WO2022022360A1 - 聚乙二醇偶联药物、其制备方法及用途 - Google Patents
聚乙二醇偶联药物、其制备方法及用途 Download PDFInfo
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Definitions
- the invention belongs to the technical field of medicine, and in particular relates to a polyethylene glycol conjugated drug, a preparation method and application thereof.
- the polymer conjugated drug can greatly increase the water solubility of the drug molecule; it can prevent or reduce the agglomeration, immunogenicity and antigenicity of the drug; most small molecule drugs can only remain in the blood circulation for a few minutes, while the polymer
- the conjugated drug can be maintained for tens, hundreds of hours or even longer, which is beneficial to the "enhanced penetration and retention" effect (ie, EPR effect) due to leakage of tumor capillaries; the drug is attenuated due to the increase in hydrodynamic volume
- EPR effect enhanced penetration and retention
- the renal elimination of the drug can protect the drug from being degraded by enzymes, prolong the half-life of the drug in the plasma, and increase the bioavailability of the drug.
- anticancer drugs are highly enriched in cancerous organs, tissues or cells, which greatly reduces the toxic and side effects caused by the full body of small molecule anticancer drugs; It is limited to the endocytosis pathway, which is conducive to the delivery of drugs to the lysosome, thereby avoiding the drug resistance caused by the pumping of p-glycoprotein; stimulating or restoring immune function is conducive to killing cancer cells.
- Polyethylene glycol is the most successful carrier in the field of polymer conjugated drug nanomedicine, and is called the "gold standard" carrier. In the past 30 years, great achievements have been made in PEGylated drug technology.
- PEGylated drugs There are 17 PEGylated drugs approved by the US FDA to enter the market, 1 PEGylated drug has been approved by the Chinese NMPA for marketing, and there are also Nearly 40 new clinical drugs are undergoing Phase I, Phase II, Phase III clinical trials and entering the NDA stage, half of which are PEGylated small molecule drugs.
- small molecules such as folic acid and RGD short peptides to create actively targeted polymer conjugated drugs is a popular strategy for targeting drugs to tumor cells.
- Small molecule targeting accessories have the advantages of low immunogenicity, good storage stability, small size, easy modification, easy coupling with polymer carriers, good compatibility with various organic solvents and water solvents, and low cost. for antibodies and other ligands.
- Folic acid is currently the most widely studied small molecule targeting ligand. It is a vitamin that can specifically bind to folate receptors on the cell surface. Folate receptors cannot enter healthy cells in the circulation, but are in the ovary. It is overexpressed in various cancer cells such as cancer, lung cancer, breast cancer, kidney cancer, endometrial cancer and colon cancer.
- As an active targeting ligand folic acid has the unique advantage that it has a high binding affinity (K d ⁇ 10 -10 M) to the folate receptor. Due to its small size and simple structure, the interference with pharmacokinetics is negligible.
- the active carboxyl groups in the structure of folic acid are highly reactive and can be easily coupled to polymer carriers containing hydroxyl or amino groups without impairing the intrinsic activity of folic acid.
- Certain short peptides can specifically target cancer cells or tumor vascular endothelial cells, and some of these peptides are called cell-targeting peptides, which show a high degree of specificity and affinity for the corresponding target cells through interaction with receptors .
- Cell-targeting peptides have been used in various therapeutic trials, of which the most extensively studied sequence is arginine-glycine-aspartic acid (RGD), the first homing peptide discovered.
- RGD arginine-glycine-aspartic acid
- RGD can bind to up-regulated integrins in tumor cells and vascular endothelial cells, and the RGD-mediated drug delivery system can improve the efficiency of targeted delivery in chemotherapy.
- the recently developed internalizing RGD polypeptide is a tumor-targeting and cell-penetrating cyclic peptide that increases conjugate entry in a neuropeptide-1-dependent, tumor-specific manner Extravascular tumor tissue.
- iRGD-regulated polymer-drug conjugates can significantly improve the efficacy of tumor therapy by enhancing the enrichment and penetration of drugs at tumor sites.
- the present invention aims to solve one of the technical problems in the related art at least to a certain extent.
- the present invention provides a polyethylene glycol conjugated drug, which has excellent tumor suppressing activity.
- the inventors used a unique chemical synthesis method to graft small molecular targeting ligands such as folic acid and iRGD polypeptides and anticancer drugs on the same polyethylene glycol polymer carrier at the same time, so as to improve the efficiency of polyethylene glycol conjugated drugs. Efficacy.
- the polyethylene glycol conjugated drug of the present invention can be prepared efficiently and conveniently.
- the present invention provides the polyethylene glycol conjugated drug represented by formula (A) or a pharmaceutically acceptable salt thereof,
- M is selected from Or PEG m
- PEG m is a single-arm or multi-arm (such as four-arm, eight-arm, preferably four-arm) polyethylene glycol segment
- PEG m is connected with L 1 , L 3 , L 5 or L 6 through carbonyl
- PEG m m has a number average molecular weight of 5k-40k, preferably 5k-10k or 10k-40k, more preferably 5k or 10k;
- j 1 , j 2 , j 3 , j 4 are each independently 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, and not 0 at the same time;
- PEG 1 , PEG 2 , PEG 3 and PEG 4 are single-arm polyethylene glycol segments.
- PEG 1 , PEG 2 , PEG 3 and PEG 4 are respectively connected to L 1 , L 4 , L 5 and L 6 through carbonyl groups.
- the number average molecular weights of PEG 2 , PEG 3 and PEG 4 are each independently 5k-40k, preferably 5k-10k or 10k-40k, more preferably 5k, 10k or 40k;
- L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are each independently a direct bond, When L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are not direct bonds at the same time, and L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M,
- each r 1 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2;
- V 2 is -L 2V -T 2 ;
- V 3 is -P 3 .
- P 3 is -L 3V -T 3 ;
- L 1V , L 2V , and L 3V are independently each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2;
- T 1 , T 2 , T 3 are
- Y 2 , Y 1 , and Y 0 are each independently r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, and each r2 is independently more preferably 1 or 2;
- L V is r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, and each r2 is independently more preferably 1 or 2;
- W 1 , W 2 , and W 3 are each independently
- Z 3 , Z 2 , Z 1 , and Z 0 are each independently each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2, each r4 is independently is 1, 2, 3, 4, 5 or 6, each r 4 is independently preferably 1, 2, 3 or 4, each r 4 is independently more preferably 3 or 4, and r 5 is 1, 2, 3, 4 , 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6, r 6 is 1, 2, 3, 4, 5 or 6, r 6 is preferably 2, 3, 4 or 5, r 6 is more preferably 3 or 4;
- Q is -N-AC
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N, N1, N2 are each independently G or GFLG;
- AC, AC1, AC2 are anticancer drug molecules, preferably, AC, AC1, AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT.
- L 1 , L 2 , L 3 , L 4 , L 5 , L 6 are each independently a direct bond, for When L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are not direct bonds at the same time, and L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M.
- L 1 is Each r 1 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4.
- L 1 is N
- L is Each r2 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2.
- L is N
- L is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4.
- L is N
- L4 is Each r2 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2.
- L4 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L5 is r 1 is 1, 2, 3, 4, 5 or 6, r 1 is preferably 1, 2, 3 or 4, r 1 is more preferably 3 or 4, and r 2 is 1, 2, 3, 4, 5 or 6 , r 2 is preferably 1, 2, 3 or 4, and r 2 is more preferably 1 or 2.
- L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L is a direct bond
- r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4
- r 2 is 1, 2, 3, 4, 5 or 6, r 2 is preferably is 1, 2, 3 or 4, r 2 is more preferably 1 or 2, and when L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M.
- L is a direct bond
- PEG 4 does not exist
- V3 is directly connected to M.
- L 1V , L 2V , L 3V are each independently
- Y 2 , Y 1 , Y 0 are each independently
- LV is
- Z 3 , Z 2 , Z 1 , Z 0 are each independently
- the present invention provides a polyethylene glycol conjugated drug represented by formula (A') or a pharmaceutically acceptable salt thereof,
- M is selected from Or PEG m
- PEG m is a single-arm or multi-arm (such as four-arm, eight-arm, preferably four-arm) polyethylene glycol segment
- PEG m is connected with L 1 , L 3 , L 5 or L 6 through carbonyl
- PEG m m has a number average molecular weight of 5k-40k, preferably 5k-10k or 10k-40k, more preferably 5k or 10k;
- j 1 , j 2 , j 3 , j 4 are each independently 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, and not 0 at the same time;
- PEG 1 , PEG 2 , PEG 3 and PEG 4 are single-arm polyethylene glycol segments.
- PEG 1 , PEG 2 , PEG 3 and PEG 4 are respectively connected to L 1 , L 4 , L 5 and L 6 through carbonyl groups.
- the number average molecular weights of PEG 2 , PEG 3 and PEG 4 are each independently 5k-40k, preferably 5k-10k or 10k-40k, more preferably 5k, 10k or 40k;
- L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are each independently a direct bond, When L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are not direct bonds at the same time, and L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M,
- each r 1 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2;
- V 2 is -L 2V -T 2 ;
- L 1V , L 2V , and L 3V are independently each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2;
- T 1 , T 2 , T 3 are
- Y 2 , Y 1 , and Y 0 are each independently r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, and each r2 is independently more preferably 1 or 2;
- L V is r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, and each r2 is independently more preferably 1 or 2;
- W 1 , W 2 , and W 3 are each independently
- Z 3 , Z 2 , Z 1 , and Z 0 are each independently each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2, each r4 is independently is 1, 2, 3, 4, 5 or 6, each r4 is independently preferably 1, 2, 3 or 4, each r4 is independently more preferably 3 or 4 , and r5 is 1, 2, 3, 4 , 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6, r 6 is 1, 2, 3, 4, 5 or 6, r 6 is preferably 2, 3, 4 or 5, r 6 is more preferably 3 or 4;
- Q is -N-AC
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N, N1, N2 are each independently G or GFLG;
- AC, AC1, AC2 are anticancer drug molecules, preferably, AC, AC1, AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT.
