WO2022166719A1 - 一种ca4衍生物及其配体-药物偶联物 - Google Patents
一种ca4衍生物及其配体-药物偶联物 Download PDFInfo
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- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Definitions
- the present invention relates to a CA4 derivative and its ligand-drug conjugate.
- ADCs Ligand-drug conjugates
- ADCs as new targeted drugs, generally consist of three parts: antibodies or antibody-like ligands, small molecule drugs, and linkers that couple the ligands and drugs.
- Antibody-drug conjugates utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve therapeutic purposes.
- the drug molecules used in the early development of ADCs tend to be highly toxic molecules, but such ADCs can produce large toxic side effects.
- Enhertu and Trodelvy launched in 2019 and 2020, respectively, use moderately toxic camptothecin derivatives as drug molecules.
- ADC toxin cell killing activity is at the sub-nanomolar (0.1 nM) level.
- CA4 compounds are difficult to be directly formulated into drugs, and in order to improve the biological activity of their ligand-drug conjugates, the applicant creatively invented a higher activity CA4 derivative and its ligand-drug conjugates. It is used in cancer targeted therapy.
- the present invention discloses a CA4 derivative represented by general formula D, or a pharmaceutically acceptable salt or solvate thereof;
- R is selected from hydrogen atom, deuterium atom, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, aryl, substituted aryl or heteroaryl;
- X is selected from -C(O) -CRaRb- (CR1R2) m - O- , -C(O) -CRaRb- ( CR1R2 ) m - NH- or -C ( O)-CR a R b -(CR 1 R 2 ) m -S-;
- Ra is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
- R b is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
- R a , R b and the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
- R 1 and R 2 are the same or different, and are each independently a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a substituted alkyl group, a deuterated alkyl group, an alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a hydroxyalkane group radical, cycloalkyl or heterocyclyl;
- R 1 , R 2 and the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
- n is selected from an integer of 0-4.
- the X is non-limitingly selected from the following structures:
- the wavy line on the left is connected with the CA4 derivative part, and the wavy line on the right is connected with the connecting unit.
- the compound is selected from the structures shown below without limitation:
- R is selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a substituted alkyl group, a deuterated alkyl group, a cycloalkylalkyl group, an alkoxyalkyl group, an aryl group, a substituted aryl group or a heteroaryl group.
- the compound is non-limitingly selected from the structures shown below:
- the present invention also discloses a linker-drug conjugate comprising a CA4 derivative or a pharmaceutically acceptable salt or solvate thereof:
- R is selected from hydrogen atom, deuterium atom, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, aryl, substituted aryl or heteroaryl;
- X is selected from -C(O) -CRaRb- (CR1R2) m - O- , -C(O) -CRaRb- ( CR1R2 ) m - NH- or -C ( O)-CR a R b -(CR 1 R 2 ) m -S-;
- Ra is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or Heteroaryl;
- R b is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or Heteroaryl;
- R a , R b and the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
- R 1 and R 2 are the same or different, and are each independently a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, an alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a hydroxyalkyl group , cycloalkyl or heterocyclyl;
- R 1 , R 2 and the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
- n is selected from an integer from 0 to 4.
- L is -L 1 -L 2 -L 3 -L 4 -.
- -L- is -L 1 -L 2 -L 3 -L 4 -, wherein the L 1 end is connected to the ligand Ab, and the L 4 end is connected to X.
- L 1 is non-limitingly selected from:
- L 2 is selected from: -NC(R 3 R 4 )C(O), -NR 5 (CH 2 ) o C(O)-, -NR 5 (CH 2 CH 2 O) o CH 2 C( O)-, -S(CH 2 ) p C(O)- or a chemical bond, wherein o is selected from an integer of 0-20; p is selected from an integer of 0-20;
- R 3 and R 4 are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, substituted alkyl groups, deuterated alkyl groups, heteroalkyl groups, carboxyl groups, amino groups, and substituted amino groups;
- R is selected from hydrogen atom, deuterium atom, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, aryl, substituted aryl or heteroaryl;
- L 1 and L 2 share N atoms.
- L3 is selected from peptide residues consisting of amino acids, wherein optional amino acids are further selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, carboxyl, alkyl, substituted alkyl, alkoxy and cycloalkyl Or substituted by one or more substituents in the substituted cycloalkyl; preferably by one, two or more selected from phenylalanine (F), glycine (G), valine (V), lysine Peptide residues formed from amino acids of (K), citrulline, serine (S), glutamic acid (E) or aspartic acid (D).
- optional amino acids are further selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, carboxyl, alkyl, substituted alkyl, alkoxy and cycloalkyl Or substituted by one or more substituents in the substituted cycloalkyl; preferably by one, two or more selected from
- L 4 is selected from: -NR 6 (CR 7 R 8 ) q -, -C(O)NR 6 -, -C(O)NR 6 (CH 2 ) q - or chemical bond, q is selected from 0- an integer of 6;
- R 6 , R 7 and R 8 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl, alkoxy alkyl, heterocyclyl, aryl, substituted aryl or heteroaryl.
- the linking unit -L- is non-limitingly selected from the following structures;
- the left wavy line is connected with the ligand part
- the right wavy line is connected with X.
- linker-drug conjugate is non-limitingly selected from the following structures:
- the 1- and 2-position carbon atoms have absolute chirality in either the R or S configuration.
- the present invention further discloses a ligand-drug conjugate comprising a linker-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, the ligand-drug conjugate comprising the compound represented by formula I structure:
- R is selected from hydrogen atom, deuterium atom, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, aryl, substituted aryl or heteroaryl;
- X is selected from -C(O) -CRaRb- (CR1R2) m - O- , -C(O) -CRaRb- ( CR1R2 ) m - NH- or -C ( O)-CR a R b -(CR 1 R 2 ) m -S-;
- Ra is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
- R b is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
- R a , R b and the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
- R 1 and R 2 are the same or different, and are each independently a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a substituted alkyl group, a deuterated alkyl group, an alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, and a hydroxyalkane group radical, cycloalkyl or heterocyclyl;
- R 1 , R 2 and the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
- Ab is a ligand unit selected from antibodies, antibody fragments, targeting proteins, Fc-fusion proteins, etc.;
- L is the linking unit with Ab
- X is the modification unit of the drug part
- n is selected from an integer or a decimal of 1-20.
- Ab is an antibody, which can form a linking bond with a linking unit through its heteroatom, and the antibody is selected from murine antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, antibody fragments, bispecific antibodies or multispecific antibodies.
- the antibody or its antigen-binding fragment is selected from, without limitation: anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti-TDGF1 antibody, Anti-ETBR Antibody, Anti-MSLN Antibody, Anti-TIM-1 Antibody, Anti-LRRC15 Antibody, Anti-LIV-1 Antibody, Anti-CanAg/AFP Antibody, Anti-cladin 18.2 Antibody, Anti-Mesothelin Antibody, Anti-HER2(ErbB2) Antibody, Anti-EGFR Antibody, Anti-c-MET Antibody, Anti-SLITRK6 Antibody, Anti-KIT/CD117 Antibody, Anti-STEAP1 Antibody, Anti-SLAMF7/CS1 Antibody, Anti-NaPi2B/SLC34A2 Antibody, Anti-GPNMB Antibody, Anti-HER3(ErbB3) Antibody, Anti-MUC1/CD227 Antibody, Antibody
- the ligand-drug conjugate is selected from the following structures without limitation:
- Ab is a ligand unit; n is selected from the integer or decimal of 1-20;
- the invention discloses a method for preparing a linker-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps:
- the linker-drug conjugate represented by the general formula L a -D is obtained by the substitution reaction between the linking unit La and the compound D 1 of the general formula ;
- L 2 , L 3 , R, R 8 , R 9 , R 10 , q and X are as described in the general formula LXD.
- the present invention also discloses a method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps:
- a pharmaceutical composition comprising a therapeutically effective amount of a CA4 derivative, a linker-drug conjugate or a ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier , diluent or excipient.
- a compound comprising a CA4 derivative, a linker-drug conjugate or a ligand-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, in Use in the preparation of medicaments for treating or preventing tumors.
- the tumor is breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophagus cancer, lung cancer, Colon cancer, rectal cancer, colorectal cancer, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, melanoma, glioma, neuroblastoma, glioblastoma multiforme, sarcoma, lymphoma and leukemia, etc. Solid tumors or hematological tumors.
- trade name includes the product formulation, generic drug and active ingredients of the trade name product.
