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CN109106951A - A kind of camptothecine-antibody coupling matter - Google Patents

A kind of camptothecine-antibody coupling matter Download PDF

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Publication number
CN109106951A
CN109106951A CN201810943764.2A CN201810943764A CN109106951A CN 109106951 A CN109106951 A CN 109106951A CN 201810943764 A CN201810943764 A CN 201810943764A CN 109106951 A CN109106951 A CN 109106951A
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China
Prior art keywords
compound
camptothecine
antibody
pharmaceutically acceptable
acceptable salt
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Inventor
朱义
李�杰
万维李
卓识
李刚锐
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Chengdu duote antibody medicine Co.,Ltd.
Sichuan Baili Pharmaceutical Co Ltd
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Sichuan Baili Pharmaceutical Co Ltd
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Abstract

The invention discloses a kind of camptothecine-antibody coupling matter, such ADC drug can effectively improve its drugloading rate, while above-mentioned clustering phenomena being avoided to occur, and improve drug PK, obtain ideal drug effect in model in vivo.

Description

A kind of camptothecine-antibody coupling matter
Technical field
The present invention relates to application camptothecine-antibody coupling matters to treat tumour or other diseases, more particularly to application A kind of special hydrophily Exatecan antibody coupling matter reduces aggregation to increase stability of the drug in blood plasma, improves medicine Object dynamic metabolism (PK).
Background technique
Antibody coupling drug (ADC) is generally consisted of three parts as novel targeted drug: antibody or antibody class are matched Body, small-molecule drug and the connexon that ligand and drug coupling get up.Spy of the antibody coupling drug utilization antibody to antigen Drug molecule is transported near target cell and drug molecule is released effectively, reaches therapeutic purposes by opposite sex identification.In August, 2011, What approval Seattle Genetics Inc. of U.S. Food and Drug Administration (FDA) developed is used to treat Hodgkin lymphoma and answers The ADC new drug Adecteis of hair property denaturation large celllymphoma (ALCL)TMListing, clinical application have been proven that such drug Safety and validity.
DNA topoisomerase I inhibitor Exatecan is camptothecin derivative, by the one or three company's exploitation altogether, early period It is used as independent chemotherapeutics and is advanced into three phases clinic, principal indication is osteocarcinoma, prostate cancer, breast cancer, cancer of pancreas etc.. However, fat-solubility, low aqueous solubility seriously affects it and uses curative effect as most of camptothecines.In addition, as opening up Isomerase inhibitors are flutterred, the specificity to tumour cell is lacked, it is big using side effect, limit its clinical application.Increase water-soluble Property, improve the big advantage that targeting is ADC class drug.The combination of specific antibody and antigen carries toxin to target cell Around, by discharging toxin near target cell, tumour cell is effectively killed, reduces toxic side effect.Therefore, Exatecan exists There is considerable application prospect in ADC drug.
Another key factor in antibody-drug conjugates design is the amount for the drug that each targeting agent can deliver (that is, be connected to the quantity of the cytotoxic agent of each targeting agent (for example, antibody), referred to as drug carrying capacity (drug load) or drugloading rate (drugloading)).Once there is hypothesis to think, higher drug carrying capacity will be better than lower drug carrying capacity (for example, 8- unit Carrying capacity compares 4- unit carrying capacity).The theory is that the higher conjugate of drugloading rate will deliver more drug (cells to target cell Toxic agent).The theory is supported by observing result as follows: being had in vitro for cell line with the conjugate compared with high drug load higher Activity.However, subsequent certain researchs disclose, which is not confirmed in animal model.Observe that there is certain The conjugate of 4 or 8 unit medicament carrying capacity of auspicious statin difficult to understand has shares activity in mouse model.See, for example, Hamblett Deng the ADC that Clinical Cancer Res.10:7063-70 (2004) .Hamblett etc. further reports higher carrier exists Circulation will be cleared out of faster in animal model.The faster substance for showing higher carrying capacity of removing is compared to lower carrying capacity The PK of substance more unstable tendency, referring to Hamblett etc..In addition, the conjugate of higher carrying capacity have in mouse it is lower MTD, and therefore there is relatively narrow report therapeutic index.On the contrary, carrying medicine at site engineered in report monoclonal antibody Amount has identical or better PK property and therapeutic index compared with certain 4- unit carrying capacity ADC for 2 ADC.For example, with reference to Therefore, recent trend is that exploitation has low load medicine to Junutula etc., Clinical Cancer Res.16:4769 (2010) The ADC of amount.
Exatecan belongs to moderate toxicity class drug, and such medicinal application can be reduced in ADC and be brought because toxin falls off Toxic side effect.To reach ideal therapeutic effect, compared with common hypertoxic type drug ADC, Exatecan ADC drug is improved It is insufficient that antibody ratio (DAR) can make up moderate toxicity bring drug effect.However, will definitely increase because of the fat-soluble increase of high DAR according to happiness For assembling in health class ADC body, drug effect is reduced instead.Patent CN104755494 describes a kind of Exatecan ADC, and core is Using tetrapeptide as endonuclease bamhi, collocation ammonia methoxyl group is that self eliminates structure, realizes DAR=8 using non-site-directed coupling technology.So And defect is it is clear that at high DAR, molecular hydrophylic deficiency causes drug effect in Exatecan ADC body to reduce.
The present inventor on the basis of to Exatecan class ADC Integrated Understanding, design it is a kind of with hydrophilic unit according to Health ADC is replaced in happiness, and has surprisingly found that such ADC drug can effectively improve its drugloading rate, while avoid above-mentioned aggregation by experiment Phenomenon occurs, and improves drug PK, obtains ideal drug effect in model in vivo.
Summary of the invention
The present invention is intended to provide a kind of hydrophilic Exatecan antibody coupling matter, different from CN104755494, nitrogen-containing heterocycle with Using molecular hydrophylic is significantly increased while PEG, so that the Exatecan conjugate of high DAR has better PK and medicine Effect.Specifically, the present invention provides a kind of antibody drug conjugates or its pharmaceutically acceptable salt shown in formula I:
Wherein
Ab is antibody, antibody fragment or albumen；
L1 is the hydrophilic extension apparatus of nitrogen-containing heterocycle and PEG composition,
A, A1 is l-amino acid, and the integer of n 0,1,2,3,4, m is the integer of 1-8
L2 is that self eliminates unit；
L3 is spacer units；
D is drug Exatecan, is connected with 1 bit amino with L3, and wave indicates the link position with L3
In another preferred example, L1 includes with flowering structure:
Wherein A is optional extension apparatus, and Ar is nitrogen-containing heterocycle, and BB1 is hydrophilic amino acid or is made of hydrophilic amino acid Oligopeptides, it is the integer of 1-30, left and right wave respectively indicates the company with succimide and AA1 that p, which is PEG number of repeat unit, Site, a, b are connect, c is selected from 0,1.And a+b+c >=2.
In another preferred example, AA1 is selected from group consisting of: alanine, arginine, asparagine, aspartic acid, half Cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylpropyl alcohol ammonia Acid, proline, serine, threonine, tryptophan, tyrosine, valine.
In another preferred example, BB1 is selected from group consisting of: lysine, arginine, histidine, aspartic acid, paddy ammonia In another preferred example, wherein self eliminates unit and is selected from the group being made up of: ethanol amine, 4- hydroxy-benzyl alcohol, 4- amino acid Benzylalcohol, ethylenediamine and substituted ethylenediamine.
