CN118108786A - 10-Amino camptothecine compound cleaved by connective tissue proteinase B and its synthesis and application - Google Patents

10-Amino camptothecine compound cleaved by connective tissue proteinase B and its synthesis and application Download PDF

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CN118108786A
CN118108786A CN202410021967.1A CN202410021967A CN118108786A CN 118108786 A CN118108786 A CN 118108786A CN 202410021967 A CN202410021967 A CN 202410021967A CN 118108786 A CN118108786 A CN 118108786A
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朱书雷
吕伟
丁梦园
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East China Normal University
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Abstract

The invention discloses a 10-amino camptothecine compound prodrug intermediate for cleavage by connective tissue proteinase B shown in a formula I, and a synthesis method and application thereof. The invention also discloses a cathepsin B cleavage type 10-amino camptothecin derivative prodrug shown in a formula III, and a synthetic method and application thereof. The invention also discloses a pharmaceutical composition and application thereof.

Description

10-Amino camptothecine compound cleaved by connective tissue proteinase B and its synthesis and application
Technical Field
The invention relates to synthesis of compounds, in particular to a 10-amino camptothecine compound which is used as a medical intermediate and is cracked by connective tissue proteinase B, and a synthesis method and application thereof.
Background
Camptothecins (CPT) are a plant type of drug which is widely studied in traditional antitumor drugs, and are also the most popular topoisomerase 1 (TOP 1) inhibitors currently studied. Camptothecin and derivatives thereof as topoisomerase I inhibitors selectively capture TOP1 cleavage complexes and become very potential antitumor drugs. Camptothecin derivatives are widely used in drug delivery systems, where antibody drug conjugates (Anti-body drug conjugate, ADC) are the most representative drugs in targeted drug delivery systems. To increase the accumulation of TOP1 inhibitors in cancer cells by targeting tumors, ADCs of the TOP1 inhibitor class are widely developed. The first three co-drugs Enhertu (DS-8201) were successful, and more particularly, the development of camptothecins ADC was hot-strived to peak. However, the larger molecular weight of ADC, the poorer permeability to tumor tissue, results in a very low proportion of effector molecules that can effectively enter the tumor, less than 2%. In addition, the preparation process of ADC is complex and synthesis is difficult, which results in high treatment cost, thereby limiting its clinical application. In addition, many 10-hydroxycamptothecin derivatives, such as the active metabolite SN38 of the topoisomerase 1 inhibitor irinotecan, while effective against many malignant tumors, have poor water solubility, low bioavailability, and severe dose limiting toxicity, and a series of prodrugs of SN-38 have been developed to address these problems. Prodrugs based on camptothecin derivatives other than SN-38 have also been developed successively, for example European Journal of MEDICINAL CHEMISTRY (2021) 1 13851 reports a quaternary ammonium salt albumin binding prodrug Mal-glu-CPTS0001 based on the novel camptothecin derivative CPTS0001. The prodrug significantly reduces toxicity of the parent drug, enhances in vivo selectivity of the drug while increasing the maximum tolerated dose, and improves accumulation of the prodrug in tumors.
Cathepsins (CATHEPSIN B) are a class of proteases found in the cells (particularly lysosomal parts) of various animal tissues, and are closely related to various important diseases such as stomach, lung, endometrial cancer, etc. and are a class of target proteases which have been attracting attention in recent years. Cathepsin B has carboxypeptidase activity and selectively recognizes certain amino acid sequences and cleaves dipeptide linkers at the C-terminus of the sequence, such as Val-Cit, val-Ala, GGFG, and the like, which linkers are widely used in research or ex-situ ADCs. Enzyme-cleaved linkers, which generally have higher plasma stability and are effective in preventing premature release of the drug, have been clinically successful. However, due to the large ADC molecular weight, tumor tissue permeability is poor and less than 2% of the payload can reach the tumor site. In addition, the synthetic route is difficult, the process is complex, and high treatment cost is caused. Therefore, the development of a camptothecin derivative prodrug which is relatively simple in preparation process and low in cost and is cleaved by cathepsin B can effectively meet clinical demands.
Disclosure of Invention
The invention aims to overcome the defects of the existing medicines and provides a 10-amino camptothecin prodrug cleaved by cathepsin B, and a synthesis method and application thereof. The 10-aminocamptothecin derivative is linked to the HSP90 inhibitor via a cathepsin B cleavage linker. After intravenous injection, the compound is triggered to be cracked in tumor extracellular matrix or tumor cell lysosome by cathepsin B to release 10-amino camptothecine derivative. The compound can also be combined with albumin in blood plasma after intravenous injection to form a macromolecular drug carrying system, so that the half life of the drug in vivo circulation is prolonged, the clearance rate is reduced, and a better treatment effect is achieved.
The invention provides a prodrug intermediate of a cathepsin B cleavage type 10-amino camptothecine compound, which has a structure shown in a formula I:
wherein,
R is hydrogen,N represents a natural number of 0 to 8,/>N represents a natural number of 0 to 8;
r' is hydrogen, Wherein R' is/> Etc.
Specifically, the 10-aminocamptothecin compound prodrug intermediate cleaved by connective tissue proteinase B comprises the following compounds:
the invention also provides a synthesis method of the 10-amino camptothecin compound prodrug intermediate cleaved by the connective tissue proteinase B, which comprises the following specific steps: the compound of the formula I' and the compound of the formula II are dissolved in a first solvent, and condensation reaction is carried out by adding a condensing agent and alkali to obtain the compound of the formula I, wherein the reaction route is as follows:
Wherein:
R is hydrogen, N represents a natural number of 0 to 8,/>N represents a natural number of 0 to 8;
r' is hydrogen, Wherein R' is/> Etc.
In the step, the temperature of the reaction is controlled between 0 and 35 ℃; preferably 25 ℃.