- L 1 , L 2 , L 3 , L 4 , L 5 , L 6 are each independently a direct bond, for When L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are not direct bonds at the same time, and L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M.
- L 1 is Each r 1 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4.
- L 1 is N
- L is Each r2 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2.
- L is N
- L is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4.
- L is N
- L4 is Each r2 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2.
- L4 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L5 is r 1 is 1, 2, 3, 4, 5 or 6, r 1 is preferably 1, 2, 3 or 4, r 1 is more preferably 3 or 4, and r 2 is 1, 2, 3, 4, 5 or 6 , r 2 is preferably 1, 2, 3 or 4, and r 2 is more preferably 1 or 2.
- L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L is a direct bond or r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4, and when L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M .
- L is a direct bond or And when L 6 is a direct bond, PEG 4 does not exist, and V3 is directly connected to M.
- L 1V , L 2V , L 3V are each independently
- Y 2 , Y 1 , Y 0 are each independently
- LV is
- Z 3 , Z 2 , Z 1 , Z 0 are each independently
- the present invention provides the polyethylene glycol conjugated drug represented by formula (I) or a pharmaceutically acceptable salt thereof,
- j 2 is 3 or 4;
- PEG 2 is a single-arm polyethylene glycol segment, PEG 2 is connected to L 4 through a carbonyl group, and the number-average molecular weight of PEG 2 is 5k-40k, preferably 5k-10k or 10k-40k, more preferably 10k;
- L3 is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- L4 is each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- V 2 is -L 2V -T 2 ,
- L 2V is each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Z 3 , Z 2 , Z 1 , and Z 0 are each independently Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2, and r4 is 1, 2, 3, 4, 5 or 6, r 4 is preferably 1, 2, 3 or 4, r 4 is more preferably 3 or 4,
- Q is -N-AC
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N, N1, N2 are each independently G or GFLG, preferably, N, N1 and N2 are GFLG,
- AC, AC1, AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, preferably, AC, AC1, AC2 are each independently LPT or PCB, more preferably, AC1 is LPT, AC and AC2 for the PCB.
- L is N
- L4 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L2V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- Z is r 3 is 1 or 2, and r 4 is 3 or 4.
- Z is
- Z is Each r 3 is independently 1 or 2.
- Z is
- Z 1 is r3 is 1 or 2.
- Z 1 is
- Z 0 is r3 is 1 or 2.
- Z 0 is
- the present invention provides the polyethylene glycol conjugated drug represented by formula (II) or a pharmaceutically acceptable salt thereof,
- M is selected from Or PEG m , PEG m is a single-arm or multi-arm (such as four-arm, eight-arm, preferably four-arm) polyethylene glycol segment, PEG m is connected with L 1 through carbonyl, and the number-average molecular weight of PEG m is 5k-40k , preferably 5k-10k or 10k-40k, more preferably 5k or 10k;
- j 1 is 3 or 4;
- PEG 1 is a single-arm polyethylene glycol segment, PEG 1 is connected to L 1 through a carbonyl group, and the number average molecular weight of PEG 1 is 5k-40k, preferably 5k-10k or 10k-40k, more preferably 5k, 10k or 40k ;
- L1 is each r 1 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- L2 is each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- V 1 is -L 1V -T 1 ,
- L 1V is each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Z 2 , Z 1 , and Z 0 are each independently Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2, and r4 is 1, 2, 3, 4, 5 or 6, r 4 is preferably 1, 2, 3 or 4, r 4 is more preferably 3 or 4, r 5 is 1, 2, 3, 4, 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6, r 6 is 1, 2, 3, 4, 5 or 6, r 6 is preferably 2, 3, 4 or 5, r 6 is more preferably 3 or 4,
- Q is -N-AC
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N, N1, N2 are each independently G or GFLG,
- AC, AC1, AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, preferably, AC, AC1, AC2 are each independently SB7, NPB, SN38, LPT or PCB, more preferably , AC is SB7, NPB or SN38, AC1 is NPB or LPT, and AC2 is PCB.
- L 1 is N
- L is N
- Z is Each r 3 is independently 1 or 2.
- Z is
- Z 1 is Each r 3 is independently 1 or 2, r 4 is 3 or 4, and r 5 is 5 or 6.
- Z 1 is
- Z 0 is Each r 3 is independently 1 or 2, and r 6 is 3 or 4.
- Z 0 is
- the present invention provides a polyethylene glycol conjugated drug represented by formula (III) or a pharmaceutically acceptable salt thereof,
- PEG 3 and PEG 4 are single-arm polyethylene glycol segments, PEG 3 and PEG 4 are respectively connected to L 5 and L 6 through carbonyl groups, and the number-average molecular weights of PEG 3 and PEG 4 are independently 5k-40k, preferably 5k-10k or 10k-40k, more preferably 5k or 10k;
- L 5 is r 2 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- L6 is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- V 3 is -L 3V -T 3 ,
- L 3V is r 2 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Z 2 , Z 1 , and Z 0 are each independently Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2 , and r5 is 1, 2, 3, 4, 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6,
- N is G, or GFLG, preferably, N is G or
- AC is SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, preferably, AC is DOX or PTX.
- L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L6 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L3V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- Z 1 and Z 2 are Each r 3 is independently 1 or 2.
- Z 1 and Z 2 are identical
- Z 0 is r 3 is 1 or 2, and r 5 is 5 or 6.
- Z 0 is
- the present invention provides the polyethylene glycol conjugated drug represented by formula (IV) or a pharmaceutically acceptable salt thereof,
- PEG 3 is a single-arm polyethylene glycol segment, PEG 3 is connected to L 5 through a carbonyl group, and the number-average molecular weight of PEG 3 is 5k-40k, preferably 5k-10k or 10k-40k, more preferably 10k;
- L 5 is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- V3 is or -P 3 .
- Y 0 is r 2 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- L 3V is each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Z 2 , Z 1 , and Z 0 are each independently Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2 , and r5 is 1, 2, 3, 4, 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6,
- Q is -N-AC
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N, N1, N2 are each independently G, GFLG or Preferably, N1 and N2 are GFLG, preferably, N is G or
- AC, AC1, AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, preferably, AC1, AC2 are each independently PCB or LPT, preferably, AC is PTX or DOX.
- L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- Y 0 is
- L3V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- Z is Each r 3 is independently 1 or 2.
- Z is
- Z 1 is r3 is 1 or 2.
- Z 1 is
- Z 0 is Each r 3 is independently 1 or 2 and r 5 is 5 or 6.
- Z 0 is
- the present invention provides the polyethylene glycol conjugated drug represented by formula (IV') or a pharmaceutically acceptable salt thereof,
- PEG 3 is a single-arm polyethylene glycol segment, PEG 3 is connected to L 5 through a carbonyl group, and the number-average molecular weight of PEG 3 is 5k-40k, preferably 5k-10k or 10k-40k, more preferably 10k;
- L 5 is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- V 3 is -L 3V -T 3 ,
- L 3V is each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Z 2 , Z 1 , and Z 0 are each independently each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2,
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N1 and N2 are each independently G or GFLG, preferably, N1 and N2 are GFLG,
- AC1 and AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT.
- AC1 and AC2 are each independently PCB or LPT.
- L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- L3V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- Z is Each r 3 is independently 1 or 2.
- Z is
- Z 1 is r3 is 1 or 2.
- Z 1 is
- Z 0 is r3 is 1 or 2.
- Z 0 is
- the present invention provides the polyethylene glycol conjugated drug represented by formula (V) or a pharmaceutically acceptable salt thereof,
- PEG 1 is a single-arm polyethylene glycol segment, PEG 1 is connected to L 1 through a carbonyl group, and the number-average molecular weight of PEG 1 is 5k-40k, preferably 5k-10k or 10k-40k, more preferably 10k;
- L1 is r 1 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4,
- L2 is r 2 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Y 1 and Y 0 are each r is independently 1, 2 , 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- L V is r 2 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Z 1 and Z 0 are independently Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2, and r4 is 1, 2, 3, 4, 5 or 6, r 4 is preferably 1, 2, 3 or 4, r 4 is more preferably 3 or 4,
- Q1 is -N1-AC1
- Q2 is -N2-AC2
- N1 and N2 are each independently G or GFLG, preferably, N1 and N2 are GFLG,
- AC1 and AC2 are each independently SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT.
- AC1 and AC2 are each independently PCB or LPT. More preferably, AC1 is LPT and AC2 is PCB.
- L 1 is N
- L is N
- Y 1 , Y 0 are
- LV is
- Z 1 is Each r 3 is independently 1 or 2, and r 4 is 3 or 4.
- Z 1 is
- Z 0 is r3 is 1 or 2.
- Z 0 is
- the present invention provides a polyethylene glycol conjugated drug represented by formula (VI) or a pharmaceutically acceptable salt thereof,
- PEG 3 and PEG 4 are single-arm polyethylene glycol segments, PEG 3 and PEG 4 are respectively connected to L 5 and L 6 through carbonyl groups, and the number-average molecular weights of PEG 3 and PEG 4 are independently 5k-40k, preferably 5k-10k or 10k-40k, more preferably 10k;
- L 5 and L 6 are independently Each r 1 is independently 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 3 or 4; r 2 is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, more preferably 1 or 2,
- Y 2 , Y 1 , and Y 0 are each independently r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, each r2 is independently more preferably 1 or 2,
- L V is r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, each r2 is independently more preferably 1 or 2,
- Z 2 , Z 1 , Z 0 are each independently or Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2 , and r5 is 1, 2, 3, 4, 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6,
- N is G or GFLG
- AC is SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, preferably, AC is SB7, LPT, PTX, DOX or AXT.
- L 5 , L 6 are each independently
- Y 2 , Y 1 are Each r 2 is independently 1 or 2.