- ligand is a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell.
- the role of the ligand is to present the drug to the target cell population to which the ligand binds, including but not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells.
- the ligand is represented as Ab, and the ligand can form a linking bond with the connecting unit through the heteroatom on the ligand, preferably an antibody or an antigen-binding fragment thereof, the antibody is selected from chimeric antibodies, human-derived antibody, fully human antibody or murine antibody; preferably a monoclonal antibody.
- Ligand units are targeting agents that specifically bind to the target moiety.
- the ligands are capable of specifically binding to cellular components or to cellular components or to other target molecules of interest.
- the target moiety or target is usually on the cell surface.
- the function of the Ligand unit is to deliver the Drug unit to a specific target cell population with which the Ligand unit interacts.
- Ligands include, but are not limited to, proteins, polypeptides and peptides, as well as non-proteins such as sugars.
- Suitable Ligand units include, for example, antibodies, such as full-length (intact) antibodies and antigen-binding fragments thereof.
- the Ligand unit is a non-antibody targeting agent
- it may be a peptide or polypeptide, or a non-proteinaceous molecule.
- targeting agents include interferons, lymphokines, hormones, growth and colony stimulating factors, vitamins, nutrient transport molecules, or any other cell binding molecule or substance.
- the linker is covalently attached to the sulfur atom of the ligand.
- the sulfur atom is that of a cysteine residue, which forms an interchain disulfide bond of the antibody.
- the sulfur atom is one that has been introduced into a cysteine residue of the Ligand unit, which forms an interchain disulfide bond of the antibody.
- the sulfur atom is one that has been introduced into a cysteine residue of the Ligand unit (eg, by site-directed mutagenesis or chemical reaction).
- the sulfur atom to which the linker binds is selected from cysteine residues that form interchain disulfide bonds of the antibody or frontal cysteine residues that have been introduced into the Ligand unit (eg, by site-directed mutagenesis or chemical reaction).
- the EU according to the EU in Kabat ⁇ [Kabat E.A et al., (1991)] Sequences of proteins of Immunological Interest, Fifth Edition, NIH publication 91-3242 ⁇ Index numbering system.
- an "antibody” or “antibody unit” is within its scope to include any portion of an antibody structure. This unit may bind, reactively associate, or complex with a receptor, antigen or other receptor unit possessed by the targeted cell population.
- An antibody can be any protein or protein-like molecule that can bind, complex, or react with a portion of the cell population to be treated or bioengineered. The antibody constituting the antibody-drug conjugate in the present invention maintains the antigen-binding ability of the original wild state. Therefore, the antibody of the present invention can specifically bind to the antigen.
- Antigens involved include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, regulators of cell survival, regulators of cell proliferation, molecules associated with tissue growth and differentiation (as known or predicted) functional), lymphokines, cytokines, molecules involved in the regulation of the cell cycle, molecules involved in angiogenesis, and molecules involved in angiogenesis (as known or predicted to be functional).
- TAAs tumor-associated antigens
- cell surface receptor proteins and other cell surface molecules regulators of cell survival, regulators of cell proliferation, molecules associated with tissue growth and differentiation (as known or predicted) functional)
- lymphokines cytokines
- molecules involved in the regulation of the cell cycle molecules involved in angiogenesis
- angiogenesis as known or predicted to be functional
- the tumor-associated factor can be a cluster differentiation factor (eg, CD protein).
- Antibodies for use in antibody drug conjugates include, but are not limited to, antibodies directed against cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are well known in the art and can be prepared by methods and information well known in the art for preparing antibodies.
- tumor-associated antigens are well known in the art and can be prepared by methods and information well known in the art for preparing antibodies.
- To develop effective cellular-level targets for cancer diagnosis and therapy researchers seek to find transmembrane or other tumor-associated polypeptides. These targets can be specifically expressed on the surface of one or more cancer cells with little or no expression on the surface of one or more non-cancer cells. Typically, such tumor-associated polypeptides are more overexpressed on the surface of cancer cells relative to the surface of non-cancer cells. Identifying such tumor-associated factors could greatly improve the specific targeting properties of antibody-based cancer therapy.
- tumor-associated antigens For convenience, antigen-related information that is well known in the industry is indicated below, including name, other names, and GenBank accession numbers. Nucleic acid and protein sequences corresponding to tumor-associated antigens can be found in public databases such as Genbank. Antibodies targeting corresponding tumor-associated antigens include all amino acid sequence variants and isotypes that are at least 70%, 80%, 85%, 90%, or 95% homologous to sequences identified in references, or have The tumor-associated antigen sequences in the literature have completely identical biological properties and characteristics.
- inhibitor refers to reducing by a detectable amount, or preventing completely.
- cancer refers to a physiological condition or disease characterized by unregulated cell growth.
- Tumor includes cancer cells.
- autoimmune disease is a disease or disorder that results from targeting an individual's own tissues or proteins.
- drug refers to a cytotoxic drug, where drug designates d, a chemical molecule capable of strongly disrupting normal growth within tumor cells.
- cytotoxic drugs can kill tumor cells at a sufficiently high concentration, but due to the lack of specificity, when killing tumor cells, they can also lead to apoptosis of normal cells, resulting in serious side effects.
- toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, radioisotopes (eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 ) , P 32 and Lu 176 radioisotopes), toxic drugs, chemotherapeutic drugs, antibiotics and nucleolysins, preferably toxic drugs.
- radioisotopes eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212
- P 32 and Lu 176 radioisotopes radioisotopes
- toxic drugs eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212
- antibiotics and nucleolysins preferably toxic drugs.
- linker or “linker fragment” or “linker unit” refers to a chemical structural fragment or bond that is linked to a ligand at one end and a drug at the other end, and can also be linked to a drug after other linkers are attached.
- Linkers including stretchers, spacers and amino acid units, can be synthesized by methods known in the art, such as those described in US2005-0238649A1.
- the linker can be a "cleavable linker" that facilitates the release of the drug in the cell.
- acid-labile linkers eg, hydrazones
- protease-sensitive linkers eg, peptidase-sensitive linkers
- photolabile linkers eg, dimethyl linkers, or disulfide-containing linkers
- linkers or “linkers of antibody drug conjugates” can be divided into two categories: non-cleavable linkers and cleavable linkers.
- the drug release mechanism is as follows: after the conjugate binds to the antigen and is endocytosed by cells, the antibody is enzymatically hydrolyzed in the lysosome to release the small molecule drug, Linker, an active molecule composed of antibody amino acid residues. The resulting changes in the molecular structure of the drug do not reduce its cytotoxicity, but because the active molecule is charged (amino acid residues), it cannot penetrate into adjacent cells. Thus, such active drugs cannot kill adjacent tumor cells that do not express the target antigen (antigen-negative cells) (bystander effect) (Ducry et al., 2010, Bioconjugate Chem. 21:5-13).
- antibody-drug conjugate refers to an antibody linked to a biologically active drug through a stable linking unit.
- ligand-drug conjugate is preferably antibody-drug conjugate (antibody drug conjugate, ADC), which refers to linking a monoclonal antibody or antibody fragment with a biologically active toxic drug through a stable linking unit .
- alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms atomic alkyl groups, most preferably those containing 1 to 6 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
- lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
- Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
- substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclo
- R', R" and R"' each independently refers to hydrogen, unsubstituted C 1-8 alkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, unsubstituted C 1-8 alkyl, C 1- 8 alkoxy or C 1-8 thioalkoxy, or unsubstituted aryl-C 1-4 alkyl.
- R' and R" When R' and R" are attached to the same nitrogen atom, they may form together with the nitrogen atom 3-, 4-, 5-, 6- or 7-membered rings.
- -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl.
- heteroalkyl refers to an alkyl group containing one or more heteroatoms selected from N, O, or S, wherein alkyl is as defined above.
- alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane, which are A straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
- Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- , 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene (-CH2CH ) 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene ( -CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), etc.
- the alkylene groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkyne group, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy substituted with one or more of the substituents among the radicals, cycloalkylthio, heterocycloalkylthio and oxo.
- alkoxy refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl or cycloalkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms carbon atoms, most preferably 3 to 8 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- ring atoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably the cycloalkyl ring contains 3 to 10 ring atoms.
- Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
- Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
- cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, preferably one cycloalkyl group, wherein alkyl is as defined above, wherein cycloalkyl is as defined above.
- haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
- deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
- hydroxyl refers to the -OH group.