In another preferred example, wherein the PEG is the PEG with the determination of 1-30 monomeric unit, preferably The PEG of determination with 1-12 monomeric unit.
In another preferred example, AA1 is peptide moiety, it is therefore preferable to which dipeptides is selected from Val-Cys, Val-Alt.
In another preferred example, Ar is nitrogen-containing heterocycle, it is therefore preferable to triazole, tetrazole and with flowering structure
In another preferred example, substituted ethylenediamine includes with flowering structure:
In another preferred example, L3 preferably is selected from
Left and right wave respectively indicates the connection site that unit and 1 bit amino of drug Exatecan are eliminated with self.
Specific embodiment
Abbreviation and definition
Unless otherwise stated, following term as used herein and phrase are intended to have following meanings.When herein When using brand name, unless otherwise indicated in context, otherwise brand name includes that the product of the brand name product is matched Side, universal medication and active pharmaceutical ingredient.
Term " alkylidene " refers to the divalent straight saturated hydrocarbons group with 1-20 carbon atom, including from 1 to 10 carbon original The group of son.The embodiment of alkylidene group includes but is not limited to methylene (- CH2-), ethylidene (- CH2-CH2-), Asia positive third Base, sub- normal-butyl, sub- n-pentyl and sub- n-hexyl.Unless otherwise indicated, term " aryl " refers to how unsaturated, is usually aromatics Hydroxyl groups, it can be monocycle or condensed or polycyclic (at most three rings) that be covalently attached.Term " heterocyclic base " refers to containing 1-5 A heteroatomic aryl (or ring) selected from N, O or S, wherein the nitrogen and sulphur atom are optionally oxidized, the nitrogen-atoms is optional It is quaternized.Heteroaryl group can be connected to the rest part of molecule by hetero atom.The non-limitative example of aryl group includes: Phenyl, naphthalene and diphenyl, and the non-limitative example of heteroaryl group includes: pyridyl group, pyridazinyl, pyrazinyl, pyrimidine radicals (pyrimindinyl), triazine radical, quinolyl, quinoxalinyl, quinazolyl, cinnoline base, phthalazinyl (phthalaziniyl), It is phentriazine base, purine radicals, benzimidazolyl, benzopyrene oxazolyl, benzotriazole base, benzo isoxazolyl, isobenzofuran-base, different Indyl, indolizine base, phentriazine base, thienopyridine base, Thienopyrimidine base, Pyridopyrimidine base, imidazopyridine, benzene Benzothiazolyl (benzothiaxolyl), benzofuranyl, benzothienyl, indyl, quinolyl, isoquinolyl, isothiazole Base, pyrazolyl, indazolyl, pteridyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, thiadiazolyl group, pyrrole radicals, Thiazolyl, furyl and thienyl etc..When being described as " substituted ", the substituent group of above-mentioned aromatic ring and heteroaromatic ring system is selected From following acceptable substituent groups.
Unless otherwise indicated herein, alkyl (including being typically referred to as those of alkylidene, alkenyl, alkynyl and naphthenic base) Substituent group can be a variety of groups selected from the group below :-halogen ,-OR ' ,-NR ' R " ,-SR ' ,-SiR ' R " R " ' ,-OC (O) R ' ,-C (O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O)2R’、-NH-C (NH2)=NH ,-NR ' C (NH2)=NH ,-NH-C (NH2)=NR ' ,-S (O) R ' ,-S (O)2R’、-S(O)2NR’R”、-NR’S(O)2R " ,-CN and-NO2, substituent group quantity is 0 to (2m '+1), and wherein m ' is the sum of carbon atom in the group.R ', R " and R " ' it is each From independent reference hydrogen, unsubstituted C1-8Alkyl, unsubstituted aryl, aryl, the unsubstituted C replaced by 1-3 halogen1-8 Alkyl, C1-8Alkoxy or C1-8Thio alkoxy or unsubstituted aryl-C1-4Alkyl.R ' and R " is connected to the same nitrogen-atoms When, they can be formed together 3-, 4-, 5-, 6- or 7- member ring with the nitrogen-atoms.For example,-NR ' R " includes 1- pyrrolidinyl and 4- Morpholinyl.
" derivative " of compound used herein refers to chemical structure similar with compound but also containing extremely Lack the chemical group being not present in a compound and/or the substance for lacking chemical group present at least one compound. The compound that derivative is compared is referred to as " parent " compound.In general, " derivative " can be in one or more chemical reaction step It is generated in rapid by parent compound.
L- ligand
With the targeting agent that body unit is with target moiety specific binding.The ligand can be specifically bound to groups of cells Divide or is bound to cellular component or is bound to other interested target molecules.Target moiety or target are usually in cell surface On.In certain aspects, the effect with body unit is that drug unit is delivered to the particular target interacted therewith with body unit Cell mass.Ligand includes but is not limited to protein, polypeptide and peptide and nonprotein such as sugar.It suitably include example with body unit Such as, antibody, such as overall length (complete) antibody and its antigen-binding fragment.It is being the embodiment party of non-antibody target reagent with body unit In formula, peptide or polypeptide or non-proteinaceous molecule can be.The example of this kind of targeting agent includes interferon, lymphokine, swashs Element, growth factor and colony stimulating factor, vitamin, Nutrient transport molecule or any other cell binding molecule or substance.? In some embodiments, connexon is covalently attached to the sulphur atom of ligand.In certain aspects, sulphur atom is cysteine residues Sulphur atom, formed antibody interchain disulfide bond.In another aspect, sulphur atom is to have been introduced into the half Guang ammonia with body unit The sulphur atom of sour residue forms the interchain disulfide bond of antibody.In another aspect, sulphur atom has been introduced into body unit The sulphur atom (for example, passing through direct mutagenesis or chemical reaction) of cysteine residues.In in other respects, the sulphur of connexon combination Atom is selected from the cysteine residues for forming the interchain disulfide bond of antibody or has been incorporated into the volume cysteine residues with body unit (for example, passing through direct mutagenesis or chemical reaction).In some embodiments, according to Kabat (Kabat E.A etc., (1991)) " the interested protein sequence of immunology " (Sequences of proteins of Immunological Interest), 5th edition, NIH publication 91-3242) in EU index number system.
As used herein, in the range of " antibody " or " antibody units " belonging to it, any part including antibody structure. This unit can combine, reactivity association, or complexing one receptor, antigen, or targeting cell colony have it is other Receptor unit.Antibody can be any albumen or proteinaceous molecule, it can be combined, complexing, or with it is to be treated or biological change The a part for the cell colony made reacts.