- Y 2 , Y 1 are
- Y 0 is r 0 is 5 or 6, and each r 2 is independently 1 or 2.
- Y 0 is
- LV is
- Z is Each r 3 is independently 1 or 2 and r 5 is 5 or 6.
- Z is
- Z 1 is r3 is 1 or 2.
- Z 1 is
- Z 0 is Each r 3 is independently 1 or 2.
- Z 0 is
- the present invention provides a polyethylene glycol conjugated drug represented by formula (VI') or a pharmaceutically acceptable salt thereof,
- PEG 3 and PEG 4 are single-arm polyethylene glycol segments, PEG 3 and PEG 4 are respectively connected to L 5 and L 6 through carbonyl groups, and the number-average molecular weights of PEG 3 and PEG 4 are independently 5k-40k, preferably 5k-10k or 10k-40k, more preferably 10k;
- L 5 and L 6 are independently r 1 is 1, 2, 3, 4, 5 or 6, r 1 is preferably 1, 2, 3 or 4, r 1 is more preferably 3 or 4, and r 2 is 1, 2, 3, 4, 5 or 6 , r 2 is preferably 1, 2, 3 or 4, r 2 is more preferably 1 or 2,
- Y 2 , Y 1 , and Y 0 are each independently r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, each r2 is independently more preferably 1 or 2,
- L V is r 0 is 1, 2, 3, 4, 5 or 6, r 0 is preferably 3, 4, 5 or 6, r 0 is more preferably 5 or 6, and each r 2 is independently 1, 2, 3, 4, 5 or 6, each r2 is independently preferably 1, 2, 3 or 4, each r2 is independently more preferably 1 or 2,
- Z 2 , Z 1 , Z 0 are each independently or Each r3 is independently 1, 2, 3 , 4, 5 or 6, each r3 is independently preferably 1, 2, 3 or 4 , each r3 is independently more preferably 1 or 2 , and r5 is 1, 2, 3, 4, 5 or 6, r 5 is preferably 3, 4, 5 or 6, r 5 is more preferably 5 or 6,
- N is G or GFLG
- AC is SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, preferably AC is SB7, LPT, PTX, DOX or AXT, or preferably AC is LPT, PTX, DOX or AXT.
- L 5 , L 6 are each independently
- Y 2 , Y 1 are Each r 2 is independently 1 or 2.
- Y 2 , Y 1 are
- Y 0 is r 0 is 5 or 6, and each r 2 is independently 1 or 2.
- Y 0 is
- LV is
- Z is Each r 3 is independently 1 or 2 and r 5 is 5 or 6.
- Z is
- Z 1 is r3 is 1 or 2.
- Z 1 is
- Z 0 is Each r 3 is independently 1 or 2.
- Z 0 is
- the present invention provides a polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, wherein the polyethylene glycol conjugated drug is selected from:
- the present invention provides an intermediate for preparing the aforementioned polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, the intermediate is selected from the following:
- the present invention provides a method for preparing the aforementioned polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, comprising:
- the present invention provides a method for preparing the aforementioned polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, comprising:
- the present invention provides a method for preparing the aforementioned polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, comprising:
- the present invention provides a method for preparing the aforementioned polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, comprising:
- the present invention provides a method for preparing the aforementioned polyethylene glycol conjugated drug or a pharmaceutically acceptable salt thereof, comprising:
- the present application provides a pharmaceutical composition containing the polyethylene glycol conjugated drug of the present invention or a pharmaceutically acceptable salt thereof in an effective amount for treating and/or preventing diseases; the combination
- the drug also contains one or more pharmaceutically acceptable adjuvants, such as carriers and/or excipients.
- the carriers and/or excipients include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum albumin such as human serum albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate , Partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyethylene Pyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, polyethylene-polyoxypropylene block polymer and lanolin.
- ion exchangers alumina, aluminum stearate, lecithin
- serum albumin such as human serum albumin
- buffer substances such as phosphate, glycerol, sorbic acid, potassium
- the pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form.
- the pharmaceutical composition may also be administered to an individual in need of such treatment by any suitable mode of administration, eg, oral, parenteral, rectal or pulmonary administration.
- the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions , syrup, etc.
- suitable fillers, binders, disintegrants, lubricants and the like can be added.
- parenteral administration the pharmaceutical composition can be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection.
- the injection When the injection is prepared, it can be produced by the conventional method in the existing pharmaceutical field. When the injection is prepared, no additive can be added, or an appropriate additive can be added according to the properties of the drug.
- the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be formulated into an inhaler or a spray or the like.
- the pharmaceutical composition of the present invention can be formulated into injections, such as injection solutions.
- physiological saline is used as the carrier of the injection.
- the present application provides the use of the polyethylene glycol conjugated drug of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating and/or preventing a disease (eg, cancer) , the disease is the disease treated by the active ingredient in the polyethylene glycol conjugated drug.
- a disease eg, cancer
- the present application provides a method of treating and/or preventing a disease (eg, cancer), comprising administering to an individual in need thereof an effective amount of the polyethylene glycol conjugated drug of the present invention or its Pharmaceutically acceptable salts.
- Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
- the present application provides the polyethylene glycol conjugated drug of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of diseases (eg, cancer).
- diseases eg, cancer
- cancer refers to a cell proliferative disease state, including but not limited to: colon cancer, leukemia, lymphoma, bladder cancer, bone cancer, brain tumor, medulloblastoma, glioma, breast cancer, adenoma/ Carcinoid, adrenocortical carcinoma, pancreatic islet cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, colorectal cancer, skin cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, head and neck cancer, liver cancer, melanoma, card Posterior sarcoma, kidney cancer, oral cancer, lung cancer, nasopharyngeal cancer, neuroblastoma, ovarian cancer, pancreatic cancer, thyroid cancer, parathyroid penile cancer, prostate cancer, urethral cancer, vaginal cancer, vulvar cancer, anal cancer , sarcoma, etc., including metastasis of the aforementioned cancers.
- colon cancer colon cancer
- “individual” includes humans or non-human animals.
- Exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
- non-human animals includes all vertebrates, such as non-mammals (eg birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs, cats, cows, pigs, etc.).
- the term "effective amount” refers to an amount of a compound that, when administered, will alleviate to some extent one or more symptoms of the condition being treated.
- treating means reversing, alleviating, inhibiting the progression of a disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such disorder or condition or such one or more symptoms of a disorder or condition.
- the polyethylene glycol conjugated drugs of the present invention use amino acids or polypeptides as the connecting chain, and dicarboxylic acids or polycarboxylic acids with amino groups (for example, natural amino acids with two carboxyl groups) or with diamino or polycarboxylic acids.
- Amino carboxylic acids (eg, natural amino acids with two amino groups) or polycarboxylic acids are bridges that couple together multiple identical or different drug molecules through the formation of amide bonds.
- the types, ratios and loadings of drugs can be adjusted.
- the activated PEG reacts with an amino group on the backbone through a carboxyl group to form an amide bond.
- the active ingredient suitable for coupling with polyethylene glycol can be a drug molecule with at least one amino, hydroxyl, carboxyl or acyl group, for example, one with at least one amino, hydroxyl, carboxyl or acyl group has antitumor activity , such as SB7, NPB, SN38, LPT, PCB, DOX, PTX or AXT, which represent the following meanings:
- FA stands for folic acid
- its structural formula is The connection site of FA and other parts of the overall structure of the polyethylene glycol conjugated drug is which is location shown.
- PPT-iRGD The structural formula of PPT-iRGD is The connection site of PPT-iRGD and other parts of the overall structure of the polyethylene glycol conjugated drug is the terminal sulfhydryl group which is location shown.
- connection sites of the following drug molecules and other parts of the overall structure of the polyethylene glycol conjugated drug are shown in the following table, specifically: location shown.
- PEG polyethylene glycol
- each arm of the multi-arm polyethylene glycol preferably has the same degree of polymerization.
- the molecular weight means the total molecular weight of the individual arms.
- the letter m or n in the subscript of the polyethylene glycol repeating unit represents the degree of polymerization of polyethylene glycol, and when the polyethylene glycol is multi-arm polyethylene glycol, the letter m or n represents each The degree of polymerization of the arms.
- each independently and “...and each independently” used throughout this document are interchangeable and should be construed broadly, which It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other.
- variable being a "direct bond” means that the linking group is absent.
- pharmaceutically acceptable salts of the compounds of the present invention include acid and base addition salts of the compounds.
- acid and base addition salts for example, hydrochloride, hexafluorophosphate, meglumine and the like.
- the wavy line in the structural formula means the position where other groups are bonded to the structure represented by the formula.
- FIG. 1 is a schematic diagram showing the growth trend of each group of tumors according to the embodiment of the present invention.
- FIG. 2 shows a schematic diagram of the tumor weight inhibition rate of each group in the examples of the present invention.
- the sources and structures of some of the raw materials are as follows:
- 1,2-bis(2-aminoethoxy)ethane 50g, 337.2mmol, purchased from TCI
- triethylamine 37.6mL, 270mmol
- the reaction was placed under -5 degrees Celsius and stirred
- Di-tert-butyl dicarbonate (56.5g, 270mmol, purchased from Adamas) was dissolved in dichloromethane and then added dropwise to the flask, the dropwise addition was completed, stirring was continued for 10 minutes, the reaction was completed, and silica gel powder (60g) was added.
- Fmoc-Glu(OtBu)-OH (4.93g, 11.5859mmol, purchased from Ark Pharm), 37-160 (2.74g, 11.0342mmol), HBTU (6.3g, 16.5512mmol), HOBT (2.2g, 16.5512mmol) It was added to a 500mL flask, dissolved with DMF (50mL), and the reaction was stirred at 0 degrees Celsius for about 10 minutes, and then DIEA (8.2mL, 49.6537mmol) was slowly added dropwise. After the dropwise addition, the reaction continued at 0 Stir overnight in degrees Celsius.
- reaction solution was transferred to a 1L separatory funnel, deionized water (200 mL) and ethyl acetate (200 mL) were added, shaken, and extracted.
