Drug-carrying polymer and method for preparing the same

Abstract

The present disclosure relates to drug-loaded polymers and methods for preparing the same. Specifically, the polymers are dendritic polymers that are loaded with drugs and pharmacokinetic modifiers, and in particular, the drugs are linked to the dendritic polymers by specific linkers. Such polymers can be used to control the release rate of the drug, specifically through the selection of the linker.

Description

[Technical Field]

[0001] This disclosure relates to the pharmaceutical field and to dendritic polymers that support pharmaceuticals and pharmacokinetic modifiers, and more particularly to linking pharmaceuticals to dendritic polymers using specific linkers. [Background technology]

[0002] Currently, while significant progress has been made in drug research and development, many drugs still fail in clinical trials due to their physical properties (e.g., solubility), making it impossible to prepare and administer them in a suitable formulation, or due to toxic effects caused by prolonged periods of high drug concentration after administration and low therapeutic index. Furthermore, other deficiencies include, for example, poor absorption, low bioavailability, poor in vivo stability, poor targeting leading to systemic side effects, and the inability to control their biological distribution, metabolism, and renal or hepatic clearance in the body after administration. As drug research continues to advance, several new research areas and several technological methods with great potential have emerged, such as the preparation of pharmaceutical reagents in liposomes, micelles, and polymer micelle formulations, and the covalent bonding of pharmaceutical reagents to hydrophilic polymer backbone, accelerating drug development. These measures can solubilize drug activators, and in some cases, improve bioavailability and targeting, but there are difficulties in drug activator release; the vector may be rapidly degraded and release the drug activator before the drug molecule reaches the target organ. Because the release rate of drug activators from vectors is often variable, the drug may not reach an effective therapeutic dose in the body or target organ.

[0003] In recent years, dendritic polymers have been found to have made remarkable progress in the fields of biotechnology and drug applications (Xiangyang Shi et al., Sci China Mater, 2018, 61(11), 1387-1403). Dendritic polymers are a specific type of polymer with a densely branched structure, and are polymers whose structure resembles a tree, obtained by continuously branching outward from a core molecule. That is, the core branches into two branches after growing to a certain length, and this process is repeated until it grows densely like a spherical tree bush (V Gajbhiye et al., Journal of Pharmacy and Pharmacology, 2009, 61, 989-1003). A characteristic feature is that the functional group / unit molecule volume is higher than that of general polymers. In particular, the unique properties of dendritic polymers, such as their high degree of branching, polyvalentity, spherical structure, and well-determined molecular weight, offer hope for novel stents for drug delivery. Over the past decade, research into the design and synthesis of biocompatible dendritic polymers, and their applications in many areas of bioscience, including drug delivery, has also attracted increasing attention.

[0004] Australian company Starpahrma has developed a method for loading and delivering anticancer drugs using its proprietary dendritic polylysine, which improves the pharmacological properties of the drugs and ensures that the drugs are delivered to the right place in the body at the right time. This method is called "drug delivery," and the technology has been marketed under the trademark DEP®. Of these, DEP®-docetaxel, DEP®-cabazitaxel, and DEP®-irinotecan are three anticancer drugs that the company is currently focusing on developing using DEP® technology and are in the clinical trial stage, showing excellent development prospects.

[0005] CN103796684A discloses a polymer that links a drug to a dendritic polymer by a diacid linker, particularly by a diacid linker containing saturated branched or linear chains of C1-C10 suspended by oxygen, nitrogen, or sulfur atoms. [Overview of the Initiative]

[0006] The present disclosure relates to i) a dendrimer D having surface amino groups to which at least two different end groups are covalently bonded; ii) a first end group which is a pharmaceutically active agent or a residue A thereof containing a hydroxy group, an amino group or a sulfhydryl group; iii) a second end group which is a pharmacokinetic modifier, and which is a polymer comprising wherein the first end group is covalently bonded to the surface amino group of the dendrimer by a linker -X1-L-X2-, X1 is a linking group between the linker and the pharmaceutically active agent or a residue A thereof, X2 is a linking group between the linker and the dendrimer D, both X1 and X2 are -C(O)-, and L is a C 1-10 linear or branched alkylene group, wherein the C 1-10 linear or branched alkylene group is substituted with one or more substituents selected from deuterium, a hydroxy group, a C 3-7 cycloalkyl group, a C 3-7 cycloalkylene group, a C 1-6 alkoxy group, a haloalkyl group, a haloalkoxy group, a halogen, a nitro group, a cyano group, an acyl group, a sulfhydryl group, a thioether group, a sulfinyl group, a sulfonyl group, -NR1R2, an aryl group, a heteroaryl group and a heterocyclyl group; R1 and R2 are each independently hydrogen, a hydroxy group, a C 1-6 alkyl group, a cycloalkyl group, a C 1-6 alkoxy group; providing a polymer.

[0007] In some embodiments, L is a C 1-10 linear or branched alkylene group, and the C 1-10 linear or branched alkylene group is substituted with one or more substituents selected from deuterium, a halogen, -OR1, -SR1, -NR1R2 and -C(O)R3; wherein R1 and R2 are each independently hydrogen, a hydroxy group, a C 1-6 alkyl group, a C3-7 Cycloalkyl groups, C 1-6 Selected from alkoxy groups and C(O)R4, the above C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups and C 1-6 The alkoxy group can optionally consist of a hydroxyl group, a halogen, or C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups, nitro groups, cyano groups, amino groups and C 1-6 Substituted with one or more substituents selected from alkylamino groups, R3 and R4 are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy groups.

[0008] In some embodiments, R1 is not hydrogen.

[0009] In some embodiments, the above C 1-10 The linear or branched alkylene group is substituted with one or more substituents selected from -OR1, -SR1, and -NR1R2, where R1 and R2 are independently hydrogen and C, respectively. 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, C 1-6 Selected from alkoxy groups and C(O)R4, the above C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups and C 1-6 The alkoxy group can optionally consist of a hydroxyl group, a halogen, or C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, amino group and C 1-6 Substituted with one or more substituents selected from alkylamino groups, where R4 is hydrogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl and C 1-6Selected from alkoxy groups.

[0010] In some embodiments, the above C 1-10 A linear or branched alkylene group is substituted with one or more -NR1R2 groups, where R1 and R2 are independently hydrogen and C, respectively. 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, C 1-6 Selected from alkoxy groups and C(O)R4, the above C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups and C 1-6 The alkoxy group can optionally consist of a hydroxyl group, a halogen, or C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, amino group and C 1-6 Substituted with one or more substituents selected from alkylamino groups, where R4 is hydrogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl groups and C 1-6 Selected from alkoxy groups.

[0011] In some embodiments, the above C 1-10 A linear or branched alkylene group is substituted with one or more -NR1R2 groups, where R1 and R2 are independently hydrogen and C, respectively. 1-6 Selected from alkyl groups and C(O)R4, where R4 is hydrogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy groups, preferably R1 and R2 each independently of hydrogen and C 1-6 The alkyl group is selected, and R1 and R2 cannot be hydrogen atoms at the same time.

[0012] In some embodiments, the above C 1-10 Linear or branched alkylene groups are C 1-6 It is a linear or branched alkylene group.

[0013] In some embodiments, in the linker -X1-L-X2-, X1 is -C(O)- and is linked to a pharmaceutically active agent or its residue A, and X2 is -C(O)- and is linked to a surface amino group of the dendritic polymer D to form an amide bond.

[0014] In some embodiments, the pharmaceutically active agent or its residue A contains a hydroxyl group and forms an ester bond with X1.

[0015] In some specific embodiments, the polymer structure is [ka] They are selected from among them.

[0016] In some embodiments, by selecting the linker according to the present disclosure, a desired drug release rate, such as immediate release or sustained release, can be provided.

[0017] In some embodiments, the release rate of the pharmaceutically active agent by the polymer may be faster than that which does not depend on polymer delivery, and may be at least 1 times faster. In some embodiments, the release rate of the pharmaceutically active agent by the polymer may be slower than the release rate which does not depend on polymer delivery, and may be 2, 3, 4, 5, 6, 7, 8, 9, 10, or 10 or more times, 15 or more times, 20 or more times, or 30 or more times slower. Polymers with low release rates are suitable for preparing agents that release the polymer over a long period of time, for example, from 1 week to 3 months, 1 month to 6 months, or 6 months or more. For rapid release, it is preferable to release more than 50% of the pharmaceutically active agent in 0 to 8 hours, particularly 0 to 4 hours, particularly 0 to 2 hours, and especially in 5 to 60 minutes. For moderate release, it is preferable to release more than 50% of the pharmaceutically active agent in 1 to 72 hours, particularly 2 to 48 hours. The release rate of the pharmaceutically active agent can be controlled by selecting an appropriate linker, and the release rate also depends on the properties of the pharmaceutically active agent. In some embodiments, the pharmaceutically active agent is linked to the dendritic polymer by the same linker. In some other embodiments, the pharmaceutically active agent is linked to the dendritic polymer by two or more types of linkers so that it can be released from the polymer at different release rates.

[0018] In some embodiments, the first and second terminal groups are present in a ratio of 1:2 to 2:1, particularly 1:2, 1:1, or 2:1. In some embodiments, the polymer includes a third terminal group which is a blocking group, a drug, or a target group. The blocking group may be an acyl group. In some embodiments, the ratio of the first, second, and third terminal groups is 1:1:1 to 1:2:2, particularly 1:2:1. In some embodiments, at least 50% of the terminal groups include either the first or second terminal group. In certain embodiments, the pharmacoactive agent is bonded to more than 14%, 25%, 27%, 30%, 39%, 44%, or 48% of the surface amino groups. In some embodiments, the pharmacokinetic modifier is bonded to more than 15%, 25%, 30%, 33%, or 46% of the surface amino groups.

[0019] The pharmaceutical agents described herein may be selected from anesthetics, antacids, antibodies, anti-infective agents, biological products, cardiovascular agents, contrast agents, diuretics, hematopoiesis, immunosuppressants, hormones and analogues, nutritional products, ophthalmic agents, pain relievers, respiratory agents, adjuvants, anabolic agents, anti-arthritis agents, anticonvulsants, antihistamines, anti-inflammatory agents, anti-ulcer agents, behavior modifiers, antitumor agents, central nervous system agents, contraceptives, antidiabetic agents, reproductive agents, growth promoters, hemostatic agents, immunostimulants, muscle relaxants, antiobesity agents, osteoporosis agents, peptides, sedatives and tranquilizers, urethral acidifiers, or vitamins.

[0020] In some embodiments, the pharmacoactive agent is an antitumor agent, a steroid, an opioid analgesic, a respiratory agent, a central nervous system (CNS) agent, a hypercholesterolemia agent, an antihypertensive agent, an antibacterial agent, an immunosuppressant, an antibiotic, a luteinizing hormone-releasing hormone (LHRH) agonist, an LHRH antagonist, an antiviral agent, an antiretroviral agent, an estrogen receptor modulator, a somatostatin analog, an anti-inflammatory agent, a vitamin D2 analog, a synthetic thyroxine, an antihistamine, an antifungal agent, or a nonsteroidal anti-inflammatory drug (NSAID), preferably an antitumor agent.

[0021] In some embodiments, the antitumor drug is a taxane (e.g., taxol, cabazitaxel, and docetaxel), camptothecin and its analogues (e.g., irinotecan and topotecan), a nucleoside (e.g., gemcitabine, cladribine, fludarabine, capecitabine, decitabine, azacitidine, clofarabine, and nelarabine), a kinase inhibitor (e.g., dasatinib (sprycel), temisirolimus, AZD6244, AZD1152, PI-103, R-roscovitine, oromoucin, and purvalanol) A) and epothiron B analogs (e.g., ixabepyrone), anthrocyclines (e.g., amrubicin, doxorubicin, epirubicin, and barurubicin), ectinacidin derivatives (e.g., trabectecin, lurbinectedin), proteasome inhibitors (e.g., bortezomib) and other topoisomerase inhibitors, intercalators and alkylating agents, microtubule inhibitors (e.g., eribulin, vinflunin), etc., or structural modifications of these drug molecules.

[0022] In some embodiments, the above-mentioned pharmaceutically active agent is a taxane, a camptothecin derivative, a nucleoside, anthracycline, an ectinacidin derivative, a proteasome inhibitor, a microtubule inhibitor, a BCL-2 inhibitor, or a BCL-X inhibitor. L A drug selected from inhibitors, selective nuclear export inhibitors, antimetabolites, tyrosine kinase inhibitors, PLK1 inhibitors, CDK4 / 6 inhibitors, BTK inhibitors, nonsteroidal hormone receptor antagonists, and steroids, preferably a taxane, camptothecin derivative, BCL-2 inhibitor, or BCL-X L It is an inhibitor.

[0023] In some embodiments, the above-mentioned pharmaceutically active agents are docetaxel, irinotecan, gemcitabine, capecitabine, decitabine, azacitidine, doxorubicin, epirubicin, trabectedin, lurubinectedin, bortezomib, eribulin, selinexa, venetoclax, tesetaxel, pemetrexed, cabazitaxel, cabozantinib, onvansertib, and the following compounds 2 and 3, namely, [ka] Alternatively, they are selected from structurally modified versions of those drug molecules.

[0024] In some embodiments, the steroids include synthetic steroids (e.g., testosterone, dihydrotestosterone, and ethinylestradiol) and corticosteroids (e.g., cortisone, prednisilone, budesonide, triamcinolone, fluticasone, mometasone, amcinonide, flucinolone, fluocinanide, desonide, halcinonide, prednicarbate, fluocortone, dexamethasone, betamethasone, and fluprednidine).

[0025] In some embodiments, the opioid analgesic includes morphine, oxymorphone, naloxone, codeine, oxycodone, methylnaltrexone, hydromorphone, buprenorphine, and etorphine. In some embodiments, the respiratory drug includes bronchodilators, inhaled steroids, and decongestants, and is particularly salbutamol, ipratropium bromide, montelukast, and formoterol. In some embodiments, the CNS drug includes antipsychotics (e.g., quetiapine) and antidepressants (e.g., venlafaxine). In some embodiments, the hypercholesterolemia drug includes ezetimibe and statins such as simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin. In some embodiments, the antihypertensive agent includes losartan, olmesartan, medoxomil, metoprolol, travoprost, and bosentan. In some embodiments, the immunosuppressant includes glucocorticoids, cell proliferation inhibitors, antibody fragments, anti-dependent immunosuppressants, interferons, and TNF-binding proteins, and in particular calcineurin inhibitors, such as tacrolimus, mycophenolic acid, and its derivatives, such as mycophenolate mofetil and cyclosporine. In some embodiments, the antibacterial agent includes antibiotics such as amoxicillin, meropenem, and clavulanic acid. In some embodiments, the LHRH agonist includes goserelin acetate, deslorerin, and leuprorelin. In some embodiments, the LHRH antagonist includes cetrorelix, ganirelix, abarerix, and degarelix. In some embodiments, the antiviral agent includes nucleoside analogs such as lamivudine, zidovudine, abacavir, and entecavir, and antiretroviral agents including protease inhibitors such as atazanavir, lapinavir, and ritonavir. In some embodiments, the estrogen receptor modulator includes raloxifene and fulvestrant.In some embodiments, the somatostatin analog comprises octreotide. In some embodiments, the anti-inflammatory agent comprises mesalazine and a suitable NSAID comprising paracetamol (acetaminophen). In some embodiments, the vitamin D2 analog comprises paricalcitol. In some embodiments, the synthetic thyroxine comprises levothyroxine. In some embodiments, the antihistamine comprises fexofenadine. In some embodiments, the antifungal agent comprises an azole such as viriconazole.

[0026] In some embodiments, the pharmaceutically active agent is eribulin. In some embodiments, the pharmaceutically active agent is docetaxel. In some embodiments, the pharmaceutically active agent is trabectedin. In some embodiments, the pharmaceutically active agent is lurbinectedin.

[0027] In some embodiments, the above-mentioned pharmaceutically active agent is slightly soluble or insoluble in aqueous solution.

[0028] The second terminal group is a pharmacokinetic modifier that can modify or modulate the pharmacokinetic characteristics of a pharmaceutically active agent or polymer, including absorption, distribution, metabolism, and / or excretion. In certain embodiments, the pharmacokinetic modifier extends the plasma half-life of the pharmaceutically active agent, so that the half-life of the pharmaceutically active agent linked to the polymer is longer than that of the pharmaceutically active agent in a simple pharmaceutically active agent or a non-dendritic polymer vector. Preferably, the half-life of the polymer or composition is at least twice, more preferably at least ten times, longer than that of the pharmaceutically active agent in a simple pharmaceutically active agent or a non-dendritic polymer vector.