The antigen binding energy when antibody of antibody drug conjugates is preferably maintained in its original wild state is formed in the present invention Power.Therefore, the present invention in antibody can, best specificity and antigen binding.The antigen being related to includes, for example, tumour phase It closes antigen (TAA), cell surface receptor protein and other cell surface molecules, cell survival regulatory factor, cell Proliferation is adjusted The factor, and tissue growth and the relevant molecule of differentiation (as known or precognition with functional), lymphokine, cell because Son participates in the molecule that cell cycle is adjusted, and participates in the molecule of angiogenesis, and (such as known with the molecule of associated angiogenesis Or precognition have it is functional).Tumor related genes can be cluster differentiation factor (such as CD albumen).With it is heretofore described
The antibody in antibody drug conjugates is applied to include, but are not limited to, for cell surface receptor and tumour phase Close the antibody of antigen.Such tumor associated antigen be it is known in the industry, can pass through in the industry known to preparation method for antibody It is prepared with information.In order to develop the effective cellular level object that can be used for cancer diagnosis and treatment, researcher tries hard to Look for cross-film or other tumor relative polypeptides.These objects are capable of the expression of specificity in one or more cancer cell surfaces, And one or more non-cancerous cells surface expressions seldom or do not express.In general, for non-cancerous cells surface, it is such Tumor relative polypeptide is more over-expressed in cancer cell surfaces.Confirm such tumor related genes, is greatly improved based on anti- The single-minded targeting characteristic of body treating cancer.
Tumor associated antigen includes, but are not limited to tumor associated antigen (1)-(36) being listed below.For convenience, It is as follows for antigen relevant information mark known in the industry, including title, other titles, Genbank accession number.It is related to tumour The corresponding nucleic acid of antigen and protein sequence can be found in public database, such as Genbank.The corresponding tumour correlation of antibody target is anti- Original includes all amino acid sequence mutation and of the same race, has at least 70%, 80% with the sequence confirmed in bibliography, 85%, 90% perhaps 95% homology or have with the tumor associated antigen sequence in citation have it is completely the same Biological property and feature.
Term " inhibition " or " inhibition " refer to, reduce detectable amount, or prevent completely.
Term " cancer " refers to the physiological condition or disease characterized by the growth of the cell of imbalance." tumour " includes that cancer is thin Born of the same parents.
Term " autoimmune disease " is derived from the disease or disorder of tissue or protein for individual itself.
Phrase " pharmaceutically acceptable salt " used herein refer to compound (for example, drug, agent-linker or Ligand-linker-drug conjugate) pharmaceutical acceptable to organic or inorganic salt.The compound can contain at least one amino Or carboxyl, and therefore addition salts can be formed with corresponding acid or alkali.Illustrative salt includes but is not limited to: sulfate, trifluoro Acetate, citrate, acetate, oxalates, chloride, bromide, iodide, nitrate, disulfate, phosphate, acid Acid phosphate, isonicotinic acid salt, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenic acid Salt, biatrate, ascorbate, salicylate, formates, this formates, glutamate, mesylate, esilate, Benzene sulfonate, tosilate, sylvite, sodium salt etc..In addition, pharmaceutically acceptable salt has in the structure more than one Band point atom.Plurality of charge atom is that the example of a part of pharmaceutically acceptable salt can have multiple counterions.Example Such as, there are pharmaceutically acceptable salt one or more charge atoms and/or one or more to contend with atom.
According to the mechanism of drug release in the cell, as used herein, " connexon " or " connection of antibody drug conjugates Son " can be divided into two classes: can not be broken connexon and can be broken connexon.
For containing the antibody drug conjugates that can not be broken connexon, mechanisms for drug release are as follows: conjugate and antigen In conjunction with by after cell endocytic, antibody is not digested in lysosome, release by small-molecule drug, connexon and antibody ammonia The bioactive molecule that base acid residue collectively constitutes.Thus bring drug molecular structure, which changes, does not weaken its cytotoxicity, but by It is electrically charged (amino acid residue) in bioactive molecule, adjacent cells cannot be penetrated into so as to cause it.Therefore, such active medicine Neighbouring tumour cell (bystander effect, the bystander for not expressing targeting antigen (antigen negative cells) cannot be killed Effect) (Ducry etc., 2010, Bioconjugate Chem.21:5-13).
It can be broken connexon, as its name suggests, can be broken in target cell and release active medicine (small-molecule drug Itself).Connexon, which can be broken, can be divided into two main classifications: chemically unstable connexon and the unstable connexon of enzyme.
Chemically unstable connexon can the fracture of selectivity due to the difference of blood plasma and cytoplasm property.Such property Matter includes pH value, glutathione concentrations etc..
To the connexon of pH sensitive, also commonly known as acid fracture connexon.Neutral ring of such connexon in blood (pH7.3-7.5) relatively stable under border, but in weakly acidic endosome (pH5.0-6.5) and lysosome (pH4.5-5.0) It will be hydrolyzed.The antibody drug conjugates of the first generation apply this kind of connexon, such as hydrazone, carbonic ester, acetal, ketal mostly Class.Due to acid be broken the limited plasma stability of connexon, the antibody drug conjugates based on such connexon usually have compared with Short half-life period (2-3 days).This shorter half-life period limits pH sensitive linker in antibody of new generation to a certain extent Application in drug conjugates.
For the connexon of glutathione sensitivity, also known as disulfide bond connexon.Drug release is based on intracellular gluathione In the high concentration (mM range) and blood of peptide caused by relatively low glutathione concentrations (micro-molar range) difference.It is right Especially true for tumour cell, low oxygen content leads to the increased activity of reductase, thus leads to higher glutathione Concentration.Disulfide bond has thermodynamic stability, therefore has preferable stability in blood plasma.
The unstable connexon of enzyme being capable of better Drug controlled release such as peptide connexon.Peptide connexon can be by lysosome Interior protease has such as cathepsin (Cathepsin B) or fibrinolysin (this fermentoid content increases in some tumor tissues) The cutting of effect.This peptide connection is considered highly stable in plasma circulation, this is because extracellular inapt pH value and blood Albumosease inhibitor causes protease not have activity usually.In view of higher plasma stability and good intracellular fracture Selectivity and validity, what the unstable connexon of enzyme was used as antibody drug conjugates extensively is broken connexon.Typical enzyme Unstability connexon includes Val-Cit (vc), Phe-Lys etc..
Suicide connexon, which is generally entrenched in, to be broken between connexon and active medicine, or inherently can the company of fracture Connect a part of son.The mechanism of action of suicide connexon is: after can be broken connexon and be broken under conditions of suitable, suicide Formula connexon can be spontaneous carry out structural rearrangement, and then discharge the active medicine that is attached thereto.Common suicide connexon Including to aminobenzyl alcohol class (PAB) and beta-glucuronidase class (β-Glucuronide) etc..
Present invention will be further explained below with reference to specific examples, it should be appreciated that these embodiments are served only for illustrating this hair It is bright, rather than limit the scope of the invention.The test method of actual conditions is not specified in the following example, usually according to routine Condition or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number By weight.Unless otherwise defined, it is as used herein it is all profession and science be used for known to one skilled in the art Meaning is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Text Described in preferred implement methods and materials be for illustrative purposes only.
The general step used in the following example of the present invention is:
General step A
Non- site-directed coupling method, monomer is greater than 95% antibody after preliminary purification, changes liquid to PBS, concentration 10mg/ The TCEP/DTT of 50 times of molar equivalents, 25 DEG C of incubation 4h are added in mL, to open the disulfide bond of antibody, are measured with Ellman method Free sulfhydryl groups number determines that disulfide bond fully opens.After the completion of reduction, the small molecule to be coupled of 10 times of molar equivalents is added, 25 DEG C incubate 16h is educated, after the completion of coupling, removes excessive small molecule with the ultra-filtration centrifuge tube of 30KDa.