- the aqueous phase was washed with ethyl acetate (150 mL ⁇ 2), the organic phases were combined, washed with saturated brine (200 mL ⁇ 2), concentrated and evaporated to dryness, and dried in a vacuum oven to obtain product 36-134: 7.235 g.
- Diethylene glycol amine (25.84mL, 260.59mmol, purchased from TCI) was put into a 1L flask, dichloromethane (50mL), triethylamine (72.64mL, 521.18mmol) were added, placed at 0 degrees Celsius and stirred for 1 hour. After being dissolved in dichloromethane, tert-butyl dicarbonate was slowly added dropwise to the flask, the dropwise addition was completed, and the stirring was continued at 0 degrees Celsius overnight.
- reaction solution was concentrated to a minimum amount, silica gel powder (50 g) was added, and it was evaporated to dryness to obtain a powdery solid, which was dry-loaded, subjected to column chromatography, and eluted with a mixed solution of 50%-60% ethyl acetate in petroleum ether, Product 37-88:53.4861g was obtained.
- reaction solution was transferred to a 1L separatory funnel, deionized water (200mL) and ethyl acetate (200mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 1), Combine the organic phases, concentrate and evaporate to dryness, add methanol (30 mL) and dichloromethane (120 mL) to dissolve, add silica gel powder (100 g), evaporate to dryness to obtain a powdery solid, dry sample, column chromatography, use 20% ethyl acetate The mixed solution of ester and petroleum ether was eluted to obtain product 37-148: 52.1 g with a yield of 68.6%.
- Boc-Glu-OH (20.0 g, 80.89 mmol, purchased from Ark Pharm), HBTU (92.02 g, 242.66 mmol), HOBT (32.8 g, 242.66 mmol) and H-Glu(OBn) 2 ⁇ TsOH (84.861 g, 161.8 mmol, purchased from Ark Pharm) was added to a 1000 mL flask, then DMF (200 mL) was added to dissolve it, the reaction was stirred at -5 degrees Celsius for about 30 minutes, and then DIEA (120.32 mL, 728 mmol) was slowly added dropwise. , After the dropwise addition, the reaction continued to be stirred at -5 degrees Celsius for 1 hour, and finally transferred to room temperature and stirred overnight.
- reaction solution was transferred to a 2L separatory funnel, saturated sodium bicarbonate solution (600mL) and ethyl acetate (300mL) were added for extraction, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 1), and the organic The organic phase was concentrated with saturated brine (200 mL ⁇ 2), evaporated to dryness, and the product 35-82:70 g was obtained.
- reaction solution was first transferred to a 2L separatory funnel, saturated sodium bicarbonate solution (500mL) and ethyl acetate (300mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL).
- ⁇ 1 Wash combine the organic phases, concentrate to a minimum amount, add silica gel powder, evaporate to dryness, dry sample, column chromatography, eluted with 50%-70% ethyl acetate in petroleum ether mixed solution to obtain 35-85 : 51 g, yield: 69%.
- reaction was finished, the reaction solution was concentrated, ethyl acetate (300mL) and saturated sodium bicarbonate solution (300mL) were added, a large amount of air bubbles were generated, the solid sodium bicarbonate was continued to be added, and the pH was greater than 7, then extracted, and the aqueous phase was extracted with ethyl acetate (200mL ⁇ 1) washed, combined the organic phases and evaporated to dryness to obtain 35-86: 18.2g, yield: 86%.
- reaction solution was first transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (300mL) and ethyl acetate (200mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL).
- 35-88 (7.0g, 5.1413mmol) was put into a 250mL flask, dichloromethane (20mL) was added to dissolve it, trifluoroacetic acid (5.7270mL, 77.1191mmol) was added under stirring, and the reaction was stirred at room temperature overnight .
- reaction solution was concentrated, transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (300 mL) and ethyl acetate (200 mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate Ester (150mL ⁇ 2) was washed, the organic phases were combined, washed with saturated brine (200mL ⁇ 2), concentrated and evaporated to dryness to obtain product 35-89:6.4853g.
- 35-89 (4.2g, 3.33mmol) was put into a 250mL flask, DMF (30mL) was added to dissolve it, DIEA (4.4mL, 26.64mmol) was added dropwise, the addition was completed, stirred for 1 hour, and then added with diacetyl Anhydride (0.9997 g, 9.99 mmol), the reaction was stirred at room temperature overnight.
- reaction solution was transferred to a 1L separatory funnel, deionized water (200 mL) and ethyl acetate (200 mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200 mL ⁇ 4), The organic phases were combined, washed with saturated brine (200 mL ⁇ 2), concentrated and evaporated to dryness to obtain product 37-165:4 g, yield: 89%.
- reaction solution was transferred to a 1L separatory funnel, saturated brine (200 mL) and ethyl acetate (250 mL) were added, shaken, extracted, concentrated and evaporated to dryness, and methanol (20 mL) and dichloromethane (100 mL) were added. ) was dissolved, silica gel powder (20 g) was added, evaporated to dryness to obtain a powdery solid, dry loading, column chromatography, eluted with a mixed solution of 4%-7% methanol in dichloromethane, and dried in a vacuum oven to obtain product 37 -166: 3.9 g, yield: 75%.
- Boc-Leu-OH.H2O (40g, 160.44mmol, purchased from Enoch), Gly-OBn.TsOH (56.837g, 168.462mmol, purchased from Ark pharm), HBTU (66.93g, 176.48mmol), HOBT ( 23.85g, 176.48mmol) was added to the 1000mL flask, DMF (250mL) was added to dissolve it, the reaction was placed at -5 degrees Celsius and stirred for about 20 minutes, then DIEA (145.85mL, 882.4356mmol) was slowly added dropwise, and after the dropwise addition was completed. , continued stirring at -5°C for 1 hour, then moved to room temperature and stirred overnight.
- reaction solution was transferred to a 2L separatory funnel, saturated sodium bicarbonate solution (250mL) and ethyl acetate (300mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was ethyl acetate (200mL x 3) Wash, combine the organic phases, wash the organic phase with saturated brine (200mL x 2), concentrate and evaporate to dryness, dry sample, column chromatography, eluted with a mixed solution of 30%-40% ethyl acetate in petroleum ether to obtain Product 37-53: 60.7 g.
- reaction solution was transferred to a 2L separatory funnel, saturated sodium bicarbonate solution (350mL) and ethyl acetate (300mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was ethyl acetate (200mL x 3) Wash, combine the organic phases, wash the organic phase with saturated brine (250mL x 2), concentrate and evaporate to dryness to obtain product 37-56: 84g.
- reaction solution was transferred to a 2L separatory funnel, saturated sodium bicarbonate solution (300mL) and ethyl acetate (350mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with (200mL x 3) and combined
- the organic phase was washed with saturated brine (250mL ⁇ 2), the organic phase was placed at room temperature for 1.5 hours, a solid was precipitated, filtered, and the filter cake was washed with ethyl acetate: petroleum ether (3:7) (150mL ⁇ 5) to obtain the product 37-62: 72.8 g.
- Boc-Glu-OH (5.7864 g, 23.4032 mmol, purchased from Ark pharm), 37-149 (24.85 g, 51.4871 mmol), HBTU (26.626 g, 70.2096 mmol), HOBT (9.4874 g, 70.2096 mmol) were added to 500 mL In the flask, after dissolving with DMF (150 mL), the reaction was stirred at -5 degrees Celsius for about 10 minutes, and then DIEA (34.8 mL, 210.628 mmol) was slowly added dropwise. After the addition, the reaction continued at -5 degrees Celsius. Stir for 1 hour, then move to room temperature and stir overnight.
- reaction solution was transferred to a 1L separatory funnel, saturated sodium bicarbonate (200 mL) and ethyl acetate (300 mL) were added, shaken and extracted.
- the aqueous phase was washed with ethyl acetate (150 mL ⁇ 1), the organic phases were combined, concentrated and evaporated to dryness, methanol (20 mL) and dichloromethane (100 mL) were added to dissolve, silica gel powder (50 g) was added, and the solid was evaporated to dryness.
- Boc-Gly-OH (3.4310 g, 19.5858 mmol, purchased from Ark Pharm), 37-154 (17.5 g, 16.3215 mmol), HBTU (9.2847 g, 24.4823 mmol), HOBT (3.3083 g, 24.4823 mmol) were added to 1000 mL In the flask, after dissolving with DMF (150 mL), the reaction was stirred at -5 degrees Celsius for about 10 minutes, and then DIEA (12.14 mL, 73.4468 mmol) was slowly added dropwise. After the addition, the reaction continued at -5 degrees Celsius. Stir for 1 hour, then move to room temperature and stir overnight.
- reaction solution was transferred to a 1 L separatory funnel, saturated sodium bicarbonate solution (200 mL) and ethyl acetate (300 mL) were added, shaken, and extracted.
- the aqueous phase was washed with ethyl acetate (150 mL ⁇ 1), the organic phases were combined, concentrated and evaporated to dryness, methanol (20 mL) and dichloromethane (100 mL) were added to dissolve, silica gel powder (50 g) was added, and the solid was evaporated to dryness.
- Method loading column chromatography, eluted with a mixed solution of 20%-40% petroleum ether in ethyl acetate, collected and concentrated, and dried in a vacuum oven to obtain product 45-57: 7.1 g, yield: 31%.
- reaction solution was concentrated to a minimum amount, methyl tert-butyl ether (150 mL) was added, a solid was precipitated, suction filtration, and the filter cake was washed with methyl tertiary butyl ether (50 mL x 3), and then methanol (30 mL) di Chloromethane (120mL) solution was dissolved, silica gel powder (15g) was added, evaporated to dryness, it was a powdery solid, dry loading, column chromatography, washed with a mixed solution of 1% ammonia water and 5%-10% methanol in dichloromethane Take off, collect and concentrate, evaporate to dryness to solid, and dry in a vacuum oven to obtain product 37-176: 1.143 g with a yield of 61%.