- halogen refers to fluorine, chlorine, bromine or iodine.
- amino refers to -NH2 .
- nitro refers to -NO2 .
- amido refers to -C(O)N(alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
- carboxylate refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
- the present invention also includes various deuterated forms of formula I.
- Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
- Those skilled in the art can synthesize deuterated forms of formula I with reference to the relevant literature.
- Commercially available deuterated starting materials can be used in preparing deuterated forms of Formula I, or they can be synthesized using conventional techniques using deuterated reagents, non-limiting examples of deuterated reagents include: deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
- antibody refers to an immunoglobulin, which is a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds.
- the amino acid composition and sequence of the immunoglobulin heavy chain constant region are different, so their antigenicity is also different. Accordingly, immunoglobulins can be divided into five classes, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, whose corresponding heavy chains are ⁇ , ⁇ , and ⁇ chains, respectively. , alpha chains and epsilon chains.
- IgG can be divided into different subclasses according to the difference in the amino acid composition of the hinge region and the number and position of disulfide bonds in the heavy chain.
- IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
- Light chains are classified into kappa chains or lambda chains by the difference in the constant region.
- Each of the five classes of Ig can have a kappa chain or a lambda chain.
- the antibodies of the present invention are preferably specific antibodies against cell surface antigens on target cells, non-limiting examples are the following antibodies: anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody , Anti-ENPP3 Antibody, Anti-TDGF1 Antibody, Anti-ETBR Antibody, Anti-MSLN Antibody, Anti-TIM-1 Antibody, Anti-LRRC15 Antibody, Anti-LIV-1 Antibody, Anti-CanAg/AFP Antibody, Anti-cladin 18.2 Antibody, Anti-Mesothelin Antibody, Anti-HER2 (ErbB2) Antibody, Anti-EGFR Antibody, Anti-c-MET Antibody, Anti-SLITRK6 Antibody, Anti-KIT/CD117 Antibody, Anti-STEAP1 Antibody, Anti-SLAMF7/CS1 Antibody, Anti-NaPi2B/SLC34A2 Antibody, Anti-GPNMB Antibody, Anti-HER3(ErbB3) Antibody,
- solvate refers to the ligand-drug conjugates of the invention forming pharmaceutically acceptable solvates with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile , isopropanol, DMSO, ethyl acetate.
- drug loading refers to the average amount of cytotoxic drug loaded on each antibody in Formula I, and can also be expressed as the ratio of the drug amount to the antibody amount, and the drug loading range can be that each antibody (Ab) is linked to 0. -12, preferably 1-10 cytotoxic drugs (D).
- the drug load is expressed as n, and an exemplary value may be the mean value of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
- the average amount of drug product per ADC molecule after the coupling reaction can be characterized by conventional methods such as UV/Vis spectroscopy, mass spectrometry, ELISA assay and HPLC.
- the cytotoxic drug is coupled to the sulfhydryl-SH of cysteine sulfhydryl-SH opened between antibody chains and/or the sulfhydryl-SH of site-directed mutated cysteine residues through a linking unit, generally,
- the number of drug molecules that can be conjugated to the antibody in the conjugation reaction will be less than or equal to the theoretical maximum.
- Ligand cytotoxic drug conjugate loading can be controlled by the following non-limiting methods, including:
- pharmaceutically acceptable salt refers to salts of the ligand-drug conjugates of the present invention, or salts of the compounds described in the present invention, when such salts are used in mammals With safety and efficacy, and with due biological activity, the ligand-drug conjugate compound of the present invention contains at least one carboxyl group, so it can form a salt with a base.
- pharmaceutically acceptable salts include: sodium salt, potassium salt, calcium salt or magnesium salt, etc.
- pharmaceutically acceptable salts or “pharmaceutically acceptable salts” refers to salts of the antibody-drug conjugates of the present invention, or salts of the compounds described in the present invention, which when used in mammals have Safe and effective, and have due biological activity, the ligand-drug conjugate compound of the present invention contains at least one amino group, so it can form a salt with an acid.
- Non-limiting examples of pharmaceutically acceptable salts include: hydrochloric acid Salt, Hydrobromide, Hydroiodide, Sulfate, Hydrogen Sulfate, Citrate, Acetate, Succinate, Ascorbate, Oxalate, Nitrate, Pearate, Hydrogen Phosphate, Phosphoric Acid Dihydrogenate, Salicylate, Hydrogencitrate, Tartrate, Maleate, Fumarate, Formate, Benzoate, Mesylate, Ethanesulfonate, Besylate , p-toluenesulfonate.
- Acid amino acid means that the isoelectric point of the amino acid is less than 7, and the acidic amino acid molecule often has one or more acid groups such as carboxyl groups, which can be effectively ionized into negative ions in the structure to increase hydrophilicity. Acidic amino acids may be natural or unnatural amino acids.
- Natural amino acid refers to an amino acid that is biosynthesized. Natural amino acids are generally L-form, but there are a few exceptions, such as glycine, both natural and biosynthetic.
- Unnatural amino acid refers to an amino acid obtained by synthetic means.
- N-fluorenylmethoxycarbonyl-glycine-glycine 100g, 28mmol, 1.0eq
- lead tetraacetate 175g, 395mmol, 1.4eq
- 2L dry tetrahydrofuran 670mL toluene
- reaction solution1 Add 6a (5g, 9.2mmol) and 15mL DMF to a 50mL single-neck bottle, after dissolving, under an ice-water bath, add DBU (1.68g, 11mmol), react for 1h, and record as reaction solution1;
- reaction solution1 7a (4g, 7.8mmol) and 10mL DMF to a 50mL single-necked bottle, after dissolving, under an ice-water bath, add DBU (1.42g, 9.3mmol), react for 1h, and record as reaction solution1;
- reaction solution1 Add 8a (4g, 7.6mmol) and 10mL DMF to a 50mL single-neck bottle, after dissolving, add DBU (1.39g, 9.1mmol) under an ice-water bath, react for 1h, and denote it as reaction solution1;
- N-benzyloxycarbonyl-valyl-lysyl-glycine (SM-4, 100g, 215mmol, 1.0eq)
- lead tetraacetate 133g, 300mmol, 1.0eq
- 2L of dry tetrahydrofuran and 670mL of toluene stirred evenly, under nitrogen protection, heated to 85°C and reacted for 3h.
- 25a (200mg, 0.39mmol) was added to a 25mL single-necked bottle, and after 15mL of DMF was dissolved, 200mg of 5% Pd/C was added, and the hydrogenation reaction was carried out for 2h.
- 29a (500mg, 0.9mmol) was added to a 25mL single-neck flask, 10mL of DMF was dissolved, 500mg of 5% Pd/C was added, and the hydrogenation reaction was carried out for 2h.
- Step 4 Compounds 40d-1 and 40d-2
- Step 4 Compounds 41d-1 and 41d-2
- the antibody molecules with a monomer rate greater than 95% after the preliminary purification were exchanged into phosphate buffer using an ultrafiltration centrifuge tube with a concentration of 10 mg/mL.
- a linker-drug compound (payload) 20 times the molar number of the antibody was added, and the reaction was carried out at room temperature for 2 hours.
- use an ultrafiltration centrifuge tube with a molecular weight cutoff of 30KDa to change the medium to PBS, and remove the uncoupled payload.
- the ADC samples after the liquid change were filtered through a 0.22-micron sterile filter before use.
- the samples were centrifuged at 14,000 rpm for 5 minutes, and the supernatant was taken for analysis;
- Mobile phase A: 50mM PB, 300mM NaCl, 200mM Arg, 5% IPA, pH 6.5;
- Mobile phase A was eluted isocratically for 30min, flow rate: 0.714mL/min, column temperature 25°C, detection wavelength: 280nm.
- the samples were centrifuged at 14,000 rpm for 5 minutes, and the supernatant was taken for analysis;
- Mobile phase A: 1.5M ammonium sulfate, 0.025M anhydrous sodium phosphate, pH 7.0, B: 0.025M anhydrous sodium phosphate, 25% IPA, pH 7.0;
- Mobile phase A equilibrates the chromatographic column, gradient elution of mobile phases A and B, flow rate 0.8 mL/min; column temperature 25°C, detection wavelength: 214 nm.