[0029] The pharmacokinetic modifier may be selected from polyethylene glycol, polyethyl oxazoline, polyvinylpyrrolidone, polypropylene glycol, folate, or folate derivatives that are ligands associated with cell surface receptors. In some embodiments, the pharmacokinetic modifier is polyethylene glycol. In some embodiments, the polyethylene glycol has a molecular weight in the range of 220 Da to 5500 Da, for example, 220 Da to 2500 Da, 570 Da to 2500 Da, 220 Da to 1100 Da, 570 Da to 1100 Da, 1000 Da to 5500 Da, 1000 Da to 2500 Da, or 1000 Da to 2300 Da. In some embodiments, the pharmacokinetic modifier forms an amide bond with the surface amino groups of the dendritic polymer.

[0030] Target groups are reagents that bind to target cells, organs, or tissues with several selectivity properties, thereby contributing to the introduction of macromolecules to specific targets in the body and their aggregation within those target cells, organs, or tissues. Target groups can also provide a mechanism for macromolecules to actively enter cells or tissues via receptor-mediated endocytosis. Specific examples include ligands (including small molecules) for lectins, antibodies, and other cell surface receptors. Such interactions may occur by any type of binding or association (including covalent, ionic, and hydrogen bonds, and van der Waals forces). Suitable target groups include those that bind to cell surface receptors such as folate receptors, adrenergic receptors, growth hormone receptors, luteinizing hormone receptors, estrogen receptors, epidermal growth factor receptors, fibroblast growth factor receptors (e.g., FGFR2), IL-2 receptors, CFTR, and vascular epidermal growth factor (VEGF) receptors.

[0031] In some embodiments, the target group is luteinizing hormone-releasing hormone (LHRH) or a derivative thereof that binds to the luteinizing hormone-releasing hormone receptor. In some embodiments, the target group is LYP-1, a tumor-targeting lymphoid system, rather than a normal tissue lymphoid system peptide. In some embodiments, the target group may be an RGD peptide, a peptide containing the sequence -Arg-Gly-Asp-, which is the main itegrin recognition site in extracellular matrix proteins. In some embodiments, the target group may be folic acid. Estrogen can also be used in target cells expressing the estrogen receptor.

[0032] In some embodiments, the target group may be bonded directly to the dendritic polymer core, or preferably by a linking group. The linking group may be any divalent group that can bond to the core functional group or target a functional group on the target group.

[0033] The polymers relating to this disclosure include dendritic polymers, in which the outermost generation of the constituent units has a surface amino group. The dendritic polymer of the polymer has a surface amino group as a condition, and its properties are not particularly important. For example, the dendritic polymer may be a dendritic polymer of polylysine, a polylysine analog, a polyamidoamine (PAMAM), a polyethyleneimine (PEI), or a polyetherhydroxyamine (PEHAM). In some embodiments, the dendritic polymer is polylysine or a polylysine analog. The polylysine or polylysine analog comprises a core and 2nd to 7th generation lysine or lysine analogs, for example, 2nd, 3rd, 4th, 5th, 6th, or 7th generation lysine or lysine analogs.

[0034] In some embodiments, the lysine is 1: [ka] It has the structure shown in [image / diagram].

[0035] In some embodiments, the lysine analog is 2: [ka] It has the structure shown in [image / diagram].

[0036] In some embodiments, the lysine analog is 3: [ka] It has the structure shown by , where a is 1 or 2, b and c are homologous or different, and are integers from 1 to 4.

[0037] In some embodiments, the lysine analog is 4: [ka] It has the structure shown, where a is an integer between 0 and 2, and b and c are homologous or different, and are integers between 2 and 6.

[0038] In some embodiments, the lysine analog is 5: [ka] It has the structure shown, where a is an integer from 0 to 5, and b and c are homologous or different, and are integers from 1 to 5.

[0039] In some embodiments, the lysine analog has the structure shown in 6: [ka] It has the structure shown, where a is an integer from 0 to 5, and b and c are homologous or different, and also integers from 0 to 5.

[0040] In some embodiments, the lysine analog is 7: [ka] It has the structure shown, where a is an integer from 0 to 5, and b and c are homologous or different, and are integers from 1 to 5.

[0041] In some embodiments, the lysine analog is 8: [ka] It has the structure shown, where a is an integer from 0 to 5, and b, c, and d are homologous or different and integers from 1 to 5.

[0042] In some embodiments, the lysine analog is 9: [ka] It has the structure shown, where a is an integer from 0 to 5, and b and c are homologous or different, and are integers from 1 to 5.

[0043] The core of the dendritic polymer described herein, in particular polylysine or polylysine analog, may be selected from benzhydrylamine (BHA), benzhydrylamine of lysine (BHALys), or lysine analogs, or the following: [ka] Of these, a is an integer between 1 and 9, preferably between 1 and 5. [ka] Of these, a, b, and c may be the same or different, and are integers between 1 and 5, while d is an integer between 0 and 100, preferably between 1 and 30. [ka] Among them, a and b may be the same or different, and are integers between 0 and 5. [ka] Of these, a and c may be homologous or different, and are integers between 1 and 6, and b is an integer between 0 and 6. [ka] Of these, a and d may be the same or different, and are integers from 1 to 6, and b and c may be the same or different, and are integers from 0 to 6. [ka] Of these, a and b are either identical or different, and are integers between 1 and 5, especially integers between 1 and 3, especially 1. [ka] Of these, a, b, and c are either identical or different, and are integers selected from 1 to 6. [ka] Of these, a, b, and c are either identical or different, and are integers selected from 0 to 6. [ka] Of these, a, b, and c are either identical or different, and are integers selected from 0 to 6. [ka] Of these, a, b, and c may be the same or different integers and are integers between 0 and 6, while d, e, and f may be the same or different integers and are integers between 1 and 6. [ka] Of these, a, b, and c may be the same or different, and are integers between 1 and 6. [ka] Of these, a, b, c, and d may be the same or different, and are integers between 0 and 6. [ka] Among them, a, b, c, and d may be the same or different, and are integers from 1 to 6, or [ka] Of these, a, b, c, and d may be the same or different and are integers from 0 to 6, while e, f, g, and h may be the same or different and are integers from 1 to 6. In one embodiment, the polymer is i) A dendritic polymer D having surface amino groups, wherein at least two different terminal groups are covalently bonded to the surface amino groups, ii) A pharmaceutically active agent containing a hydroxyl group, an amino group, or a sulfhydryl group, or a first terminal group which is residue A thereof, iii) comprising a second terminal group which is polyethylene glycol, which is a pharmacokinetic modifier, Of these, the first terminal group is covalently bonded to the surface amino group of the dendritic polymer by a linker, and the linker is [ka] They are selected from among them.

[0044] The above dendritic polymer D is BHALys[Lys] 16 BHALys[Lys] 32 Or BHALys[Lys] 64 They are selected from among them. The polyethylene glycol mentioned above has a molecular weight in the range of 1000 Da to 2500 Da.

[0045] This disclosure further relates to a pharmaceutical composition comprising a polymer relating to this disclosure and a pharmaceutically acceptable vector. In some embodiments, the pharmaceutical composition does not contain a solubilizing excipient such as polyethoxylated castor oil or polysorbate. In some embodiments, the pharmaceutical composition is administered by methods such as transdermal, oral, or by injection.

[0046] Compositions prepared with polymers according to this disclosure include those suitable for oral, rectal, topical, nasal, inhalation, aerosol, ocular, or parenteral administration (including intraperitoneal, intravenous, subcutaneous, and intramuscular injection). The compositions can be conveniently expressed in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. Any method involves associating the polymer with one or more vectors constituting auxiliary components. Typically, compositions are prepared by associating the polymer with a liquid vector to form a solution or suspension, or by selectively associating the polymer with a formulation component that is an optional granular product suitable for solid formation, and, if necessary, shaping the product into a desired delivery form. When the solid formulations according to this disclosure are granules, they typically include a particle size range of about 1 nanometer to about 500 microns. Typically, solid formulations intended for intravenous administration have a particle size range of about 1 nm to about 10 microns. The composition may contain the polymer according to the Disclosure, which is a nanoparticle having a particle size smaller than 1000 nm, for example, 5 nm to 1000 nm, particularly 5 nm to 500 nm, particularly 5 nm to 400 nm (for example, 5 nm to 50 nm and particularly 5 nm to 20 nm). In certain embodiments, the composition contains a polymer having an average size of 5 nm to 20 nm. In some embodiments, the polymer is polydisperse in the composition, and the PDI is between 1.01 and 1.8, particularly between 1.01 and 1.5, and particularly between 1.01 and 1.2. In certain embodiments, the polymer is monodisperse in the composition. Particularly preferably is a sterile, lyophilized composition, which is reconstituted in an aqueous medium before injection.

[0047] In some embodiments, the composition contains a polymer having an average size of 5 nm to 20 nm. In some embodiments, the particle size D of the polymer 90 or D 50 It is smaller than 1000 nm, for example, 5 nm to 1000 nm, particularly 5 nm to 500 nm, particularly 5 nm to 400 nm (for example, 5 nm to 50 nm, particularly 5 nm to 20 nm). In a particular embodiment, the composition is D 50It contains polymers with a size of 5 nm to 20 nm.

[0048] The polymers relating to this disclosure may be used to provide controlled-release and / or sustained-release formulations of pharmacoactive agents. Sustained-release formulations release polymers from the formulation over an extended period (e.g., several days, several weeks, or several months) by selecting formulation components. Such formulations include transdermal patches, implantable devices that can be subcutaneously deposited, or those administered by intravenous, subcutaneous, intramuscular, intradural, or intracranial injection. Controlled-release formulations release most of their pharmacoactive agent within a predetermined time window by selecting a diacid linker. For example, if the time required for most of the polymers to aggregate in a target organ, tissue, or tumor is known, most of the pharmacoactive agent can be released after the aggregation time has elapsed by selecting the linker. This makes it possible to deliver a high dose of the drug to the site where it needs to act at a predetermined time. Selectively, by selecting the linker, the pharmacoactive agent is released at a therapeutic level over an extended period. In some embodiments, the formulations can have a variety of controlled-release properties. For example, a formulation may contain polymers in which the drugs are linked by different linkers, allowing for a rapid release of the immediate-release drug followed by a slower release at a low but constant therapeutic level over an extended period. In some embodiments, formulations can have sustained-release and controlled-release properties. For example, by selecting formulation components, polymers can be released over an extended period, and by selecting linkers, a constant and low therapeutic level of the drug activator can be delivered. In some embodiments, the drug activator is linked to the same molecule by different linkers. In some embodiments, each drug-linker combination is linked to different polymers in the same formulation.

[0049] In some embodiments, the pharmaceutical composition is prepared so that the polymer releases more than 50% of the pharmaceutically active agent within 5 to 60 minutes. In some embodiments, the pharmaceutical composition is prepared so that the polymer releases more than 50% of the pharmaceutically active agent within 2 to 48 hours. In some embodiments, the pharmaceutical composition is prepared so that the polymer releases more than 50% of the pharmaceutically active agent within 5 to 30 days.

[0050] Another aspect of the present disclosure provides a method for treating or inhibiting tumor growth, comprising administering an effective amount of a polymer or pharmaceutical composition relating to the present disclosure, wherein the pharmacoactive agent of the first terminal group is an antitumor agent. The tumors described in the present disclosure are selected from melanoma, brain tumors, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminomas, testicular tumors, uterine cancer, head and neck tumors, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumors, ureteral tumors, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma, and pediatric tumors (such as Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatogermocyte tumor, nephroblastoma, etc.).

[0051] Another aspect of the present disclosure provides a method for reducing hypersensitivity after treatment with an antitumor agent, comprising administering a pharmaceutical composition relating to the present disclosure, wherein the composition essentially does not contain Cremophor EL and solubilizing excipients such as polysorbate 80.

[0052] In another aspect of this disclosure, a method is provided for reducing the toxicity of an antitumor agent or a formulation of an antitumor agent, wherein the antitumor agent is the first terminal group of the polymer, comprising administering the polymer according to this disclosure. In some embodiments, the toxicity to be reduced is hematological toxicity, neurotoxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, ototoxicity, or encephaloviral toxicity.

[0053] In another aspect of this disclosure, a method is provided for reducing adverse effects relating to an antitumor agent or a formulation of an antitumor agent, wherein the antitumor agent is the first terminal group of the polymer, comprising administering the polymer relating to this disclosure. In some embodiments, the adverse effects to be reduced are selected from neutropenia, leukopenia, thrombocytopenia, myelotoxicity, myelosuppression, neuropathy, fatigue, nonspecific neurocognitive impairment, dizziness, encephalopathy, anemia, dyspnea, constipation, loss of appetite, onychomycosis, fluid retention, asthenia, pain, nausea, vomiting, mucositis, alopecia, skin reactions, myalgia, and hypersensitivity.

[0054] In some embodiments, the polymers or pharmaceutical compositions containing polymers according to the present disclosure can reduce or eliminate the need for preoperative medication, such as corticosteroids and reagents like antihistamines.

[0055] Methods for preparing dendritic polymers are known in this field. For example, dendritic polymers of high molecular weight can be prepared by divergent methods, convergent methods, or a combination thereof.

[0056] In the divergent method, each generation of constituent units is added sequentially to the core or previous generation. A surface generation having one or two surface amino groups is protected. When one of the amino groups is protected, the free amino group reacts with one of the following: a linker, a linker-pharmacoactive agent, or a pharmacokinetic modifier. When both amino groups are protected, they can be protected with different protecting groups, allowing one protecting group to be removed while the other is not. One of the amino protecting groups is removed and reacts with one of the following: a linker, a linker-pharmacoactive agent, or a pharmacokinetic modifier. Once the first terminal group is linked to the dendrimer, the other amino protecting group is removed and another first and second terminal group is added. These groups are formed by amides known in this art and linked to the surface amino group.

[0057] In the convergence method, each generation of the constituent units is constructed in the previous generation so that a dendritic motif is formed. Before and after the dendritic motif is linked to the core, the first and second terminal groups may be linked to the surface amino groups as described above.

[0058] In the combination method, each generation of the constituent unit is added to the core or the previous generation of the constituent unit. However, before the last generation is added to the dendrimer, the surface amino groups and terminal groups (e.g., the first and second terminal groups, the first and third terminal groups, or the second and third terminal groups) are functionalized. Then, the functionalized final generation is added to the subsurface layer of the constituent unit to link the dendritic motif to the core.

[0059] The drug activator is formed by an ester known in this field and reacts with one of the carboxylic acids of the linker. For example, an activated carboxylic acid is formed, for example, using an acyl chloride or acid anhydride, and reacts with the hydroxyl group of the drug activator. If the drug activator has one or more hydroxyl groups, the other hydroxyl groups can be protected.

[0060] When the target reagent is linked to the core, the functional groups on the core are protected during the dendrimer formation period and then deprotected to react with the target reagent, linking group, or target reagent-linking group. Selectively, the core can react with the linking group or target reagent-linking group before dendrimer formation.

[0061] Suitable protecting groups, and methods for their introduction and removal, are described in Greene & Wuts, Protecting Groupsin Organic Synthesis, 3rd edition, 1999.

[0062] This disclosure further includes various deuterated forms of polymers or pharmaceutically acceptable salts thereof, where each available hydrogen atom in the polymer can be independently substituted with a deuterium atom. Those skilled in the art will know how to synthesize the deuterated forms of polymers or pharmaceutically acceptable salts relating to this disclosure.

[0063] This disclosure further comprises isotope-labeled polymers in which one or more atoms in the polymer are replaced by atoms having a different mass or mass number than the most commonly found atoms in nature. Examples of isotopes applicable to the polymers of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, for example, 3 H, 11 C, 14 C, 18 F, 123 I or 125 It is I.

[0064] The polymers relating to this disclosure may be in the form of pharmaceutically acceptable salts. However, pharmaceutically acceptable salts should also be understood to be included within the scope of this disclosure, as they may be available as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage and transport. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid) or salts of pharmaceutically acceptable organic acids (e.g., acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucinic acid, glucoseic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, cinnamic acid, pantothenic acid, tannic acid, ascorbic acid, and pentanoic acid). Basic salts include, but are not limited to, those formed with pharmaceutically acceptable cations (e.g., sodium, potassium, lithium, calcium, magnesium, ammonium, and alkylammonium).

[0065] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0066] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0067] "Halogenation" refers to the substitution of one or more atoms selected from fluorine, chlorine, bromine, and iodine.

