected from hydrogen or methyl, respectively, and preferably both are methyl.

[0008] The imidazoquinoline intermediate described in this invention can be azidated to form an imidazoquinoline compound containing an azide group (-N3).

[0009] For R1, R2, R3, R4, and R5, the alkyl group is an alkane (general formula C1). n H 2n+2 A carbon molecule, when stripped of one hydrogen atom, is a group consisting of an open-chain saturated organic group containing only carbon (C) and hydrogen (H) atoms. These groups can be straight-chain or branched. An alkane molecule, when stripped of two hydrogen atoms, has a group called an alkylene group. In the structure of an ether, the oxygen atom (O) is attached to two hydrocarbon groups, which can be the same or different. Furthermore, C1 to C4 refer to the number of carbon atoms, ranging from 1 to 4.

[0010] Preferably, the structure of the imidazoquinoline intermediate is as follows: R0 is a primary amino group (-NH2), which can be effectively converted to -N3. Furthermore, R1 is a C4 straight-chain alkyl group (-CH2CH2CH2CH3, n-butyl); R2 is a benzylidene group (-C6H5CH2-); R3 is selected from a C1 alkylene group (-CH2-, methylene); R4 and R5 are both methyl groups (-CH3, usually abbreviated as single bond). Equation 1-1.

[0011] Based on the above-mentioned imidazoquinoline intermediate, the present invention provides an imidazoquinoline small molecule derivative having the structure of Formula I: Formula I; Wherein, R1 is selected from C1-C4 alkyl or C1-C4 ether; R2 is selected from C1-C3 alkylene and / or phenylene; R3 is selected from C1-C3 alkylene; R4 and R5 are selected from hydrogen or methyl, respectively.

[0012] In some embodiments, R1 is methyl, ethyl, n-propyl, n-butyl, or methyl ethyl ether; that is, R1 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, or -CH2OCH2CH3.

[0013] In some embodiments, R2 is methylene, ethylene, propylene, or benzylene; that is, R2 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, or -C6H5CH2-.

[0014] In some embodiments, R3 is methylene, and R4 and R5 are both methyl.

[0015] Specifically, the structure of the imidazoquinoline small molecule derivative is shown below, which includes a riboflavin structure, an IMDQ structure and an azide group at one end; Formula I-1.

[0016] In the small molecule derivatives shown in Embodiment I-1 of this invention, the azide group is one of the key structures for ultrasonic activation, and it can be reduced to an amino group. The amino group at the distal end of the IMDQ ring structure is linked to a riboflavin (vitamin B2) structure with a certain degree of water solubility to ensure the solubility of the small molecule; at the same time, it facilitates the reduction of the azide to an amino group under ultrasonic conditions.

[0017] This invention provides a method for preparing the imidazoquinoline small molecule derivative described above, comprising the following steps: The riboflavin derivative shown in Formula 2 is reduced with the IMDQ-type substance shown in Formula 3 to obtain the imidazoquinoline intermediate shown in Formula 1. The imidazoquinoline intermediate was subjected to an azidation reaction to obtain the imidazoquinoline small molecule derivative shown in Formula I; wherein, R0 is selected from primary amino or nitro; R1 is selected from C1-C4 alkyl or C1-C4 ether; R2 is selected from C1-C3 alkylene and / or phenylene; R3 is selected from C1-C3 alkylene; R4 and R5 are selected from hydrogen or methyl, respectively; Formula 2; Formula 3; Formula 1; Formula I.

[0018] In some embodiments, the riboflavin derivative and IMDQ-like substances undergo a reduction reaction in an organic solvent under the action of a reducing agent; the organic solvent is one or more of methanol, pyridine, tetrahydrofuran (THF), and N,N-dimethylformamide (DMF); the reducing agent is one or more of sodium cyanoborohydride, sodium borohydride, and sodium triacetoxyborohydride.

[0019] The riboflavin derivative described has the structure of Formula 2, preferably aldehyde riboflavin (R3 is methylene, and R4 and R5 are both methyl). Riboflavin is vitamin B2, which can be abbreviated as Rf; it can be oxidized to form aldehyde riboflavin, as shown in the following schematic diagram: .