General step B
Pharmacokinetic
Pharmacokinetics (PK) experiment is carried out using radiolabeled antibody or ADC.PK test substances are using as follows Method carries out radioactive label.Think 500mM potassium phosphate (pH8.0) and 55 μ of antibody and the addition of ADC solution in 500mM sodium chloride Ci N- succinimidyl propionate, [propionic ester -2,3-3H]-(Moravek chemical company, catalog number (Cat.No.): MT 919,80Ci/ Mmol, 1mCi/mL, 9:1 hexane: ethyl acetate)/mg antibody or ADC.Gained mixture is handled through vortex, and it is small to be placed at room temperature for 2 When.Mixture is separated with 4000xg centrifugation 5 minutes to Amicon Ultra-15 centrifugal filter unit) (Mi Libo (millipore), catalog number (Cat.No.): UFC903024,30kDa MWCO).The radioactive activity not being coupled by 4 wheel dilution and with 4000xg centrifugation removes.Resulting product is filtered through sterile 0.22 μm of Ultrafree-MC eccentricity its unit Mi Libo, mesh Record UFC30GVOS), and final antibody or ADC concentration are measured by spectrophotometry.The ratio of each product (μ Ci/mg) living is adopted It is counted and is measured with liquid scintillation.
General step C
Hydrophobic interaction chromatography
The analysis to ADC is carried out using hydrophobic interaction chromatography (HIC).Pass through 0-100% Mobile phase B (MPB) De-, wherein mobile phase A (MPA) is made of 1.5M ammonium sulfate and .025M sodium phosphate, and MPB by 0.025M sodium phosphate, 25% Isopropanol composition.Sample applied sample amount is about 20 μ g, and gradient elution was completed at 15 minutes.It is detected with UV280nm, water transport property is got over The more late appearance of strong sample.
Embodiment 1
The synthesis of compound 1
6- (dimaleoyl imino) caproic acid succinimide ester (MC-OSu, 30g, 0.097mol) is dissolved in 200ml dichloro In methane, propargylamine (5.9g, 0.1mol), DIEA (24mL, 0.146mol) are added, is stirred to react at room temperature.TLC(PE:EA =1:1) monitoring.After fully reacting, filtrate is collected in filtering, and purified water 200mL, then the hydrochloric acid with 1mol/L are added into filtrate It is water-soluble in adjust pH to 5~6, liquid separation, saturation NaCl washing dichloromethane layer to neutrality, crude product is concentrated under reduced pressure to obtain at 40 DEG C.Slightly Product obtain white solid sterling 7.5g through silica gel column chromatography (eluant, eluent PE/EA=3/1~2/1~1/1).LC-MSm/z (ES+): 249.1 (M+H)+
Embodiment 2
The synthesis of compound 2
By compound 1 (7g, 0.028mol), nitrine polyethylene glycol carboxyl (N3-PEG8- COOH, 6.62g, 0.014mol), Cuprous iodide (3.37g) is dissolved in 200mL methylene chloride, and room temperature is slowly added dropwise DIEA (2.8mL, 0.017mol), is dripped and is finished room temperature Reaction, TLC (DCM:MeOH=8:1) monitoring process.Post-processing, filtering, filtrate decompression is concentrated to give crude product, through silica gel column chromatography color Spectrum (eluant, eluent DCM/MeOH=100/1~50/1~10:1) obtains product 9g.LC-MS m/z(ES+): 716.4 (M+H)+
Embodiment 3
The synthesis of compound 3
By compound 1 (7g, 0.028mol), nitrine polyethylene glycol carboxyl (N3-PEG4- COOH, 4.07g, 0.014mol), Cuprous iodide (3.37g) is dissolved in 200mL methylene chloride, and room temperature is slowly added dropwise DIEA (2.8mL, 0.017mol), is dripped and is finished room temperature Reaction, TLC (DCM:MeOH=8:1) monitoring process.Post-processing, filtering, filtrate decompression is concentrated to give crude product, through silica gel column chromatography color Spectrum (eluant, eluent DCM/MeOH=100/1~50/1~10:1) obtains product 7.7g.LC-MS m/z(ES+): 539.1 (M+H)+
Embodiment 4
The synthesis of compound 4
Compound 6- maleimidocaproic acid (6g, 28.4mmol) is dissolved in 100mL tetrahydrofuran, N- is sequentially added Methyl morpholine (5.74g, 56.8mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI, 6.52g, 34mmol), 10mL cyanamide is added dropwise at lower 0 DEG C of nitrogen protection by I-hydroxybenzotriazole (HOBt, 4.63g, 34mmol) The THF solution of (3.15g, 56.8mmol) drips and finishes room temperature reaction, TLC (solvent PE/EA=1/1) monitoring process.Post-processing, Filtering, filtrate decompression are concentrated to give crude product, obtain product 6g through silica gel column chromatography (eluant, eluent PE/EA=15/1~10/1). LC-MS m/z(ES+): 250.1 (M+H)+
Embodiment 5
The synthesis of compound 5
Compound 4 (5g, 0.02mol), cysteine (4.84g, 0.04mol) are dissolved in 100mL methanol and 0.1M phosphoric acid In the mixed liquor (v/v=1/1) of sodium buffer, 40 DEG C of nitrogen protection reactions, TLC (DCM:MeOH=10:1) monitoring process.Afterwards Processing, filtering, filtrate decompression concentration remove methanol, dilute hydrochloric acid are added under residue addition cooling condition and adjusts pH to 4 or so, with two Chloromethanes extraction, organic layer are dried, filtered with saturated common salt water washing, anhydrous sodium sulfate, are concentrated to get product 5.1g.LC-MS m/z(ES+): 354.1 (M+H)+
Embodiment 6
The synthesis of compound 6
Compound 5 (5g, 14.1mmol) is dissolved in 60mL tetrahydrofuran, sequentially add N-methylmorpholine (2.86g, 28.2mmol), it is poly- that 20mL amino is added dropwise at lower 0 DEG C of nitrogen protection by EDCI (3.25g, 17mmol), HOBt (2.31g, 17mmol) Ethylene glycol carboxyl (NH2-PEG8- COOH, 7.52g, 17mmol) THF solution, drip finish room temperature reaction, TLC (solvent DCM/ MeOH=6/1) monitoring process.Post-processing, filtering, filtrate decompression is concentrated to give crude product, through silica gel column chromatography (eluant, eluent DCM/ MeOH=30/1~10/1) obtain product 8.3g.LC-MS m/z(ES+): 777.3 (M+H)+
Embodiment 7
The synthesis of compound 7
By compound N-benzyloxycarbonyl group-L-phenylalanine (30g, 0.1mol), n-hydroxysuccinimide (HOSu, 13.3g, 0.115mol), N, N'- Dicyclohexylcarbodiimide (DCC, 24g, 0.115mol) is sequentially added into 1L single port bottle, It adds 500mL tetrahydrofuran (THF), is reacted at room temperature under nitrogen protection, TLC (DCM/MeOH=10/1) monitors reaction process. End of reaction, filtering, filtrate decompression are concentrated to give crude product, and crude product is stirred with the tertiary ether of first and washes to obtain white solid 37.8g.LC-MSm/z(ES+): 419.1 (M+Na)+
Embodiment 8
The synthesis of compound 8