- n-hexane (150 mL) and methyl tert-butyl ether (50 mL) were added, layering appeared, the upper layer liquid was poured, and the lower oily substance was continued to add n-hexane (200 mL) and methyl tert-butyl ether (100 mL), so Repeat 3 times to form a viscous oily substance, dissolve with methanol (30 mL) and dichloromethane (120 mL) solution, add silica gel powder (15 g), evaporate to dryness, and form a powdery solid, dry sample, column chromatography, use The mixed solution of 1% ammonia water and 7%-10% methanol in dichloromethane was eluted, collected and concentrated, evaporated to dryness, and dried in a vacuum oven.
- Boc-GFLG-OBn 14.95g, 25.654mmol, obtained according to the preparation method of 37-62 was added to the reactor, 10% Pd/C (0.300g) was added, DMF (40mL) was added to dissolve it, and a water pump was used to dissolve it.
- the air in the reaction kettle was evacuated to form a vacuum, and hydrogen was introduced, and the hydrogen pressure was 0.16 MPa, then the hydrogen was released, the water pump was pumped to a vacuum, and then the hydrogen was introduced. Repeat this for 3 times, and finally the hydrogen was introduced. Stir overnight. After the reaction was completed, the reaction solution was filtered with celite, the filter cake was washed with DMF (20 mL ⁇ 3), and the DMF solutions were combined to serve as the raw material for the next step.
- reaction solution was concentrated to 10 mL, methyl tert-butyl ether (200 mL) was added, powder was precipitated, suction filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL ⁇ 3), and then (20% methanol: 80% dichloromethane) solution (200 mL) was dissolved, silica gel powder (60 mL) was added, evaporated to dryness to form a powder solid, dry loading, column chromatography, mixed with 0.5% ammonia water: 2%-5% methanol in dichloromethane The solution was eluted, collected, concentrated and evaporated to dryness to obtain product 36-98: 8.5 g, yield: 91.4%.
- reaction solution was transferred to a 1L separatory funnel, NaHCO 3 (200 mL) and ethyl acetate (200 mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200 mL ⁇ 2) and combined The organic phase was washed with saturated brine (200 mL ⁇ 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (100 mL ⁇ 2), and evaporated to dryness to obtain 36-134: 9.74 g.
- Fmoc-Lys(Boc)-OH (2 g, 4.2686 mmol), NH 2 -Gly-OBn.TsOH (1.44 g, 4.2686 mmol, purchased from Enoch), HBTU (2.4 g, 6.4029 mmol), HOBT (0.9 g, 6.4029 mmol) was put into 500 mL, the reaction was placed at -5 ° C and stirred for about 20 minutes, then DIEA (3.2 mL, 19.2086 mmol) was slowly added dropwise, and the reaction was continued at -5 ° C for 1 hour, and then the reaction was moved to Stir overnight at room temperature.
- reaction solution was transferred to a 1L separatory funnel, NaCl (200 mL) and ethyl acetate (200 mL) were added, and extraction was performed to obtain an organic phase.
- the aqueous phase was washed with ethyl acetate (200 mL ⁇ 2), and the organic
- the organic phase was washed with saturated brine (200 mL ⁇ 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (100 mL ⁇ 2), and evaporated to dryness to obtain 36-135: 4.04 g.
- reaction solution was transferred to a 1L separatory funnel, saturated sodium chloride (300mL) and ethyl acetate (200mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 2) , the organic phases were combined, the organic phase was washed with saturated brine (200 mL ⁇ 2), evaporated to dryness, dissolved in methanol:dichloromethane (1:5), added with 40 ml of silica gel powder, evaporated to dryness, and applied to the column by dry method. After separation, gradient elution was performed with (5%-10% methanol: 95%-90% dichloromethane), collection and concentration to obtain product 36-140: 1.9 g, yield: 73%.
- reaction solution was transferred to a 1L separatory funnel, NaHCO 3 (200 mL) and ethyl acetate (200 mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200 mL ⁇ 2) and combined The organic phase was washed with saturated brine (200ml ⁇ 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (100ml ⁇ 2), evaporated to dryness to obtain 36-143: 14g, yield: 92.8% .
- reaction solution was transferred to a 1L separatory funnel, saturated sodium bicarbonate (200mL) and ethyl acetate (200mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 2) , combine the organic phases, wash the organic phase with saturated brine (200mL ⁇ 2), evaporate to dryness, add methanol:dichloromethane (1:5) to dissolve, add 30ml silica gel powder, evaporate to dryness, dry sample, column layer After analysing, carry out gradient elution with (2%-4% methanol: 98%-96% dichloromethane), collect and concentrate to obtain product 36-144: 1.398g, yield: 59.39%.
- reaction solution was concentrated to 10 mL, methyl tert-butyl ether (200 mL) was added, powder was precipitated, suction filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL ⁇ 3), and then (20% methanol: 80% dichloromethane) solution (200 mL) was dissolved, silica gel powder (60 mL) was added, evaporated to dryness to obtain a powder solid, dry loading, column chromatography, mixed with 1% ammonia water: 5%-10% methanol in dichloromethane The solution was eluted, collected, concentrated and evaporated to dryness to obtain the product 36-145: 6.2 g with a yield of 92.1%.
- reaction solution was transferred to a 1L separatory funnel, NaHCO 3 (200 mL) and ethyl acetate (200 mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200 mL ⁇ 2) and combined The organic phase was washed with saturated brine (200ml ⁇ 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (100ml ⁇ 2), evaporated to dryness to obtain product 36-161:18g.
- reaction solution was concentrated to 10 mL, methyl tert-butyl ether (200 mL) was added, powder was precipitated, suction filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL ⁇ 3), and then (20% methanol: 80% dichloromethane) solution (200 mL) was dissolved, silica gel powder (100 mL) was added, evaporated to dryness to form a powder solid, dry loading, column chromatography, using 0.5%-1% ammonia water: 4%-7% methanol The mixed solution of methyl chloride was eluted, collected, concentrated and evaporated to dryness to obtain the product 36-169: 9.4 g with a yield of 84.7%.
- 35-93 (0.61 g, 0.5772 mmol), 36-169 (6 g, 2.8858 mmol), HBTU (1.3 g, 3.4630 mmol), HOBT (0.46 g, 3.4630 mmol) were added to a 250 mL flask, and 30 mL of DMF was added to make it Dissolved, placed at -5 degrees Celsius and stirred for 30 min, and then slowly added DIEA (1.7 mL, 10.3889 mmol) dropwise. After the dropwise addition was completed, the reaction was continued for 1 hour, and then the reaction was stirred at room temperature overnight.
- reaction solution was concentrated to 10 mL, methyl tert-butyl ether (200 mL) was added, powder was separated out, suction filtered, and the filter cake was washed with methyl tertiary butyl ether (50 mL ⁇ 3), and then (20% methanol: 80% dichloromethane) solution (200 mL) was dissolved, silica gel powder (40 mL) was added, evaporated to dryness to obtain a powder solid, dry loading, column chromatography, mixed with 1% ammonia water: 5%-10% methanol in dichloromethane The solution was eluted, collected, concentrated and evaporated to dryness to obtain the product 36-174: 4 g with a yield of 70.5%.
- reaction solution was concentrated to 10 mL, methyl tert-butyl ether (200 mL) was added, powder was separated out, suction filtered, and the filter cake was washed with methyl tertiary butyl ether (50 mL ⁇ 3), and then (20% methanol: 80% dichloromethane) solution (200 mL) was dissolved, silica gel powder (40 mL) was added, evaporated to dryness to form a powder solid, dry loading, column chromatography, mixed with 1% ammonia water: 5%-8% methanol in dichloromethane The solution was eluted, collected, concentrated and evaporated to dryness to obtain the product 36-238: 2.3 g with a yield of 39.4%.
- n-hexane 100 mL ⁇ 3 was added for sedimentation, the oily solid in the lower layer was dissolved with a small amount of dichloromethane, methyl tert-butyl ether was added, the solid was precipitated, and the filter cake was filtered with methyl tert-butyl ether (50 mL ⁇ 3).
- the filter cake was washed with methanol/dichloromethane (1:5). ) was dissolved, 30 mL of silica gel powder was added, evaporated to dryness, dry loading, column chromatography, eluted with (1% ammonia water: 5%-10% methanol: 94%-89% dichloromethane), and collected The filtrate was concentrated and evaporated to dryness to obtain the product 36-253: 0.58g with a yield of 54.7%.
- Gly-OtBu.HCl (3.6 g, 21.6 mmol, purchased from Accela), HBTU (12.28 g, 32.4 mmol), HOBT (4.4 g, 32.4 mmol) and Fmoc-Glu(OBn)-OH (10.12 g, 21.6 mmol) were combined , purchased from Ark Pharm) was added to a 500mL round-bottomed flask, dissolved with DMF (100mL), the reaction was stirred at 0 degrees Celsius for about 30 minutes, and then DIEA (19.6mL, 118.8mmol) was slowly added dropwise, and the addition was completed. After that, the reaction was continued to stir overnight at 0 °C.
- reaction solution was first transferred to a 1L separatory funnel, saturated brine (300mL) and ethyl acetate (200mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 1 ) was washed, the organic phases were combined and evaporated to dryness to obtain 43-124: 12.37g.
- reaction solution was first transferred to a 1L separatory funnel, saturated brine (300mL) and ethyl acetate (200mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 1 ) was washed, the organic phases were combined and evaporated to dryness to obtain 43-135: 6.4g.
- Pentatetramine.disulfate (1.0g, 3.05mmol, purchased from Kanglong Chemical), HBTU (6.94g, 18.3mmol), HOBT (2.47g, 18.3mmol) and tert-butyl succinate (3.72g) g, 21.34 mmol) was added to a 250 mL round-bottomed flask, dissolved with DMF (30 mL), the reaction was stirred at -5 degrees Celsius for about 30 minutes, and then DIEA (9.07 mL, 54.9 mmol) was slowly added dropwise, and the dropwise addition was completed. After that, the reaction was continued to stir at 15°C for 1 hour, then moved to room temperature and stirred overnight.