In the step, the reaction time is 2-8 hours; preferably 4 hours.
In the step, the molar ratio of the compound of the formula I' to the compound of the formula II to the alkali is 1:1.01-1.2:1.1-2:1.5-3; preferably 1:1:1.5:3.
In the step, the alkali is selected from one or more of triethylamine, DMAP, DIPEA, NMP and imidazole; preferably DIPEA.
In the step, the first solvent is selected from one or more of anhydrous dichloromethane, anhydrous chloroform, anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide and anhydrous N, N-methylacetamide; preferably, it is anhydrous dichloromethane.
In the step, the condensing agent is selected from one or more of HATU, HBTU, EDCI, HOBT, HOAT, DCC, EEDQ, DMTMM, T 3P、T4 P; preferably HATU.
The invention also provides a cathepsin B cleavage type 10-amino camptothecin derivative prodrug, which is characterized in that the structure is shown in a formula III:
wherein,
R 1 is hydrogen,
R is hydrogen,N represents a natural number of 0 to 8,/>N represents a natural number of 0 to 8;
r' is hydrogen, Wherein R' is/> Etc.
Specifically, the cathepsin B cleaved type 10-aminocamptothecin derivative prodrug (III) comprises the following compounds:
the invention also provides a method for synthesizing the cathepsin B cleavage type 10-amino camptothecin derivative prodrug, which is characterized by comprising the following steps: the compound of the formula IV and the compound of the formula I are dissolved in a second solvent, and condensation reaction is carried out by adding a condensing agent and alkali to obtain a compound of the formula III; the reaction scheme is as follows:
wherein,
R 1 is hydrogen,
R is hydrogen,N represents a natural number of 0 to 8,/>N represents a natural number of 0 to 8;
r' is hydrogen, Wherein R' is/> Etc.
In the step, the temperature of the reaction is controlled between 0 and 30 ℃; preferably 25 ℃.
In the step, the reaction time is 4-12 hours; preferably, 6 hours.
In the step, the alkali is selected from one or more of triethylamine, DMAP, DIPEA, NMP and imidazole; preferably DIPEA.
In the step, the second solvent is selected from one or more of anhydrous dichloromethane, anhydrous chloroform, anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide and anhydrous N, N-dimethylacetamide; preferably, it is anhydrous dichloromethane.
In the step, the condensing agent is selected from one or more of HATU, HBTU, EDCI, HOBT, HOAT, DCC, EEDQ, DMTMM, T 3P、T4 P; preferably HATU.
In the step, the mol ratio of the compound of the formula I to the compound of the formula IV to the condensing agent to the alkali is 1:1.01-1.2:1.1-2:1.5-3; preferably 1:1:1.5:3.
The invention also provides a pharmaceutical composition comprising the 10-aminocamptothecin prodrug intermediate cleaved by connective tissue proteinase B, namely a compound of formula I; or a cathepsin B cleavage type 10-aminocamptothecin derivative prodrug, namely a compound or a pharmaceutical composition shown in a formula III, and a pharmaceutically acceptable carrier.
The invention also provides a 10-amino camptothecine compound prodrug intermediate cleaved by the connective tissue proteinase B, namely a compound of a formula I; or cathepsin B cleavage type 10-amino camptothecine derivative prodrug, namely the application of a compound or a pharmaceutical composition shown in a formula III in preparing antitumor drugs.
The invention also provides a 10-amino camptothecine compound prodrug intermediate which is obtained by enzyme cleavage of the connective tissue proteinase B, namely a compound shown in a formula I; or cathepsin B cleavage type 10-amino camptothecine derivative prodrug, namely a compound or a pharmaceutical composition shown in a formula III, and application thereof in preparation and targeted drug delivery of antitumor drugs.
Wherein the tumor comprises colorectal cancer, gastric cancer, breast cancer, lung cancer, prostate cancer and the like.
Wherein the targeted administration comprises a non-covalent/covalent binding prodrug of albumin in a cathepsin B cleaved type 10-amino camptothecin derivative, an antibody coupling drug based on the cathepsin B cleaved type 10-amino camptothecin derivative as an effector molecule, and the like.
The invention has the beneficial effects that: the compound of the formula III is simple in synthetic route and easy to purify; the raw materials are easy to obtain, the production cost is low, and the preparation can be carried out in a large quantity so as to meet the requirements of the current and future clinical medicine research.
Drawings
1 H NMR spectrum of compound 20 of fig. 1;
13 C NMR spectrum of compound 20 of fig. 2;
FIG. 3 is a 1 H NMR spectrum of compound 22;
13 C NMR spectrum of compound 22 of fig. 4;
1 H NMR spectrum of compound 24 of fig. 5;
13 C NMR spectrum of compound 24 of fig. 6;
FIG. 7 is a 1 H NMR spectrum of compound 25 a;
FIG. 8 is a 13 C NMR spectrum of compound 25 a;
FIG. 9 is a 1 H NMR spectrum of compound 25 b;
FIG. 10 is a 13 C NMR spectrum of compound 25 b;
FIG. 11 is a 1 H NMR spectrum of compound 25 c;
FIG. 12 is a 13 C NMR spectrum of compound 25C;
FIG. 13 shows the enzymatic release profile of compounds 20, 22, 25 c;
FIG. 14 growth inhibitory effect of Compound 25c on human colorectal carcinoma HCT-116 nude mouse transplantation tumor;
FIG. 15 effect of compound 25c on human colorectal cancer HCT-116 tumor-bearing murine body weight;
FIG. 16 effect of Compound 25c on tumor weight of human colorectal carcinoma HCT-116 tumor-bearing mice;
FIG. 17A schematic of the structure of Compound 1 (drug released by cathepsin B).