[0020] Taking the preparation of aldehyde riboflavin as an example, the specific process can be as follows: riboflavin is oxidized to aldehyde riboflavin in a solvent under the action of an oxidizing agent. For example, the ratio of riboflavin to solvent can be 20~40 mg / mL, preferably 30 mg / mL; the molar ratio of riboflavin to oxidizing agent can be 1 / 5~1 / 10, preferably 1 / 10. The solvents involved mainly refer to one or more of pure water, saturated saline solution, acetonitrile, and DMF, preferably acetonitrile, which is beneficial for improving the yield; acidic aqueous solutions such as dilute sulfuric acid can also be used.

[0021] The oxidant mainly refers to periodic acid and / or sodium periodate, preferably periodic acid; the raw material mixture can be stirred at room temperature for 10-15 hours, filtered, and the filter cake washed several times with appropriate amounts of water and methyl tert-butyl ether, and then dried to obtain the riboflavin derivative solid.

[0022] In a preferred embodiment of the present invention, under light-protected conditions, the riboflavin derivative, IMDQ (CAS: 1258457-59-8, corresponding to formula 3: R0 is -NH2, R1 is n-butyl, R2 is benzylene), and an organic solvent are added to a reactor and stirred and mixed; then a reducing agent is slowly added, and a reduction reaction is carried out at room temperature to generate a bonded product of riboflavin derivative and IMDQ, which is the imidazoquinoline intermediate shown in formula 1.

[0023] For example, the ratio of IMDQ to organic solvent can be 1~5 mg / mL, preferably 3 mg / mL; the molar ratio of IMDQ to reducing agent can be 1~1 / 3, preferably 1 / 2. The organic solvent mainly refers to methanol, pyridine, DMF, THF, or a mixture of these solvents; the volume ratio of all mixed solvents ranges from 1 / 9 to 9 / 1, preferably a mixture of methanol and pyridine at a volume ratio of 9 / 1. The reducing agent mainly refers to one or more of sodium cyanoborohydride, sodium borohydride, and sodium triacetoxyborohydride, preferably sodium cyanoborohydride. The reduction reaction is preferably carried out at room temperature with stirring for 10-15 hours; the room temperature mentioned in the steps of this embodiment is a temperature condition well known to those skilled in the art, for example, 15-25°C.

[0024] In this embodiment of the invention, the reduced mixture can be distilled under reduced pressure, and the resulting solid can be extracted with pure water and dichloromethane. The aqueous phase can be collected and freeze-dried to obtain the imidazoquinoline intermediate solid.

[0025] In some embodiments, the imidazoquinoline intermediate undergoes an azidation reaction under the action of an azidating agent to generate a small molecule product having the structure of Formula I; wherein, the azidating agent is preferably the product of the reaction of 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-onium trifluoromethanesulfonate with sodium azide. The molar ratio of the raw material intermediate to the azidating agent is generally 1 / 2 to 1 / 10, preferably 1 / 10.

[0026] The embodiments of the present invention can prepare the azide reagent involved; for example, sodium azide (NaN3) is dissolved in water, and MTBE (MTBE is methyl tert-butyl ether, a safe, stable, and readily available chemical reagent used in industrial production to replace diethyl ether) is added; preferably, under stirring conditions, 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-onium trifluoromethanesulfonate solid is added, and the azide reagent is obtained by reaction.

[0027] In some embodiments, the imidazoquinoline intermediate is dissolved in N,N-dimethylformamide, an azide reagent is added, and an azide reaction is carried out at room temperature with stirring. Afterwards, the mixture is distilled under reduced pressure, washed, and dried to obtain the solid imidazoquinoline small molecule derivative. The stirring in each step of the embodiments of this invention is a conventional operating technique for those skilled in the art and is not particularly limiting.

[0028] This invention provides an application of the imidazoquinoline small molecule derivative described above in the preparation of an ultrasound-activated prodrug.

[0029] Prodrugs, also known as precursor drugs, drug precursors, or predrugs, are compounds obtained by modifying the chemical structure of a drug. These compounds are inactive or have low activity in vitro, but release their active drug function in vivo through enzymatic or non-enzymatic conversion.

[0030] In this embodiment of the invention, the imidazoquinoline small molecule derivative can be formulated into an aqueous solution and then activated by ultrasound using a physiotherapy ultrasound device to transform it into an IMDQ-like substance.