By compound N-ε-Boc-L- lysine (14.3g, 0.058mol), sodium bicarbonate (12.4g, 0.117mol), 300mLTHF is added into 1L single port bottle, and the THF solution of 200mL compound 7 (35g, 0.087mol) is added dropwise at room temperature, drips and finishes room Temperature reaction, TLC (DCM/MeOH=8/1) monitor reaction process.Post-processing: the potassium hydrogen sulfate solution of 1M is added into reaction solution 300mL is extracted with ethyl acetate (400mLx3), merges organic phase, and with saturated common salt water washing, anhydrous sodium sulfate is dry.It crosses Filter, is concentrated to give white solid 36g.LC-MS m/z(ES+): 550.6 (M+Na)+
Embodiment 9
The synthesis of compound 9
By compound 8 (20g, 37.9mmol), N-methylmorpholine (7.66g, 75.8mmol), 250mLTHF be added to In 500mL there-necked flask, nitrogen protection drops to 0 DEG C, adds 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride 50mL is added dropwise to amino benzyl in (EDCI, 8.68g, 45.48mmol), I-hydroxybenzotriazole (HOBt, 6.19g, 45.48mmol) The THF solution of alcohol (8.4g, 68.22mmol), drop, which finishes, is warmed to room temperature reaction, TLC (DCM/MeOH=15/1) monitoring process.After Reason: being added 1M aqueous potassium hydrogen sulfate, and stirring is extracted with dichloromethane, and merges organic phase, saturated common salt water washing, anhydrous sulphur Sour sodium, which dries, filters, is concentrated to give crude product, then stirs through isopropyl ether and wash to obtain yellow solid 15g.LC-MS m/z(ES+): 655.3 (M+ Na)+
Embodiment 10
The synthesis of compound 10
By compound 9 (15g, 23.7mmol), two (p-nitrophenyl) carbonic esters (21.6g, 71.1mmol), 150mLDMF, The lower 0 DEG C of stirring of nitrogen protection, is added dropwise n,N-diisopropylethylamine (DIEA, 8.2mL, 71.1mmol), drips and finish room temperature reaction, TLC (DCM/MeOH=20/1) reaction process is monitored.Post-processing: being concentrated under reduced pressure major part DMF, and addition isopropyl ether, which stirs, washes crystallization, mistake Filter, drying, obtains off-white powder 17g.LC-MS m/z(ES+): 698.3 (M+H)+-Boc。
Embodiment 11
The synthesis of compound 11
By compound N, N'- dimethyl-ethylenediamine (20g, 0.226mol) is dissolved in 100mL methylene chloride, drips under ice-water bath Add the methylene chloride mixed liquor of 50mLBoc acid anhydrides (14.8g, 0.068mol), drips and finish room temperature reaction, TLC (DCM:MeOH=10: 1) reaction process is monitored.Filtering, 40 DEG C are concentrated under reduced pressure dry filtrate.Column is crossed, product 9g is obtained.LC-MS m/z(ES+): 89.3 (M+H)+- Boc。
Embodiment 12
The synthesis of compound 12
Compound glycolic acid benzyl ester (30g, 0.18mol) is dissolved in 500mLDMF, two (p-nitrophenyl) carbonic acid are added Ester (45.8g, 0.15mol), DIEA (49mL, 0.3mol) react at room temperature under nitrogen protection, TLC (DCM:MeOH=10:1) prison Control.Crude product is concentrated under reduced pressure to obtain in oil pump at 45 DEG C after completion of the reaction, and crude product is through silica gel column chromatography (eluant, eluent PE/EA=10/ 1~8/1~6/1) product 29g is obtained.LC-MS m/z(ES+): 332.1 (M+H)+
Embodiment 13
The synthesis of compound 13
Compound 12 (21g, 63.8mmol) is dissolved in 100mLDMF, add compound 11 (10g, 53mmol), DIEA (17.5mL, 0.1mol) is reacted at room temperature under nitrogen protection, TLC (DCM:MeOH=8:1) monitoring.After completion of the reaction in 45 Crude product is concentrated under reduced pressure to obtain in oil pump at DEG C, and crude product obtains product through silica gel column chromatography (eluant, eluent PE/EA=8/1~4/1) 12.3g。LC-MS m/z(ES+): 281.2 (M+H)+-Boc
Embodiment 14
The synthesis of compound 14
Compound 13 (12g) is dissolved in dry 50mlDCM, trifluoroacetic acid 20ml is added, reaction is stirred at room temperature, TLC (PE:EA=3:1) monitoring.After fully reacting, 45 DEG C of reduced pressures are dry, do not purify and directly cast single step reaction.
Embodiment 15
The synthesis of compound 15
14 gained compound 14 of embodiment is dissolved in 80mLDMF, sequentially add Fmoc-Val-Cit-PAB-PNP (8g, 10.4mmol), DIEA (7mL, 41.6mmol), room temperature reaction, TLC (DCM:MeOH=12:1) monitoring.Post-processing, at 45 DEG C Oil pump is concentrated under reduced pressure most of DMF, and 200ml methyl tertiary butyl ether(MTBE) crystallization, filtering, dry solid 7g is added.LC-MS m/z (ES+): 908.4 (M+H)+
Embodiment 16
The synthesis of compound 16
Compound 15 (9g) is dissolved in the mixed solution of 2.8L methanol and tetrahydrofuran (3:1), adds 2.7g Pd/ BaSO4, hydrogen replace three times, be stirred at room temperature reaction 72 hours.After TLC (DCM:MeOH=8:1) monitors fully reacting, filtering, 45 DEG C of reduced pressures are dry, obtain yellow solid 7.5g.LC-MS m/z(ES+): 818.3 (M+H)+
Embodiment 17
The synthesis of compound 17
8g compound 16 is dissolved in 80ml DMF, 16ml diethylamine is added, nitrogen protection is stirred to react at room temperature. After TLC (DCM:MeOH=1:1) monitors fully reacting, 45 DEG C of oil pump decompressions are spin-dried for, and are not purified, are directly used in the next step.
Embodiment 18
The synthesis of compound 18
The compound 14 (6g, 21.4mmol) being prepared according to embodiment 14, is dissolved in 60mLDMF, successively plus Enter compound 10 (11g, 14.3mmol), DIEA (14mL, 85.7mmol), reacts at room temperature, TLC (DCM:MeOH=10:1) prison Control.Post-processing, oil pump is concentrated under reduced pressure most of DMF at 45 DEG C, and 200ml methyl tertiary butyl ether(MTBE) crystallization is added, and filters, dry Obtain solid 7.6g.LC-MS m/z(ES+): 954.4 (M+H)+
Embodiment 19
The synthesis of compound 19
Compound 18 (7g) is dissolved in the mixed solution of 1L methanol and tetrahydrofuran (3:1), adds 2.1g Pd/ BaSO4, three times, room temperature reaction, TLC (DCM:MeOH=2:1) monitoring is reacted for hydrogen displacement.Post-processing, filtering, 45 DEG C of decompressions are dense Contracting is dry, obtains yellow solid 4.8g.LC-MS m/z(ES+): 729.3 (M+H)+
Embodiment 20
The synthesis of compound 20
Compound N-methy ethanol amine (20g, 0.267mol) is dissolved in 200mL methylene chloride, triethylamine is added The methylene chloride mixed solution that 150mLBoc acid anhydrides (29.62g, 0.293mol) is added dropwise is stirred at room temperature in (40mL, 0.293mol), Drop finishes, room temperature reaction, TLC (PE:EA=1:1) monitoring process.Saturated ammonium chloride solution 300mL, stirring point is added in post-processing Liquid, organic layer water, saturated sodium-chloride washing, anhydrous sodium sulfate dry, filter, and product 45g is concentrated under reduced pressure to obtain.