[0068] An alkyl group refers to a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms. In some cases, an alkyl group may have a specified number of carbon atoms, for example, C 1-4 The alkyl group is an alkyl group having one, two, three, or four carbon atoms in a linear or branched chain arrangement. Suitable examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl, and decyl groups.

[0069] An "alkylene group" refers to a linear or branched divalent alkyl group having 1 to 10 carbon atoms. The term "alkenyl group" includes branched and linear olefins having 2 to 12 carbon atoms, or olefins having an aliphatic hydrocarbon group, or, if a specified number of carbon atoms is defined, that specific number. For example, "C 2-6 An "alkenyl group" refers to an alkenyl group having two, three, four, five, or six carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl groups, allyl groups, 1-propenyl groups, 1-butenyl groups, 2-butenyl groups, 3-butenyl groups, 2-methylbuto-2-enyl groups, 3-methylbuto-1-enyl groups, 1-pentenyl groups, 3-pentenyl groups, and 4-hexenyl groups.

[0070] The term "alkynyl group" includes branched and linear alkynyl groups or aliphatic hydrocarbon groups having 2 to 12 carbon atoms, or, if a specified number of carbon atoms is defined, refers to that specific number. Examples include the ethynyl group, propynyl group (e.g., 1-propynyl group, 2-propynyl group), 3-butynyl group, pentynyl group, hexynyl group, and 1-methylpento-2-inyl group.

[0071] An "alkenylene group" or "alkynylene group" is a partially unsaturated branched or linear divalent hydrocarbon group derived from an alkenyl or alkynyl group. In some examples, such alkenylene groups are optionally substituted. Non-limiting examples of alkenylene groups include etenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenylene, and such groups, and non-limiting examples of alkynylene groups include ethynylene, propynylene, butynylene, pentynylene, hexynylene, and such groups.

[0072] A "cycloalkyl group" refers to a saturated or unsaturated cyclic hydrocarbon. A cycloalkyl group may contain a specified number of carbon atoms. For example, a 3-membered to 8-membered cycloalkyl group contains 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, the cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, 1,4-cyclohexadienyl group, cycloheptyl group, and cyclooctyl group.

[0073] A "cycloalkylene group" refers to a divalent cyclic hydrocarbon group derived from a cycloalkyl group. For example, [ka] That is the case.

[0074] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), of which the definition of alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group. Alkoxy groups may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently substituted with one or more substituents selected from H atom, D atom, halogen, alkyl group, alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0075] An "aryl group" refers to any stable monocyclic or bicyclic carbon ring having seven or fewer atoms in each ring, where at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, or binaphthyl groups.

[0076] A "heterocycloalkyl group" or "heterocyclyl group" refers to a cyclic hydrocarbon in which 1 to 4 carbon atoms are independently substituted with heteroatoms selected from N, N(R), S, S(O), S(O)2, and O. The heterocycle may be saturated or unsaturated. Suitable examples of heterocyclyl groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidyl, pyrrolidyl, pyrazolinyl, pyranyl, piperidyl, pyrazolinyl, dithioheterocyclopentadienyl, azathioheterocyclopentadienyl, dioxyheterocyclohexyl, dioxyheterocyclohexenyl, morpholino, and oxazinyl groups.

[0077] A "heteroaryl group" refers to a stable monocyclic or dicyclic group having seven or fewer atoms in each ring, where at least one ring is aromatic, and at least one ring contains one to four heteroatoms selected from O, N, and S. Heteroaryl groups within this definition range include acridinyl, carbazolyl, synnorinyl, quinoxanillyl, quinazolinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, 3,4-propylenedioxythiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxyheterocyclohexene, quinolyl, and isoquinolyl groups. This includes, but is not limited to, oxazolyl groups, isoxazolyl groups, imidazolyl groups, pyrazinyl groups, pyridadinyl groups, pyridyl groups, pyrimidinyl groups, pyrrolyl groups, tetrahydroquinolines, thiazolyl groups, isothiazolyl groups, 1,2,4-triazolyl groups, 1,2,3-triazolyl groups, 1,2,4-oxadiazolyl groups, 1,2,4-thiadiazolyl groups, 1,3,5-triazinyl groups, 1,2,4-triazinyl groups, 1,2,4,5-tetradinyl groups, and tetrazolyl groups.

[0078] A "dendritic polymer" is a molecule comprising a core and at least one dendritic motif linked to the core. Each dendritic motif consists of at least one layer or one generation of branched structural units, resulting in an increasingly branched structure with each generation of structural units. The maximum number of dendritic motifs linked to the core is limited by the number of functional groups on the core.

[0079] A "constituent unit" refers to a branched molecule having at least three functional groups, one of which is for linking to the core or previous generation of the constituent unit, and at least two functional groups for linking to the next generation of the constituent unit or for forming the surface of the dendrimer polymer.

[0080] "Generation" refers to the number of layers of constituent units that make up the dendritic motif or dendritic polymer. For example, a 1st generation dendritic polymer has one layer of branched constituent units connected to the core, for example, core-[[constituent unit]]u, where u is the number of dendritic motifs connected to the core. A 2nd generation dendritic polymer has two layers of constituent units in each dendritic motif connected to the core, and if the constituent unit has one branching point, the dendritic polymer may be core[[constituent unit][constituent unit]2]u. A 3rd generation dendrimer has three layers of constituent units in each dendritic motif connected to the core, for example, core-[[constituent unit][constituent unit]2[constituent unit]4]u. A 6th generation dendritic polymer has six layers of constituent units connected to the core, for example, core-[[constituent unit][constituent unit]2[constituent unit]4[constituent unit]8[constituent unit]16[constituent unit]32]u. The final generation (outermost generation) of the constituent units provides the number of functional groups available for surface functionalization of the dendritic polymer and for bonding with end groups. For example, in a dendritic polymer (u=2) with two dendritic motifs linked to a core, where each constituent unit has one branch point and there are six generations, the outermost generation has 64 constituent units and 128 functional groups available for bonding with end groups.

[0081] "Slightly soluble" refers to drugs or drug activators that have a solubility of 1 mg / mL to 10 mg / mL in water. Drugs with a solubility of less than 1 mg / mL in water are considered insoluble.

[0082] "Solubilizing excipients" refer to pharmaceutical additives that dissolve insoluble or slightly soluble pharmaceutically active agents in aqueous formulations. Examples include surfactants, such as polyethoxylated castor oil containing Cremophor EL, Cremophor RH40, and Cremophor RH60, D-α-tocopherol-polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, solutol HS15, sorbitan monoleate, poloxamer 407, and Labrasol.

[0083] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and the description includes both cases in which the event or situation occurs and cases in which it does not. For example, "L is optionally interrupted by one or more oxygen, sulfur or nitrogen atoms." 1-10 "It is a linear alkylene group" means C 1-10 This means that the linear alkylene group may be interrupted by an oxygen, sulfur, or nitrogen atom, but may not be interrupted, and this explanation is C 1-10 When a linear alkylene group is interrupted by an oxygen, sulfur, or nitrogen atom, C 1-10 This includes cases where the linear alkylene group is not interrupted by an oxygen, sulfur, or nitrogen atom.

[0084] "Substitution" means that one or more hydrogen atoms in a group, preferably five or fewer, more preferably one to three hydrogen atoms, are substituted by a number of substituents that correspond to each other independently. Of course, substituents can only be located at their chemically possible sites, and those skilled in the art can determine possible or impossible substitutions with little effort (by experiment or theory).

[0085] In the chemical structure of the compounds described in this disclosure, [ka] This combination does not specify a placement, that is, [ka] The combination is [ka] It may be, or [ka] The two configurations described herein may be included simultaneously. [ka] This bond has no specified configuration, i.e., it may be in the Z or E configuration, or may contain both configurations simultaneously.

[0086] Any isotope-labeled derivative of the compounds described in this disclosure, or their pharmaceutically acceptable salts, or their isomers, is covered by this disclosure. Atoms that can be labeled with isotopes include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They are isotopes of 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc. and can be substituted. Unless otherwise specified, when a particular position is designated as deuterium (D), it should be understood that the position has a deuterium abundance ratio that is at least 3000 times higher than the natural abundance of deuterium (0.015%), i.e., at least 45% deuterium is incorporated.

[0087] The pharmaceutically active agent or its residue, pharmaceutically active agent, pharmaceutically active agent or its residue A in this disclosure can be used interchangeably with each other and all refer to molecules or groups having pharmaceutically activity.

Brief Description of the Drawings

[0088] [Figure 1] It is the drug PK curve in rat plasma in Test Example 1. [Figure 2] It is the beagle dog plasma PK curve (0 hour - 168 hours) in Test Example 2. [Figure 3] It is the beagle dog plasma PK curve (0 hour - 24 hours) in Test Example 2. [Figure 4] It is the growth curve of the tumor volume of mice in each group in the subcutaneous transplanted tumor model of human lung cancer cell A549 in Test Example 3. [Figure 5] This is the plasma PK curve of a Beagle dog in Test Example 4. [Figure 6] This describes the therapeutic effect of the compound on subcutaneous transplant tumors in human acute lymphoblastic leukemia RS4;11 mice in Test Example 6. [Modes for carrying out the invention]

[0089] The present disclosure will be further described and interpreted in conjunction with the following examples, but these examples are not intended to limit the scope of the present disclosure.

[0090] In the examples of this disclosure, experimental methods for which specific conditions are not specified generally follow conventional conditions or conditions recommended by the raw material or product manufacturers. Reagents for which the specific source is not specified are commercially available, common reagents.

[0091] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). A Bruker AVANCE-400 nuclear magnetic spectrometer was used for NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard. The chemical shift was 10 -6 The values ​​were expressed in ppm (parts per million).

[0092] A Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX) was used for the MS measurements.

[0093] For high-performance liquid chromatography (HPLC) measurements, an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150 mm × 4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150 mm × 4.6 mm column) were used.

[0094] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for product separation and purification by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0095] Column chromatography typically used silica gel of 200-300 mesh size from Yantai Huanghai as a vector.

[0096] The known starting materials relating to this disclosure may be synthesized by employing or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

[0097] Unless otherwise specified in the examples, all reactions were carried out in an argon or nitrogen atmosphere.

[0098] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a capacity of approximately 1 L.

[0099] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a capacity of approximately 1 L.

[0100] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen generator or an HC2-SS type hydrogenator were used.

[0101] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0102] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0103] Unless otherwise specified in the examples, the solution used in the reaction refers to an aqueous solution.

[0104] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0105] Room temperature is the optimal reaction temperature, with a temperature range of 20°C to 30°C.

[0106] Preparation of pH=6.5 PBS buffer in the example: 8.5 g of KH2PO4, 8.56 g of K2HPO43H2O, 5.85 g of NaCl, and 1.5 g of EDTA were placed in a flask, the volume was adjusted to 2 L, and all of these were dissolved using sonication and then shaken to obtain the buffer.

[0107] The eluent systems used in column chromatography and the developing solvent systems in thin-layer chromatography for the purification of compounds include A: dichloromethane and isopropanol systems, B: dichloromethane and methanol systems, and C: petroleum ether and ethyl acetate systems. The volume ratio of the solvents may be adjusted according to the polarity of the compound, or by adding small amounts of triethylamine and acidic or basic reagents.

[0108] Some of the compounds disclosed herein have been characterized by Q-TOF LC / MS. Q-TOF LC / MS was performed using an Agilent 6530 high-precision mass number quadrupole time-of-flight mass spectrometer and an Agilent 1290-Infinity ultrafast liquid chromatograph (Agilent Poroshell 300SB-C8 5 μm, 2.1 mm × 75 mm column).

[0109] Referring to the synthesis method of patent CN110312531A, the following dendritic polymer was synthesized and obtained, in which the first amino terminal group is used for linking with a pharmacoactive agent and the second terminal group is used for linking with the pharmacokinetic modifier PEG. [ka]

[0110] The dendritic polymers shown in the following examples include the core of such dendritic polymers and the structural units in the outermost generation of the dendritic polymers. From the first generation, the subsurface generations are not depicted. Dendritic polymer BHAL y s[Lys] 32 is a fifth-generation dendritic polymer having the following formula BHALys [Lys]2[Lys]4[Lys]8[Lys] 16 [Lys] 32 and having 64 surface amino groups available for bonding to end groups.

[0111] BHALys[Lys], a stent of the dendritic polymer 32 [α-NH2.TFA] 32 [ε-PEG 570 32 BHALys[Lys] 32 [α-NH2.TFA] 32 [ε-PEG 1100 ] 32 BHALys[Lys] 32 [α-NH2.TFA] 32 [ε-t-PEG 2300 32 BHALys[Lys] 32 [α-4-HSBA] 32 [ε-PEG 1100 32 BHALys[Lys] 32 [α-GILGVP-NH2.TFA] 32 [ε-PEG 1100 32 [[ID=五十二]]及びBHALys[Lys] 32 [α-GILGVP-NH2.TFA] 32 [ε-t-PEG 2300 32 The preparation of may refer to Kaminskas et al., J Control. Release(2011)(doi:10.1016 / j. jconrel. 2011. 02. 005). 4-Azidobenzamide-PEG, a stent of the dendritic polymer 12 -NEOEOEN[Su(NPN)2][Lys] 16 [NH2.TFA] 32 ​​​​​​For the preparation of this, refer to WO08 / 017122.

[0112] 1-A00, 1-B00, and 1-C00 were synthesized according to patent WO2012167309, with their linked pharmaceutically active agent being docetaxel, and 2-A00 was synthesized according to patent WO2018154004A, with its linked pharmaceutically active agent being compound 2 (synthesized according to patent WO2012017251). BHALys[Lys] is a dendritic polymer stent. 32 [α-NH2.TFA] 32 [ε-PEG 1100 ] 32 In the examples, this is referred to as dendritic polymer 1, and BHALys[Lys] 32 [α-NH2.TFA] 32 [ε-PEG 2100 ] 32 This is referred to as the dendritic polymer 1-PEG2K in the examples and was synthesized by the method of WO2018154004A. [ka]

[0113] Basic Procedure Basic Procedure A Linker and drug installation At 0°C, a carboxylic acid linker (0.2 mmol to 0.5 mmol) was magnetically stirred, to which a coupling agent in the form of EDC or DCC (1.2 equivalents) was added in a solution of solvent DMF or acetonitrile (1 mL to 5 mL). After the mixture was allowed to stand and stirred for 5 minutes, a solution of solvent (1 mL) containing a mixture of the drug (0.4 equivalents to 1 equivalent) and DMAP (0.4 equivalents to 1 equivalent) was added dropwise. The mixture was held at 0°C for 1 hour, and then heated to ambient temperature. Subsequently, volatile substances were removed by vacuum, and the residue was purified by preparative HPLC (BEH300 Waters XBridge C18, 5 μM, 30 mm × 150 mm, 40% to 80% ACN / water (5 min to 40 min), no buffer) to obtain the desired product.

[0114] Basic Procedure B Linker and drug installation A solution of the drug (0.3 mmol to 1.0 mmol) and acid anhydride (2 equivalents) was magnetically stirred, and DIPEA (3 equivalents) was added in DMF (3 mL to 5 mL). The mixture was stirred overnight at ambient temperature. Then, volatile substances were removed by vacuum, and the residue was purified by preparative HPLC (BEH300 Waters XBridge C18, 5 μM, 30 mm × 150 mm, 40% to 70% ACN / water (5 min to 40 min), no buffer, RT = 34 min). The desired product was obtained by vacuum concentration of an appropriate fraction.

[0115] Basic Procedure C Dendritic polymers with drug-linker support BHALys[Lys] being magnetically stirred at room temperature 32 [α-NH2.TFA] 32 [ε-PEG 1100 ] 32 In a mixture of (0.5 μmol~1.0 μmol) and DIPEA (1.2 equivalents / amine) with DMF, linker-drug (1.2 equivalents / amine) and PyBOP (1.2 equivalents / amine) were added. After stirring at room temperature for 1.5 hours, volatile substances were removed and the residue was purified by SEC (sephadex, LH2O, MeOH). The desired product was obtained by combining and concentrating appropriate fractions (e.g., determined by HPLC).

[0116] Basic Procedure D Click response To a magnetically stirred dendritic polymer, an alkyne reagent (2 equivalents), sodium ascorbate solution (2 equivalents), and CuSO4 solution (20 mol%) were added in a 1:1 H2O / t-BuOH solution (approximately 0.5 mL) (0.5 mmol to 1.0 mmol). The solution was heated to 80°C and monitored by HPLC. Additional amounts of sodium ascorbate and CuSO4 were added as needed to accelerate the completion of the reaction. After determining that the reaction was complete, the reactants were concentrated under vacuum and then purified.