[0031] This invention primarily modifies the chemical structure of IMDQ, blocking its active groups (two amino groups), and then uses ultrasound technology to activate this small molecule prodrug. This directly avoids the problems associated with nanomedicines, and ultrasound technology, unlike radiotherapy, has virtually no harmful effects on the human body. Simultaneously, the ultrasound probe can be adjusted to focus precisely on the tumor site, effectively improving drug accumulation at the tumor location. Attached Figure Description

[0032] Figure 1 This is a schematic diagram of the synthetic route for the imidazoquinoline small molecule derivative Rf-IMDQ-N3 in some embodiments of the present invention; Figure 2 The 1H NMR spectrum of the riboflavin derivative Rf-CHO prepared in Example 1 of this invention; Figure 3 The 1H NMR spectrum of the imidazoquinoline intermediate prepared in Example 4 of this invention; Figure 4 The 1H NMR spectrum of the imidazoquinoline small molecule derivative Rf-IMDQ-N3 of Example 11 of this invention; Figure 5 The overall spectrum of the liquid chromatography-mass spectra obtained by ultrasonication of the imidazoquinoline small molecule derivative Rf-IMDQ-N3 in Example 11; Figure 6 The image shows a partial chromatogram obtained by liquid chromatography-mass spectrometry (LC-MS) of the imidazoquinoline small molecule derivative Rf-IMDQ-N3 obtained after sonication in Example 11. Detailed Implementation

[0033] The technical solutions in the embodiments of this application are described clearly and completely below. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0034] Figure 1 The following is a schematic diagram of the synthetic route of the imidazoquinoline small molecule derivative Rf-IMDQ-N3 in some embodiments of the present invention. It starts with riboflavin as a starting material, which is oxidized to generate aldehyde riboflavin; it is then reduced and bonded to IMDQ, and finally azidated to obtain the IMDQ small molecule derivative shown in Formula I-1.

[0035] The specific steps for preparing the IMDQ small molecule derivative are as follows: 1) Riboflavin (i.e., vitamin B2, abbreviated as Rf) is oxidized to aldehyde riboflavin in a solvent under the action of an oxidizing agent; 2) Aldehyde riboflavin and IMDQ are reacted in an organic solvent with a reducing agent to generate a bonded product (intermediate) of aldehyde riboflavin and IMDQ. 3) The bonding product of aldehyde riboflavin and IMDQ is reacted with an azide reagent to generate the small molecule product described above.

[0036] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0037] Example 1

[0038] Under light-protected conditions, riboflavin (4.00 g) and acetonitrile (160 mL) were added to a round-bottom flask and stirred to form a suspension. Periodic acid (7.27 g) was added to the suspension, and the resulting mixture was stirred at room temperature for 12 hours. The mixture was filtered, and the filter cake was washed three times successively with appropriate amounts of water and methyl tert-butyl ether. After drying, the resulting solid product was aldehyde riboflavin, denoted as Rf-CHO. The yield was 82.3%.

[0039] The dried solid obtained in Example 1 was subjected to nuclear magnetic resonance (NMR) testing using deuterated trifluoroacetic acid as a solvent, and its proton NMR spectrum was obtained, as shown below. Figure 2 As shown.

[0040] Example 2

[0041] Under light-protected conditions, riboflavin (4.00 g) and saturated saline (160 mL) were added to a round-bottom flask and stirred to form a suspension. Periodic acid (7.27 g) was added to the suspension, and the resulting mixture was stirred at room temperature for 12 hours. The mixture was filtered, and the filter cake was washed three times successively with appropriate amounts of water and methyl tert-butyl ether; it was then dried, and the resulting solid was designated Rf-CHO. The yield was 65.6%.

[0042] Example 3

[0043] Under light-protected conditions, riboflavin (4.00 g) and dilute sulfuric acid (160 mL 1M) were added to a round-bottom flask and stirred to form a suspension. Periodic acid (7.27 g) was added to the suspension, and the resulting mixture was stirred at room temperature for 2 hours. The pH of the solution was adjusted to neutral with an appropriate amount of sodium bicarbonate, and the mixture was filtered. The filter cake was washed three times successively with appropriate amounts of water and methyl tert-butyl ether; dried, and the resulting solid was designated Rf-CHO. Yield: 73.4%.

[0044] Rf-CHO was prepared in Examples 1-3, with product purities of 99.2%, 98.3%, and 98.7%, respectively.