- ADC-1 was prepared according to the general coupling method of Example 65:
- ADC-2 was prepared according to the general coupling method of Example 65:
- ADC-3 was prepared according to the general coupling method of Example 65:
- ADC-4 was prepared according to the general coupling method of Example 65:
- ADC-5 was prepared according to the general coupling method of Example 65:
- ADC-6 was prepared according to the general coupling method of Example 65:
- ADC-7 was prepared according to the general coupling method of Example 65:
- ADC-8 was prepared according to the general coupling method of Example 65:
- ADC-9 was prepared according to the general coupling method of Example 65:
- ADC-10 was prepared according to the general coupling method of Example 65:
- ADC-11 was prepared according to the general coupling method of Example 65:
- ADC-12 was prepared according to the general coupling method of Example 65:
- ADC-13 was prepared according to the general coupling method of Example 65:
- ADC-14 was prepared according to the general coupling method of Example 65:
- ADC-15 was prepared according to the general coupling method of Example 65:
- ADC-16 was prepared according to the general coupling method of Example 65:
- ADC-17 was prepared according to the general coupling method of Example 65:
- ADC-18 was prepared according to the general coupling method of Example 65:
- ADC-19 was prepared according to the general coupling method of Example 65:
- ADC-20 was prepared according to the general coupling method of Example 65:
- ADC-21 was prepared according to the general coupling method of Example 65:
- ADC-22 was prepared according to the general coupling method of Example 65:
- ADC-23 was prepared according to the general coupling method of Example 65:
- ADC-24 was prepared according to the general coupling method of Example 65:
- ADC-25 was prepared according to the general coupling method of Example 65:
- ADC-26 was prepared according to the general coupling method of Example 65:
- ADC-27 was prepared according to the general coupling method of Example 65:
- ADC-28 was prepared according to the general coupling method of Example 65:
- ADC-29 was prepared according to the general coupling method of Example 65:
- ADC-30 was prepared according to the general coupling method of Example 65:
- ADC-31 was prepared according to the general coupling method of Example 65:
- ADC-32 was prepared according to the general coupling method of Example 65:
- ADC-33 was prepared according to the general coupling method of Example 65:
- ADC-34 was prepared according to the general coupling method of Example 65:
- ADC-35 was prepared according to the general coupling method of Example 65:
- ADC-36 was prepared according to the general coupling method of Example 65:
- ADC-37 was prepared according to the general coupling method of Example 65:
- ADC-38 was prepared according to the general coupling method of Example 65:
- ADC-39 was prepared according to the general coupling method of Example 65:
- ADC-40 was prepared according to the general coupling method of Example 65:
- ADC-41 was prepared according to the general coupling method of Example 65:
- ADC-42 was prepared according to the general coupling method of Example 65:
- ADC-43 was prepared according to the general coupling method of Example 65:
- ADC-44 was prepared according to the general coupling method of Example 65:
- ADC-45 was prepared according to the general coupling method of Example 65:
- ADC-46 was prepared according to the general coupling method of Example 65:
- ADC-47 was prepared according to the general coupling method of Example 65:
- ADC-48 was prepared according to the general coupling method of Example 65:
- ADC-49 was prepared according to the general coupling method of Example 65:
- ADC-50 was prepared according to the general coupling method of Example 65:
- ADC-51 was prepared according to the general coupling method of Example 65:
- ADC-52 was prepared according to the general coupling method of Example 65:
- ADC-53 was prepared according to the general coupling method of Example 65:
- ADC-54 was prepared according to the general coupling method of Example 65:
- ADC-55 was prepared according to the general coupling method of Example 65:
- ADC-56 was prepared according to the general coupling method of Example 65:
- ADC-57 was prepared according to the general coupling method of Example 65:
- ADC-58 was prepared according to the general coupling method of Example 65:
- ADC-59 was prepared according to the general coupling method of Example 65:
- ADC-60 was prepared according to the general coupling method of Example 65:
- ADC-61 (control example) was prepared according to the general coupling method of Example 65:
- Example 127 Plasma Stability
- ADC samples Take a certain amount of ADC samples and add them to human plasma from which human IgG has been removed. Repeat three tubes for each ADC and place them in a 37°C water bath to incubate. After incubation for 72h and 144h respectively, take out the ADC samples and add ProteinA resin (MabSelect) to each tube. SuReTM LX Lot: #10221479GE, use 100uL (washed with PBS), shake and adsorb with a vertical mixer for 2h, and obtain the incubated ADC after washing and elution steps. RP-HPLC was performed on ADC samples incubated for specific times.
- the ADC disclosed in the present invention has excellent properties of high DAR value (>7.5) and high monomer ratio (>97%).
- the DAR value of the ADC disclosed in the present invention can still maintain a high level after 7 days of incubation in plasma, which proves that the ADC of the present invention has excellent stability in plasma.
- Example 128 In vitro activity test
- Tumor cell culture medium Gibco;
- Detection medium (with 1% FBS, Penicillin/streptomycin (100U/mL);
- the growth medium, detection medium, D-PBS and pancreatin were preheated in a 37°C constant temperature water bath, and then the surfaces were disinfected with alcohol and placed in a biological safety cabinet.
- Select cells with a confluence of ⁇ 80% (logarithmic growth phase) put them in a biological safety cabinet, aspirate the old medium, rinse with D-PBS, aspirate and discard, digest with trypsin for 2-3 minutes, and then add growth Trypsin was stopped in the medium and centrifuged at 500 ⁇ g for 5 min.
- 80uL/well was plated in a 96-well plate, only 80uL detection medium was added to wells E11, F11, and G11, and 200uL of DPBS was added to the edge wells to seal the edges.
- test sample prepare 1.0mL, 2.5 ⁇ M (5 ⁇ Top Dose) of the test sample with the detection medium, and dispense it in V Type 96-well plate in the first column, 200 ⁇ L per well; add 180 ⁇ L of detection medium to the second to eighth columns, add 30 ⁇ L from the first column to the second column, mix up and down with a row gun 10 times, discard the pipette tip , the remaining detection concentration points are operated in sequence, and a 7-fold gradient concentration dilution is performed.
- test samples with gradient concentrations were added to the cells according to the amount of 20uL per well, and only 20uL of detection medium was added in the 11th column, and 3 replicate wells were set for each concentration, and then the 96-well plate was placed in 5% CO 2 , 37 °C cell incubator, cultured for 5 days.
- Table 3 IC50 values of in vitro proliferation inhibition of N87 tumor cells by antibody drug conjugates and toxins.
- Table 4 IC50 values of in vitro proliferation inhibition of SK-BR-3 tumor cells by antibody-drug conjugates and toxins.
- the ligand-drug conjugate for HER2 target of the present invention has obvious in vitro proliferation inhibitory activity on HER2 positive cell N87, which is significantly better than that of naked antibody (Trastuzumab) and control group ADC-61.
- the ADC and the single drug disclosed in the present invention also have obvious in vitro proliferation inhibitory activity on the HER2-positive cell SK-BR-3.
- Example 129 In vivo activity test
- Tumor cell culture medium Gibco;
- Balb/c-nu nude mice female, 5-7 weeks (mouse age at tumor cell inoculation), body weight 18.0-24.0 g, 170 (110 plus 60 surplus mice). Purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.;
- Test samples ADC-61 and ADC-1 were provided by Chengdu Dote Antibody Drug Co., Ltd.
- Histidine buffer was provided by Chengdu Dote Antibody Drug Co., Ltd.
- NCI-H1975 human non-small cell lung cancer adenocarcinoma cells
- RPMI1640 medium The NCI-H1975 cells in exponential growth phase were collected and resuspended in RPMI1640 medium to an appropriate concentration for subcutaneous tumor inoculation in mice.
- NCI-N87 human gastric cancer cells
- RPMI1640 medium NCI-N87 cells in exponential growth phase were collected and resuspended in RPMI1640 medium to an appropriate concentration for subcutaneous tumor inoculation in mice.
- mice 85 female nude mice were subcutaneously inoculated with 5 ⁇ 10 7 NCI-H1975 cells on the right shoulder.
- the average tumor volume was about 170 mm 3
- the patients were randomly divided into groups according to tumor size.
- Fifty-five tumor-bearing mice with appropriate tumor volume were selected, randomly divided into groups and started to be administered (tail vein injection, the administration volume was 0.1 ml/10 g).
- the grouping day is defined as day 0.
- mice 85 female nude mice were subcutaneously inoculated with 5 ⁇ 10 7 NCI-N87 cells on the right shoulder.
- the average tumor volume was about 170 mm 3
- the patients were randomly divided into groups according to tumor size.