[0117] The polymers in this disclosure may be synthesized according to a route selected from the following, where PG is a carboxylic acid protecting group: [ka] or [ka]

[0118] or [ka]

[0119] or [ka]

[0120] or [ka]

[0121] or [ka] or [ka]

[0122] or [ka] or [ka]

[0123] Example 1: Preparation of Compound 3 [ka] [Chemical]

[0124] Step 1 (S)-2-(2-(((Benzyloxy)carbonyl)amino)-3-methoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylic acid tert-butyl 3c 3a (2.49 g, 7.53 mmol, Shaoyuan) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C in an ice bath, N,N-lithium diisopropylamide (661 mg, 6.17 mmol) was added dropwise, and the reaction was carried out with stirring at 0 °C for 1 hour. Then, the reaction system was cooled to -78 °C, and a 20 mL tetrahydrofuran solution of (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl 3b (1.00 g, 5.02 mmol, Yoshiishi) was added dropwise. After the addition was complete, the dry ice-acetone bath was removed, and the temperature was raised to room temperature and reacted for 12 hours. Saturated ammonium chloride (20 mL) was added for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3c (1.90 g, yield: 94.1%). MS m / z (ESI): 305.0 [M + H - 100].

[0125] Step 2 (2S)-2-(2-Amino-3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylic acid tert-butyl 3d 3c (1.90 g, 4.7 mmol) was dissolved in isopropanol (50 mL), palladium carbon (380 mg, content 10%, dry) was added, and the mixture was replaced with hydrogen gas three times and stirred at room temperature for 8 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (20 mL) and methanol (20 mL), the filtrate was concentrated, and the crude title product 3d (1.28 g) was obtained. The product was used in the next step without purification.

[0126] Step 3 (S)-2-((S)-2-((((9H-Fluorene-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylic acid tert-butyl 3e (S)-2-((R)-2-((((9H-Fluorene-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylic acid tert-butyl 3f The crude product 3d (1.28 g, 4.7 mmol) was dissolved in 1,4-dioxane (40 mL), water (10 mL), sodium hydrogen carbonate (1.17 g, 14.1 mmol) and 9-fluorenylmethyl chloroformate (1.21 g, 4.7 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title products 3e (1.03 g, 44.2%, peak ①) and 3f (513 mg, 22.1%, peak ②). MS m / z (ESI): 495.2 [M+1]. Peak ①: UPLC analysis: retention time 2.77 minutes (column: ACQUITY UPLC BEHC18 50 mm * 2.1 mm, 1.7 μm, mobile phase: gradient elution of acetonitrile / water / formic acid = 10 / 90 / 0.1 (v / v / v) to 95 / 5 / 0.1 (v / v / v)). Peak ②: UPLC analysis: retention time 2.69 minutes (column: ACQUITY UPLC BEHC18 50 mm * 2.1 mm, 1.7 μm, mobile phase: gradient elution of acetonitrile / water / formic acid = 50 / 50 / 0.1 (v / v / v) to 95 / 5 / 0.1 (v / v / v)).

[0127] Step 4 (S)-2-((R)-2-((((9H-Fluorene-9-yl)methoxy)carbonyl)amino)-3-hydroxypropyl)pyrrolidine-1-carboxylic acid tert-butyl 3g 3f (169 mg, 0.34 mmol) was dissolved in tetrahydrofuran (8 mL), and ethanol (8 mL), sodium borohydride (77 mg, 2.05 mmol), and potassium chloride (94 mg, 2.22 mmol) were added in sequence. The mixture was stirred at 28°C for 2.5 hours, and the reaction was quenched by adding saturated ammonium chloride (5 mL) dropwise. The solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), washed with water (10 mL), washed with saturated sodium chloride (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain 3 g (125 mg, 78.4%) of the title product. MS m / z (ESI): 467.2 [M+1].

[0128] Step 5 (S)-2-((R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(phenylthio)propyl)pyrrolidine-1-carboxylate tert-butyl 3h 3 g (120 mg, 0.26 mmol) was dissolved in toluene (5 mL), diphenyl disulfide (168 mg, 0.77 mmol) and tributylphosphine (156 mg, 0.77 mmol) were added, and the reaction system was stirred under a nitrogen atmosphere at 80°C for 12 hours. The solution was concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 3h (135 mg, 93.9%). MS m / z (ESI): 559.2 [M+1].

[0129] Step 6 (S)-2-((R)-2-amino-3-(phenylthio)propyl)pyrrolidine-1-carboxylate tert-butyl 3i 3h (135 mg, 0.24 mmol) was dissolved in dichloromethane (4 mL), diethylamine (4 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent and obtain the title product 3i (81.6 mg). The product was then carried out directly to the next step without purification.

[0130] Step 7 (S)-2-((R)-4-(phenylthio)-3-((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)pyrrolidine-1-carboxylate tert-butyl 3k Crude product 3i (81.6 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide 3j (82 mg, 0.27 mmol) and N,N-diisopropylethylamine (314 mg, 2.4 mmol) were added. The reaction system was heated to 50°C under a nitrogen atmosphere and stirred for 12 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 3k (105 mg, yield: 69.3%). MS m / z (ESI): 622.1 [M-1].

[0131] Step 8 (S)-2-((R)-2-((4-(N-(4-(4-((R)-(4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidine-1-yl)benzoyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-3-(phenylthio)propyl)pyrrolidine-1-carboxylate tert-butyl 3m 3k (30 mg, 0.048 mmol) was dissolved in dichloromethane (3 mL), 3 L (24 mg, 0.058 mmol, synthesized by the method provided for intermediate 40 on page 79 of the specification in patent "CN103153954 B") was added, followed by the sequential addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.096 mmol) and 4-dimethylaminopyridine (12 mg, 0.096 mmol). After incorporation, the mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours, and then 3 L (12 mg, 0.038 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.096 mmol) and 4-dimethylaminopyridine (12 mg, 0.096 mmol) were added. After incorporation, the mixture was stirred overnight at room temperature. The reaction mixture was washed with water (5 mL), then with saturated saline solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified using solvent system A by thin-layer chromatography to obtain the title product 3 m (30 mg, yield: 60.7%). MS m / z (ESI): 1027.2 [M+1].

[0132] Step 9 4-(4-((R)-(4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidine-1-yl)-N-((4-(((R)-1-(phenylthio)-3-((S)-pyrrolidine-2-yl)propan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 3n 3m (30 mg, 0.029 mmol) was dissolved in dichloromethane (2 mL), and 1,4-dioxane solution in 4 M hydrogen chloride (2 mL) was added. The mixture was stirred at room temperature for 20 minutes, and the reaction mixture was concentrated under reduced pressure to remove the organic solvent. The residue was dissolved in dichloromethane, concentrated under reduced pressure until dry, and this process was repeated three times. The resulting residue was purified by high-performance liquid chromatography (isolation conditions: column: Sharpsil-T Prep C18, mobile phase: ammonium bicarbonate, water, acetonitrile), and the corresponding components were collected and concentrated under reduced pressure to obtain the title product 3n (25 mg, yield: 92.3%). MS m / z (ESI): 927.1 [M+1]. 1 H NMR (500 MHz, CD3OD) δ 8.24 (d, 1H), 8.05-8.01 (m, 1H), 7.82 (d, 2H), 7.60 (d, 1H), 7.45-7.39 (m, 3H), 7.37 (d, 2H), 7.34-7.28 (m, 3H), 7.23 (t, 2H), 7.20-7.14 (m, 2H), 6.80 (d, 2H), 6.72 (d, 1H), 4.42 (d, 1H), 3.97 (br, 1H), 3.84-3.74 (m, 1H), 3.27-3.21 (m, 2H), 3.19-3.07 (m, 3H), 3.06-2.97 (m, 1H), 2.69-2.61 (m, 1H), 2.55-2.48 (m, 1H), 2.16-2.00 (m, 5H), 1.98-1.89 (m, 2H), 1.88-1.80 (m, 1H), 1.78-1.69 (m, 1H), 1.63-1.57 (m, 2H), 1.54-1.49 (m, 1H), 1.26-1.20 (m, 1H), 1.15-1.04 (m, 1H), 1.01-0.94 (m, 1H).

[0133] Step 10 4-(4-((R)-(4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidine-1-yl)-N-((4-(((R)-1-((S)-1-(2-hydroxyethyl)pyrrolidine-2-yl)-3-(phenylthio)propan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 3 3n (15 mg, 0.016 mmol) was dissolved in acetonitrile (2 mL), and triethylamine (16 mg, 0.16 mmol) and bromoethanol (20 mg, 0.16 mmol) were added in sequence. The reaction system was heated to 70°C under a nitrogen atmosphere and reacted for 12 hours. The mixture was purified by high-performance liquid chromatography (isolation conditions: column: Sharpsil-T Prep C18, mobile phase: ammonium bicarbonate, water, acetonitrile), and the corresponding components were collected and concentrated under reduced pressure to obtain the title product 3 (10 mg, yield: 63.4%). MS m / z (ESI): 971.2 [M+1]. 1 H NMR (500 MHz, CD3OD) δ 8.25 (d, 1H), 8.06 (dd, 1H), 7.80 (d, 2H), 7.61 (dd, 1H), 7.49-7.35 (m, 5H), 7.35-7.28 (m, 3H), 7.24 (dd, 2H), 7.20-7.14 (m, 2H), 6.79 (t, 3H), 4.42 (d, 1H), 4.02 (t, 1H), 3.84-3.70 (m, 3H), 3.61 (d, 2H), 3.28-3.14 (m, 2H), 3.06 (br, 1H), 2.96 (br, 1H), 2.71-2.59 (m, 1H), 2.56-2.45 (m, 1H), 2.45-2.35 (m, 1H), 2.32-2.22 (m, 1H), 2.10-1.97 (m, 4H), 1.96-1.86 (m, 1H), 1.85-1.69 (m, 2H), 1.60 (t, 2H), 1.26-1.18 (m, 1H), 1.06-1.08 (m, 1H), 1.01-0.92 (m, 1H), 0.92-1.86 (m, 1H).

[0134] Example 2: Preparation of compound 3-TMS [ka]

[0135] Step 1 3n (6 g, 6.47 mmol) was dissolved in DCM (120 mL), triethylamine (3.22 g, 32.35 mmol) was added, and the mixture was cooled to 0°C in an ice bath. Trimethylsilyl trifluoromethanesulfonate (7.2 g, 32.35 mmol) was gradually added dropwise to the reaction mixture, and the reaction was carried out for 2 hours with stirring while maintaining the ice bath. Methanol (12 mL) was added dropwise in an ice bath to quench the mixture, and the mixture was stirred for 10 minutes while maintaining the ice bath. The solvent was removed under reduced pressure to obtain 16.5 g of crude product 3o, which was then carried out to the next step without purification. MS-ESI:m / z 999.1 [M+1] + .

[0136] Step 2 3o (calculated as 16.5 g, 6.47 mmol) was dissolved in acetonitrile (90 mL), and triethylamine (7.86 g, 77.64 mmol) and bromoethanol (9.7 g, 77.64 mmol) were added. The mixture was purged three times with nitrogen gas, and the temperature was raised to 70°C and the reaction was allowed to proceed overnight (approximately 16 h). The solvent was removed under reduced pressure, and EA (120 mL) and water (120 mL) were added. The mixture was stirred and separated, the aqueous phase was extracted with EA (60 mL x 2), the organic phase was combined, washed with water (120 mL), washed with saturated brine (120 mL), dried, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM:CH3OH = 20:1~10:1) to obtain 5.03 g of compound 3-TMS. The two-step process yielded 74.5% and had a purity of 95.9%. MS-ESI: m / z 1043.05 [M+1] + . 11H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.05 (s, 1H), 7.74 (d, 2H), 7.55 (t, 1H), 7.43 - 7.33 (m, 3H), 7.29 (dd, 3H), 7.24 - 7.06 (m, 6H), 6.97 (d, 1H), 6.72 (d, 2H), 6.63 (d, 1H), 4.54 (d, 1H), 3.98 (s, 1H), 3.82 - 3.46 (m, 5H), 3.02 (d, 5H), 2.82 - 2.44 (m, 4H), 2.26 (dd, 1H), 2.07 (d, 1H), 1.90 (dd, 3H), 1.74 (d, 2H), 1.58 - 1.41 (m, 1H), 1.40 - 1.15 (m, 4H), -0.06 (s, 9H).

[0137] Example 3: Preparation of Compound 1-Z00 [Chemical formula] [Chemical formula]

[0138] Step 1<​​​​​​

[0139] Step 2 Under a nitrogen atmosphere, 1-Z01 (1.59 g, 1.70 mmol) and PyBOP (1.70 g, 3.27 mmol) were dissolved in anhydrous DMF (28.0 mL) and mixed uniformly. Then, dendritic polymer 1 (2.00 g, 4.25 × 10) was added. -2 A solution of ( mmol) and DIPEA (0.42 g, 3.27 mmol) in anhydrous DMF (28.0 mL) was added dropwise to the reaction mixture and reacted for 2 hours. The reaction mixture was diluted with acetonitrile (56.0 mL), and then purified by ultrafiltration with acetonitrile using an ultrafiltration apparatus (10 kD, Hydrosart®) to obtain 2.70 g of crude product. The product was dissolved in pure water (150 mL) by vortexing, filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 2.40 g of compound 1-Z00, with a yield of 85%. 1 ¹H NMR showed a 25 DTX / dendrimer. The actual molecular weight was approximately 66.4 kDa (30.39% wt% DTX). 1 H NMR(400 MHz, CD3OD)δ(ppm)8.05-8.24 (m, 64 H), 7.11-7.78 (m, 272 H), 5.98-6.25 (m, 25 H), 5.55-5.71 (m, 29 H), 5.19-5.49 (m, 84 H), 4.93-5.07 (s, 47 H), 4.10-4.64 (m, 162 H), 3.40-4.08 (m, 3200 H), 3.33-3.37 (S, 96 H), 3.02-3.23 (m, 126 H), 2.14-2.63 (m, 271 H), 0.99-2.10 (m, 1109 H). Example 4: Preparation of compound 1-Z00-J

[0140] [ka] [ka]

[0141] Step 1 Compound 1-Z01-J-1 (7 g, 29.5 mmol) was dissolved in methanol (150 mL), and formaldehyde solution (15 mL) and NaBH(AcO)3 (63 g, 295 mmol) were added. The mixture was reacted at room temperature for 1 hour. After concentration, the mixture was purified by column chromatography to obtain 5.9 g of compound 1-Z01-JP, with a yield of 75%. 1 H-NMR (400 MHz, DMSO-d6) δ 7.36-7.32 (m, 5H), 5.09 (s, 2H), 3.12 (t, J = 7.2 Hz, 1H), 2.5-2.44 (m, 2H), 2.38 (s, 6H), 1.87-1.84 (m, 2H). MS-ESI:m / z 266.2 [M+H] + .

[0142] Step 2 Compound 1-Z01-JP (1.44 g, 5.45 mmol) and docetaxel (4 g, 4.96 mmol) were dissolved in dichloromethane (50 mL), and EDCI (1.04 g, 5.45 mmol) and DMAP (665 mg, 5.45 mmol) were added. The mixture was stirred overnight at room temperature. Water was added to quench the mixture, and it was extracted with dichloromethane. After concentration, the mixture was purified by column chromatography to obtain 5 g of compound 1-Z01-J-Bn, with a yield of 95%. MS-ESI: m / z 1055.5 [M+H] + .

[0143] Step 3 Compound 1-Z01-J-Bn (5.75 g, 5.46 mmol) was dissolved in tetrahydrofuran (60 mL), Pd / C (600 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted overnight at room temperature. After filtration and concentration, the mixture was purified by column chromatography to obtain 3.2 g of compound 1-Z01-J, with a yield of 57%. MS-ESI: m / z 965.3 [M+H] + .