Embodiment 21
The synthesis of compound 21
Compound 20 (10g, 57mmol) is dissolved in the dry methylene chloride of 250mL, nitrogen is bubbled, and is added in batches at 0 DEG C Enter Dess-Martin oxidant (DMP, 26.6g), finish room temperature reaction, TLC (PE/EA=1/1) monitors reaction process.After 500mL saturated sodium bicarbonate aqueous solution, 500mL saturated aqueous sodium thiosulfate and the stirring of 800mL methylene chloride is added in reason 30min, layering, organic layer saturated sodium bicarbonate, saturated sodium-chloride wash, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure Yellow oil 8.65g.LC-MS m/z(ES+): 174.2 (M+H)+
Embodiment 22
The synthesis of compound 22
Compound 21 (8.6g, 50mmol), diglycolamine (5.25g, 50mmol) are dissolved in 100mL methanol, room temperature is anti- It answers, TLC (PE/EA=3/2) monitoring process.After completion of the reaction.Reaction solution is cooled to 0 DEG C, sodium borohydride is added portionwise (3.78g, 100mmol) is finished and is warmed to room temperature reaction, and TLC (PE/EA=3/2) has reacted, crude product is concentrated under reduced pressure to obtain.Through silica gel Column chromatography chromatogram (eluant, eluent DCM/MeOH=80/1~50/1~30/1) obtains product 5.6g.LC-MS m/z(ES+): 263.3 (M +H)+
Embodiment 23
The synthesis of compound 23
Compound 22 (4.5g, 17.25mmol) is dissolved in the dry methylene chloride of 150mL, compound 12 is sequentially added (8.55g, 25.8mmol), DIEA (5.6mL, 34.5mmol), room temperature reaction, TLC (DCM:MeOH=10:1) monitoring react into Journey.Post-processing, crude product is concentrated under reduced pressure to obtain, through through silica gel column chromatography (eluant, eluent DCM/MeOH=800/1~500/1~ 100/1) product 4.4g is obtained.LC-MS m/z(ES+): 355.3 (M+H)+-Boc
Embodiment 24
The synthesis of compound 24
Compound 23 (4.4g, 9.7mmol) is dissolved in 50mL dry methylene chloride, trifluoroacetic acid 5mL is added, room temperature is anti- It answering, TLC (DCM:MeOH=15:1) monitors reaction process,.Post-processing is concentrated under reduced pressure, does not purify, directly cast single step reaction.
Embodiment 25
The synthesis of compound 25
24 gained compound 24 of embodiment is dissolved in 40mLDMF, sequentially add Fmoc-Val-Cit-PAB-PNP (5g, 6.5mmol), DIEA (6.3mL, 38.8mmol), room temperature reaction, TLC (DCM:MeOH=6:1) monitoring.Post-processing, at 45 DEG C Oil pump is concentrated under reduced pressure most of DMF, and 100ml methyl tertiary butyl ether(MTBE) crystallization, filtering, dry solid 3.2g is added.LC-MS m/z(ES+): 968.4 (M+H)+
Embodiment 26
The synthesis of compound 26
Compound 25 (3g) is dissolved in the mixed solution of 600mL methanol and tetrahydrofuran (3:1), adds 0.9g Pd/ BaSO4, hydrogen replace three times, reaction is stirred at room temperature.TLC (DCM:MeOH=8:1) monitors process.After fully reacting, filtering, 45 It DEG C is concentrated under reduced pressure dry, obtains yellow solid 2.53g.LC-MS m/z(ES+): 878.3 (M+H)+
Embodiment 27
The synthesis of compound 27
Compound 26 (2.5g) is dissolved in 20mLDMF, 4mL diethylamine is added, is reacted at room temperature under nitrogen protection, TLC (DCM:MeOH=1:1) reaction process is monitored.Post-processing is concentrated under reduced pressure removing DMF and obtains product, do not purify, be directly used in lower step Reaction.
Embodiment 28
The synthesis of compound 28
Compound 2 (7g, 9.8mmol) is dissolved in 100ml acetonitrile, HOSu (1.24g, 10.8mmol), DCC are added (2.24g, 10.78mmol), dissolved clarification are warming up to 70 DEG C of reactions.After TLC (DCM:MeOH=8:1) monitors fully reacting, filtering, Filtrate is concentrated under reduced pressure in 40 DEG C, does not purify, and directly throws in next step.
Embodiment 29
The synthesis of compound 29
Compound 3 (6g, 11.1mmol) is dissolved in 100ml acetonitrile, HOSu (1.41g, 12.3mmol), DCC are added (2.55g, 12.3mmol), dissolved clarification are warming up to 70 DEG C of reactions.It after TLC (DCM:MeOH=8:1) monitors fully reacting, filters, filter Liquid is concentrated under reduced pressure in 40 DEG C, does not purify, and directly throws in next step.
Embodiment 30
The synthesis of compound 30
Compound 6 (8g, 10.3mmol) is dissolved in 100ml acetonitrile, HOSu (1.3g, 11.3mmol), DCC are added (2.35g, 11.3mmol), dissolved clarification are warming up to 70 DEG C of reactions.It after TLC (DCM:MeOH=8:1) monitors fully reacting, filters, filter Liquid is concentrated under reduced pressure in 40 DEG C, does not purify, and directly throws in next step.