[0045] Example 4

[0046] Under light-protected conditions, Rf-CHO (1.9 g, prepared in Example 1, the same applies to the following examples), IMDQ (CAS: 1258457-59-8, 2 g), methanol (1300 mL), and pyridine (130 mL) were added to a round-bottom flask and stirred for 20 minutes. Sodium cyanoborohydride (0.7 g) was slowly added to the same round-bottom flask, and the resulting mixture was stirred and reacted at room temperature for 12 hours. The reaction mixture was then distilled under reduced pressure to obtain a solid, which was then reacted with pure water (300 mL) and dichloromethane (300 mL). 3) Extract, collect the aqueous phase, freeze dry to obtain a solid product, denoted as Rf-IMDQ; yield 50.9%.

[0047] The bonding product of aldehyde riboflavin Rf-CHO and IMDQ is the intermediate Rf-IMDQ, and its proton NMR spectrum is shown below. Figure 3 As shown.

[0048] Example 5

[0049] Under light-protected conditions, Rf-CHO (1.9 g), IMDQ (CAS: 1258457-59-8, 2 g), methanol (600 mL), and pyridine (600 mL) were added to a round-bottom flask and stirred for 20 minutes. Sodium cyanoborohydride (0.7 g) was then slowly added to the flask, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then distilled under reduced pressure to obtain a solid, which was then reacted with pure water (300 mL) and dichloromethane (300 mL). 3) Extract, collect the aqueous phase, freeze dry to obtain a solid product, denoted as Rf-IMDQ; yield 35.9%.

[0050] Example 6

[0051] Under light-protected conditions, Rf-CHO (1.9 g), IMDQ (CAS: 1258457-59-8, 2 g), DMF (1300 mL), and pyridine (130 mL) were added to a round-bottom flask and stirred for 20 minutes. Sodium cyanoborohydride (0.7 g) was then slowly added to the flask, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then distilled under reduced pressure to obtain a solid, which was then treated with pure water (300 mL) and dichloromethane (300 mL). 3) Extraction, collection of aqueous phase, freeze-drying to obtain solid, denoted as Rf-IMDQ; yield 41.3%.

[0052] Example 7

[0053] Under light-protected conditions, Rf-CHO (1.9 g), IMDQ (CAS: 1258457-59-8, 2 g), THF (1300 mL), and pyridine (130 mL) were added to a round-bottom flask and stirred for 20 minutes. Sodium borohydride (0.7 g) was slowly added to the flask, and the resulting mixture was stirred and reacted at room temperature for 12 hours. The reaction mixture was then distilled under reduced pressure to obtain a solid, which was then reacted with pure water (300 mL) and dichloromethane (300 mL). 3) Extract, collect the aqueous phase, freeze dry to obtain a solid product, denoted as Rf-IMDQ; yield 28.9%.

[0054] Rf-IMDQ was prepared in Examples 4-7, with essentially the same purity of 99.2%, 98.6%, 98.3%, and 98.4%, respectively.

[0055] Example 8

[0056] Dissolve 1.3 g of NaN3 in 40 mL of water, and add 40 mL of MTBE while stirring continuously. Add 3.28 g of 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazolium-3-onium trifluoromethanesulfonate solid to the above solution and stir rapidly at room temperature for 10 minutes. Remove the lower layer of liquid, and then add 40 mL of water. 3) Wash three times to obtain the azide reagent, denoted as FSO2N3 solution.

[0057] Example 9

[0058] Dissolve 1.3 g of NaN3 in 40 mL of water and add 30 mL of MTBE, stirring continuously. Add 3.28 g of 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazolium-3-onium trifluoromethanesulfonate solid to the above solution and stir rapidly at room temperature for 10 minutes. Remove the lower layer of liquid and then add 40 mL of water. 3) Wash three times to obtain the azide reagent, denoted as FSO2N3 solution.

[0059] Example 10

[0060] Dissolve 1.3 g of NaN3 in 40 mL of water and add 20 mL of MTBE, stirring continuously. Add 3.28 g of 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazolium-3-onium trifluoromethanesulfonate solid to the above solution and stir rapidly at room temperature for 10 minutes. Remove the lower layer of liquid and then add 40 mL of water. 3) Wash three times to obtain the azide reagent, denoted as FSO2N3 solution.

[0061] The above are established methods for preparing this azide reagent, which are commonly used in laboratories.

[0062] Example 11

[0063] To a round-bottom glass flask, add Rf-IMDQ (627 mg) solid and DMF (30 mL) from Example 4 sequentially, stir to dissolve, and finally add FSO2N3 solution (40 mL); stir the resulting mixture at room temperature for 12 hours. Distill under reduced pressure, add ethyl acetate (40 mL), and then dilute the mixture sequentially with brine (60 mL) and water (60 mL). 2) Wash, collect the organic phase, dry it, and obtain a solid product, denoted as Rf-IMDQ-N3; ​​yield 43.5%.