Detailed Description
The method for synthesizing the 10-aminocamptothecin compound by cleavage with connective tissue proteinase B is described in more detail in the following examples, which are not to be construed as limiting the invention. The synthesis method comprises the following steps:
Reacting the compound of the formula II with active esters of PEG chains with different lengths to obtain a 10-amino camptothecin compound prodrug intermediate with tert-butyl ester protection and cleavage by cathepsin B; removing tert-butyl ester protection from the compound under an acidic condition to obtain a 10-amino camptothecin compound prodrug intermediate cleaved by cathepsin B, namely a compound of a formula I; or constructing a linker for connecting three pharmacophores through benzyl-protected serinol to obtain a prodrug intermediate, namely the compound of the formula I. Then, the obtained compound of the formula I and HSP90 inhibitor fragments are subjected to amide condensation reaction in a solvent, and the compound of the formula III is obtained after reverse phase column purification. The required reaction raw materials are easy to obtain and can be purchased through the market; the reaction condition is simple, the purification is easy, the preparation can be carried out in a large amount, and the requirements of clinical medicine research and development are met.
Example 1
In example 1, n is 1,3 or 4.
1-1
Compound II (80 mg,0.113 mmol) was dissolved in anhydrous DMF under nitrogen, DIEA (14.6 mg,0.113 mmol) and compounds 2 a-c (37.3 mg,0.113 mmol) were added and reacted at room temperature for 12h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 80mg of a yellow solid, the yield was 89.9%, and the mixture was directly fed into the next step.
1-2
Compounds 3 a-c (80 mg,0.101 mmol) were dissolved in anhydrous DCM of 20% TFA under nitrogen and reacted at room temperature for 2h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 83mg of a yellowish-brown solid, and the yield was 97.9%. Compound 4a：1H NMR(400MHz,CDCl3)δ8.31(s,2H),7.81(s,2H),7.02(s,2H),6.17(s,2H),5.76(d,J＝10.5Hz,4H),5.60(s,2H),5.37(s,2H),5.00(t,J＝32.9Hz,6H),3.75(s,2H),3.67(s,4H),3.62(s,2H),3.47(s,2H),3.07(s,4H),2.97(s,2H),2.73(s,1H),2.58(s,2H),2.23(d,J＝13.4Hz,4H),1.98(s,2H),1.44(s,6H),1.31(s,4H),0.96(s,12H),0.89(s,3H). Compound 4b：1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.03(s,1H),7.81(s,1H),7.01(s,1H),6.97(s,1H),5.99(s,1H),5.78(s,1H),5.74(s,1H),5.32(s,1H),5.06(s,1H),4.97(d,J＝6.0Hz,2H),3.75(s,1H),3.67(s,2H),3.62(s,2H),3.52(s,8H),3.41(s,1H),3.07(s,2H),2.97(s,1H),2.73(s,1H),2.60(s,2H),2.24(s,1H),2.19(s,1H),2.10(s,1H),1.44(d,J＝1.1Hz,5H),0.96(s,6H),0.89(s,2H). Compound 4c：1H NMR(400MHz,DMSO)δ9.76(s,1H),8.26(d,J＝6.7Hz,1H),7.91(d,J＝8.9Hz,2H),7.77(d,J＝9.1Hz,1H),5.39(s,2H),5.21(s,2H),4.52-4.47(m,1H),4.20(d,J＝8.2Hz,1H),3.51(s,4H),3.47-3.45(m,14H),3.11(s,2H),2.38(d,J＝6.5Hz,3H),1.90(ddd,J＝21.5,13.8,6.8Hz,6H),1.35(d,J＝6.8Hz,2H),1.30(d,J＝6.5Hz,2H),1.19(s,3H),0.83(dd,J＝7.4,4.3Hz,9H).
Example 2
2-1
Compound 5 (1 g,3.68 mmol) was dissolved in 10mL of toluene under nitrogen atmosphere, tetrabutylammonium bisulfate (186.2 mg,0.55 mmol), t-butyl bromoacetate (compound 6) (2.15 g,11.04 mmol) and 8mL of 30% NaOH solution were added sequentially and heated to 45℃for reaction. After the reaction was completed, the layers were separated, the lower aqueous phase was extracted with EA, washed with saturated brine, and dried over anhydrous magnesium sulfate. The crude product was purified by Flash column (PE: ea=0% →20%) to give 1.2g of pale yellow oil, yield 65.2％.1H NMR(400MHz,CDCl3)δ7.32(s,6H),7.27-7.22(m,4H),3.97(s,4H),3.86(d,J＝13.6Hz,4H),3.68(d,J＝6.0Hz,4H),3.09(d,J＝1.3Hz,1H),1.50(d,J＝5.9Hz,18H).
2-2
Compound 7 (400 mg,0.8 mmol) was dissolved in 10mL of methanol, 10% palladium on charcoal (5 mol%) was added in place of hydrogen, and the mixture was heated to 45℃to react for 12h. After the reaction is finished, filtering palladium-carbon, collecting filtrate, and spin-drying the filtrate to obtain 238mg of colorless oily substance with the yield of 93.1%, wherein the next reaction can be directly carried out.
2-3
Compound 8 (3.7 g,11.6 mmol) was dissolved in 50mL anhydrous DCM under nitrogen, DIEA (1.79 g,13.9 mmol) was added, fmoc-C1 (3.6 g,13.9 mmol) was added with stirring and reacted at room temperature for 8h. After the reaction was completed, the solvent was removed, and the crude product was purified by Flash column (PE: ea=0% > 20%) to give 6g of a pale yellow oil, yield 95.5％.1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.5Hz,2H),7.65(d,J＝7.3Hz,2H),7.37(d,J＝7.5Hz,2H),7.31(d,J＝7.3Hz,2H),6.14(d,J＝6.7Hz,1H),4.35(d,J＝7.1Hz,2H),4.25-4.11(m,2H),4.02-3.95(m,4H),3.79-3.63(m,4H),1.48(s,18H).