Embodiment 31
The synthesis of compound 31
Compound 17 (400mg, 6.7mmol) is dissolved in 6mlDMF, DIEA (0.22mL, 13.4mmol) is added, changes It closes object 28 (544mg, 6.7mmol), nitrogen protection, reaction, TLC (DCM:MeOH=1:1) monitoring reaction is stirred at room temperature.After Reason is concentrated under reduced pressure in 45 DEG C of oil pumps, and residue is purified with efficient preparation liquid phase.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 90%A, 10-25min, 90%A~70%A, 25-60min, 70%A~20%A
The fraction with 31-34min retention time and freeze-drying are collected, product 410mg is obtained.LC-MS m/z(ES+): 1315.5(M+Na)+
Embodiment 32
The synthesis of compound 32
By compound 31 (200mg, 0.15mmol), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 402mg, 0.77mmol) is dissolved in 10mLDMF, and DIEA (0.2mL, 1.23mmol) room temperature is added under nitrogen protection and stirs 30min is mixed, then Exatecan (45mg, 0.1mmol) is added dropwise, is reacted at room temperature, monitors reaction process with high performance liquid chromatography.After Reason is concentrated under reduced pressure, and residue is prepared with efficient liquid phase and purified.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 80%A, 10-25min, 80%A~65%A, 25-70min, 65%A~30%A
The fraction with 50-52min retention time and freeze-drying are collected, product 90mg is obtained.LC-MS m/z(ES+): 1732.8 (M+Na)+
Embodiment 33
The synthesis of compound 33
Compound 17 (400mg, 0.67mmol) is dissolved in 6mlDMF, DIEA (0.22mL, 1.34mmol) is added, changes It closes object 29 (426mg, 0.67mmol), nitrogen protection, reaction, TLC (DCM:MeOH=1:1) monitoring reaction is stirred at room temperature.After Reason, oil pump is concentrated under reduced pressure at 45 DEG C, and residue is purified with efficient preparation liquid phase.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 90%A, 10-25min, 90%A~70%A, 25-60min, 70%A~20%A
The fraction with 28-30min retention time and freeze-drying are collected, product 337mg is obtained.LC-MS m/z(ES+): 1138.1(M+Na)+
Embodiment 34
The synthesis of compound 34
By compound 33 (200mg, 0.179mmol), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 465mg, 0.895mmol) is dissolved in 10mLDMF, and DIEA (0.24mL, 1.43mmol) room temperature is added under nitrogen protection 30min is stirred, then Exatecan (52mg, 0.12mmol) is added dropwise, is reacted at room temperature, monitors reaction process with high performance liquid chromatography. Post-processing is concentrated under reduced pressure, and residue is prepared with efficient liquid phase and purified.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 80%A, 10-25min, 80%A~60%A, 25-70min, 60%A~25%A
The fraction with 49-51min retention time and freeze-drying are collected, product 95mg is obtained.LC-MS m/z(ES+): 1556.6 (M+Na)+
Embodiment 35
The synthesis of compound 35
Compound 17 (400mg, 0.67mmol) is dissolved in 6mlDMF, DIEA (0.22mL, 1.34mmol) is added, changes It closes object 30 (585mg, 0.67mmol), nitrogen protection, reaction, TLC (DCM:MeOH=1:1) monitoring reaction is stirred at room temperature.After Reason, oil pump is concentrated under reduced pressure at 45 DEG C, and residue is purified with efficient preparation liquid phase.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 90%A, 10-25min, 90%A~70%A, 25-60min, 70%A~20%A
The fraction with 33-35min retention time and freeze-drying are collected, product 389mg is obtained.LC-MS m/z(ES+): 1376.3(M+Na)+
Embodiment 36
The synthesis of compound 36
By compound 35 (200mg, 0.147mmol), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 384mg, 0.39mmol) is dissolved in 10mLDMF, and DIEA (0.19mL, 1.18mmol) room temperature is added under nitrogen protection and stirs 30min is mixed, then Exatecan (43mg, 0.10mmol) is added dropwise, is reacted at room temperature, monitors reaction process with high performance liquid chromatography.Afterwards Processing is concentrated under reduced pressure, and residue is prepared with efficient liquid phase and purified.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 80%A, 10-25min, 80%A~60%A, 25-70min, 60%A~25%A
The fraction with 52-54min retention time and freeze-drying are collected, product 93mg is obtained.LC-MS m/z(ES+): 1793.7 (M+Na)+
Embodiment 37
The synthesis of compound 37
Compound 19 (500mg, 0.686mmol) is dissolved in 6mlDMF, add DIEA (0.22mL, 1.34mmol), Reaction, TLC (DCM:MeOH=1:1) monitoring reaction is stirred at room temperature in compound 28 (557mg, 0.686mmol), nitrogen protection.Afterwards Processing, oil pump is concentrated under reduced pressure at 45 DEG C, and residue is purified with efficient preparation liquid phase.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 90%A, 10-25min, 90%A~75%A, 25-50min, 75%A~30%A
The fraction with 32-34min retention time and freeze-drying are collected, product 440mg is obtained.LC-MS m/z(ES+): 1448.7(M+Na)+
Embodiment 38
The synthesis of compound 38
By compound 37 (300mg, 0.21mmol), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 547mg, 1.05mmol) is dissolved in 10mLDMF, and DIEA (0.28mL, 1.68mmol) room temperature is added under nitrogen protection and stirs 30min is mixed, then Exatecan (61mg, 0.14mmol) is added dropwise, is reacted at room temperature, monitors reaction process with high performance liquid chromatography.Afterwards Processing is concentrated under reduced pressure, and residue is prepared with efficient liquid phase and purified.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 80%A, 10-25min, 80%A~55%A, 25-70min, 55%A~20%A
The fraction with 51-53min retention time and freeze-drying are collected, product 118mg is obtained.LC-MS m/z(ES+): 1851.8(M+Na)+
Embodiment 39
The synthesis of compound 39
100mg compound 38 is dissolved in 5mL methylene chloride, trifluoroacetic acid, room temperature reaction, HPLC monitoring is added in 0.5mL Process.Post-processing, is concentrated under reduced pressure to obtain product 80mg.LC-MS m/z(ES+): 1751.8 (M+Na)+
Embodiment 40
The synthesis of compound 40
Compound 27 (500mg, 0.76mmol) is dissolved in 6mlDMF, DIEA (0.25mL, 1.52mmol), compound 28 are added Reaction, TLC (DCM:MeOH=1:1) monitoring reaction is stirred at room temperature in (665mg, 0.76mmol), nitrogen protection.Post-processing, in 45 Oil pump is concentrated under reduced pressure at DEG C, and residue is purified with efficient preparation liquid phase.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 90%A, 10-25min, 90%A~75%A, 25-60min, 75%A~30%A
The fraction with 36-28min retention time and freeze-drying are collected, product 472mg is obtained.LC-MS m/z(ES+): 1375.7(M+Na)+
Embodiment 41
The synthesis of compound 41
By compound 40 (200mg, 0.147mmol), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 384mg, 0.739mmol) it is dissolved in 10mLDMF, DIEA (0.19mL, 1.18mmol) is added under nitrogen protection and is stirred at room temperature 30min, then Exatecan (43mg, 0.1mmol) is added dropwise, it reacts at room temperature, monitors reaction process with high performance liquid chromatography.After Reason is concentrated under reduced pressure, and residue is prepared with efficient liquid phase and purified.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 80%A, 10-25min, 80%A~55%A, 25-70min, 55%A~20%A
The fraction with 45-47min retention time and freeze-drying are collected, product 92mg is obtained.LC-MS m/z(ES+): 1792.8 (M+Na)+
Embodiment 42
The synthesis of compound 42
Compound 17 (400mg, 0.67mmol) is dissolved in 6mlDMF, DIEA (0.22mL, 1.34mmol) is added, changes It closes object 6- (dimaleoyl imino) caproic acid succinimide ester (MC-OSu, 30g, 0.67mmol), nitrogen protection, is stirred at room temperature anti- It answers, TLC (DCM:MeOH=8:1) monitoring reaction.Post-processing, oil pump is concentrated under reduced pressure at 45 DEG C, and residue is with through silica gel column layer Analysis chromatography (eluant, eluent DCM/MeOH=25/1~15/1) obtains sterling 300mg.LC-MS m/z(ES+): 789.3 (M+H)+
Embodiment 43
The synthesis of compound 43
By compound 42 (200mg, 0.25mmol), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP, 660mg, 1.27mmol) is dissolved in 10mLDMF, and DIEA (0.33mL, 2.03mmol) room temperature is added under nitrogen protection and stirs 30min is mixed, then Exatecan (79mg, 0.18mmol) is added dropwise, is reacted at room temperature, monitors reaction process with high performance liquid chromatography.Afterwards Processing is concentrated under reduced pressure, and residue is prepared with efficient liquid phase and purified.
(column: YMC-C18,50mm*450mm, 10 μm, using acetonitrile/water (0.2%TFA), flow velocity 50mL/min, in λ= 205nm detection)
Solvent A: 0.2%TFA water
Solvent B: acetonitrile
Gradient: 0-10min 80%A, 10-25min, 80%A~50%A, 25-60min, 50%A~30%A
The fraction with 44-46min retention time and freeze-drying are collected, product 106mg is obtained.LC-MS m/z(ES+): 1228.5(M+Na)+
Embodiment 44
The synthesis of compound 44
The synthetic method of compound 44: using MC-OSu and N- ε-Boc-L- lysine as raw material, referring to the method for embodiment 1 It is synthesized into.LC-MS m/z(ES+): 440.1 (M+H)+
Embodiment 45
The synthesis of compound 45
The synthesis of compound 45 is referring to embodiment 28.