[0064] The dried solid obtained in Example 11 was subjected to nuclear magnetic resonance (NMR) testing using deuterated trifluoroacetic acid as a solvent, and its proton NMR spectrum was obtained, as shown below. Figure 4 As shown.

[0065] Example 12

[0066] To a round-bottom glass flask, add Rf-IMDQ (627 mg) solid and DMF (40 mL) from Example 4 sequentially, stir to dissolve, and finally add FSO2N3 solution (40 mL); stir the resulting mixture at room temperature for 12 hours. Distill under reduced pressure, add ethyl acetate (40 mL), and then dilute the mixture sequentially with brine (60 mL) and water (60 mL). 2) Wash, collect the organic phase, dry it, and obtain a solid product, denoted as Rf-IMDQ-N3; ​​yield 35.7%.

[0067] Example 13

[0068] To a round-bottom glass flask, add Rf-IMDQ (627 mg) solid and DMF (50 mL) from Example 4 sequentially, stir to dissolve, and finally add FSO2N3 solution (40 mL); stir the resulting mixture at room temperature for 12 hours. Distill under reduced pressure, add ethyl acetate (40 mL), and then dilute the mixture sequentially with brine (60 mL) and water (60 mL). 2) Wash, collect the organic phase, dry it, and obtain a solid product, denoted as Rf-IMDQ-N3; ​​yield 26.2%.

[0069] Example 14

[0070] Prepare 1 mL of Rf-IMDQ-N3 aqueous solution (0.1 mg / mL) and perform ultrasound using a physiotherapy ultrasound device. The parameters are set as follows: ultrasound time 2 minutes; duty cycle 50%; power 2.5 W / cm². 2 ; Frequency 1 MHz.

[0071] The resulting solution was analyzed by liquid chromatography-mass spectrometry (LC-MS), and the concentration of IMDQ was found to be 6.8 μg / mL. Figure 5 and Figure 6 As shown. Figure 5 This is a summary spectrum of liquid chromatography-mass spectra obtained after sonication of the imidazoquinoline small molecule derivative Rf-IMDQ-N3. Figure 6 The sub-graphs demonstrate the production of the effective substance IMDQ.

[0072] By observing the generation of IMDQ, Rf-IMDQ-N3 is transformed into IMDQ under ultrasonic conditions.

[0073] Example 15

[0074] Prepare 1 mL of Rf-IMDQ-N3 aqueous solution (0.1 mg / mL) and perform ultrasound using a physiotherapy ultrasound device. The parameters are set as follows: ultrasound time 3 minutes; duty cycle 50%; power 2.5 W / cm². 2 The frequency was 1 MHz. The resulting solution was sent for analysis using liquid chromatography-mass spectrometry (LC-MS), and the concentration of IMDQ was measured to be 7.3 μg / mL.

[0075] Example 16

[0076] Prepare 1 mL of Rf-IMDQ-N3 aqueous solution (0.1 mg / mL) and perform ultrasound using a physiotherapy ultrasound device. The parameters are set as follows: ultrasound time 5 minutes; duty cycle 50%; power 2.5 W / cm². 2 The frequency was 1 MHz. The resulting solution was sent for analysis using liquid chromatography-mass spectrometry (LC-MS), and the concentration of IMDQ was measured to be 8.1 μg / mL.

[0077] Comparative Example 1

[0078] Prepare 1 mL of IMDQ-N3 aqueous solution (0.1 mg / mL) and perform ultrasound using a physiotherapy ultrasound device. The parameters are set as follows: ultrasound time 2 minutes; duty cycle 50%; power 2.5 W / cm². 2 The frequency was 1 MHz. The resulting solution was sent for analysis using liquid chromatography-mass spectrometry (LC-MS), and the concentration of IMDQ was measured to be 0.8 μg / mL.

[0079] Comparative Example 2

[0080] Prepare 1 mL of IMDQ-N3 aqueous solution (0.1 mg / mL) and perform ultrasound using a physiotherapy ultrasound device. The parameters are set as follows: ultrasound time 3 minutes; duty cycle 50%; power 2.5 W / cm². 2 The frequency was 1 MHz. The resulting solution was sent for LC-MS analysis, and the IMDQ concentration was found to be 1.5 μg / mL.