2-4
Compound 9 (3 g,5.54 mmol) was dissolved in 40% TFA in DCM and reacted at room temperature for 4h under nitrogen. After the reaction is finished, the solvent is removed, the remainder PE reprecipitates to separate out solid, and 1.8g of white solid is obtained after filtration, the yield is 75.7％.1H NMR(400MHz,DMSO)δ7.89(d,J＝7.5Hz,2H),7.70(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.31(dd,J＝15.9,8.2Hz,3H),4.34-4.16(m,3H),4.06-3.91(m,4H),3.81-3.72(m,1H),3.49(dd,J＝11.9,6.0Hz,4H).
2-5
Compound 10 (200 mg, 0.463 mmol) was dissolved in 8mL of anhydrous DCM under nitrogen, DIEA (60.2 mg, 0.463 mmol) was added followed by pentafluorophenyl trifluoroacetate (compound 11) (130.4 mg, 0.463 mmol) and reacted at room temperature for 10h. The starting material was incompletely reacted and purified by column chromatography after removal of the solvent (DCM: meOH=50:1→20:1) to give 100mg of a pale yellow oil in yield 36.0％.1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.5Hz,2H),7.61(d,J＝7.4Hz,2H),7.38(t,J＝7.4Hz,2H),7.29(t,J＝7.3Hz,2H),4.50(s,2H),4.36(d,J＝7.2Hz,2H),4.22(t,J＝7.0Hz,1H),4.10(t,J＝21.0Hz,3H),3.893.59(m,4H).
2-6
Compound 4c (50 mg,0.061 mmol) was dissolved in 5mL of anhydrous DCM under nitrogen and compound 12 (36.3 mg,0.061 mmol) and DIEA (11.8 mg,0.091 mmol) were added and the reaction solution was allowed to stand at room temperature for 5h. After the reaction is finished, the solvent is removed, EA is pulped to obtain light yellow solid with 40mg and yield 53.2％.1H NMR(400MHz,DMSO)δ9.85(s,1H),8.46(s,1H),8.06(s,1H),7.95(d,J＝9.0Hz,1H),7.86(d,J＝7.5Hz,2H),7.83-7.75(m,2H),7.68(d,J＝7.0Hz,2H),7.39(t,J＝7.2Hz,2H),7.31(d,J＝8.5Hz,3H),6.52(s,1H),5.43(s,2H),5.24(s,2H),4.55-4.49(m,1H),4.22(dd,J＝19.2,11.6Hz,4H),4.02(dd,J＝14.2,7.1Hz,2H),3.93(s,2H),3.85(s,2H),3.77(s,1H),3.58(t,J＝6.0Hz,2H),3.47(d,J＝3.8Hz,18H),3.14(s,2H),2.96(s,2H),1.99(s,4H),1.87(dt,J＝14.5,7.2Hz,2H),1.39(d,J＝6.7Hz,3H),1.17(t,J＝7.1Hz,2H),0.87(dd,J＝15.2,8.6Hz,9H).
2-7
Compound 13 (40 mg,0.032 mmol) was dissolved in 5mL of anhydrous DMF under nitrogen, and pentafluorophenyl trifluoroacetate (compound 11) (10.9 mg,0.039 mmol) and DIEA (5.0 mg,0.039 mmol) were added and reacted at room temperature for 4h. After the reaction was completed, the solvent was removed and the crude product was purified by Flash column (DCM: meoh=5% →10%) to give a pale yellow solid .1H NMR(400MHz,CDC13)δ9.11(s,1H),7.877.67(m,5H),7.587.48(m,3H),7.377.33(m,2H),7.27(s,1H),7.24(s,1H),5.945.65(m,1H),5.284.75(m,3H),4.49(s,1H),4.34(d,J＝6.4Hz,2H),4.164.11(m,1H),3.96(s,2H),3.693.65(m,12H),3.58(s,8H),3.113.08(m,8H),2.87(d,J＝41.0Hz,4H),2.58(d,J＝30.2Hz,2H),1.91(dd,J＝36.9,30.5Hz,4H),1.52(d,J＝6.4Hz,3H),0.99(dd,J＝14.0,6.3Hz,9H).
2-8
Compound 14 (180 mg,0.129 mmol) was immersed in 10mL of anhydrous DMF under nitrogen, and compound 15 (60 mg,0.129 mmol) and DIEA (25.0 mg,0.194 mmol) were added and reacted at room temperature for 4h. After the reaction is finished, the solvent is removed, EA is pulped to obtain 150mg of pale yellow solid with yield 69.3％.1H NMR(400MHz,CDCl3)δ8.30(s,2H),8.22(s,2H),7.90(s,4H),7.81(d,J＝7.4Hz,6H),7.60(s,2H),7.34(d,J＝1.4Hz,7H),7.26-7.10(m,9H),6.92(s,2H),6.37(s,2H),6.19(s,2H),5.84(d,J＝15.5Hz,4H),5.66(d,J＝9.0Hz,4H),5.08(d,J＝4.5Hz,6H),4.74(d,J＝6.0Hz,4H),4.66(s,2H),4.56-4.45(m,8H),3.82(d,J＝73.9Hz,6H),3.65(t,J＝12.5Hz,11H),3.60-3.33(m,45H),3.30-3.22(m,7H),3.09-2.85(m,12H),2.94(s,1H),2.73(s,1H),2.56(s,2H),2.48(s,5H),2.24(s,2H),1.88(s,2H),1.43(d,J＝12.8Hz,8H),1.09(d,J＝50.0Hz,19H),1.00(d,J＝16.3Hz,2H),0.96(s,12H),0.89(s,3H).