- Fifty-five tumor-bearing mice with appropriate tumor volume were selected, randomly divided into groups and started to be administered (tail vein injection, the administration volume was 0.1 ml/10 g).
- the grouping day is defined as day 0.
- tumor inoculation After tumor inoculation, routine monitoring included tumor growth (tumors were measured twice a week) and the effects of treatment on the animals' normal behavior, including animal activity, food and water intake, and weight gain or loss (body weight was measured weekly. 2) conditions, eyes, coat and other abnormalities. The clinical symptoms observed during the experiment were all recorded in the raw data.
- Tumor volume calculation formula: tumor volume (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ) (where a represents the long diameter, and b represents the short diameter). The data were recorded manually in the experiment, including the measurement of the long and short diameters of the tumor and the weighing of the animal's body weight.
- the relative tumor proliferation rate, T/C% is the percentage value of the relative tumor volume or tumor weight of the treatment group and the control group at a certain time point. Calculated as follows:
- T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively].
- Table 8 The effect of administration of antibody-drug conjugates (3.75 mg/kg) on the body weight of NCI-H1975 xenografted mice.
Abstract
一种CA4衍生物及其偶联物或其药学上可接受的盐,包括其制备方法和在预防或治疗癌症中的作用。所述偶联物能够特异性地结合肿瘤细胞中高表达的受体。具有良好的水溶性,稳定性及均一性,可用于预防或治疗肿瘤等疾病。
Description
本发明涉及一种CA4衍生物及其配体-药物偶联物。
配体-药物偶联物(ADC)作为新型的靶向药物,一般由三部分组成:抗体或抗体类配体,小分子药物以及将配体和药物偶联起来的连接子。抗体药物偶联物利用抗体对抗原的特异性识别,将药物分子运输至靶细胞附近并有效释放药物分子,达到治疗目的。早期研发ADCs中所使用的药物分子倾向于毒性极高的分子,但这类ADCs会产生较大的毒副作用。Enhertu和Trodelvy分别于2019和2020年上市,它们均采用毒性适中的喜树碱类衍生物作为药物分子。新一代ADCs的研发中开始关注并重视细胞杀伤活性适中的药物分子,然而,因为ADC药物能携带的药物数量有限,目前已上市药物中,单个ADC中最多携带8个药物分子,因此文献报道,ADC毒素细胞杀伤活性理想的IC50为次纳摩尔(0.1nM)水平。
上世纪80年代科学人员从南非的一种灌木(Combretum caffrum)中分离出来一系列活性成分(Srivastava V.et al.,Bioorg.Med.Chem.2005,13,5892-5908),此系列化合物不仅能够阻断肿瘤血供对肿瘤细胞有抑制作用而且也能抑制微管蛋白的聚合,其中以Combretastin A-4(CA-4)的活性最好,以此研究者们开展了对CA-4的研究,一系列衍生物被合成出来,其中AmCA-4(AVE8063)的抗肿瘤作用、抗微管蛋白聚合的能力与CA-4接近(Koji,Ohsumi etal.,J.Med.Chem.1998,41,3022-3032)。专利CN112209990A设计了以CA4为毒素的ADC药物。然而,CA4作为ADC毒素使用,其活性为1~100nM,难以达到最佳治疗效果。
发明内容
针对CA4类化合物难以直接成药的问题,且为提高其配体-药物偶联物的生物活性,申请人创造性的发明了一种更高活的CA4衍生物及其配体-药物偶联物并将其用在癌症靶向治疗中。
本发明公开一种如通式D所示的CA4衍生物,或其药学上可接受的盐或溶剂化物;
其中:
R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;
X选自-C(O)-CR
aR
b-(CR
1R
2)
m-O-、-C(O)-CR
aR
b-(CR
1R
2)
m-NH-或-C(O)-CR
aR
b-(CR
1R
2)
m-S-;
R
a选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;
R
b选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;
或者,R
a、R
b及其所连接碳原子构成C
3-6环烷基、环烷基烷基或杂环基;
R
1、R
2相同或者不同,且分别独立地为氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基;
或者,R
1、R
2及其所连接碳原子构成C
3-6环烷基、环烷基烷基或杂环基;
m选自0-4的整数。
作为优选方式,所述X非限制性地选自以下结构:
其中左侧波浪线与CA4衍生物部分相连,右侧波浪线与连接单元相连。
作为优选方式,所述化合物非限制性地选自以下所示的结构:
其中R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基。
进一步优选,所述化合物非限制性地选自以下所示的结构:
本发明还公开了一种包括CA4衍生物的连接子-药物偶联物或其药学上可接受的盐或溶剂化物:
其中:
R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;
X选自-C(O)-CR
aR
b-(CR
1R
2)
m-O-、-C(O)-CR
aR
b-(CR
1R
2)
m-NH-或-C(O)-CR
aR
b-(CR
1R
2)
m-S-;
R
a选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;
R
b选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;
或者,R
a、R
b及其所连接碳原子构成C
3-6环烷基、环烷基烷基或杂环基;
R
1、R
2相同或者不同,且分别独立地为氢原子、氘原子、卤素、烷基、卤代烷基、氘代烷基、烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基;
或者,R
1、R
2及其所连接碳原子构成C
3-6环烷基、环烷基烷基或杂环基;
m选自0-4的整数;
L为-L
1-L
2-L
3-L
4-。
作为优选方式,-L-为-L
1-L
2-L
3-L
4-,其中L
1端与配体Ab相连,L
4端与X相连。
进一步优选,L
1非限制性地选自:
进一步优选,L
2选自:-NC(R
3R
4)C(O)、-NR
5(CH
2)
oC(O)-、-NR
5(CH
2CH
2O)
oCH
2C(O)-、-S(CH
2)
pC(O)-或者化学键,其中o选自0-20的整数;p选自0-20的整数;
R
3、R
4相同或者不同,且各自独立地选自氢原子、氘原子、烷基、取代烷基、氘代烷基、杂烷基、羧基、氨基、取代氨基;
R
5选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;
L
1与L
2共用N原子。
进一步优选,
L
3选自由氨基酸构成的肽残基,其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、羧基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代;优选由一个、两个或者多个选自苯丙氨酸(F)、甘氨酸(G)、缬氨酸(V)、赖氨酸(K)、瓜氨酸、丝氨酸(S)、谷氨酸(E)或者天冬氨酸(D)中的氨基酸形成的肽残基。
进一步优选,L
4选自:-NR
6(CR
7R
8)
q-、-C(O)NR
6-、-C(O)NR
6(CH
2)
q-或者化学键,q选自0-6的整数;
R
6、R
7和R
8相同或者不同,且各自独立地选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
作为优选方式,所述连接单元-L-非限制性地选自以下结构;
其中:左侧波浪线与配体部分相连,右侧波浪线与X相连。
进一步优选,所述连接子-药物偶联物非限制性地选自以下结构:
其中:
1位和2位碳原子具有R或S两种构型的绝对手性。
本发明进一步公开了一种包括连接子-药物偶联物的配体-药物偶联物或其药学上可接受的盐或溶剂化物,所述配体-药物偶联物包含式Ⅰ所示的结构:
其中:
R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;
X选自-C(O)-CR
aR
b-(CR
1R
2)
m-O-、-C(O)-CR
aR
b-(CR
1R
2)
m-NH-或-C(O)-CR
aR
b-(CR
1R
2)
m-S-;
R
a选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;
R
b选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;
或者,R
a、R
b及其所连接碳原子构成C
3-6环烷基、环烷基烷基或杂环基;
R
1、R
2相同或者不同,且分别独立地为氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基;
或者,R
1、R
2及其所连接碳原子构成C
3-6环烷基、环烷基烷基或杂环基;
Ab为配体单元,选自抗体、抗体片段、靶向蛋白、Fc-融合蛋白等;
L为与Ab连接单元;X为药物部分修饰单元;
m选自0-4的整数;n选自1-20的整数或小数。
作为优选方式,Ab为抗体,可通过其杂原子与连接单元形成连接键,所述抗体选自鼠源抗体、嵌合抗体、人源化抗体、全人源抗体、抗体片段、双特异性抗体或多特异性抗体。
进一步优选,所述的抗体或其抗原结合片段,非限制性地选自:抗EGFRvIII抗体、抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3 抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin 18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗Integrin Av抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin 6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD47抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体。
更进一步优选,所述配体-药物偶联物非限制性地选自以下结构:
其中:
Ab为配体单元;n选自1-20的整数或小数;
本发明公开了一种制备连接子-药物偶联物或其药学上可接受的盐或溶剂化物的方法,包括如下步骤:
通过连接单元L
a与通式化合物D
1取代反应,得到如通式L
a-D所示的连接子-药物偶联物;
其中:L
2、L
3、R、R
8、R
9、R
10、q及X如通式L-X-D所述。
本发明还公开了一种制备配体-药物偶联物或其药学上可接受的盐或溶剂化物的方法,包括如下步骤:
通过还原的抗体、抗体片段或者其抗原结合片段与通式(L-X-D)偶联反应,得到如通式Ab-L-X-D所示配体-药物偶联物;
其中:Ab、L、X、R及n如通式Ⅰ所述。
一种CA4衍生物、连接子-药物偶联物或配体-药物偶联物或其药学上可接受的盐或溶剂化物,所述药学上可接受的盐包括与结构式中酸性官能团形成的钠盐、钾盐、钙盐或镁盐等;或与结构中碱性官能团形成的醋酸盐、三氟乙酸盐、柠檬酸盐、草酸盐、酒石酸盐、苹果酸盐、硝酸盐、氯化物、溴化物、碘化物、硫酸盐、硫酸氢盐、磷酸盐、乳酸盐、油酸盐、抗坏血酸盐、水杨酸盐、甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐。
一种药物组合物,其含有治疗有效量的CA4衍生物、连接子-药物偶联物或配体-药物偶联物或其药学上可接受的盐或溶剂化物,以及药学上可接受的载体、稀释剂或赋形剂。
一种包括CA4衍生物、连接子-药物偶联物或配体-药物偶联物或其药学上可接受的盐或溶剂化合物,以及药学上可接受的载体、稀释剂或者赋形剂,在制备用于治疗或预防肿瘤的药物中的用途。
作为优选,其中所述的肿瘤为乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤和白血病等实体瘤或血液瘤。
缩写和定义
除非另有说明,否则如本文所用的以下术语和短语旨在具有以下含义。当本文中使用商标名称时,除非上下文中另有指明,否则商标名称包括所述商标名称产品的产品配方、通用药物和活性成分。
除非有相反陈述,本文权利要求书和说明书中使用的术语具有下述含义。
术语“配体”是能识别和结合目标细胞相关的抗原或受体的大分子化合物。配体的作用是将药物呈递给与配体结合的目标细胞群,这些配体包括但不限于蛋白类激素、凝集素、生长因子、抗体或其他能与细胞结合的分子。在本发明实施方式中,配体表示为Ab,配体可通过配体上的杂原子与连接单元形成连接键,优选为抗体或其抗原结合片段,所述抗体选自嵌合抗体、人源化抗体、全人抗体或鼠源抗体;优选为单克隆抗体。
配体单元是与靶标部分特异性结合的靶向剂。所述配体能够特异性结合至细胞组分或结合至细胞组分或结合至其他感兴趣的靶标分子。靶标部分或靶标通常在细胞表面上。在一些方面中,配体单元的作用是将药物单元递送至配体单元与之相互作用的特定靶细胞群。配体包括但不限于蛋白质、多肽和肽,以及非蛋白质如糖。合适的配体单元包括,例如,抗体,例如全长(完整)抗体及其抗原结合片段。在配体单元是非抗体靶向试剂的实施方式中,其可以是肽或多肽,或非蛋白质分子。这类靶向试剂的示例包括干扰素、淋巴因子、激素、生长因子和集落刺激因子、维生素、营养转运分子、或任何其他细胞结合分子或物质。在一些实施方式中,连接子共价连接至配体的硫原子。在一些方面中,硫原子是半胱氨酸残基的硫原子,其形成抗体的链间二硫键。在另一方面中,硫原子是已经导入配体单元的半胱氨酸残基的硫原子,其形成抗体的链间二硫键。在另一方面中,硫原子是已经导入配体单元的半胱氨酸残基的硫原子(例如,通过定点诱变或化学反应)。在其他方面中,连接子结合的硫原子选自形成抗体的链间二硫键的半胱氨酸残基或已经引入配体单元的额半胱氨酸残基(例如,通过定点诱变或化学反应)。在一些实施方式中,按照Kabat{[Kabat E.A等,(1991)]《免疫学感兴趣的蛋白质序列》(Sequences of proteins of Immunological Interest),第五版,NIH出版物91-3242}中的EU索引编号系统。
如本文所用,“抗体”或“抗体单元”在其所属的范围内,包括抗体结构的任何部分。这一单元可以结合,反应性关联,或者络合一个受体,抗原或者靶向细胞群体具有的其它受体单元。抗体可以是任何蛋白或蛋白类分子,它可以结合、络合或者与待治疗或生物改造的细胞群体的一部分发生反应。本发明中组成抗体药物偶联物的抗体保持其原有野生状态时的抗原结合能力。因此,本发明中的抗体能够专一性地与抗原结合。涉及的抗原包括,例如,肿瘤相关抗原(TAA),细胞表面受体蛋白和其他细胞表面分子,细胞存活调节因子,细胞增殖调节因子,与组织生长与分化相关的分子(如已知或预知的具有功能性的),淋巴因子,细胞因子,参与细胞循环调节的分子,参与血管生成的分子,以及与血管生成有关的分子(如已知或预知的具有功能性的)。肿瘤相关因子可以是簇分化因子(如CD蛋白)。
应用在抗体药物偶联物中的抗体包括,但不局限于,针对细胞表面受体和肿 瘤相关抗原的抗体。这样的肿瘤相关抗原是业内所熟知的,可以通过业内熟知的抗体制备方法和信息来制备。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物,研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性的表达在一种或多种癌细胞表面,而在一种或多种非癌细胞表面表达很少或不表达。通常,相对于非癌细胞表面而言,这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子,可大大提高基于抗体治疗癌症的专一靶向特性。为方便起见,为业内所熟知的抗原相关信息标示如下,包括名称,其他名称,基因库登录号。与肿瘤相关抗原对应的核酸和蛋白序列可参见公开数据库,例如Genbank。抗体靶向对应的肿瘤相关抗原包括所有的氨基酸序列变种和同种,与参考文献中确认的序列具有至少70%,80%,85%,90%或者95%的同源性,或者具备与引用文献中的肿瘤相关抗原序列具有完全一致的生物性质和特征。
术语“抑制”或“的抑制”指,减少了可检测的量,或完全阻止。
术语“癌症”指的是以失调的细胞生长为特征的生理病症或疾病。“肿瘤”包括癌细胞。
术语“自身免疫疾病”是源自针对个体自身的组织或蛋白质的疾病或紊乱。
术语“药物”是指细胞毒性药物,药物表示d,能在肿瘤细胞内具有较强破坏其正常生长的化学分子。细胞毒性药物原则上在足够高的浓度下都可以杀死肿瘤细胞,但是由于缺乏特异性,在杀伤肿瘤细胞的同时,也会导致正常细胞的凋亡,导致严重的副作用。该术语包括毒素,如细菌、真菌、植物或动物来源的小分子毒素或酶活性毒素,放射性同位素(例如At
211、I
131、I
125、Y
90、Re
186、Re
188、Sm
153、Bi
212、P
32和Lu
176的放射性同位素),毒性药物,化疗药物,抗生素和核溶酶,优选为毒性药物。
术语“连接子”或“连接片段”或“连接单元”是指一端与配体连接而另一端与药物相连的化学结构片段或键,也可以连接其他接头后再与药物相连。
接头,包括延伸物、间隔物和氨基酸单元,可以通过本领域己知方法合成,诸如US2005-0238649A1中所记载的。接头可以是便于在细胞中释放药物的“可切割接头”。例如,可使用酸不稳定接头(例如腙)、蛋白酶敏感(例如肽酶敏感)接头、光不稳定接头、二甲基接头、或含二硫化物接头(Chari等Cancer Research 52:127-131,1992);美国专利No.5,208,020。
按照在细胞内药物释放的机制,如本文所用,“连接子”或“抗体药物偶联物的连接子”可被分为两类:不可断裂连接子和可断裂连接子。对于含有不可断裂连接子的抗体-药物偶联物,其药物释放机制为:偶联物与抗原结合并被细胞内吞后,抗体在溶酶体中被酶解,释放出由小分子药物,连接子,和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性,但由于活性分子是带电荷的(氨基酸残基),从而导致其不能渗入邻近细胞。因此,此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应,bystander effect)(Ducry等,2010,Bioconjugate Chem.21:5-13)。