- reaction solution was first transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (300mL) and ethyl acetate (200mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL).
- ⁇ 1 Wash combine the organic phases, evaporate to dryness, add methanol (40 mL) and dichloromethane (160 mL) to dissolve, add silica gel powder (30 g), evaporate to dryness to obtain a powdery solid, dry sample, column chromatography, use The mixed solution of 3%-6% methanol in dichloromethane was eluted to obtain product 43-134: 2.3g.
- reaction solution was first transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (300mL) and ethyl acetate (200mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL).
- Boc-GFLG-OBn (9.9g, 17mmol, synthesized according to the method of 37-62) was added to the hydrogenation reactor, 10% Pd/C (0.025g) was added, DMF (40mL) was added to dissolve it, and hydrogen was introduced, The hydrogen pressure was 2.1 MPa and the reaction was stirred at room temperature overnight. After the reaction, the reaction solution was filtered with diatomaceous earth, and the diatomaceous earth was washed 3 times with DMF (20 mL x 3), and the filtrate was loaded into a 500 mL round-bottomed flask as the raw material for the next step.
- SB-743921 (8.000g, 15.4718mmol, referred to as SB7, purchased from Nanjing Yaoshi), HBTU (8.814g, 23.2078mmol), HOBT (3.136g, 23.2078mmol) were added to the solution containing 43-116 (7.3g, 17mmol).
- DMF 110 mL
- DIEA 11.5 mL, 69.75 mmol
- the dropwise addition was completed in 10 minutes, and the reaction was continued at -5 degrees Celsius for 1 hour, and then the reaction was placed in Stir overnight at room temperature.
- reaction solution was transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (250mL) and ethyl acetate (300mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was treated with ethyl acetate (200mL x 2) Wash, combine the organic phases, wash the organic phase with saturated brine (200mL x 2), evaporate to dryness to solid, and dry in a vacuum oven to obtain product 43-119:15.37g.
- reaction solution was transferred to a 1L separatory funnel, saturated brine (200mL) and ethyl acetate (300mL) were added, and extraction was performed to obtain an organic phase, which was washed with saturated brine (200mLx2) and evaporated to dryness to solid to obtain product 35-100:11.41g.
- reaction solution was transferred to a 1L separatory funnel, saturated brine (200mL) and ethyl acetate (250mL) were added, and extraction was performed to obtain an organic phase, which was washed with saturated brine (200mLx2) and evaporated to dryness to solid to obtain product 35-102: 11.7g.
- 35-102 (11.7 g, 5.72 mmol) was added to a 500 mL flask, dichloromethane (20 mL), trifluoroacetic acid (4.2 mL, 57.2 mmol) were added, and the reaction was stirred at room temperature overnight.
- reaction solution was concentrated to a minimum amount, methyl tert-butyl ether (150 mL) was added, a solid was precipitated, suction filtered, the filter cake was washed with methyl tertiary butyl ether (50 mL x 3), and then methanol (30 mL) and Dichloromethane (120mL) solution was dissolved, silica gel powder (10g) was added, evaporated to dryness, it was a powdery solid, dry loading, column chromatography, mixed solution of 1% ammonia water and 7%-8% methanol in dichloromethane Elution, collection and concentration, evaporation to dryness to solid, and drying in a vacuum oven to obtain product 43-132: 2.4 g, with a yield of 51%.
- reaction solution was transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (150mL) and ethyl acetate (200mL) were added, and extraction was performed to obtain an organic phase, and ethyl acetate (200mL ⁇ 2) was used for the aqueous phase.
- reaction solution was concentrated to a minimum amount, methyl tert-butyl ether (150 mL) was added, a solid was precipitated, suction filtered, the filter cake was washed with methyl tertiary butyl ether (50 mL x 3), and then methanol (30 mL) and Dichloromethane (120mL) solution was dissolved, silica gel powder (10g) was added, evaporated to dryness, it was a powdery solid, dry loading, column chromatography, mixed solution of 1% ammonia water and 7%-10% methanol in dichloromethane Elution, collection and concentration, evaporation to dryness to solid, and drying in a vacuum oven to obtain product 43-150: 0.24 g with a yield of 26%.
- the dry method was used for sample loading, column chromatography, eluted with a mixed solution of 1% ammonia water and 6%-7% methanol in dichloromethane, collected and concentrated. Evaporate to dryness to solid, and dry in a vacuum oven to obtain the product.
- n-hexane (100 mL) and methyl tert-butyl ether (60 mL) were added, the supernatant was poured, and n-hexane (100 mL) and methyl tert-butyl ether (60 mL) were added to the lower liquid.
- reaction solution After the reaction, transfer the reaction solution to a 1L separatory funnel, add saturated sodium chloride solution (200mL) and ethyl acetate (200mL), shake, extract, concentrate to 100mL, use deionized water (150mL ⁇ 2) After washing, the organic phase was evaporated to dryness and dried to obtain product 37-170: 6.73 g.
- Fmoc-L-Lys(Boc)-OH (4.4 g, 11.1641 mmol, purchased from Accela), 37-175 (4.12 g, 11.7517 mmol), HBTU (6.6851 g, 17.6276 mmol), HOBT (2.3820 g, 17.6276 mmol) ) was added to a 250mL flask, the reaction was placed at 0°C and stirred for about 30 minutes, then DIEA (8.74mL, 52.8827mmol) was slowly added dropwise, the addition was completed, and the stirring was continued at 0°C overnight.
- reaction solution was transferred to a 1L separatory funnel, saturated brine (200mL) and ethyl acetate (250mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 1), The organic phases were combined, washed with saturated brine (200 mL ⁇ 1), concentrated and evaporated to dryness to obtain product 37-178: 8.94 g.
- reaction solution was first transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200 mL).
- reaction solution was first transferred to a 1L separatory funnel, deionized water (100mL) and ethyl acetate (150mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with dichloromethane (100mL ⁇ 3 ) washed, combined the organic phases, concentrated, added silica gel powder (10 g), evaporated to dryness to give a powdery solid, dry-loaded, column chromatography, eluted with a mixed solution of 3%-5% methanol in dichloromethane to obtain Product 37-210: 0.9 g, yield: 61%.
- reaction solution was first transferred to a 1L separatory funnel, saturated sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL) were added, shaken and extracted to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200 mL).
- n-hexane (150 mL) and methyl tert-butyl ether (40 mL) were added for sedimentation, the upper layer liquid was poured, and n-hexane (150 mL) and methyl tertiary butyl ether (40 mL) were added to the lower oily matter, and this was repeated. 4 times, it was a viscous oily substance, added methyl tert-butyl ether (100mL) to separate out the solid, suction filtered, the filter cake was washed with methyl tert-butyl ether (50mL x 3), and the filter cake was dried to obtain the product 37- 215: 0.9767 g.
- n-hexane (150 mL) and methyl tert-butyl ether (40 mL) were added for sedimentation, the upper layer liquid was poured, and n-hexane (150 mL) and methyl tertiary butyl ether (40 mL) were added to the lower oily matter, and this was repeated. 4 times, it was a viscous oily substance. Methyl tert-butyl ether (100 mL) was added to separate out the solid, which was filtered with suction.
- reaction solution was transferred to a 1L separatory funnel, saturated aqueous sodium chloride solution (300 mL) and ethyl acetate (200 mL) were added, shaken, extracted, and the aqueous phase was separated; then ethyl acetate ( 200 mL), shaken, extracted, and the aqueous phase was separated.
- the organic phases were combined, and saturated aqueous sodium chloride solution (300 mL) was added to the organic phase, shaken, extracted, and the aqueous phase was separated. Then, deionized water (300 mL) was added to the organic phase, shaken, extracted, and the aqueous phase was separated. Finally, the organic phase is concentrated and evaporated to dryness, and then placed in an oven to dry. To Product 42-89: 11.3695g.
- the filter cake was dissolved in a 20% methanol/dichloromethane mixed solvent (60 mL), silica gel powder (65 mL) was added, evaporated to dryness, and the samples were loaded by dry method and subjected to column chromatography. Elution was performed with an eluent (0%-2% methanol: 100%-98% dichloromethane), the liquid was collected, concentrated, evaporated to dryness, and dried. Product 42-90 was obtained: 8.6 g, yield: 86.6%.
- the 44-153 solution (1.7026g, 2.6168mmol), 42-90 (8.3637g, 12.0373mmol), HBTU (5.9543g, 15.7006mmol) and HOBT (2.1215g, 15.7006mmol) were added to a 500mL round bottom flask with After DMF (80 mL) was dissolved, the reaction flask was stirred at -5 degrees Celsius for about 30 minutes, and then DIEA (7.8 mL, 47.1018 mmol) was slowly added dropwise. After the addition was completed, the reaction flask was placed in -5 The reaction was stirred at degrees Celsius for 1 hour, and finally transferred to room temperature and stirred for 3 hours.
- the filter cake was dissolved in a 20% methanol/dichloromethane mixed solvent (100 mL), silica gel powder (60 mL) was added, evaporated to dryness, sampled by dry method, and subjected to column chromatography. Elution was carried out with an eluent (1% ammonia water: 1%-8% methanol: 98%-91% dichloromethane), the liquid was collected, concentrated, evaporated to dryness, and dried. Product 44-158 was obtained: 6.8199 g, yield: 80%.