Example 3
3-1
Compound 16 (150 mg,0.089 mmol) was dissolved in 20% diethyl amine/THF and reacted at room temperature for 3h. After the reaction is finished, the solvent is removed, PE is pulped to remove small polar impurities, and then the mixture is purified by a reverse phase column (0.1 percent TFA-water: acetonitrile=5% > 35%) and freeze-dried to obtain 100mg of light yellow solid with the yield 76.9％.1H NMR(400MHz,DMSO)δ9.75(d,J＝11.3Hz,1H),8.27(d,J＝6.6Hz,1H),8.09(s,2H),8.05-7.77(m,4H),7.48(d,J＝27.7Hz,2H),7.30(s,1H),6.65(s,1H),6.31(s,1H),5.43(s,2H),5.27(s,2H),4.52(d,J＝6.3Hz,2H),4.41-4.23(m,4H),3.94(s,3H),3.49(d,J＝6.2Hz,35H),3.22(d,J＝45.8Hz,9H),2.97(s,4H),2.04-1.85(m,4H),1.39(d,J＝6.5Hz,2H),1.05(t,J＝7.2Hz,2H),0.92-0.83(m,12H).
3-2
Compound 17 (40 mg,0.027 mmol) was dissolved in anhydrous DMF under nitrogen, and compound 18 (25.5 mg,0.027 mmol) and DIEA (4.2 mg,0.032 mmol) were added and reacted at room temperature for 4h. After the reaction is finished, the solvent is removed, EA is pulped to obtain 47mg of light yellow solid with the yield of 76.2 percent, and the light yellow solid can be directly put into the next step.
3-3
Compound 19 (45 mg,0.019 mmol) was dissolved in 30% TFA/DCM and reacted at room temperature for 5h. After the reaction was completed, the solvent was removed, and the mixture was purified by reverse phase column (0.1% tfa-water: acetonitrile=5% →42%) and lyophilized to give 28mg of a pale yellow solid, whose yield 65.4％.1H NMR(400MHz,DMSO)δ12.22(s,1H),10.36-9.65(m,2H),9.08-8.27(m,1H),8.077.63(m,5H),7.48(d,J＝37.1Hz,3H),7.31(s,1H),6.59(d,J＝69.9Hz,1H),5.35(d,J＝68.1Hz,2H),4.30(dd,J＝105.3,63.8Hz,4H),3.94(dd,J＝40.8,16.7Hz,5H),3.49(t,J＝26.8Hz,32H),3.22(d,J＝36.2Hz,10H),2.97(s,3H),2.62(s,1H),2.33(s,2H),2.04(ddd,J＝136.7,62.0,29.1Hz,10H),1.43(d,J＝26.9Hz,4H),1.28(d,J＝45.5Hz,22H),1.05(s,3H),0.88(s,13H).(1H NMR spectrum is shown in fig. 1 and whose )13C NMR(101MHz,DMSO)δ174.98,174.02,172.97,172.84,171.89,171.78,171.53,170.74,169.79,169.71,169.51,169.31,168.15,157.77,157.35,156.57,155.95,155.10,151.28,150.51,148.02,146.70,146.57,141.81,133.03,131.92,129.12,128.76,128.46,127.36,127.21,126.93,125.94,125.68,119.15,103.31,102.89,96.95,72.87,70.61,70.40,70.23,70.17,70.00,69.93,69.79,69.55,69.34,67.38,67.02,65.73,57.79,57.06,51.93,51.04,49.99,49.27,40.60,40.39,40.18,39.98,39.77,39.56,39.35,38.95,38.50,38.38,36.34,35.53,34.12,34.02,33.02,32.15,31.15,30.72,29.54,29.47,29.38,29.30,29.21,29.11,29.01,27.49,26.82,25.85,25.70,25.48,24.96,22.90,21.34,19.63,18.54,18.32,15.00,8.25.(13C NMR spectrum is shown in fig. 2), HR-MS (ESI): m/z Calc for, [ M+H ] +: 2172.1408, found:2172.1422.
Example 4
Compound 17 (60 mg,0.0412 mmol) was dissolved in 5mL anhydrous DMF under nitrogen, and compound 21 (12.7 mg,0.0412 mmol) and DIEA (7.9 mg,0.062 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the solvent was removed, and the mixture was purified by reverse phase column (0.1% tfa-water: acetonitrile=5% →32%) and lyophilized to give 40mg of a pale yellow solid, whose yield 58.9％.1H NMR(400MHz,DMSO)δ9.77(s,2H),9.00(s,1H),8.29(d,J＝6.3Hz,1H),7.97-7.88(m,3H),7.84-7.74(m,2H),7.45(d,J＝49.0Hz,4H),7.30(s,1H),7.00(d,J＝7.6Hz,2H),6.65(s,1H),6.51(s,1H),6.32(s,1H),5.43(s,2H),5.26(s,2H),4.56-4.50(m,1H),4.24(dd,J＝17.3,9.2Hz,3H),4.04(s,1H),3.86(s,2H),3.58(d,J＝7.3Hz,3H),3.49-3.41(m,20H),3.26(d,J＝5.8Hz,3H),3.16(d,J＝5.6Hz,4H),3.00-2.88(m,4H),2.40(dd,J＝23.6,16.9Hz,3H),2.06(d,J＝7.2Hz,2H),2.00(d,J＝6.2Hz,3H),1.88(dd,J＝14.5,7.2Hz,2H),1.50-1.44(m,4H),1.39(d,J＝7.0Hz,4H),1.21(d,J＝16.4Hz,8H),1.04(t,J＝7.1Hz,3H),0.86(d,J＝5.4Hz,15H).(1H NMR spectrum is shown in fig. 3 and whose )13C NMR(101MHz,DMSO)δ172.98,172.42,171.84,171.54,170.73,169.56,157.76,157.35,156.59,155.05,151.28,150.52,148.33,148.08,146.70,146.58,141.81,134.91,133.04,129.09,128.78,127.21,126.94,125.93,125.69,119.15,111.36,110.42,102.93,96.94,72.87,70.58,70.23,70.17,70.00,69.93,69.36,67.38,65.74,57.79,49.99,49.27,48.56,40.61,40.40,40.19,39.98,39.77,39.57,39.36,38.50,37.43,36.34,35.60,34.79,34.01,31.76,31.62,31.15,30.72,30.30,29.46,28.24,26.83,26.21,25.80,25.21,22.88,22.56,21.35,19.63,18.55,18.32,14.99,14.43,8.26.(13C NMR spectrum is shown in fig. 4) HR-MS (ESI): m/z Calc for, [ M+H ] +: 1649.7892, found:1649.7791.