[0144] Step 4 Under a nitrogen atmosphere, compound 1-Z01-J (819 mg, 849.5 μmol) and PyBOP (853 mg, 1640 μmol) were dissolved in anhydrous N,N-dimethylformamide (14 mL). A solution of the compound dendritic polymer 1 (1000 mg, 21.24 μmol) and DIPEA (212 mg, 1640 μmol) in anhydrous N,N-dimethylformamide (14 mL) was added dropwise, and the mixture was reacted for 2 hours. The reaction mixture was diluted with acetonitrile (28 mL), and then purified by ultrafiltration with acetonitrile using an ultrafiltration apparatus (10 kD, Hydrosart®) to obtain 1.42 g of crude product. This product was dissolved in pure water (100 mL), filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 1.42 g of compound 1-Z00-J, with a yield of 95%. 1 ¹H NMR showed a 25 DTX / dendrimer. The actual molecular weight was approximately 67.1 kDa (30.0% wt% DTX). 1 H NMR (400 MHz, CD3OD) δ 7.15-8.31 (m, 405H), 6.00-6.31 (m, 25H), 5.57-5.73 (m, 25H), 5.20-5.54 (m, 83H), 4.96-5.08 (m, 35H), 4.10-4.68 (m, 141H), 3.40-4.08 (m, 3200H), 3.33-3.37 (s, 103H), 3.07-3.24 (m, 92H), 2.14-2.69 (m, 260H), 1.00-2.10 (m, 1183H).

[0145] Example 5: Preparation of compound 1-Z00-K [ka] [ka]

[0146] Step 1 Compound 1-Z01-J01 (5.0 g, 21.09 mmol, Gilles Biochemical (Shanghai) Co., Ltd.) was dissolved in MeOH (100 mL) and stirred, and then aqueous formaldehyde (37% wt, 10 mL) was added. While cooling in an ice bath, NaBH(AcO)3 (22.3 g, 105.4 mmol) was added in several batches, and after the addition was complete, the reaction was allowed to proceed at room temperature for 18 hours. Upon detection that the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain 3.2 g of compound 1-Z01-K-2, with a yield of 57%. MS-ESI: m / z 266.1 [M+H] + . 1 H-NMR:(CDCl3, 400 MHz) δ 7.36-7.27 (m, 5 H), 5.18 (dd, J1=20.0 Hz, J2= 12.0 Hz, 2 H), 3.42-3.36 (m, 2 H), 2.48-2.46 (m, 2 H), 2.45 (s, 6 H), 2.05-2.00 (m, 2 H).

[0147] Step 2 Under a nitrogen atmosphere, compound 1-Z01-K-2 (1.0 g, 1.23 mmol), docetaxel (1.0 g, 1.23 mmol), EDCI (261 mg, 1.36 mmol), and DMAP (166 mg, 1.36 mmol) were added to a reaction flask, anhydrous DMF (10 mL) was added, and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution and ethyl acetate were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 1.021 g of compound 1-Z01-K-3, with a yield of 71%. MS-ESI: m / z 1055.4 [M+H] + .

[0148] Step 3 The starting material 1-Z01-K-3 (1.0 g, 0.947 mmol) and wetted palladium-carbon (10% wt, 200 mg) were added to a reaction flask, tetrahydrofuran (20 mL) was added, and the mixture was purged three times with hydrogen gas. The reaction was allowed to proceed at room temperature for 18 hours. The reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, the filtrate was concentrated, and the mixture was vacuum-dried to obtain 736 mg of compound 1-Z01-K, with a yield of 80%. MS-ESI: m / z 965.3 [M+H] + .

[0149] Step 4 Under a nitrogen atmosphere, compounds 1-Z01-K (162 mg, 0.168 mmol) and PyBOP (168 mg, 0.323 mmol) were dissolved in anhydrous DMF (6.0 mL) and mixed uniformly, and then dendritic polymer 1 (200 mg, 4.2 × 10) was added. -3 A solution of ( mmol) and DIPEA (42 mg, 0.323 mmol) in anhydrous DMF (6.0 mL) was added dropwise to the reaction mixture and reacted for 2 hours. The reaction mixture was diluted with acetonitrile and purified by ultrafiltration with acetonitrile using an ultrafiltration apparatus (10 kD, Hydrosart®) to obtain 0.215 g of crude product. This product was dissolved in pure water (50 mL), filtered through a filtration membrane (0.22 μm), and freeze-dried to obtain 0.21 g of compound 1-Z00-K, with a yield of 76%. 1 ¹H NMR showed a 24 DTX / dendrimer. The actual molecular weight was approximately 66.1 kDa (29.30% wt% DTX). 1H NMR(400 MHz, CD3OD)δ(ppm)8.00-8.23 (m, 55 H), 7.11-7.78 (m, 239 H), 5.95-6.30 (m, 24 H), 5.51-5.75 (m, 24 H), 5.15-5.45 (m, 72 H), 4.93-5.07 (s, 19 H), 4.10-4.64 (m, 157 H), 3.40-4.08 (m, 3200 H), 3.33-3.37 (s, 102 H), 2.93-3.23 (m, 167 H), 2.12-2.63 (m, 212 H), 0.99-2.10 (m, 1145 H).

[0150] Example 6: Preparation of compound 1-Z00-L [ka] [ka]

[0151] Step 1 Compound 1-Z01-J-1 (1.0 g, 4.2 mmol, Shanghai Bi De Pharmaceutical) was dissolved in MeOH (20 mL) and stirred. Then, aqueous acetaldehyde solution (40% wt, 2 mL) was added, followed by the addition of NaBH(AcO)3 (4.472 g, 21.0 mmol) under an ice bath. The mixture was reacted at room temperature for 20 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 733 mg of compound 1-Z01-L-1, with a yield of 59.6%. MS-ESI: m / z 294.1 [M+H] + . 1H-NMR:(CDCl3, 400 MHz)δ 7.35~7.28 (m, 5H), 5.10(dd, J1=18 Hz, J2= 12.4 Hz, 2H), 4.15 (brs 1 H), 3.56(t, J=6.8 Hz 1H), 3.27~3.22(m, 2H), 3.07-3.02 (m, 2H), 2.86~2.69 (m, 2H), 2.05 ~2.00 (m, 2H), 1.30 (t, J=7.6 Hz, 6H).

[0152] Step 2 Compound 1-Z01-L-1 (399 mg, 1.36 mmol), docetaxel (1.0 g, 1.23 mmol), EDCI (261 mg, 1.36 mmol), and DMAP (166 mg, 1.36 mmol) were added to a reaction flask, anhydrous DMF (10 mL) was added, and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution and ethyl acetate were added, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 798 mg of compound 1-Z01-L-2, with a yield of 54%. MS-ESI: m / z 1083.4 [M+H] + .

[0153] Step 3 Compound 1-Z01-L-2 (790 mg, 0.729 mmol) and wetted palladium-carbon (10% wt, 158 mg) were added to a reaction flask, tetrahydrofuran (16 mL) was added, and the mixture was purged three times with hydrogen gas. The reaction was carried out at room temperature for 18 hours with stirring. The reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, and the filtrate was concentrated and dried to obtain 616 mg of compound 1-Z01-L, with a yield of 85%. MS-ESI:m / z 993.4 [M+H] + .

[0154] Step 4 Under a nitrogen atmosphere, compounds 1-Z01-L (530 mg, 0.53 mmol) and PyBOP (537 mg, 1.03 mmol) were dissolved in anhydrous DMF (9.0 mL), and the mixture was homogenized and stirred. Subsequently, dendritic polymer 1 (629 mg, 13.4 × 10) was dissolved. -3 A solution of ( mmol) and DIPEA (133 mg, 1.03 mmol) in anhydrous DMF (9.0 mL) was added dropwise to the reaction mixture and reacted for 2 hours. The reaction mixture was diluted with acetonitrile and purified by ultrafiltration with acetonitrile using an ultrafiltration apparatus (10 kD, Hydrosart®) to obtain 0.66 g of crude product, which was dissolved in pure water (100 mL), filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 0.65 g of compound 1-Z00-L, with a yield of 71%. 1 ¹H NMR showed a 26 DTX / dendrimer. The actual molecular weight was approximately 68.8 kDa (30.51% wt% DTX). 1 H NMR(400 MHz, CD3OD)δ(ppm)7.20-8.25 (m, 288 H), 5.98-6.30 (m, 26 H), 5.52-5.78 (m, 28 H), 5.15-5.45 (m, 84 H), 4.92-5.08 (s, 31 H), 4.10-4.64 (m, 212 H), 3.40-4.08 (m, 3200 H), 3.33-3.37 (S, 102 H), 2.93-3.23 (m, 172 H), 2.12-2.63 (m, 262 H), 0.99-2.10 (m, 1186 H).

[0155] Example 7: Preparation of compound 1-Z00-M [ka] [ka]

[0156] Step 1 Compound 1-Z01-J-1 (5.1 g, 21.496 mmol, Shanghai Bi De Pharmaceutical) was dissolved in MeOH (100 mL) and stirred. Then propionaldehyde (6.3 g, 108.47 mmol) was added, the mixture was cooled in an ice bath, and NaBH(AcO)3 (22.9 g, 108.02 mmol) was added. After the addition was complete, the mixture was reacted at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, water was added to the residue and stirred, the insoluble matter was filtered, and the filtrate was purified by column chromatography to obtain 4.85 g of compound 1-Z01-M-1, with a yield of 68.7%. MS-ESI: m / z 322.2 [M+H] + . 1 H-NMR (CDCl3, 400 MHz) δ 7.37-7.26 (m, 5 H), 5.12 (s, 2 H), 3.53 (brs 1 H), 3.04-2.72 (m, 7 H), 2.09-1.98 (m, 2 H), 1.79-1.67 (m, 4 H), 0.97-0.93 (m, 6H).

[0157] Step 2 Under a nitrogen atmosphere, compound 1-Z01-M-1 (367 mg, 1.1 mmol), docetaxel (801 g, 0.991 mmol), EDCI (212 mg, 1.1 mmol), and DMAP (136 mg, 1.1 mmol) were added to a reaction flask, anhydrous DMF (10 mL) was added, and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution and ethyl acetate were added, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 732 mg of compound 1-Z01-M-2, with a yield of 66%. MS-ESI:m / z 1111.4 [M+H] + .

[0158] Step 3 Compound 1-Z01-M-2 (732 mg, 0.658 mmol) and wetted palladium-carbon (10% wt, 133 mg) were added to a reaction flask, and tetrahydrofuran (18 mL) was added. The mixture was purged three times with hydrogen gas and the reaction was carried out at room temperature for 18 hours with stirring. The reaction mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain 669 mg of compound 1-Z01-M, with a yield of 99%. MS-ESI:m / z 1021.4 [M+H] + .

[0159] Step 4 Under a nitrogen atmosphere, compound 1-Z01-M (500 mg, 0.49 mmol) and PyBOP (490 mg, 0.943 mmol) were dissolved in anhydrous DMF (7.5 mL) and mixed uniformly. Then, dendritic polymer 1 (543 mg, 12.25 × 10) was added. -3 A solution of ( mmol) and DIPEA (122 mg, 0.943 mmol) in anhydrous DMF (7.5 mL) was added dropwise to the reaction mixture and reacted for 2 hours. The reaction mixture was diluted with acetonitrile and purified by ultrafiltration with acetonitrile using an ultrafiltration apparatus (10 kD, Hydrosart®) to obtain 0.64 g of crude product. This product was dissolved in pure water (100 mL), filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 0.63 g of compound 1-Z00-M, with a yield of 83%. 1 ¹H NMR showed a 21 DTX / dendrimer. The actual molecular weight was approximately 61.7 kDa (27.4% wt% DTX). 1H NMR(400 MHz, CD3OD)δ(ppm)8.00-8.22 (m, 45 H), 7.09-7.81 (m, 198 H), 5.95-6.30 (m, 21 H), 5.51-5.75 (m, 20 H), 5.13-5.45 (m, 62 H), 4.93-5.07 (s, 17 H), 4.10-4.64 (m, 175 H), 3.40-4.08 (m, 3000 H), 3.33-3.37 (S, 91 H), 2.93-3.23 (m, 127 H), 2.12-2.63 (m, 217H), 0.79-2.10 (m, 1396H).

[0160] Example 8: Preparation of compound 1-Z00-Q [ka] [ka]

[0161] Step 1 Compound 1-Z01-J-1 (5 g, 21.1 mmol, Shanghai Bi De Pharmaceutical) was dissolved in DCM (50 mL), and triethylamine (6.41 g, 63.3 mmol) was added under a nitrogen atmosphere. The mixture was cooled in an ice bath, and anhydride acetic acid (2.37 g, 23.2 mmol) was added dropwise. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was washed with water, the aqueous phase was combined, and the pH was adjusted to 1 with concentrated hydrochloric acid under an ice bath. The mixture was extracted three times with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.8 g of a white solid. A mixed solution of ethyl acetate and petroleum ether was added and a slurry was formed overnight. The slurry was filtered to obtain 4.9 g of compound 1-Z01-Q-1, with a yield of 83%. This was used directly in the next step. MS-ESI: m / z 280.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br, 1 H), 8.14 (d, J = 8 Hz, 1 H), 7.40-7.31 (m, 5 H), 5.09 (s, 2 H), 4.24-4.18 (m, 1 H), 2.48-2.38 (m, 2 H), 2.05-2.00 (m, 1 H), 1.98-1.77 (m, 1 H), 1.97 (s, 3 H).

[0162] Step 2 Compound 1-Z01-Q-1 (377 mg, 1.350 mmol), docetaxel (1 g, 1.239 mmol), and DMAP (166 mg, 1.363 mmol) were weighed and placed in a reaction flask. Under a nitrogen atmosphere, 10 mL of dried DMF (10 mL) and EDCI (261 mg, 1.363 mmol) were added under an ice bath. After incorporation was complete, the mixture was reacted overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the organic phase was washed sequentially with saturated sodium bicarbonate solution and saturated NaCl solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain 805 mg of compound 1-Z01-Q-2, with a yield of 60.8%. MS-ESI: m / z 1069.5 [M+H] + .

[0163] Step 3 Compound 1-Z01-Q-2 (1.1 g, 1.029 mmol) was dissolved in THF (20 mL), wet palladium-carbon (10% wt, 220 mg) was added, and the mixture was purged three times with hydrogen gas. The mixture was then stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the mixture was vacuum-dried to obtain 962 mg of compound 1-Z01-Q, with a yield of 95.5%. MS-ESI: m / z 979.4 [M+H] + .

[0164] Step 4 Under a nitrogen atmosphere, compounds 1-Z01-Q (500 mg, 0.511 mmol) and PyBOP (513 mg, 0.986 mmol) were dissolved in anhydrous DMF (7.9 mL) and mixed uniformly. Subsequently, dendritic polymer 1 (567 mg, 12.8 × 10) was added. -3 A solution of ( mmol) and DIPEA (127 mg, 0.986 mmol) in anhydrous DMF (7.9 mL) was added dropwise to the reaction mixture and reacted for 2 hours. The reaction mixture was diluted with acetonitrile and purified by ultrafiltration with acetonitrile using an ultrafiltration apparatus (10 kD, Hydrosart®) to obtain 0.625 g of crude product. This product was dissolved in pure water (100 mL), filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 0.62 g of compound 1-Z00-Q, with a yield of 74%. 1 ¹H NMR showed a 26 DTX / dendrimer. The actual molecular weight was approximately 65.7 kDa (31.96% wt% DTX). 1 H NMR(400 MHz, CD3OD)δ 8.00-8.22 (m, 55 H), 7.09-7.81 (m, 253 H), 5.95-6.31 (m, 26 H), 5.51-5.77 (m, 28 H), 5.13-5.45 (m, 91H), 4.92-5.08 (s, 41 H), 4.10-4.64 (m, 225 H), 3.40-4.08 (m, 3000 H), 3.33-3.37 (s, 91 H), 2.93-3.23 (m, 102 H), 2.12-2.63 (m, 310 H), 0.96-2.10 (m, 1119 H).

[0165] Example 9: Preparation of compound 3-L00 [ka] [ka]

[0166] Step 1 Compound 1-Z01-J01 (5.0 g, 18.3 mmol) was dissolved in methanol (100 mL), cooled to 0°C, and aqueous formaldehyde solution (10 mL, 40 wt%) and NaBH(OAc)3 (20.0 g, 91.6 mmol) were added. The mixture was reacted overnight at room temperature. After concentration, the mixture was purified by column chromatography to obtain 3.4 g of compound 1-Z01-J02, with a yield of 61%. MS-ESI: m / z 266.1 [M+H] + .

[0167] Step 2 Compound 1-Z01-J02 (3.4 g, 12.8 mmol), trimethylsilylethanol (3.0 g, 26.0 mmol), DMAP (780 mg, 6.4 mmol), and N,N-diisopropylethylamine (6.6 g, 51.2 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). The mixture was cooled to 0°C, HATU (6.3 g, 16.6 mmol) was added, and the mixture was reacted at room temperature for 16 hours. Water (50 mL) was added to quench the mixture, and the solution was extracted with ethyl acetate (50 mL x 3). After concentration, the solution was purified by column chromatography to obtain 4.0 g of compound 1-Z01-J03 in 85% yield. MS-ESI: m / z 366.2 [M+H] + .