- Fmoc-Glu-OtBu (8.0 g, 18.8027 mmol, purchased from Ark Pharm), HBTU (10.6961 g, 28.2041 mmol), HOBT (3.8110 g, 28.2041 mmol) and H-Glu(OBzl)-OBzl ⁇ TosOH (9.8631 g , 19.7429mmol, purchased from Ark Pharm), added to a 250mL round-bottomed flask, dissolved with DMF (80mL), then the reaction flask was placed at -5 degrees Celsius and stirred for about 30 minutes, and then slowly added dropwise DIEA ( 17.1 mL, 103.4150 mmol), after the dropwise addition, the reaction flask was placed at -5 degrees Celsius and stirred for 1 hour, and finally transferred to room temperature and stirred for 3 hours.
- DIEA 17.1 mL, 103.4150 mmol
- reaction solution was transferred to a 1L separatory funnel, saturated aqueous sodium chloride solution (300 mL) and ethyl acetate (200 mL) were added, shaken, extracted, and the aqueous phase and the organic phase were separated; then acetic acid was added to the aqueous phase ethyl ester (100 mL), shaken, extracted, and the aqueous and organic phases were separated. Then, the organic phases were combined, and saturated aqueous sodium chloride solution (300 mL) was added to the organic phase, shaken, extracted, and the aqueous phase and the organic phase were separated.
- reaction solution was then transferred to a 1L separatory funnel, saturated aqueous sodium chloride solution (300 mL) and ethyl acetate (200 mL) were added thereto, shaken, extracted, and the aqueous and organic phases were separated; then acetic acid was added to the aqueous phase ethyl ester (100 mL), shaken, extracted, and the aqueous and organic phases were separated. Then, the organic phases were combined, and saturated aqueous sodium chloride solution (300 mL) was continuously added to the organic phase, shaken, extracted, and the aqueous phase was separated.
- reaction solution was first transferred to a 1L separatory funnel, and saturated aqueous sodium chloride solution (300 mL) and ethyl acetate (200 mL) were added to it, shaken, extracted, and the water phase was separated; Ethyl acetate (100 mL) was added, shaken, extracted, and the aqueous phase was separated. Then, the organic phases were combined, and a saturated aqueous sodium chloride solution (300 mL) was added to the organic phase, shaken, extracted, and the aqueous phase was separated. Then, deionized water (300 mL) was added to the organic phase, shaken, extracted, and the aqueous phase was separated. Finally, the organic phase is concentrated, evaporated to dryness and dried. Product 44-133 was obtained: 14.8895 g.
- Fmoc-Lys(Boc)-OH (7.3415 g, 15.6689 mmol), 44-134 (10.7110 g, 18.8027 mmol), HBTU (8.9134 g, 23.5034 mmol) and HOBT (3.1758 g, 23.5034 mmol) were added to 500 mL round bottom In the flask, after dissolving it with DMF (80 mL), the reaction flask was stirred at -5 degrees Celsius for about 30 minutes, and then DIEA (13.0 mL, 78.3445 mmol) was slowly added dropwise. After continuing to stir at -5°C for 1 hour, the reaction was finally transferred to room temperature and stirred overnight.
- reaction flask was placed at -5 degrees Celsius and stirred for 1 hour. Finally, the reaction flask was transferred to room temperature and stirred. After the reaction was completed, the reaction solution was first transferred to a 1L separatory funnel, saturated aqueous sodium bicarbonate solution (400 mL) and ethyl acetate (300 mL) were added, shaken, extracted, and the aqueous phase and the organic phase were separated. Next, deionized water (300 mL) was added to the organic phase, shaken, extracted, and the aqueous and organic phases were separated.
- reaction product solution 44-150 (0.9221g, 0.3539mmol, self-made) and 10% Pd/C (50mg) were put into the hydrogenation reactor, then DMF (30mL) was added to dissolve it, the hydrogenation reactor was closed, and hydrogen was introduced to make the inside of the reactor. The pressure reached 1.6 MPa, and the hydrogenation reactor was stirred at room temperature overnight. After the reaction, the reaction kettle was taken out, and the reaction solution was evenly added dropwise to the sand core funnel equipped with compacted diatomite, filtered with suction, and the diatomite was washed with DMF until no product was contained to obtain a reaction product solution.
- the 44-152 solution (0.7308g, 0.3539mmol), 44-158 (7.6092g, 2.3357mmol), HBTU (1.2079g, 3.1851mmol) and HOBT (0.4304g, 3.1851mmol) were added to a 250mL round bottom flask with After DMF (80 mL) was dissolved, the reaction flask was stirred at -5 degrees Celsius for about 30 minutes, and then DIEA (1.6 mL, 9.5553 mmol) was slowly added dropwise. After the addition was completed, the reaction flask was placed in -5 The reaction was stirred at degrees Celsius for 1 hour, and finally the reaction flask was transferred to room temperature and stirred.
- n-hexane (150 mL) and methyl tert-butyl ether (20 mL) were added to the reaction solution for sedimentation, the supernatant was poured, and n-hexane (150 mL) and methyl tert-butyl ether (30 mL) were added to the lower oily matter. ) sedimentation, repeated three times to obtain an oily solid.
- the oily solid was dissolved in dichloromethane (10 mL), then methyl tert-butyl ether (60 mL) was added for sedimentation to give a powdery solid, and the solid product was obtained by filtration.
- n-hexane (150 mL) and methyl tert-butyl ether (30 mL) were added to the reaction solution for sedimentation, the supernatant was poured, and n-hexane (150 mL) and methyl tert-butyl ether ( 30 mL) sedimentation, repeated three times to obtain an oily solid.
- the oily solid was dissolved in dichloromethane (10 mL), then methyl tert-butyl ether (150 mL) was added for sedimentation to give a powdery solid, and the solid product was obtained by filtration. The solid product was washed with methyl tert-butyl ether (60 mL).
- the solid product was dissolved in a mixed solvent of 20% methanol/dichloromethane (60 mL), silica gel powder (70 mL) was added, evaporated to dryness, sampled by dry method, and subjected to column chromatography. Elution was performed with an eluent (1% ammonia water: 3%-8% methanol: 96%-91% dichloromethane), the liquid was collected, concentrated, evaporated to dryness, and dried. Product 44-174 was obtained: 0.4393 g, yield: 55.21%.
- Fmoc-Lys(Boc)-OH (2 g, 4.2686 mmol, purchased from Accela), H-Gly-OBzl.TosOH (1.44 g, 4.2686 mmol, purchased from Ark Pharm), HBTU (2.4 g, 6.4029 mmol), HOBT (0.9g, 6.4029mmol) was put into 500mL, the reaction was placed at -5 degrees Celsius and stirred for about 20 minutes, then DIEA (3.2mL, 19.2086mmol) was slowly added dropwise, and the reaction was continued at -5 degrees Celsius for 1 hour, and then the reaction was Move to room temperature and stir overnight.
- reaction solution was transferred to a 1L separatory funnel, saturated NaCl solution (200mL) and ethyl acetate (200mL) were added, and extraction was performed to obtain an organic phase, and the aqueous phase was washed with ethyl acetate (200mL ⁇ 2), Combine the organic phases, wash the organic phases with saturated brine (200 mL ⁇ 2), combine the organic phases, wash the organic phases with saturated sodium chloride solution (100 mL ⁇ 2), and evaporate to dryness to obtain 36-135: 4.04 g.
- Fmoc-Glu-(OtBu)(OH) (3.0 g, 7.0510 mmol, purchased from Ark Pharm)
- Glu-OBn (3.6987 g, 7.4036 mmol, purchased from Ark Pharm)
- HBTU (4.0110 g, 10.5765 mmol)
- HOBT (1.4292 g, 10.5765 mmol) was added to a flask containing 500 ml, an appropriate amount of DMF (50 mL) was added to dissolve it, and the reaction was stirred at 0 degrees Celsius for 30 minutes.
- DIEA (5.2439 mL, 31.7295 mmol) was slowly added dropwise and stirring was continued at 0 degrees Celsius overnight.
- Morpholine and a small amount of DMF were added to a 500 ml flask containing 47-33 to dissolve and the reaction was stirred at room temperature for an additional hour. After the reaction, take out the reaction solution and add deionized water (200mL), extract with ethyl acetate (100mL ⁇ 3), combine the organic phases, add saturated sodium chloride solution (200mL) to the organic phase, wash twice, concentrate and evaporate to dryness, vacuum Oven drying to obtain crude product.
- Morpholine and a small amount of DMF were added to a 500 ml flask containing 47-36 to dissolve and the reaction was stirred at room temperature for an additional hour. After the reaction, take out the reaction solution and add deionized water (200mL), extract with ethyl acetate (100mL ⁇ 3), combine the organic phases, add saturated sodium chloride solution (200mL) to the organic phase, wash twice, concentrate and evaporate to dryness, vacuum Oven drying to obtain crude product.
- Morpholine (3.5 mL, 40.5884 mmol) and a small amount of DMF were added to a 500 mL flask containing 47-39 (4.6 g, 4.0588) to dissolve and the reaction was stirred at room temperature for an additional hour. After the reaction, take out the reaction solution and add deionized water (200mL), extract with ethyl acetate (100mL ⁇ 3), combine the organic phases, add saturated sodium chloride solution (200mL) to the organic phase, wash twice, concentrate and evaporate to dryness, vacuum Oven drying to obtain crude product.
- deionized water 200mL
- extract with ethyl acetate 100mL ⁇ 3
- SN38 (15.00g, 38.23mmol) was placed in a 1000ml round bottom flask, 150ml of dichloromethane was added to dissolve it, tert-butyldiphenylchlorosilane (59.64ml, 229.36mmol), triethylamine (31.88ml, 229.36 mmol) and the reaction was stirred overnight in a 37°C oil bath. After the reaction was completed, the reaction solution was steamed to a viscous state, n-hexane (150 ml) was added to settle the product to a solid, suction filtration, and drying were carried out to obtain product 47-96: 23.15 g with a yield of 96%.
- the powdery solid in the reaction solution was separated out, and the filter cake was filtered with methyl tert-butyl ether (40 mL ⁇ 3 ) cleaning, collecting the filter cake, drying in a vacuum oven to obtain a crude product 47-119:1.33g in a yield of 87%.