Example 5
Compound 23 (36.9 mg,0.071 mmol) was dissolved in anhydrous DMF under nitrogen, EDCI (16.3 mg,0.085 mmol), compound 1 or Compound 4 a-c (50 mg,0.071 mmol) and DIEA (18.4 mg,0.142 mmol) were added sequentially and reacted at room temperature for 12h. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with EA (15 mL. Times.2). The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Column chromatography of the crude product (DCM/MeOH=30:1→15:1) gave 30mg of a yellow solid in 39.2% yield. A map of compound 24：1H NMR(400MHz,DMSO)δ10.62(s,1H),9.80(d,J＝23.9Hz,2H),8.97(s,1H),8.45(s,1H),8.027.67(m,3H),7.34(d,J＝27.4Hz,4H),6.54(d,J＝16.3Hz,2H),6.34(s,1H),5.76(s,1H),5.35(d,J＝68.6Hz,4H),4.44(d,J＝86.8Hz,2H),3.50(s,3H),3.16(s,4H),2.94(d,J＝35.8Hz,5H),1.95(d,J＝64.9Hz,6H),1.40(s,3H),1.23(s,6H),1.02(s,6H),0.84(d,J＝33.4Hz,12H).(1H NMR as shown in fig. 5 and )13C NMR(101MHz,DMSO)δ172.97,171.79,171.16,169.45,157.73,157.35,156.60,156.55,154.86,151.30,150.51,148.19,146.71,146.58,141.81,140.06,133.03,129.62,129.11,128.79,127.81,127.80,127.23,126.95,126.30,125.90,125.69,119.15,117.85,103.04,102.97,96.93,87.44,72.87,65.74,53.26,50.01,49.23,34.01,31.67,31.63,30.73,30.30,29.48,26.82,25.72,25.52,22.78,21.36,19.78,18.33,18.08,17.73,14.95,8.26.(13C NMR as shown in fig. 6), a map of compound 25a：1H NMR(400MHz,DMSO)δ10.59(s,1H),9.77(d,J＝7.8Hz,2H),8.97(t,J＝5.6Hz,1H),8.31(d,J＝6.4Hz,1H),7.95(d,J＝8.8Hz,2H),7.82(d,J＝9.1Hz,1H),7.66(s,1H),7.37(d,J＝7.9Hz,2H),7.29(d,J＝8.1Hz,2H),6.56(s,1H),6.52(s,1H),6.33(s,1H),5.43(s,2H),5.26(s,2H),4.56-4.51(m,1H),4.29-4.25(m,1H),3.59(t,J＝6.3Hz,2H),3.49(s,2H),3.39(s,3H),3.26(s,1H),3.23(d,J＝5.8Hz,2H),3.18-3.13(m,4H),2.97(s,2H),2.89(d,J＝12.2Hz,3H),2.47-2.40(m,6H),2.02-1.98(m,2H),1.91-1.83(m,2H),1.39(d,J＝6.8Hz,3H),1.23(s,4H),1.03(t,J＝7.1Hz,3H),0.87(dd,J＝13.3,6.3Hz,9H),0.79(d,J＝6.8Hz,6H).(1H NMR as shown in fig. 7 and )13C NMR(101MHz,DMSO)δ173.02,171.90,171.60,170.93,169.86,157.71,157.41,156.63,156.48,154.84,151.22,150.59,148.19,146.68,146.55,141.95,134.43,132.95,130.27,129.72,129.25,128.85,127.72,127.15,126.88,126.32,126.00,125.69,119.10,103.01,102.91,97.14,72.88,69.07,67.08,65.71,61.80,61.46,57.89,53.15,52.93,49.97,49.32,49.06,38.55,36.30,34.04,31.07,30.74,29.42,26.81,25.67,25.46,22.74,22.53,21.29,19.60,18.50,18.25,14.90,8.21.(13C NMR as shown in fig. 8), a map of compound 25b：1H NMR(400MHz,DMSO)δ10.60(s,1H),9.76(s,2H),8.97(t,J＝5.8Hz,1H),8.29(d,J＝6.5Hz,1H),7.94(t,J＝8.3Hz,2H),7.82(d,J＝9.1Hz,1H),7.67(s,1H),7.37(d,J＝8.1Hz,2H),7.29(d,J＝7.4Hz,2H),6.56(s,1H),6.52(s,1H),6.33(s,1H),5.43(s,2H),5.25(s,2H),4.55-4.50(m,1H),4.26(t,J＝7.7Hz,1H),3.59(t,J＝6.3Hz,2H),3.49(s,10H),3.41(t,J＝5.7Hz,2H),3.27-3.23(m,2H),3.16(t,J＝6.6Hz,6H),2.97(s,2H),2.89(d,J＝12.7Hz,3H),2.42(dd,J＝24.2,6.9Hz,8H),2.00(d,J＝6.2Hz,2H),1.86(dd,J＝14.7,7.2Hz,2H),1.39(d,J＝6.7Hz,3H),1.23(s,2H),1.03(t,J＝7.1Hz,3H),0.87(d,J＝4.3Hz,6H),0.84(d,J＝7.0Hz,3H),0.79(d,J＝6.8Hz,6H).(1H NMR as shown in fig. 9 and )13C NMR(101MHz,DMSO)δ172.97,171.83,171.54,170.75,169.64,157.73,157.35,156.61,156.52,154.87,151.27,150.51,148.19,146.70,146.57,141.80,134.46,133.03,129.59,129.08,128.76,127.77,127.20,126.91,126.32,125.92,125.68,119.14,103.03,102.97,96.96,72.87,70.25,70.19,69.98,69.46,67.39,65.73,61.86,61.64,57.80,53.29,53.05,49.98,49.27,49.07,38.54,36.36,34.01,31.14,30.73,29.44,26.81,25.69,25.47,22.78,21.33,19.63,18.54,18.31,14.95,8.25.(13C NMR as shown in fig. 10), a map of compound 25c：1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.81(d,J＝5.8Hz,2H),8.95(s,1H),8.30(d,J＝6.7Hz,1H),7.95(dd,J＝8.8,5.2Hz,2H),7.82(d,J＝9.1Hz,1H),7.41(d,J＝7.3Hz,2H),7.31(d,J＝5.4Hz,3H),6.58(s,1H),6.50(s,1H),6.37(s,1H),5.43(s,2H),5.25(s,2H),4.564.50(m,1H),4.25(t,J＝7.7Hz,1H),3.59(t,J＝6.1Hz,4H),3.48(d,J＝6.4Hz,12H),3.443.39(m,3H),3.25(d,J＝5.9Hz,3H),3.15(d,J＝7.2Hz,6H),2.97(s,3H),2.91(dd,J＝15.8,8.6Hz,2H),2.39(dd,J＝13.6,6.9Hz,3H),1.94(ddd,J＝22.1,13.8,7.0Hz,7H),1.39(d,J＝6.8Hz,3H),1.28(dd,J＝12.0,6.2Hz,1H),1.11(t,J＝7.1Hz,1H),1.03(t,J＝7.1Hz,3H),0.890.84(m,9H),0.80(d,J＝6.8Hz,6H).(1H NMR as shown in fig. 11 and )13C NMR(101MHz,DMSO)δ172.97,171.86,171.52,170.73,158.44,158.14,157.79,157.35,156.62,156.43,154.94,152.81,151.27,150.52,148.17,146.70,146.58,141.80,133.06,129.11,128.79,127.84,127.61,127.20,126.92,126.46,125.89,125.68,124.87,119.14,103.04,96.93,72.87,70.26,70.17,69.99,69.94,69.43,67.39,65.74,57.83,49.29,49.06,48.25,40.62,40.41,40.20,39.99,39.78,39.57,39.37,38.61,37.61,36.35,34.01,31.13,30.73,26.82,25.72,25.51,22.81,21.35,21.01,19.64,18.55,18.35,14.96,14.85,8.26.(13C NMR as shown in fig. 12.