[0168] Step 3 Compound 1-Z01-J03 (4.0 g, 10.9 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), Pd / C (200 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted at room temperature for 16 hours. After filtration and concentration, 3.6 g of crude product was obtained, anhydrous tetrahydrofuran (30 mL) was added and slurryed for 30 minutes, and then filtered to obtain 1.6 g of compound 1-Z01-J-TMS, with a yield of 45%. MS-ESI: m / z 276.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ 4.14-4.18 (m, 2H), 3.44-3.47 (m, 1H), 2.87(s, 6H), 2.66-2.70 (m,2H), 2.03-2.12 (m, 2H), 0.96-0.99 (m,2H), 0.04 (s, 9H).

[0169] Step 4 Compounds 1-Z01-J-TMS (118 mg, 0.431 mmol), 3-TMS (300 mg, 0.287 mmol), and DMAP (17.5 mg, 0.216 mmol) were dissolved in anhydrous dichloromethane (10 mL), DCC (88.8 mg, 0.431 mmol) was added, and the mixture was reacted at room temperature for 16 hours. After filtration and concentration, the mixture was purified by column chromatography to obtain 373 mg of compound 3-L00-1, with a yield of 98%. MS-ESI: m / z 650.8 [1 / 2M+H] + .

[0170] Step 5 Compound 3-L00-1 (373 mg, 0.288 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and TBAF (2.9 mL, 2.88 mmol, 1.0 mol / L THF solution) was added. The mixture was reacted at room temperature for 2 hours. Water (10 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (10 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 238 mg of compound 3-L00-2, with a yield of 73%. MS-ESI: m / z 564.5 [1 / 2M+H] + .

[0171] Step 6 Under a nitrogen atmosphere, compounds 3-L00-2 (0.390 g, 0.346 mmol) and PyBOP (0.216 g, 0.415 mmol) were dissolved in anhydrous N,N-dimethylformamide (5.4 mL). A solution of the dendritic polymer 1-PEG2K (0.535 g, 6.92 μmol, synthesized according to the Journal of Controlled Release, 2011, 152, 241-248) and NMM (0.139 g, 1.38 mmol) in anhydrous N,N-dimethylformamide (5.4 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with acetonitrile (11 mL), and then purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.55 L, 25 V) to obtain 0.625 g of crude product. The compound 3-L00 was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and freeze-dried to obtain 0.62 g of compound 3-L00, with a yield of 89%. 1 ¹H NMR revealed 24 drug molecules / dendrimers. The actual molecular weight was approximately 100.2 kDa (23.22% by weight of compound 3). 1 H NMR (400 MHz, CD3OD) δ6.40-8.51 (m, 498H), 4.19-4.68 (m, 111H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 106H), 2.79-3.20 (m, 112H), 2.22-2.74 (m, 246H), 0.61-1.92 (m, 643H).

[0172] Example 10: Preparation of compound 3-M00 [ka] [ka]

[0173] Step 1 Compound 1-Z01-J-1 (7 g, 29.5 mmol) was dissolved in methanol (150 mL), and aqueous formaldehyde solution (15 mL, 40 wt%) and NaBH(OAc)3 (63 g, 295 mmol) were added. The mixture was reacted at room temperature for 1 hour. After concentration, the mixture was purified by column chromatography to obtain 5.9 g of compound 1-Z01-JP, with a yield of 75%. MS-ESI: m / z 266.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.36-7.32 (m, 5H), 5.09 (s, 2H), 3.12 (t, J = 7.2 Hz, 1H), 2.5-2.44 (m, 2H), 2.38 (s, 6H), 1.87-1.84 (m, 2H).

[0174] Step 2 Compound 1-Z01-JP (4.2 g, 15.8 mmol), trimethylsilylethanol (2.24 g, 19 mmol), DMAP (0.193 g, 1.58 mmol), and N,N-diisopropylethylamine (6.1 g, 47.5 mmol) were dissolved in dichloromethane (42 mL), cooled to 0°C, HATU (7.2 g, 19 mmol) was added, and the mixture was reacted at room temperature for 16 hours. Saturated sodium bicarbonate solution (150 mL) was added to quench the mixture, and the solution was extracted with dichloromethane (50 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 4.9 g of compound 1-Z01-K-1, with a yield of 86%. MS-ESI: m / z 366.2 [M+H] + .

[0175] Step 3 Under a nitrogen atmosphere, compound 1-Z01-K-1 (900 mg, 2.46 mmol) was dissolved in tetrahydrofuran (18 mL), Pd / C (180 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted at room temperature for 16 hours. The mixture was filtered and concentrated to obtain 670 mg of compound 1-Z01-K-TMS, with a yield of 99%. MS-ESI: m / z 276.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 4.22 (dd, J=10.0 Hz, J=8.4 Hz, 2H), 3.39 (t, J = 7.2 Hz, 1H), 2.65-2.58 (m, 1H), 2.49 (s, 6H), 2.47-2.39 (m, 1H), 2.02 (dd, J=12.8 Hz, J=6.8 Hz, 2H), 1.04-1.00 (m,2H), 0.04 (s, 9H).

[0176] Step 4 Under a nitrogen atmosphere, compounds 3-TMS (800 mg, 0.767 mmol), 1-Z01-K-TMS (316 mg, 0.767 mmol), and DMAP (46 mg, 0.383 mmol) were dissolved in dichloromethane (16 mL), cooled to 0°C, and DCC (237 mg, 1.15 mmol) was added. The mixture was reacted at room temperature for 18 hours. After filtration and concentration, the mixture was purified by column chromatography to obtain 1.036 g of compound 3-M00-1, with a yield of 100%. MS-ESI: m / z 650.8 [1 / 2M+H] + .

[0177] Step 5 Under a nitrogen atmosphere, compound 3-M00-1 (1.0 g, 0.768 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and TBAF (7.7 mL, 7.68 mmol, 1.0 mol / L THF solution) was added. The mixture was reacted at room temperature for 1 hour. Water (30 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (50 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 670 mg of compound 3-M00-2, with a yield of 77%. MS-ESI: m / z 1128.3 [M+H] + .

[0178] Step 6 Under a nitrogen atmosphere, compounds 3-M00-2 (0.400 g, 0.355 mmol) and PyBOP (0.222 g, 0.426 mmol) were dissolved in anhydrous N,N-dimethylformamide (5.6 mL). A solution of dendritic polymer 1-PEG2K (0.548 g, 7.10 μmol) and NMM (0.144 g, 1.42 mmol) in anhydrous N,N-dimethylformamide (5.6 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with acetonitrile (11 mL), and then purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.55 L, 25 V) to obtain 0.614 g of crude product. The compound 3-M00 was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and freeze-dried to obtain 0.61 g of compound 3-M00, with a yield of 88%. 1 ¹H NMR revealed 22 drug molecules / dendrimers. The actual molecular weight was approximately 98.0 kDa (21.77% by weight of compound 3). 1 H NMR (400 MHz, CD3OD) δ6.40-8.52 (m, 440H), 4.13-4.70 (m, 137H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 109H), 2.79-3.25 (m, 99H), 2.22-2.74 (m, 246H), 0.61-1.92 (m, 622H).

[0179] Example 11: Preparation of compound 3-N00 [ka] [ka]

[0180] Step 1 Compound 1-Z01-J01 (10.0 g, 36.6 mmol) was dissolved in methanol (200 mL), cooled to 0°C, and aqueous acetaldehyde solution (20 mL, 40 wt%) was added. NaBH(OAc)3 (40.0 g, 183.2 mmol) was then added, and the mixture was reacted overnight at room temperature. After concentration, the mixture was purified by column chromatography to obtain 5.4 g of compound 1-Z01-L02, with a yield of 50.4%. MS-ESI: m / z 294.1 [M+H] + .

[0181] Step 2 Compound 1-Z01-L02 (500 mg, 1.7 mmol), trimethylsilylethanol (404 mg, 3.4 mmol), DMAP (104 mg, 0.85 mmol), and N,N-diisopropylethylamine (658 mg, 5.1 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C, HATU (840 mg, 2.2 mmol) was added, and the mixture was reacted at room temperature for 16 hours. Water (20 mL) was added to quench the mixture, and the solution was extracted with ethyl acetate (20 mL x 3). After concentration, the solution was purified by column chromatography to obtain 476 mg of compound 1-Z01-L03, with a yield of 71%. MS-ESI: m / z 394.2 [M+H] + .

[0182] Step 3 Compound 1-Z01-L03 (476 mg, 1.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), Pd / C (50 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted at room temperature for 16 hours. After filtration and concentration, 366 mg of compound 1-Z01-L-TMS was obtained, with a yield of 100%. MS-ESI:m / z 304.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 4.14-4.18 (m, 2H), 3.58-3.60 (m, 1H), 3.26-3.30 (m, 2H), 3.06-3.13 (m, 2H), 2.66-2.77 (m,2H), 2.00-2.06 (m, 2H), 1.33-1.38 (m,6H),0.94-0.99 (m,2H),0.04 (s, 9H).

[0183] Step 4 Compounds 1-Z01-L-TMS (366 mg, 1.21 mmol), 3-TMS (800 mg, 0.767 mmol), and DMAP (47.0 mg, 0.38 mmol) were dissolved in anhydrous dichloromethane (25 mL), and DCC (246.0 mg, 1.2 mmol) was added. The mixture was reacted at room temperature for 16 hours. After filtration and concentration, the mixture was purified by column chromatography to obtain 1.0 g of compound 3-N00-1, with a yield of 98%. MS-ESI: m / z 664.8 [1 / 2M+H] + .

[0184] Step 5 Compound 3-N00-1 (1.0 g, 0.75 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and TBAF (7.5 mL, 7.5 mmol, in a 1.0 mol / L THF solution) was added. The mixture was reacted at room temperature for 2 hours. Water (20 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (50 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 740 mg of compound 3-N00-2, with a yield of 85%. MS-ESI: m / z 578.7 [1 / 2M+H] + .

[0185] Step 6 Under a nitrogen atmosphere, compounds 3-N00-2 (0.400 g, 0.346 mmol) and PyBOP (0.215 g, 0.414 mmol) were dissolved in anhydrous N,N-dimethylformamide (5.6 mL). A solution of the dendritic polymer compound 1-PEG2K (0.535 g, 6.90 μmol) and NMM (0.139 g, 1.38 mmol) in anhydrous N,N-dimethylformamide (5.6 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with acetonitrile (11 mL), and then purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.56 L, 25 V) to obtain 0.631 g of crude product. The compound 3-N00 was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and freeze-dried to obtain 0.625 g of compound 3-N00, with a yield of 91%. 1 ¹H NMR revealed 23 drug molecules / dendrimers. The actual molecular weight was approximately 99.8 kDa (22.36% by weight of compound 3). 1 H NMR (400 MHz, CD3OD) δ6.40-8.52 (m, 477H), 4.19-4.68 (m, 184H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 108H), 2.79-3.20 (m, 101H), 2.22-2.74 (m, 158H), 0.61-1.92 (m, 726H).

[0186] Example 12: Preparation of compound 3-O00 [ka] [ka]

[0187] Step 1 Compound 1-Z01-J01 (5.0 g, 21.1 mmol) was dissolved in methanol (100 mL), cooled to 0°C, and propionaldehyde (6.1 g, 105.0 mmol) and NaBH(OAc)3 (31.1 g, 105.0 mmol) were added. The mixture was reacted overnight at room temperature. After concentration, the mixture was purified by column chromatography to obtain 5.0 g of compound 1-Z01-M02, with a yield of 74%. MS-ESI: m / z 322.1 [M+H] + .

[0188] Step 2 Compound 1-Z01-M02 (890 mg, 2.8 mmol), trimethylsilylethanol (393.3 mg, 3.3 mmol), DMAP (33.8 mg, 0.3 mmol), and N,N-diisopropylethylamine (1.1 g, 9.3 mmol) were dissolved in anhydrous dichloromethane (20 mL), cooled to 0°C, HATU (1.3 g, 3.3 mmol) was added, and the mixture was reacted at room temperature for 16 hours. Water (40 mL) was added to quench the mixture, and the solution was extracted with ethyl acetate (20 mL x 3). After concentration, the solution was purified by column chromatography to obtain 1 g of compound 1-Z01-M03, with a yield of 86%. MS-ESI: m / z 422.2 [M+H] + .

[0189] Step 3 Compound 1-Z01-M03 (1 g, 2.4 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), Pd / C (200 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted at room temperature for 16 hours. After filtration and concentration, 766 mg of compound 1-Z01-M-TMS was obtained, with a yield of 100%. MS-ESI: m / z 332.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 4.10-4.14 (m, 2H), 3.50-3.53 (m, 1H), 2.84-3.04 (m, 4H), 2.63-2.69 (m,2H), 1.95-2.01 (m, 2H), 1.69-1.77 (m,4H), 0.90-0.96 (m,8H), 0.04 (s, 9H).

[0190] Step 4 Compounds 1-Z01-M-TMS (381.7 mg, 1.2 mmol), 3-TMS (800 mg, 0.767 mmol), and DMAP (46.08 mg, 0.38 mmol) were dissolved in anhydrous dichloromethane (20 mL), and DCC (237.0 mg, 1.2 mmol) was added. The mixture was reacted at room temperature for 16 hours. After filtration and concentration, the mixture was purified by column chromatography to obtain 890 mg of compound 3-O00-1, with a yield of 86%. MS-ESI: m / z 678.8 [1 / 2M+H] + .

[0191] Step 5 Compound 3-O00-1 (890 mg, 0.66 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and TBAF (6.6 mL, 6.6 mmol, in a 1.0 mol / L THF solution) was added. The mixture was reacted at room temperature for 3 hours. Water (20 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (50 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 810 mg of compound 3-O00-2, with a yield of 100%. MS-ESI: m / z 592.8 [1 / 2M+H] + .

[0192] Step 6 Under a nitrogen atmosphere, compounds 3-O00-2 (0.409 g, 0.346 mmol) and PyBOP (0.216 g, 0.415 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). A solution of dendritic polymer 1-PEG2K (0.52 g, 6.8 μmol) and NMM (0.137 g, 1.36 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with acetonitrile (10 mL), and then purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.5 L, 25 V) to obtain 0.605 g of crude product. This product was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 0.60 g of compound 3-O00, with a yield of 87%. 1 1H NMR revealed 24 drug molecules / dendrimers. The actual molecular weight was approximately 101.5 kDa (22.92% by weight of compound 3). 1 H NMR (400 MHz, CD3OD) δ 6.40-8.51 (m, 496H), 4.19-4.68 (m, 126H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 100H), 2.79-3.20 (m, 136H), 2.22-2.74 (m, 199H), 0.61-1.92 (m, 683H).

[0193] Example 13: Preparation of compound 3-R00 [ka] [ka]

[0194] Step 1 Compound 1-Z01-J01 (5.01 g, 18.3 mmol) was dissolved in methanol (100 mL), cooled to 0°C, and acetone (5.5 g, 94.7 mmol) and NaBH(OAc)3 (11.9 g, 56.13 mmol) were added. The mixture was reacted at room temperature for 2 hours. Aqueous formaldehyde solution (14 mL, 40 wt%) and NaBH(OAc)3 (8.26 g, 38.96 mmol) were added, and the mixture was reacted overnight at room temperature. After concentration, the mixture was purified by column chromatography to obtain 5 g of compound 1-Z01-P02, with a yield of 93%. MS-ESI: m / z 294.1 [M+H] + .

[0195] Step 2 Compound 1-Z01-P02 (2.58 g, 8.8 mmol), trimethylsilylethanol (2 g, 16.9 mmol), DMAP (540 mg, 4.43 mmol), and N,N-diisopropylethylamine (2.98 g, 23.1 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), and HATU (3.38 g, 8.89 mmol) was added. The mixture was reacted at room temperature for 17 hours. Water (20 mL) was added to quench the mixture, and the solution was extracted with ethyl acetate (20 mL x 3). After concentration, the solution was purified by column chromatography to obtain 3.09 g of compound 1-Z01-P03, with a yield of 89%. MS-ESI: m / z 394.2 [M+H] + .