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Abstract
Description
缩写 | 名称 | CAS号或结构式 |
LPT | 拉帕替尼 | 231277-92-2 |
PCB | 帕布惜利布 | 571190-30-2 |
SB7 | SB-743921 | 940929-33-9 |
NPB | Niraparib(MK-4827) | 1038915-60-4 |
SN38 | 7-乙基-10-羟基喜树碱 | 86639-52-3 |
DOX | 阿霉素 | 23214-92-8 |
PTX | 紫杉醇 | 33069-62-4 |
AXT | Axitinib | 319460-85-0 |
Claims (16)
- 式(A)所示的聚乙二醇偶联药物或其药学上可接受的盐,其中:M选自 或PEG m,PEG m为单臂或多臂(如四臂、八臂,优选四臂)聚乙二醇链段,PEG m通过羰基与L 1、L 3、L 5或L 6相连,PEG m的数均分子量为5k-40k,优选为5k-10k或10k-40k,更优选为5k或10k;j 1、j 2、j 3、j 4各自独立地为0、1、2、3、4、5或6,优选为0、1、2、3或4,且不同时为0;PEG 1、PEG 2、PEG 3、PEG 4为单臂聚乙二醇链段,PEG 1、PEG 2、PEG 3、PEG 4分别通过羰基与L 1、L 4、L 5、L 6相连,PEG 1、PEG 2、PEG 3、PEG 4的数均分子量各自独立地为5k-40k,优选为5k-10k或10k-40k,更优选为5k、10k或40k;各r 1独立地为1、2、3、4、5或6,优选为1、2、3或4,更优选为3或4,各r 2独立地为1、2、3、4、5或6,优选为1、2、3或4,更优选为1或2;或者优选地,L 6为直接键、 r 1为1、2、3、4、5或6,优选为1、2、3或4,更优选为3或4,r 2为1、2、3、4、5或6,r 2优选为1、2、3或4,r 2更优选为1或2,且L 6为直接键时,PEG 4不存在,V3与M直接相连;V 2为-L 2V-T 2;P为-L V-T;P 3为-L 3V-T 3;Y 2、Y 1、Y 0各自独立地为 r 0为1、2、3、4、5或6,r 0优选为3、4、5或6,r 0更优选为5或6,各r 2独立地为1、2、3、4、5或6,各r 2独立地优选为1、2、3或4,各r 2独立地更优选为1或2;Z 3、Z 2、Z 1、Z 0各自独立地为 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,各r 4独立地为1、2、3、4、5或6,各r 4独立地优选为1、2、3或4,各r 4独立地更优选为3或4,r 5为1、2、3、4、5或6,r 5优选为3、4、5或6,r 5更优选为5或6,r 6为1、2、3、4、5或6,r 6优选为2、3、4或5,r 6更优选为3或4;Q为-N-AC;Q1为-N1-AC1;Q2为-N2-AC2;AC、AC1、AC2为抗癌药物分子,优选地,AC、AC1、AC2各自独立地为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT。
- 权利要求1的聚乙二醇偶联药物或其药学上可接受的盐,其中,所述聚乙二醇偶联药物具有式(I)所示结构,其中:j 2为3或4;PEG 2为单臂聚乙二醇链段,PEG 2通过羰基与L 4相连,PEG 2的数均分子量为5k-40k,优选为5k-10k或10k-40k,更优选为10k;V 2为-L 2V-T 2,Z 3、Z 2、Z 1、Z 0各自独立地为 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,r 4为1、2、3、4、5或6,r 4优选为1、2、3或4,r 4更优选为3或4,Q为-N-AC,Q1为-N1-AC1,Q2为-N2-AC2,N、N1、N2各自独立地为G或GFLG,优选地,N、N1和N2为GFLG,AC、AC1、AC2各自独立地为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT,优选地,AC、AC1、AC2各自独立地为LPT或PCB,更优选地,AC1为LPT,AC和AC2为PCB。
- 权利要求1的聚乙二醇偶联药物或其药学上可接受的盐,其中,所述聚乙二醇偶联药物具有式(II)所示结构,其中:M选自 或PEG m,PEG m为单臂或多臂(如四臂、八臂,优选四臂)聚乙二醇链段,PEG m通过羰基与L 1相连,PEG m的数均分子量为5k-40k,优选为5k-10k或10k-40k,更优选为5k或10k;j 1为3或4;PEG 1为单臂聚乙二醇链段,PEG 1通过羰基与L 1相连,PEG 1的数均分子量为5k-40k, 优选为5k-10k或10k-40k,更优选为5k、10k或40k;V 1为-L 1V-T 1,Z 2、Z 1、Z 0各自独立地为 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,r 4为1、2、3、4、5或6,r 4优选为1、2、3或4,r 4更优选为3或4,r 5为1、2、3、4、5或6,r 5优选为3、4、5或6,r 5更优选为5或6,r 6为1、2、3、4、5或6,r 6优选为2、3、4或5,r 6更优选为3或4,Q为-N-AC,Q1为-N1-AC1,Q2为-N2-AC2,N、N1、N2各自独立地为G或GFLG,AC、AC1、AC2各自独立地为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT,优选地,AC、AC1、AC2各自独立地为SB7、NPB、SN38、LPT或PCB,更优选地,AC为SB7、NPB或SN38,AC1为NPB或LPT,AC2为PCB。
- 权利要求1的聚乙二醇偶联药物或其药学上可接受的盐,其中,所述聚乙二醇偶联药物具有式(III)所示的结构,其中:PEG 3、PEG 4为单臂聚乙二醇链段,PEG 3、PEG 4分别通过羰基与L 5、L 6相连,PEG 3、PEG 4的数均分子量各自独立地为5k-40k,优选为5k-10k或10k-40k,更优选为5k或10k;V 3为-L 3V-T 3,Z 2、Z 1、Z 0各自独立地为 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,r 5为1、2、3、4、5或6,r 5优选为3、4、5或6,r 5更优选为5或6,Q为-N-AC,AC为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT,优选地,AC为DOX或PTX。
- 权利要求1的聚乙二醇偶联药物或其药学上可接受的盐,其中,所述聚乙二醇偶联药物具有式(IV)所示结构,其中:PEG 3为单臂聚乙二醇链段,PEG 3通过羰基与L 5相连,PEG 3的数均分子量为5k-40k,优选为5k-10k或10k-40k,更优选为10k;P 3为-L 3V-T 3,Z 2、Z 1、Z 0各自独立地为 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,r 5为1、2、3、4、5或6,r 5优选为3、4、5或6,r 5更优选为5或6,Q为-N-AC,Q1为-N1-AC1,Q2为-N2-AC2,AC、AC1、AC2各自独立地为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT,优选地,AC1、AC2各自独立地为PCB或LPT,优选地,AC为PTX或DOX。
- 权利要求1的聚乙二醇偶联药物或其药学上可接受的盐,其中,所述聚乙二醇偶联药物具有式(V)所示结构,其中:PEG 1为单臂聚乙二醇链段,PEG 1通过羰基与L 1相连,PEG 1的数均分子量为5k-40k,优选为5k-10k或10k-40k,更优选为10k;P为-L V-T,Z 1、Z 0各自独立地为 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,r 4为1、2、3、4、5或6,r 4优选为1、2、3或4,r 4更优选为3或4,Q1为-N1-AC1,Q2为-N2-AC2,N1、N2各自独立地为G或GFLG,优选地,N1、N2为GFLG,AC1、AC2各自独立地为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT,优选地,AC1、AC2各自独立地为PCB或LPT,更优选地,AC1为LPT,AC2为PCB。
- 权利要求1的聚乙二醇偶联药物或其药学上可接受的盐,其中,所述聚乙二醇偶联药物具有式(VI)所示结构,其中:PEG 3、PEG 4为单臂聚乙二醇链段,PEG 3、PEG 4分别通过羰基与L 5、L 6相连,PEG 3、PEG 4的数均分子量各自独立地为5k-40k,优选为5k-10k或10k-40k,更优选为10k;Y 2、Y 1、Y 0各自独立地为 r 0为1、2、3、4、5或6,r 0优选为3、4、5或6,r 0更优选为5或6,各r 2独立地为1、2、3、4、5或6,各r 2独立地优选为1、2、3或4,各r 2独立地更优选为1或2,P为-L V-T,Z 2、Z 1、Z 0各自独立地为或 各r 3独立地为1、2、3、4、5或6,各r 3独立地优选为1、2、3或4,各r 3独立地更优选为1或2,r 5为1、2、3、4、5或6,r 5优选为3、4、5或6,r 5更优选为5或6,Q为-N-AC,AC为SB7、NPB、SN38、LPT、PCB、DOX、PTX或AXT,优选地,AC为SB7、LPT、PTX、DOX或AXT。
- 药物组合物,其包含权利要求1-8任一项所述的聚乙二醇偶联药物或其药学上可接受的盐;任选地,所述组合物还包含一种或多种药学上可接受的辅料。
- 权利要求1-8任一项所述的聚乙二醇偶联药物或其药学上可接受的盐在制备治疗和/或预防疾病的药物中的用途,所述疾病为所述聚乙二醇偶联药物中的活性成分所治疗的疾病;优选地,所述疾病为癌症,所述癌症选自:结肠癌、白血病、淋巴瘤、膀胱癌、骨癌、脑瘤、髓母细胞瘤、胶质瘤、乳腺癌、腺瘤/类癌、肾上腺皮质癌、胰岛细胞癌、子宫颈癌、子宫内膜癌、卵巢癌、结肠直肠癌、皮肤癌、食管癌、眼癌、胆囊癌、胃癌、头颈癌、肝癌、黑色素瘤、卡波氏肉瘤、肾癌、口腔癌、肺癌、鼻咽癌、神经母细胞瘤、卵巢癌、胰腺癌、甲状腺癌、甲状旁腺阴茎癌、前列腺癌、尿道癌、阴道癌、外阴癌、肛门癌、肉瘤,以及所述癌症的转移。
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