Example 6
In vitro enzyme release experiments of compounds 20, 22 and 25c prepared in the examples of the present invention, the results of enzyme release are shown in fig. 13.
Mu.L of the mother liquor (containing maleimide in the structure of compound 22, 10. Mu.L of 10mM aqueous solution of N-acetylcysteine was added in advance, and incubated in a constant temperature shaker at 37℃for 30 min), and diluted to 500. Mu.L with ABS (pH=5.0). 40. Mu.L of cathepsin B mother liquor was taken, 80. Mu.L of enzyme activation solution was added, and the mixture was placed in a constant temperature shaker at 37℃for activation for 15min. And then adding the activated cathepsin B mother liquor into an ABS solution containing the to-be-detected object, and placing the ABS solution in a constant-temperature oscillator at 37 ℃ for incubation. 40. Mu.L of the sample was taken at 15min,30min,1h,2h,4h,6h,18h, and protein precipitation was performed with 160. Mu.L of cold methanol, and the supernatant was centrifuged at 13000rpm at 4℃to determine if the prodrug was able to effectively release Compound 1 under the conditions of cathepsin B by measuring the content of the payload released in the system by HPLC (n=3) using external standard quantification, the structure of Compound 1 being shown in FIG. 17.
Example 7
The compound 25c prepared by the embodiment of the invention has the growth inhibition effect on subcutaneous transplantation tumor of a human colon cancer HCT-116 nude mouse.
Under aseptic condition, tumor tissue in vigorous growth stage is sheared into about 1.5mm3, and inoculated under armpit skin on right side of nude mice. Nude mice were transplanted with subcutaneous tumor diameter by vernier caliper measurement, and animals were randomly grouped after tumor growth to an average volume of about 90mm 3. 00332-4825mg/kg, once every three days for tail vein injection, for 2 weeks (5 times total, 6 times on the day of the end of the experiment); JJY-07001mg/kg, administered by tail vein injection once every three days for 2 weeks (5 times total, 6 times on the day of the end of the experiment). The Vehicle group was given equal amounts of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b2, where a and b represent length and width, respectively. The relative tumor volume (relative tumor volume, RTV) is calculated from the measured results, the calculation formula being: rtv=vt/V0. Where V0 is the tumor volume measured at the time of divided cage administration (i.e., d 0), and Vt is the tumor volume at each measurement. The evaluation indexes of the antitumor activity are as follows: 1) Relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (TRTV/CRTV) ×100%, TRTV: treatment group RTV; CRTV: negative control RTV; 2) Tumor volume increase inhibition rate GI), the calculation formula is as follows: GI% = [1- (TVt-TV 0)/(CVt-CV 0) ]x100%, TVt is the tumor volume measured each time in the treatment group; TV0 is the tumor volume obtained when therapeutic component is administered in the cage; CVt is the tumor volume measured each time in the control group; CV0 is the tumor volume obtained when the control component is administered in a cage; 3) Tumor weight inhibition rate was calculated as follows: tumor weight inhibition% = (Wc-WT)/wc×100%, wc: tumor weight of control group, WT: treating the tumor weight of the group. After all experiments of the project are finished, the residual compounds are kept for 3 months, and overdue will be treated by self in the room and are no longer responsible for storage.