[0196] Step 3 Compound 1-Z01-P03 (3 g, 7.62 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), Pd / C (152 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted at room temperature for 15 hours. After filtration and concentration, 2.32 g of crude product 1-Z01-P-TMS was obtained. Methyl tert-butyl ether (20 mL) was added and the mixture was slurryed for 30 minutes, then filtered to obtain 0.92 g of compound 1-Z01-P-TMS, with a yield of 39%. MS-ESI:m / z 304.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 4.05-4.10 (m, 2H), 3.26-3.30 (m, 1H), 3.12-3.15 (m, 1H), 3.35-3.43 (m, 2H), 2.31 (s,3H), 1.75-1.85 (m, 2H), 1.03-1.07 (m,6H), 0.89-0.94 (m,2H),0.01 (s, 9H).

[0197] Step 4 Compounds 1-Z01-P-TMS (379 mg, 1.25 mmol), 3-TMS (805 mg, 0.772 mmol), and DMAP (54.0 mg, 0.44 mmol) were dissolved in anhydrous dichloromethane (16 mL), and DCC (239.0 mg, 1.16 mmol) was added. The mixture was reacted at room temperature for 16 hours. After filtration and concentration, the mixture was purified by column chromatography to obtain 863 mg of compound 3-R00-1, with a yield of 84%. MS-ESI: m / z 664.8 [1 / 2M+H] + .

[0198] Step 5 Compound 3-R00-1 (847 mg, 0.64 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), and TBAF (6 mL, 6 mmol, 1.0 mol / L THF solution) was added. The mixture was reacted at room temperature for 2 hours. Water (20 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (50 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 702 mg of compound 3-R00-2, with a yield of 95%. MS-ESI: m / z 578.8 [1 / 2M+H] + .

[0199] Step 6 Under a nitrogen atmosphere, compounds 3-R00-2 (0.299 g, 0.259 mmol) and PyBOP (0.162 g, 0.311 mmol) were dissolved in anhydrous N,N-dimethylformamide (4 mL). A solution of the dendritic polymer compound 1-PEG2K (0.400 g, 5.177 μmol) and NMM (0.209 g, 2.071 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added dropwise, and the mixture was heated to 38°C and reacted for 3 hours. The reaction mixture was diluted with acetonitrile and purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.4 L, 13 V) to obtain 0.470 g of crude product. The compound 3-R00 was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and freeze-dried to obtain 0.465 g of compound 3-R00, with a yield of 88%. 1 1H NMR revealed 25 drug molecules / dendrimers. The actual molecular weight was approximately 102.0 kDa (23.76% by weight of compound 3). 1 H NMR (400 MHz, CD3OD) δ 6.40-8.51 (m, 514H), 4.13-4.72 (m, 123H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 93H), 2.79-3.25 (m, 73H), 2.22-2.74 (m, 206H), 0.61-1.92 (m, 810H).

[0200] Example 14: Preparation of compound 3-S00 [ka] [ka]

[0201] Step 1 Under a nitrogen atmosphere, compound 1-Z01-J01 (5 g, 18.3 mmol) was dissolved in dichloromethane (50 mL), triethylamine (5.5 g, 54.9 mmol) was added, the mixture was cooled to 0°C, and anhydride acetic acid (2 g, 18.7 mmol) was added dropwise. The mixture was reacted overnight at room temperature. The mixture was washed with water (20 mL x 2), the aqueous phases were combined, the pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL x 3). After concentration, 4.7 g of compound 1-Z01-Q-02 was obtained, with a yield of 91%. MS-ESI: m / z 280.2 [M+H] + .

[0202] Step 2 Under a nitrogen atmosphere, compound 1-Z01-Q-02 (4.5 g, 16.1 mmol) and trimethylsilylethanol (5.7 g, 48.3 mmol) were dissolved in dichloromethane (5 mL), cooled to 0°C, thionyl chloride (1.9 g, 16.1 mmol) was added, and the mixture was reacted overnight at room temperature. After concentration, the mixture was purified by column chromatography to obtain 1.6 g of compound 1-Z01-Q-03, with a yield of 26%. MS-ESI: m / z 380.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 6.20 (d, J = 7.6 Hz, 1H), 5.14 (s, 2H), 4.61-4.63 (m, 1H), 4.19-4.04 (m, 2H), 2.21-2.26 (m, 3H), 2.02-1.94 (m, 4H), 1.02-0.90 (m, 2H), 0.05-0.02 (m, 9H).

[0203] Step 3 Compound 1-Z01-Q-03 (0.9 g, 2.3 mmol) was dissolved in tetrahydrofuran (10 mL), wet Pd / C (180 mg, 10 wt%) was added, and the mixture was purged three times with hydrogen gas and reacted overnight at room temperature. After filtration and concentration, 621 mg of compound 1-Z01-Q-TMS was obtained, with a yield of 93%. MS-ESI: m / z 290.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 6.9 Hz, 1H), 4.54-4.42 (m, 1H), 4.22-4.07 (m, 2H), 2.56-2.32 (m, 2H), 2.24-2.12 (m, 1H), 2.09-1.90 (m, 4H), 1.03-0.90 (m, 2H), 0.00 (s, 9H).

[0204] Step 4 Under a nitrogen atmosphere, compound 1-Z01-Q-TMS (400 mg, 1.3 mmol) was dissolved in dichloromethane (20 mL), and DMAP (56 mg, 0.46 mmol), 3-TMS (962 mg, 0.92 mmol), and DCC (285 mg, 1.3 mmol) were added. The mixture was reacted overnight at room temperature. 1-Z01-Q-TMS (150 mg, 0.5 mmol) and DCC (143 mg, 0.6 mmol) were added, and the mixture was reacted overnight at room temperature. After filtration and concentration, the mixture was purified by column chromatography to obtain 560 mg of compound 3-S00-1, with a yield of 33%. MS-ESI: m / z 1314.3 [M+H] + .

[0205] Step 5 Under a nitrogen atmosphere, compound 3-S00-1 (560 mg, 0.426 mmol) was dissolved in tetrahydrofuran (8 mL), and TBAF (4.3 mL, 4.3 mmol, in a 1.0 mol / L THF solution) was added. The mixture was reacted for 2 hours. Water (10 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (50 mL x 3). After concentration, the mixture was purified by column chromatography to obtain 420 mg of compound 3-S00-2, with a yield of 86%. MS-ESI: m / z 1142.3 [M+H] + .

[0206] Step 6 Under a nitrogen atmosphere, compounds 3-S00-2 (0.074 g, 0.065 mmol) and PyBOP (0.041 g, 0.078 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL). A solution of dendritic polymer 1-PEG2K (0.100 g, 1.30 μmol) and NMM (0.026 g, 0.258 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with acetonitrile, purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.3 L, 25 V), and concentrated to obtain 0.124 g of crude product. This product was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and lyophilized to obtain 0.12 g of compound 3-S00, with a yield of 87%. 1 1H NMR revealed 30 drug molecules / dendrimers. The actual molecular weight was approximately 107.3 kDa (27.12% by weight of compound 3). 1 H NMR (400 MHz, CD3OD) δ 6.40-8.52 (m, 609H), 4.19-4.68 (m, 184H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 102H), 2.79-3.20 (m, 102H), 2.22-2.74 (m, 146H), 0.61-1.92 (m, 767H).

[0207] Example 15: Preparation of compound 3-T00 [ka] [ka]

[0208] Step 1 Under a nitrogen atmosphere, compound 3 (1.0 g, 1.02 mmol) was dissolved in dichloromethane (20 mL), and a solution of NMM (322 mg, 3.18 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol) in dichloromethane (5 mL) was added dropwise. Glutaric anhydride (141 mg, 1.23 mmol) was added, and the mixture was reacted at room temperature for 20 hours. Glutaric anhydride (94 mg, 0.82 mmol) was added, and the mixture was reacted at room temperature for 3 hours. After concentration, the mixture was purified by column chromatography to obtain 1.030 g of compound 3-T00-1, with a yield of 92%. MS-ESI: m / z 1085.2 [M+H] + .

[0209] Step 2 Under a nitrogen atmosphere, compounds 3-T00-1 (0.352 g, 0.325 mmol) and PyBOP (0.203 g, 0.390 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). A solution of dendritic polymer 1-PEG2K (0.500 g, 6.50 μmol) and NMM (0.131 g, 1.300 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with acetonitrile, purified by ultrafiltration (10 kD, Hydrosart®) using acetonitrile (0.5 L, 25 V), and concentrated to obtain 0.585 g of crude product. This product was dissolved in pure water, filtered through a filtration membrane (0.22 μm), and freeze-dried to obtain 0.580 g of compound 3-T00, with a yield of 84%. 1 1H NMR revealed 31 drug molecules / dendrimers. The actual molecular weight was approximately 106.6 kDa (28.19% by weight of compound 3). 1H NMR (400 MHz, CD3OD) δ 6.40-8.52 (m, 623H), 4.19-4.67 (m, 173H), 3.40-4.10 (m, 5900H), 3.33-3.36 (s, 95H), 2.75-3.10 (m, 73H), 2.22-2.74 (m, 217H), 0.61-1.92 (m, 613H).

[0210] Biological evaluation Study Example 1: Pharmacokinetic study of single intravenous injection of different compounds into rats 1. Test sample Docetaxel (G1), compounds 1-Z00 (G2), 1-Z00-J (G3), 1-Z00-K (G4), 1-Z00-M (G5), and 1-C00 (G6) related to this disclosure.

[0211] Sample preparation method: (1) Preparation of docetaxel: Take commercially available docetaxel injection solution (0.5 mL: 20 mg) and dilute it with physiological saline to 4 mg / mL. (2) Preparation of other compounds awaiting detection: The compounds were dissolved in DMSO with a final concentration of 5%, and then diluted to 4 mg / mL with physiological saline.

[0212] 2. Test animals Female SD rats weighing 160g-180g, 6 weeks old, SPF grade. 3. Examination Method Blood samples were collected at different time points after intravenous administration (dosage: 10 mg / kg) (Group G1: 0 h, 0.0833 h, 0.5 h, 1 h, 4 h, 8 h, 24 h; Groups G2-G6: 0 h, 0.0833 h, 1 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h), anticoagulated with EDTAK2, separated the plasma samples, added the esterase inhibitor DDVP, and stored frozen at -80°C to detect docetaxel levels (N=3).

[0213] [Table 1]

[0214] 4. Experimental results As shown in Table 2 and Figure 1 below, after intravenous administration, the AUC levels for the 10 mg / kg 1-Z00-J group, 1-Z00-K group, and 1-Z00-M group were as follows: 0-t All of these drugs were significantly superior to those in the other groups, and the 1-Z00-J and 1-Z00-M groups showed lower plasma clearance and better sustained-release effects.

[0215] [Table 2]

[0216] 5. Conclusion of the experiment Compared to the rapid plasma clearance and low exposure of typical docetaxel injection, 1-Z00-J, 1-Z00-K, and 1-Z00-M all exhibit significantly sustained-release effects and higher exposure. Compared to 1-C00 and 1-Z00, the compounds according to this disclosure all significantly increase drug exposure and have lower drug clearance.

[0217] Study Example 2: Pharmacokinetic study of single intravenous injection of different compounds in beagle dogs 1. Test sample Compounds 1-B00, 1-Z00, 1-Z00-J, and docetaxel related to this disclosure. Sample preparation method: For 1-B00, 1-Z00, and 1-Z00-J, 84 mg / ampoule of the test substance, an appropriate volume of physiological saline was added to obtain an administration solution with a concentration of 0.6 mg / mL, which was used for intravenous injection.

[0218] A commercially available docetaxel at 84 mg / ampoule was dissolved by adding 5% DMSO, 30% PEG300, 5% Tween 80, and 60% deionized water by final volume to obtain a 0.6 mg / mL dosage formulation, which was used for intravenous injection.

[0219] 2. Test animals A non-naive grade Beagle dog supplied by Medicilon / MPI Animal Bank: 999M-004.

[0220] 3. Examination Method Administration method: Body weight was measured before administration, and the dosage was calculated based on body weight. The drug was administered by slow intravenous injection. Blood was collected from the jugular vein or by another suitable method, and approximately 1 mL was collected in each sample. Plasma samples were collected at different time points before and after administration, and the level of free docetaxel in the plasma was detected. Samples for the docetaxel group were collected before and after administration at 0.083 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h, while samples for the other test substance groups were collected before and after administration at 0.083 h, 1 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h.

[0221] [Table 3]

[0222] 4. Test results The pharmacokinetic data for each group are shown in Table 4 and Figures 2 and 3 below.

[0223] [Table 4]

[0224] As is clear from the test results, 1-Z00-J has a higher in vivo exposure and lower drug clearance compared to docetaxel and 1-Z00.

[0225] Test Example 3: Pharmacological evaluation, efficacy, and hematological evaluation in BALB / C nude mice, a subcutaneous xenograft tumor model of human lung cancer cells A549. 1. Test sample Docetaxel, 1-Z00, 1-Z00-J The sample preparation method is as shown in Table 5 below:

[0226] [Table 5]

[0227] 2. Laboratory animals Female BALB / C nude mice, 6-7 weeks old (age at tumor cell inoculation), weighing 16.5 g-22.6 g, purchased from Jiangsu GemPharmatech Co., Ld., with animal conformity certificate number: 320727210100243463. Rearing environment: SPF grade.

[0228] 3. Experimental Method 3.1 Cell Culture A549 cells (Cell Bank of the Committee for the Preservation of Typical Cultures of the Chinese Academy of Sciences / Cell Resource Center of the Shanghai Institute of Biosciences, Chinese Academy of Sciences (cellbank.org.cn, SIBS)) were cultured in 10% fetal bovine serum F12K culture medium (Gibco). After growth to the exponential growth phase, the cells were collected for subcutaneous tumor inoculation in mice and resuspended in PBS to an appropriate concentration.

[0229] 3.2 Animal Modeling and Randomization 5 x 10 under the skin on the right side of a female mouse 6 A549 cells (inoculation volume 0.1 mL / mouse) were inoculated. Day 0 was defined as the day of inoculation, and the mean tumor volume was 142.96 mm². 3 At this point (13 days after cell inoculation), patients were randomized according to tumor size as shown in Table 6 below (administered at a volume of 10 μL / g):

[0230] [Table 6]

[0231] 3.3 Experimental observation and data collection Following tumor inoculation, routine monitoring included tumor growth and the impact of treatment on the animals' normal behavior, as well as the activity level, feeding and water intake, weight gain or loss (weight was measured twice a week), eyes, coat, and other abnormalities of the experimental animals. Any clinical symptoms observed during the experiment were recorded in the original data. Tumor volume calculation formula: Tumor volume (mm²) 3 ) = 1 / 2 × (a × b 2 (where a represents the major axis and b represents the minor axis). The experiment involved collecting data using StudyDirector™ software (version 3.1.399.19, supplied by Studylog System, Inc., S. San Francisco, CA, USA), including measuring the major and minor axes of the tumors and weighing the animals. The raw data was measured using a balance and calipers and then directly imported into the software, with any changes in the data being recorded in the software.

[0232] 3.4 Treatment of animal weight reduction during experiments If an animal's body weight decreased by more than 15% (BWL ≥ 15%), that animal / the animals in that group were given a drug-free period until the weight loss recovered to within 15% (BWL < 15%). One mouse was euthanized in accordance with animal welfare standards if its weight loss was >20%.

[0233] 3.5 Criteria for Evaluating Drug Efficacy The relative tumor growth rate is expressed as T / C (%), which is the percentage of the relative tumor volume or tumor mass between the treatment group and the control group at a given point in time. The formula is: T / C% = TRTV / CRTV × 100% (TRTV: mean RTV of the treatment group, CRTV: mean RTV of the control group, RTV = Vt / V0, where V0 is the tumor volume of the animal at the time of group division and Vt is the tumor volume of the animal after treatment).

[0234] The relative tumor suppression rate is expressed as TGI (%), and the formula for calculation is TGI% = (1 - T / C) × 100% (where T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific point in time, respectively).

[0235] 3.6 Experimental endpoints After the final dose, plasma was collected according to the time points designed in Table 7 (using an EDTA anticoagulant tube (with the esterase inhibitor DDVP added at the time of blood collection)). After the plasma collection at the final time point for the mouse was completed, it was euthanized, the tumor was removed, and it was rapidly frozen and stored.

[0236] [Table 7]

[0237] 3.7 Statistical analysis All experimental results are shown as mean tumor volume ± SEM (mean standard error). Statistical analysis between different groups was performed using the optimal drug treatment point (generally after the last dose). Two-way ANOVA comparisons showed no significant difference in tumor volume between the treatment group and the control group. A p<0.05 value indicates a statistically significant difference. All statistical analyses and graph creation were performed in the R language environment (version 3.3.1). Unless otherwise noted, all tests are two-sided, and a p-value less than 0.05 is considered statistically significant.