[0081] Comparative Example 3

[0082] Prepare 1 mL of MDQ-N3 aqueous solution (0.1 mg / mL) and perform ultrasound using a physiotherapy ultrasound device. The parameters are set as follows: ultrasound time 5 minutes; duty cycle 50%; power 2.5 W / cm². 2 The frequency was 1 MHz. The resulting solution was sent for analysis using liquid chromatography-mass spectrometry (LC-MS), and the concentration of IMDQ was measured to be 2.3 μg / mL.

[0083] In the comparative example, the substance IMDQ-N3 does not have a riboflavin structure and is relatively stable; while in the present invention, Rf-IMDQ-N3 contains a riboflavin structure, which is a sensitizer for azide ultrasound, making Rf-IMDQ-N3 more susceptible to the effects of ultrasound.

[0084] As can be seen from the above embodiments, the imidazoquinoline small molecule compound Rf-IMDQ-N3 described in the embodiments of the present invention can be converted into IMDQ under ultrasound conditions; it can be used as an ultrasound-activated prodrug with almost no harmful effects on the human body, and at the same time can improve the accumulation of drugs at the tumor site.

[0085] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention. The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values; these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of various ranges, the endpoint values ​​of various ranges and individual point values, and individual point values ​​can be combined to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. An imidazoquinoline intermediate, characterized in that, It has the structure of Formula 1: Formula 1; Wherein, R0 is selected from primary amino or nitro; R1 is selected from C1~C4 alkyl or C1~C4 ether. R2 is selected from C1-C3 alkylene and / or phenylene; R3 is selected from C1-C3 alkylene; R4 and R5 are selected from hydrogen or methyl, respectively.

2. A small molecule derivative of imidazoquinoline, characterized in that, It has the structure of Formula I: Equation I; Wherein, R1 is selected from C1-C4 alkyl or C1-C4 ether; R2 is selected from C1-C3 alkylene and / or phenylene; R3 is selected from C1-C3 alkylene; R4 and R5 are selected from hydrogen or methyl, respectively.

3. The imidazoquinoline small molecule derivative according to claim 2, characterized in that, R1 is methyl, ethyl, n-propyl, n-butyl, or methyl ethyl ether.

4. The imidazoquinoline small molecule derivative according to claim 2, characterized in that, R2 is methylene, ethylene, propylene, or benzylidene.

5. The imidazoquinoline small molecule derivative according to any one of claims 2-4, characterized in that, R3 is methylene, while R4 and R5 are both methyl.

6. A method for preparing the imidazoquinoline small molecule derivative according to any one of claims 2-5, characterized in that, Includes the following steps: The riboflavin derivative shown in Formula 2 is reduced with the IMDQ-type substance shown in Formula 3 to obtain the imidazoquinoline intermediate shown in Formula 1. The imidazoquinoline intermediate was subjected to an azide reaction to obtain the imidazoquinoline small molecule derivative shown in Formula I. Formula 2; Formula 3; Formula 1; Equation I; Wherein, R0 is selected from primary amino or nitro; R1 is selected from C1~C4 alkyl or C1~C4 ether. R2 is selected from C1-C3 alkylene and / or phenylene; R3 is selected from C1-C3 alkylene; R4 and R5 are selected from hydrogen or methyl, respectively.

7. The preparation method according to claim 6, characterized in that, The riboflavin derivative and IMDQ-type substances undergo a reduction reaction in an organic solvent under the action of a reducing agent; the organic solvent is one or more of methanol, pyridine, tetrahydrofuran, and N,N-dimethylformamide; the reducing agent is one or more of sodium cyanoborohydride, sodium borohydride, and sodium triacetoxyborohydride.

8. The preparation method according to claim 6, characterized in that, The imidazoquinoline intermediate undergoes an azidation reaction in the presence of an azidating agent; the azidating agent is the product of the reaction between 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazo-3-onium trifluoromethanesulfonate and sodium azide.

9. The preparation method according to claim 8, characterized in that, The imidazoquinoline intermediate was dissolved in N,N-dimethylformamide, and an azide reagent was added. The azide reaction was carried out at room temperature and under stirring conditions. After vacuum distillation, the product was washed and dried to obtain a solid imidazoquinoline small molecule derivative.

10. The use of an imidazoquinoline small molecule derivative according to any one of claims 2-5 in the preparation of an ultrasound-activated prodrug.

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