On the day of the end of the experiment, each group continued to be administered with the compound, plasma was taken 30 minutes after administration, one tumor was frozen, and the main organs (heart, liver, spleen, lung, kidney, stomach, eyeball) were frozen. The experimental results are shown in table 1 below:
TABLE 1 Experimental therapeutic Effect on human colorectal cancer HCT-116 nude mouse transplantable tumor (d 14)
＊p<0.05，＊＊p<0.001
The 25mg/kg dose group of the compound 25C is administrated by intravenous injection once every three days for two weeks and is practically administrated for 6 times, and has extremely obvious inhibition effect on the growth of subcutaneous transplantation tumor of the HCT-116 nude mice with colorectal cancer of human, and the T/C percentage obtained on the 14 th day is 13.01%. On day 7 of the experiment, one mouse in the group lost more than 15% of weight, but considering that the mice were still in a satisfactory state, and the mice in the solvent control group also lost different degrees of weight, so that the drug was not stopped; on the day of the end of the experiment, one mouse in the group lost more than 15% of weight, and two mice lost 33% of weight.
The positive control compound 1mg/kg group was administered once every three days by tail intravenous injection for two weeks, and 6 times of actual administration, and had a partial inhibition effect on the growth of human colorectal cancer HCT-116 nude mice subcutaneous transplantation tumor, and a partial inhibition effect on the growth of human colon cancer HCT-116 nude mice subcutaneous transplantation tumor, and the percentage of T/C obtained on day 14 was 49.19%.
Animal experiment data show that: compound 25c showed excellent anti-tumor activity compared to the positive control, and compound 25c treated mice showed significant reduction in tumor weight. (experimental results see FIGS. 14-16)
The above embodiments are provided to illustrate 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 the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims (6)

1. The 10-amino camptothecine compound prodrug intermediate for cleavage by connective tissue proteinase B is characterized in that the structure is shown in a formula I:
wherein,
R is hydrogen,Represents natural number 0-8 or/>Represents natural number 0-8;
R' is hydrogen or Wherein R' is/>
2. A method for synthesizing a prodrug intermediate of a 10-aminocamptothecin compound cleaved by connective tissue proteinase B, the method comprising the steps of: the compound of the formula II and the compound of the formula I' are dissolved in a first solvent, and the compound of the formula I is obtained by adding a condensing agent and alkali; the reaction scheme is as follows:
wherein,
R is hydrogen,Represents natural number 0-8 or/>Represents natural number 0-8;
R' is hydrogen or Wherein R' is/>
The mol ratio of the compound of the formula II, the compound of the formula I' and the condensing agent to the alkali is 1:1.01-1.2:1.1-2:1.5-3; the alkali is selected from one or more of triethylamine, DMAP, DIPEA, NMP and imidazole; the first solvent is selected from one or more of anhydrous dichloromethane, anhydrous chloroform, anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide and anhydrous N, N-dimethylacetamide; the condensing agent is selected from one or more of HATU, HBTU, EDCI, HOBT, HOAT, DCC, EEDQ, DMTMM, T 3P、T4 P; the reaction temperature is 0-35 ℃; the reaction time is 2-8 hours.
3. The cathepsin B cleavage type 10-amino camptothecin derivative prodrug is characterized in that the structure is shown as a formula III:
wherein,
R 1 is hydrogen or
R is hydrogen,Represents natural number 0-8 or/>Represents natural number 0-8;
R' is hydrogen or Wherein R' is/>
4. A method for synthesizing a cathepsin B cleaved type 10-aminocamptothecin derivative prodrug, which is characterized by comprising the following steps: the compound of the formula IV and the compound of the formula I are dissolved in a second solvent, and condensation reaction is carried out by adding a condensing agent and alkali to obtain a compound of the formula III; the reaction scheme is as follows:
wherein,
R 1 is hydrogen or
R is hydrogen,Represents natural number 0-8 or/>Represents natural number 0-8;
R' is hydrogen or Wherein R' is/>
The alkali is selected from one or more of triethylamine, DMAP, DIPEA, NMP and imidazole; the second solvent is selected from one or more of anhydrous dichloromethane, anhydrous chloroform, anhydrous tetrahydrofuran, anhydrous N, N-dimethylformamide and anhydrous N, N-dimethylacetamide; the condensing agent is selected from one or more of HATU, HBTU, EDCI, HOBT, HOAT, DCC, EEDQ, DMTMM, T 3P、T4 P; the mol ratio of the compound of the formula I to the compound of the formula IV to the condensing agent to the alkali is 1:1.01-1.2:1.1-2:1.5-3; the reaction temperature is 0-30 ℃; the reaction time is 4-12 hours.
5. A pharmaceutical composition comprising a 10-aminocamptothecin compound prodrug intermediate (I) cleaved by cathepsin B according to claim 1 or a cathepsin B cleaved 10-aminocamptothecin derivative prodrug (III) according to claim 4 together with a pharmaceutically acceptable carrier.
6. Use of a 10-aminocamptothecin compound prodrug intermediate (I) cleaved by connective tissue proteinase B according to claim 1, a 10-aminocamptothecin derivative prodrug cleaved by tissue proteinase B according to claim 4 (III) or a pharmaceutical composition according to claim 7 in the preparation of an antitumor drug and an antitumor drug targeted drug delivery system.
CN202410021967.1A 2024-01-08 2024-01-08 10-Amino camptothecine compound cleaved by connective tissue proteinase B and its synthesis and application Pending CN118108786A (en)

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