Embodiment 46
The synthesis of compound 46
The synthesis of compound 46 is prepared referring to embodiment 31 with compound 45 and compound 17 for raw material.LC-MSm/ z(ES+): 1440.8 (M+H)+
Embodiment 47
The synthesis of compound 47
The synthesis of compound 47 is referring to embodiment 34.LC-MS m/z(ES+): 1571.8 (M+Na)+
Embodiment 48
The synthesis of compound 48
The synthesized reference embodiment 39 of compound 48.LC-MS m/z(ES+): 1471.6 (M+Na)+
Embodiment 49
The synthesis of compound 49
The synthesis of compound 49 is referring to embodiment 2, using nitrine polyethylene glycol carboxyl and Fmoc-N- allylamine as raw material system ?.LC-MS m/z(ES+): 745.4 (M+H)+
Embodiment 50
The synthesis of compound 50
3g compound 49 is added into 50mL reaction flask, concentrated sulfuric acid 15mL dissolution is added, is added dropwise under the conditions of ice-water bath Concentrated nitric acid 6mL, drop, which finishes, to be slowly increased to react at room temperature.TLC detects reaction process, after completion of the reaction pours into reaction solution in ice water, It is extracted with ethyl acetate.Crude product purifies by silica gel chromatography, obtains yellow solid 2.5g.LC-MS m/z(ES+): 791.4 (M+H)+
Embodiment 51
The synthesis of compound 51
Compound 50 (2.5g, 3.16mmol) is dissolved in 15mL methanol, 0.25g5%Pd/C, hydro-reduction nitre is added Base.End of reaction, filters palladium carbon, and solvent concentration obtains crude product.It is added 10mL1,4- dioxane and 10mL water into crude product, then plus Enter DIEA (0.79mL, 4.74mmol), instill Boc acid anhydrides (3.43g, 15.8mmol) at room temperature, drips and finish room temperature reaction, use TLC Detect reaction process.It is concentrated under reduced pressure after fully reacting and removes dioxane, DCM extraction is added, yellow oil is concentrated under reduced pressure to obtain Crude product separates to obtain product 2.3g through silica gel column chromatography.LC-MS m/z(ES+): 760.3 (M+H)+- Boc, 860.2 (M+H)+
Embodiment 52
The synthesis of compound 52
2g compound 51 is dissolved in 20mLDMF, piperidines 2mL is added, de- Fmoc, TLC monitoring is stirred at room temperature.After having reacted DMF is removed under reduced pressure in oil pump, obtains crude product.Crude product is calculated as theoretical, obtains compound 52 referring to embodiment 1.LC-MSm/z(ES+): 831.5(M+H)+
Embodiment 53
The synthesis of compound 53
The synthesis of compound 53 is referring to embodiment 28.
Embodiment 54
The synthesis of compound 54
The synthesis of compound 53 is referring to embodiment 31.LC-MS m/z(ES+): 1408.5 (M+H)+
Embodiment 55
The synthesis of compound 55
Compound 55 is made referring to embodiment 32.LC-MS m/z(ES+): 1847.8 (M+Na)+
Embodiment 56
The synthesis of compound 56
Compound 56 is made in reference implementation example 39.LC-MS m/z(ES+): 1747.8 (M+Na)+
Embodiment 57
The synthesis of compound 57
Synthetic method is referring to patent CN104755494.LC-MS m/z(ES+): 1056.5 (M+Na)+
Embodiment 58
The preparation of antibody drug conjugates H-32 obtains conjugate averagely DAR=7.4 after measured with reference to general step A.

Claims (14)

1. a kind of camptothecine-antibody coupling matter or its pharmaceutically acceptable salt shown in formula I:
Wherein:
Ab is antibody, antibody fragment or albumen；
L1 is hydrophilic extension apparatus；
A、A1For l-amino acid, n is selected from the integer that 0,1,2,3 or 4, m is selected from 1-8；
L2 is that self eliminates unit；
L3 is spacer units；
D is drug Exatecan, is connected with 1 bit amino with L3, and wave indicates the link position with L3
2. camptothecine-antibody coupling matter as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that L1 packet Containing with flowering structure:
Wherein A is optional extension apparatus, and Ar is nitrogen-containing heterocycle, and BB1 is hydrophilic amino acid or the widow being made of hydrophilic amino acid Peptide, p are PEG number of repeat unit, and the integer selected from 1-30, left and right wave respectively indicates the connection with succimide and AA1 Site, a, b, c are selected from 0 or 1, and a+b+c >=2.
3. camptothecine-antibody coupling matter as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that AA1 choosing From group consisting of: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, sweet ammonia Acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, color ammonia One of acid, tyrosine or valine are a variety of.
4. camptothecine-antibody coupling matter as claimed in claim 2 or its pharmaceutically acceptable salt, which is characterized in that BB1 choosing From group consisting of: one of lysine, arginine, histidine, aspartic acid or glutamic acid are a variety of.
5. camptothecine-antibody coupling matter as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that wherein Self is eliminated unit and is selected from the group being made up of: ethanol amine, 4- hydroxy-benzyl alcohol, 4- aminobenzyl alcohol, ethylenediamine or substituted second One of diamines is a variety of.
6. camptothecine-antibody coupling matter as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, which is characterized in that its Described in PEG be the PEG with the determination of 1-30 monomeric unit, preferably with the determination of 1-12 monomeric unit PEG。
7. camptothecine-antibody coupling matter as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that AA1 is Peptide moiety.
8. camptothecine-antibody coupling matter as claimed in claim 7 or its pharmaceutically acceptable salt, which is characterized in that AA1 is Dipeptides is selected from Val-Cys or Val-Alt.
9. camptothecine-antibody coupling matter as claimed in claim 2 or its pharmaceutically acceptable salt, which is characterized in that AA1, Ar is nitrogen-containing heterocycle.
10. camptothecine-antibody coupling matter as claimed in claim 9 or its pharmaceutically acceptable salt, which is characterized in that AA1, Ar is for triazole, tetrazole or with flowering structure
One of or it is a variety of.
11. camptothecine-antibody coupling matter as claimed in claim 3 or its pharmaceutically acceptable salt, which is characterized in that replace Ethylenediamine include with flowering structure:
One of or it is more Kind.
12. camptothecine-antibody coupling matter as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that L3 choosing From
Left and right wave respectively indicates the connection site that unit and 1 bit amino of drug Exatecan are eliminated with self.
13. the 1-12 any camptothecine-antibody coupling matter or its pharmaceutically acceptable salt, treatment in a kind of claim The purposes of tumour, autoimmune disease or infectious diseases.
14. purposes as claimed in claim 13, which is characterized in that the camptothecine-antibody coupling matter or its pharmaceutically may be used The antibody specificity of the salt of receiving is bound to the target cell of the cancer, autoimmune disease.
CN201810943764.2A 2017-08-18 2018-08-18 A kind of camptothecine-antibody coupling matter Pending CN109106951A (en)

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