[0238] 4. Experimental results 4.1 Research results on the antitumor effects of drugs in a human lung cancer cell A549 subcutaneous transplant tumor model In the solvent control group (Vehicle), the average tumor volume of mice was 1620.93 mm² on day 21 after the start of administration. 3 That is the case. In the docetaxel 20 mg / kg group, the mean tumor volume on day 21 after the start of administration was 564.93 mm². 3 This showed a statistically significant difference compared to the control group (p<0.001), with a relative tumor suppression rate (TGI) of 66.24%. In the 1-Z00 20 mg / kg group, the mean tumor volume on day 21 after the start of administration was 576.02 mm². 3 This showed a statistically significant difference compared to the control group (p<0.001), with a relative tumor suppression rate (TGI) of 64.85%. In the 1-Z00-J 10 mg / kg group, the mean tumor volume on day 21 after the start of administration was 285.12 mm². 3 This showed a statistically significant difference compared to the control group (p<0.001), with a relative tumor suppression rate (TGI) of 83.02%. The tumor growth status of each treatment group and the control group is shown in Tables 8 and 9 and Figure 4 below.

[0239] [Table 8] Note: Data is shown as "mean ± standard error".

[0240] [Table 9] Note: 1. Data is shown as "mean ± standard error". 2. T / C%=TRTV / CRTV×100%;TGI%=(1-T / C)×100%. 3. P-value: Obtained by comparing the tumor volume of the treatment group with the tumor volume of the control group using a two-way ANOVA.

[0241] 4.2 Drug efficacy and hematological study results in a human lung cancer cell A549 subcutaneous transplant tumor model As shown in Table 10 below, compared to the solvent control group, the intravenous injection 20 mg / kg docetaxel group showed a 2- to 3-fold decrease in leukocytes, lymphocytes, monocytes, etc., in mouse blood, demonstrating significant lymphoid toxicity of docetaxel. Compared to the intravenous injection 20 mg / kg docetaxel group, the 10 mg / kg intravenous injection 1-Z00-J showed significantly improved safety for the lymphoid system.

[0242] [Table 10] Note: Data is shown as "mean ± standard error".

[0243] 5. Conclusion of the experiment Compared to general docetaxel injection and 1-Z00, 1-Z00-J exhibits significantly superior efficacy at half the dose. Furthermore, the 1-Z00-J molecule significantly reduces hematological toxicity, such as the reduction of lymphocytes and neutrophils, compared to docetaxel injection.

[0244] Study Example 4: Pharmacokinetic study of single intravenous injection of different compounds in beagle dogs 1. Test sample Compounds relating to this disclosure: 3-L00, 3-M00, 3-N00, 3-O00, 3-R00, and 3-T00. Sample preparation method: To the 80 mg / ampoule test substances 3-L00, 3-M00, 3-N00, 3-O00, and 3-R00, 5% DMSO and 95% physiological saline were added by final volume and dissolved by vortexing to obtain a 1.5 mg / mL dosage preparation. To the 3-T00:120 mg / ampoule test substance, 5% DMSO and 95% physiological saline were added by final volume, and the mixture was dissolved by vortexing to obtain a 1.5 mg / mL dosage preparation.

[0245] 2. Test animals A non-naive grade Beagle dog supplied by Medicilon / MPI Animal Bank: 999M-004.

[0246] 3. Examination Method Administration Method: Body weight was measured before administration, and the dosage was calculated based on body weight. The administration plan is as shown in Table 11 below. Blood collection times were 0.083 h, 1 h, 4 h, 8 h, 24 h, 48 h, 72 h, and 96 h after administration. Blood was collected at specific time points after administration using the jugular vein or other appropriate method, with approximately 1 mL of sample collected from each group. The collected blood samples were placed in EDTA-K2 anticoagulant blood collection tubes, and each group's blood sample required special treatment with the addition of an esterase inhibitor. 200 mM DDVP was added to 1 / 40 of the blood collection volume in the EDTA-K2 anticoagulant blood collection tube (for example, if the blood collection volume was 1 mL, 25 μL of 200 mM DDVP was added). After blood collection, the samples were placed on ice, and the plasma was centrifuged within 1 hour (centrifugation conditions: 2200 g centrifugation force, 10 minutes, 2°C-8°C). Subsequently, drug concentrations in plasma were measured, pharmacokinetic data were calculated, and plasma samples were stored in a -70°C refrigerator before detection.

[0247] [Table 11]

[0248] 4. Test results The pharmacokinetic (PK) results for 3-L00, 3-M00, 3-N00, 3-O00, 3-R00, and 3-T00 in beagle dogs are shown in Figure 5 and Table 12.

[0249] [Table 12]

[0250] The test results clearly show that the exposure levels (AUC) of the dendritic polymers 3-L00, 3-M00, 3-N00, 3-O00, and 3-R00 according to this disclosure are significantly higher than those of 3-T00, indicating a remarkable sustained-release effect. The dendritic polymers according to this disclosure can link to alkyl linkers having nitrogen bonds in their side chains, thereby promoting the release of low molecular weight molecules compared to all-carbon chain linkers.

[0251] Test Example 5: Effects of single intravenous administration of compounds 3, 3-M00 and 3-O00 on platelet count in beagle dogs. 1. Test sample Compounds relating to this disclosure: Compound 3, 3-M00, and 3-O00. Sample preparation method: Compound 3, the test substance at a concentration of 120 mg / ampoule, was dissolved by adding 5% DMSO, 5% Tween 80, and 90% physiological saline by final volume, and then vortexed to obtain a 1.5 mg / mL dosage preparation. To the 80 mg / ampoule test substances 3-M00 and 3-O00, 5% DMSO and 95% physiological saline were added by final volume and dissolved by vortexing to obtain a 1.5 mg / mL dosage preparation.

[0252] 2. Test animals A non-naive grade Beagle dog supplied by Medicilon / MPI Animal Bank: 999M-004.

[0253] 3. Examination Method Administration Method: Before administration, the patient's body weight was measured, and the dosage was calculated based on this weight. The administration plan is as shown in Table 13 below. The drug was administered by slow intravenous injection. Blood was collected from the jugular vein or by another suitable method, and approximately 1 mL was collected in each sample. Whole blood was collected before administration and 24 hours after administration for hematological detection.

[0254] [Table 13]

[0255] 4. Test results [Table 14]

[0256] The test results show that the dendritic polymers 3-M00 and 3-O00 of this disclosure can significantly reduce thrombocytopenia, which is targeted by low molecular weight compound 3. In this test, two of the three beagle dogs in the low molecular weight compound 3 treatment group died after a single intravenous injection of 3 mg / kg of compound 3. On the other hand, no beagle dogs in the dendritic polymer 3-M00 and 3-O00 treatment groups died, further demonstrating that the dendritic polymers of this disclosure significantly improve the safety of low molecular weight compound 3.

[0257] Test Example 6: Therapeutic effects of 3-L00, 3-M00, 3-N00, 3-O00, 3-R00, and 3-T00 on subcutaneous transplant tumors in mice with human acute lymphoblastic leukemia RS4;11. 1. Test sample 3-L00, 3-M00, 3-N00, 3-O00, 3-R00, and 3-T00. Sample preparation method: 3-L00, 3-M00, 3-N00, 3-O00, 3-R00, and 3-T00: 0.25 mL of DMSO was added to each ampoule to dissolve the compound, obtaining a 20 mg / mL active solution. Then, 4.75 mL of physiological saline was added and dissolved by vortexing to obtain a 1 mg / mL dosage preparation.

[0258] 2. Test cells and animals This is human acute lymphoblastic leukemia RS4;11 purchased from the American Type Culture Collection. RS4;11 cells were cultured in 10-cm culture dishes. The culture conditions were RPMI 1640 culture medium (Gibco) with 10% fetal bovine serum (Gibco), penicillin, and streptomycin added, and cultured at 37°C in an incubator with 5% CO2. The cells were passaged twice a week, and when the cells reached the exponential growth phase, they were collected, counted, and inoculated. 5-week-old female NOD-Scid mice purchased from Beijing Huafukang Biotechnology Co., Ltd. Production license number: SCXK(Beijing)2019-0008, animal certificate number: 110322211100992176, 110322211101069023. Breeding environment: SPF grade. The use and welfare of the experimental animals were carried out in accordance with the regulations of the "Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)". The health status and death status of the animals were monitored daily. The routine examination included the observation of the effects of the test substances and drugs on the daily behavior manifestations of the animals, such as behavioral activities, weight changes, and external signs.

[0259] 3. Test method 1×10 7 RS4;11 cells were inoculated subcutaneously into each mouse. When the tumor grew to 150 - 200 mm 3 , they were grouped according to tumor volume, and the drug was injected intravenously (IV) once a week (QW) for a total of 4 times. The injection volume was 0.1 mL / 10 g of body weight. The dosage and administration schedule are shown in Table 15 below. The experimental indicators were for examining the effect of the drug on tumor growth. The specific indicators were T / C% or tumor growth inhibition rate (TGI%).

[0260] The diameter of the tumor was measured with a caliper twice a week. The calculation formula for tumor volume (V) is as follows: V = 1 / 2 × a × b 2 Among them, a and b represent the length and width respectively. T / C(%)=(T - T0) / (C - C0)×100

[0261] Among them, T and C are the tumor volumes at the end of the experiment, and T0 and C0 are the tumor volumes at the start of the experiment. Tumor growth inhibition rate (TGI)(%) = 100 - T / C(%).

[0262]

Table 15

[0263] 4. Test results [Table 16]

[0264] As is evident from the test results, in a human acute lymphoblastic leukemia RS4;11 mouse subcutaneous tumor model, 3-T00 was unable to effectively release low molecular weight compound 3 and lacked antitumor activity, while the linkers 3-L00, 3-M00, 3-N00, 3-O00, and 3-R00 were able to effectively promote the release of low molecular weight compound 3 and exhibited significant antitumor activity.

Claims

1. i) A dendritic polymer D having surface amino groups, wherein at least two different terminal groups are covalently bonded to the surface amino groups, ii) A pharmaceutically active agent containing a hydroxyl group, an amino group, or a sulfhydryl group, or a first terminal group which is residue A thereof, iii) A polymer comprising a second terminal group which is a pharmacokinetic modifier, Among them, the first terminal group is a linker -X １ -L-X ２ - is covalently bonded to the surface amino group of the dendritic polymer, and X １ is a linking group between the linker and the pharmaceutically active agent or its residue A, and X ２ is a linking group between the linker and the dendritic polymer D, and X １ and X ２ are both -C(O)-, L is C １－１０ a linear or branched alkylene group, among which the C １－１０ linear or branched alkylene group is substituted with one or more -NR １ R ２ and R １ , R ２ These are, independently, hydrogen, a hydroxyl group, and C １－６ Alkyl alkyl groups, cycloalkyl groups, and C １－６ Selected from the group consisting of alkoxy groups, The dendritic polymer D is selected from polylysine, The pharmacokinetic modifier is polyethylene glycol. The polymer.

2. i) A dendritic polymer D having surface amino groups, wherein at least two different terminal groups are covalently bonded to the surface amino groups, ii) A pharmaceutically active agent containing a hydroxyl group, an amino group, or a sulfhydryl group, or a first terminal group which is residue A thereof, iii) A polymer comprising a second terminal group which is a pharmacokinetic modifier, Of these, the first terminal group is a linker -X １ -L-X ２ - is covalently bonded to the surface amino groups of the dendritic polymer, X １ X is a linking group between the linker and the pharmaceutically active agent, ２ X is a linking group between the linker and the dendritic polymer, １ and X ２ Both are -C(O)-, and L is C １－１０ A linear or branched alkylene group, and the C １－１０ The linear or branched alkylene group is one or more -NR １ R ２ Replaced by, R １ , R ２ These are, independently, hydrogen, a hydroxyl group, and C １－６ alkyl group, C ３－７ Cycloalkyl groups, C １－６ Alkoxy groups and C(O)R ４ Selected from the group consisting of the above C １－６ alkyl group, C ３－７ Cycloalkyl groups and C １－６ The alkoxy group can optionally consist of a hydroxyl group, a halogen, or C. １－６ alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy groups, nitro groups, cyano groups, amino groups, and C １－６ Substituted with one or more substituents selected from the group consisting of alkylamino groups, R ４ is hydrogen, C １－６ alkyl group, C １－６ Haloalkyl and C １－６ Selected from the group consisting of alkoxy groups, The dendritic polymer D is selected from polylysine, The pharmacokinetic modifier is polyethylene glycol. The polymer.

3. Said C １－１０ One or more linear or branched alkylene groups -NR １ R ２ It is replaced by, and of those, R １ , R ２ However, hydrogen and C are independent of each other. １－６ Alkyl and C(O)R ４ Selected from the group consisting of R ４ is hydrogen, C １－６ alkyl group, C １－６ Haloalkyl and C １－６ Selected from the group consisting of alkoxy groups, The polymer according to claim 2.

4. R １ , R ２ However, hydrogen and C are independent of each other. １－６ Selected from the group consisting of alkyl groups, and R １ , R ２ They cannot become hydrogen at the same time. The polymer according to claim 1 or 2.

5. Said C １－１０ A linear or branched alkylene group is C １－６ It is a linear or branched alkylene group. The polymer according to claim 1 or 2.

6. Linker -X １ -L-X ２ - In X １ is -C(O)- and is linked to a pharmaceutical activator or its residue A, X ２ It is -C(O)- and links to the surface amino groups of the dendritic polymer D to form an amide bond, and the structure of the polymer is 【Chemistry 1】 The polymer according to claim 1.

7. The aforementioned pharmaceutical activators are selected from the group consisting of anesthetics, antacids, antibodies, anti-infective drugs, biological products, cardiovascular drugs, contrast agents, diuretics, blood tonics, immunosuppressants, hormones, nutritional products, ophthalmic drugs, pain relievers, respiratory drugs, adjuvants, anti-arthritis drugs, anticonvulsants, antihistamines, anti-inflammatory drugs, anti-ulcer drugs, behavior modifiers, antitumor drugs, central nervous system drugs, contraceptives, diabetes medications, reproductive drugs, growth promoters, hemostatic agents, immunostimulants, muscle relaxants, obesity treatments, osteoporosis drugs, peptides, sedatives and tranquilizers, urethral acidifiers, and vitamins. The polymer according to claim 1 or 2.

8. The polymer according to claim 7, wherein the pharmaceutically active agent is selected from antitumor drugs.

9. The aforementioned pharmaceutical activators include taxane-based drugs, camptothecin derivatives, nucleoside-based drugs, anthracycline-based drugs, proteasome inhibitors, microtubule inhibitors, BCL-2 inhibitors, and BCL-X. Ｌ Selected from the group consisting of inhibitors, selective nuclear export inhibitors, antimetabolites, tyrosine kinase inhibitors, PLK1 inhibitors, CDK4 / 6 inhibitors, BTK inhibitors, nonsteroidal hormone receptor antagonists, and steroids. The polymer according to claim 1 or 2.

10. The aforementioned pharmaceutical activators include taxane-based drugs, camptothecin derivatives, BCL-2 inhibitors, and BCL-X Ｌ A polymer according to claim 9, selected from the group consisting of inhibitors.

11. The aforementioned pharmaceutical activators are docetaxel, irinotecan, gemcitabine, capecitabine, decitabine, azacitidine, doxorubicin, epirubicin, bortezomib, eribulin, selinexa, venetoclax, tesetaxel, pemetrexed, cabazitaxel, cabozantinib, onbansertive, and the following compounds 2 and 3, namely, 【Chemistry 2】 Selected from the group consisting of, The polymer according to claim 1 or 2.

12. The aforementioned pharmaceutical activator is docetaxel, compound 2, or compound 3. The polymer according to claim 11.

13. Polyethylene glycol has a molecular weight in the range of 220 Da to 5500 Da. The polymer according to claim 1 or 2.

14. Polyethylene glycol has a molecular weight in the range of 1000 Da to 5500 Da. The polymer according to claim 13.

15. Polyethylene glycol has a molecular weight in the range of 1000 Da to 2500 Da. The polymer according to claim 14.

16. The polylysine comprises a core and 2nd to 7th generation lysine. The polymer according to claim 1 or 2.

17. The aforementioned dendritic polymer D is BHALys[Lys] １６ , BHALys[Lys] ３２ and BHALys[Lys] ６４ Selected from the group consisting of, The polymer according to claim 16.

18. A polymer according to any one of claims 1 to 17 and a pharmaceutically acceptable vector, Pharmaceutical composition.

19. Use of a polymer according to any one of claims 8 to 12 in the preparation of a drug for treating tumors.

Images