术语“抗体-药物偶联物”,指抗体通过稳定的连接单元与具有生物活性的药物相连。在本发明中“配体-药物偶联物”优选为抗体-药物偶联物(antibody drug conjugate,ADC),指把单克隆抗体或者抗体片段通过稳定的连接单元与具有生物活性的毒性药物相连。
本公开所用氨基酸三字母代码和单字母代码如J.boil.Chem.1968,243,3558.中所述。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至10个碳原子的烷基,最优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异 丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基。
术语“取代烷基”指烷基中的氢被取代基团取代,除非文中另有说明,烷基的取代基可以是选自下组的多种基团:-卤素、-OR’、-NR’R”、-SR’、-SiR’R”R”’、-OC(O)R’、-C(O)R’、-CO
2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O)
2R’、-NH-C(NH
2)=NH、-NR’C(NH
2)=NH、-NH-C(NH
2)=NR’、-S(O)R’、-S(O)
2R’、-S(O)
2NR’R”、-NR’S(O)
2R”、-CN和-NO
2,取代基数量为0至(2m’+1),其中m’为该基团中碳原子的总数。R’、R”和R”’各自独立的指代氢、未取代的C
1-8烷基、未取代的芳基、由1-3个卤素取代的芳基、未取代的C
1-8烷基、C
1-8烷氧基或C
1-8硫代烷氧基、或未取代的芳基-C
1-4烷基。R’和R”连接于同一个氮原子时,它们可与该氮原子一起形成3-,4-,5-,6-或7-元环。例如,-NR’R”包括1-吡咯烷基和4-吗啉基。
术语“杂烷基”指含有一个或多个选自N、O或S的杂原子的烷基,其中烷基如上所定义。
术语“亚烷基”指饱和的直链或支链脂肪族烃基,其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子,更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH
2-、1,1-亚乙基(-CH(CH
3)-)、1,2-亚乙基(-CH
2CH
2)-、1,1-亚丙基(-CH(CH
2CH
3)-)、1,2-亚丙基(-CH
2CH(CH
3)-)、1,3-亚丙基(-CH
2CH
2CH
2-)、1,4-亚丁基(-CH
2CH
2CH
2CH
2-)和1,5-亚丁基(-CH
2CH
2CH
2CH
2CH
2-)等。亚烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任 选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(环烷基),其中烷基或环烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至10个碳原子,最优选包含3至8个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)
m(其中
m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选环烷基环包含3至10个环原子。单环杂环基的非限制性实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“环烷基烷基”指烷基被一个或多个环烷基取代,优选被一个环烷基取代,其中烷基如上所定义,其中环烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代,其中烷基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代,其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH
2。术语“硝基”指-NO
2。
术语“酰胺基"指-C(O)N(烷基)或(环烷基),其中烷基、环烷基如上所定义。
术语“羧酸酯基"指-C(O)O(烷基)或(环烷基),其中烷基、环烷基如上所定义。
本发明还包括各种氘化形式的式I。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式I。在制备氘代形式的式I时可使用市售的氘代起始物质,或它们可使用常规技术采用氘代试剂合成,氘代试剂的非限制性实例包括:氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
术语“抗体”指免疫球蛋白,是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同,故其抗原性也不同。据此,可将免疫球蛋白分为五类,或称为免疫球蛋白的同种型,即IgM、IgD、IgG、IgA和IgE,其相应的重链分别为μ链、δ链、γ链、α链和ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别,又可分为不同的亚类,如IgG可分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中每类Ig都可以有κ链或λ链。本发明所述的抗体优选为针对靶细胞上细胞表面抗原的特异性抗体,非限制性实施例为以下抗体:抗EGFRvIII抗体、抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin 18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin 4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗Integrin Av抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin 6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体中一个或多个。
术语“溶剂化物”或“溶剂化合物”指本发明的配体-药物偶联物与一种或多种溶剂分子形成可药用的溶剂化物,溶剂分子的非限制性实例包括水、乙醇、乙腈、异丙醇、DMSO、乙酸乙酯。
术语“载药量”是指式I中每个抗体上加载的细胞毒性药物平均数量,也可以表示为药物量和抗体量的比值,药物载量的范围可以是每个抗体(Ab)连接0-12个,优选1-10个细胞毒性药物(D)。在本发明的实施方式中,载药量表示为n,示例性的可以为1,2,3,4,5,6,7,8,9,10的均值。可用常规方法如UV/可见光光谱法,质谱,ELISA试验和HPLC特征鉴定偶联反应后每个ADC分子的药物品均数量。
本发明的一个实施方式中,细胞毒性药物通过连接单元偶联在抗体链间打开的半胱氨酸巯基-SH和/或定点突变的半胱氨酸残基的巯基-SH上,一般地,偶联反应中能与抗体偶联的药物分子数将小于或等于理论上的最大值。
可以用以下非限制性方法控制配体细胞毒性药物偶联物的载量,包括:
(1)控制连接试剂和单抗的摩尔比,
(2)控制反应时间和温度,
(3)选择不同的反应试剂。
常规的药物组合物的制备见中国药典。
术语“药学上可接受的盐”或“可药用盐”是指本发明配体-药物偶联物的盐,或本发明中所述的化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性,本发明配体-药物偶联化合物至少含有一个羧基,因此可以与碱形成盐,药学上可接受的盐的非限制性实例包括:钠盐、钾盐、钙盐或镁盐等。
术语“药学上可接受的盐”或“可药用盐”是指本发明抗体-药物偶联物的盐,或本发明中所述的化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性,本发明配体-药物偶联化合物至少含有一个氨基,因此可以与酸形成盐,药学上可接受的盐的非限制性实例包括:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、草酸盐、硝酸盐、梨酸盐、磷酸氢盐、磷酸二氢盐、水杨酸盐、柠檬酸氢盐、酒石酸盐、马来酸盐、富马酸盐、甲酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺 酸盐、对甲苯磺酸盐。
“酸性氨基酸”指氨基酸的等电点小于7,酸性氨基酸分子中往往带有一个或多个羧基等酸性基团,在结构中可有效电离为负离子形式而增加亲水性。酸性氨基酸可以为天然的,也可为非天然的氨基酸。
“天然氨基酸”指由生物合成的氨基酸。天然氨基酸一般情况下是L-型的,但也有少数例外,比如甘氨酸,包括天然的和生物体合成的。
“非天然氨基酸”指通过合成手段所获得的氨基酸。
下面结合具体实施例,进一步阐述本发明,应理解,这些实施例只用于说明本发明,而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比例、比率、或份数按重量计。
实施例1
化合物D-1的合成:
于25mL单口瓶中加入化合物AMCA-4(100mg,0.32mmol),羟基乙酸(48.2mg,0.64mmol)、EDCI(91mg,0.48mmol)、HOBt(64.2mg,0.48mmol)及3mLDMF,室温反应2h,HPLC监测反应。反应结束后,反应液直接经过高效液相纯化,得到化合物D-1(93mg),收率78.7%,LC-MS:[M+H]
+=374.1。
实施例2
化合物D-2的合成:
参照实施例1的合成方法,以L-乳酸为原料,得化合物D-2(83mg),收率67.8%,LC-MS:[M+H]+=388.2。
实施例3
化合物D-3的合成:
参照实施例1的合成方法,以D-乳酸为原料,得化合物D-3(80mg),收率65.2%,LC-MS:[M+H]
+=388.2。
实施例4
化合物D-4和D-5的合成:
参照实施例1的合成方法,以三氟乳酸为原料,反应完毕后,利用手性制备柱分离纯化得到化合物D-4和D-5,LCMS:[M+NH
4]
+=459.0。
实施例5
化合物D-6和D-7的合成:
参照实施例1的合成方法,以2-环丙基-2-羟基乙酸为原料,反应完毕后,利用手性制备柱分离纯化得到化合物D-6和D-7,LCMS:[M+H]
+=414.1。
实施例6
化合物D-8和D-9的合成:
参照实施例1的合成方法,以3-环丙基-2-羟基丙酸为原料,反应完毕后,利用手性制备柱分离纯化得到化合物D-8和D-9,LCMS:[M+H]
+=428.2。
实施例7
化合物D-10的合成:
参照实施例1的合成方法,以2-环丁基-3-羟基丙酸为原料,得化合物D-10(88.8mg),收率65.5%,LC-MS:[M+H]+=428.0。
实施例8
化合物D-11的合成:
参照实施例1的合成方法,以2-羟基-2-环戊基丙酸为原料,得化合物D-11(110mg),收率81.1%,LC-MS:[M+H]+=428.3。
实施例9
化合物D-11的合成:
参照实施例1的合成方法,以2-甲基-3-羟基丙酸为原料,反应完毕后,利用手性制备柱分离纯化得到化合物D-12和D-13,LCMS:[M+H]
+=402.2。
实施例10
化合物M1的合成:
于5L单口瓶中加入N-芴甲氧羰基-甘氨酸-甘氨酸(100g,28mmol,1.0eq),四乙酸铅(175g,395mmol,1.4eq),2L干燥四氢呋喃和670mL甲苯,搅拌均匀,氮气保护,加热至85℃反应2.5h。TLC监控,原料反应完后,冷却至室温,过滤,滤液减压浓缩,残余物经柱色谱纯化(PE:EA=5:1-2:1),得化合物M1(87g), 收率84.4%,LC-MS:[M+NH
4]
+=386.0。
实施例11
化合物M3的合成:
于1000mL单口瓶中加入化合物SM-2(按照专利CN108452321A公布的方法合成)(40g,96mmol,1.0eq),三乙胺(26.7mL,2.0eq),甲苯(400mL),升温至120℃下回流反应2h。TLC监测基本完全反应,降温至50℃下减压旋除溶剂。用乙酸乙酯(150mL),水(40mL)溶解,冰浴搅拌下用1M HCl调pH至2-3,分液。水层用乙酸乙酯再萃取一次,合并有机层,加入无水硫酸钠干燥。过滤后,浓缩得到淡黄色油状粗品,粗品经柱层析纯化(DCM:MeOH=40:1),得到26.6g化合物M2;LC-MS:[M+H]
+=399.3。
于1000mL单口瓶,加入化合物M2(26.5g,60.5mmol,1.0eq)、五氟苯酚(12.2g,66.5mmol,1.1eq)、DCC(13.7g,66.5mmol,1.1eq)及THF(300mL),室温反应30min(采用TLC监测),过滤滤去不溶物。反应液直接经制备纯化,制备液水泵减压水浴35℃浓缩除去乙腈,冻干得到31.5g化合物M3,收率64%;LC-MS:[M+H]
+=565.1。
实施例12
化合物ent-M3的合成:
参照实施例2合成路线,得到化合物ent-M3(27.8g);LC-MS:[M+H]
+=565.2。
实施例13
化合物1的合成:
第一步:化合物1a
于250mL单口瓶中,加入M1(6g,16.3mmol),100mL THF,对甲苯磺酸一水合物(0.31g,1.63mmol),搅拌冷却至0℃,滴加羟乙酸苄酯(5.4g,32.6mmol),滴毕自然升温至室温反应(反应约2-4h),TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得固体1a(4g),收率52%;LC-MS:[M+H]
+=475.18。
第二步:化合物1b
于25mL单口瓶,加入1a(2g,4.2mmol),10mL DMF,0℃搅拌,加入DBU(766mg,5.04mmol),反应1h,TLC监测Fmoc脱保护完成后,待用;
另取25mL单口瓶中加入M4(参考专利CN111051330A公布的方法制备)(1.73g,4.2mmol),PyBOP(2.61g,5.04mmol),HOBt(680mg,5.04mmol)及10mL DMF,冰水浴下加入DIPEA(830uL,5.04mmol),继续搅拌30min,将上述反应液加至反应瓶中,升至室温反应。HPLC监测反应结束后,反应液经制备液相纯化,得到产品制备液,制备液经二氯甲烷萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到固体1b(1.7g),收率63%;LCMS:[M+H]
+=648.26。
第三步:化合物1c
于25mL单口瓶中加入1b(900mg,1.39mmol),15mL DMF溶清后,加入900mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第四步:化合物1d
将上步所得的1c的DMF溶液置于冰水浴中,加入DIPEA(235uL,1.39mmol),再加入化合物M3(784mg,1.39mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到1d(504mg);LC-MS:[M+H]
+=804.4。
第五步:化合物1e
于50mL单口瓶中加入1d(500mg,0.62mmol),AMCA-4(195mg,0.62mmol),PyBOP(448mg,0.86mmol),HOBt(116mg,0.86mmol)及15mL DMF,冰水浴下加入DIPEA(378uL,2.29mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物1e的制备液,制备液冻干得到固体1e(443mg),收率65%,LC-MS:[M+H]
+=1101.5。
第六步:化合物1
于25mL单口瓶中加入1e(110mg,0.1mmol),溴化锌(450mg,2.00mmol)及6mL硝基甲烷,室温反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物1(63mg);LC-MS:[M+H]
+=945.3。
实施例14
化合物2的合成:
参照实施例13的合成路线,以ent-M3替代M3,得到化合物2(51mg);LC-MS:[M+H]
+=945.3。
实施例15
化合物3的合成:
第一步:化合物3a
于25mL单口瓶中加入M1(1.5g,4.0mmol,1.0eq),对甲苯磺酸一水合物(77mg,0.4mmol,0.1eq)及15mL THF,搅拌均匀后,降至0℃,再缓慢加入L-乳酸苄酯(2.2g,12.0mmol,3eq),加完后升至室温反应。TLC监控,反应结束后,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,残余物经反相柱纯化得3a(1.03g),收率52%,LC-MS:[M+NH
4]
+=506.2。
第二步:化合物3b
于25mL单口瓶中加入化合物3a(1g,2.04mmol)和8mL DMF,搅拌均匀后,降至0℃,再缓慢加入DBU(373mg,2.45mmol),加完后升至室温反应。TLC监控,反应结束,记为反应液①;
另取25mL单口瓶中加入M4(846mg,2.04mmol),PyBOP(1.27g,2.45mmol)和6mL DMF,室温搅拌5分钟,加入反应液①,室温反应,HPLC监测。反应完毕,反应液经高效液相纯化得化合物3b(913mg),收率67.6%,LC-MS:[M+NH
4]
+=679.2。
第三步:化合物3c
于100mL单口瓶中加入3b(800mg,1.21mmol,1.0eq),DMF(15mL)溶解,再加入5%Pd/C(800mg),室温氢化反应2h(采用HPLC监测反应进程)。过滤Pd/C,滤液未经浓缩,直接用于下一步。
第四步:化合物3d
将上步所得3c的DMF溶液置于冰水浴中,加入DIPEA(219uL,1.21mmol),再加入化合物M3(683mg,1.21mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到3d(524mg),收率53%,LC-MS:[M-H]
-=816.3。
第五步:化合物3e
于100mL单口瓶中加入3d(500mg,0.61mmol),AMCA-4(193mg,0.61mmol),PyBOP(477m g,0.91mmol),HOBt(123m g,0.91mmol)及DMF(10mL),冰水浴下加入DIPEA(151uL,0.91mmol),升至室温反应2h(采用HPLC监测)。反应液直接经制备纯化,制备液水泵减压水浴35℃浓缩除去乙腈,冻干得到化合物3e(443mg),收率65%;LC-MS:[M+H]
+=1115.5。
第六步:化合物3
于50mL单口瓶中加入化合物3e(250mg,0.22mmol,1.0eq),15mL硝基甲烷,溶解后再加入溴化锌(1.01g,4.48mmol,20.0eq),室温反应1h,采用HPLC监测。反应完毕后水泵减压水浴45℃浓缩除去硝基甲烷,得粉色残余物固体。经酸法制备,得到化合物3的制备液,冻干得到化合物3(140mg),收率65%,LC-MS:[M+H]
+=959.4。
实施例16
化合物4的合成:
参考实施例15的合成方法,以化合物ent-M3替代化合物M3,得化合物4。
实施例17
化合物5的合成:
参考实施例15的合成方法,以化合物D-乳酸苄酯替代L-乳酸苄酯,得化合物5。
实施例18
化合物6A和6B制备:
第一步:化合物6a
于250mL单口瓶中加入M1(10g,27.1mmol),3,3,3-三氟乳酸苄酯(参照专利WO2020063673A1公布的方法制备)(12.7g,54.3mmol),醋酸锌(9.96g,54.3mmol)及100mL甲苯,加热至100℃反应4h。反应完毕,降至室温,过滤除去不溶物,滤液浓缩得粗品。粗品经硅胶柱层析纯化(PE:EA=10:1-5:1-2:1)得到6a(5.15)g,收率35.1%;LC-MS:[M+H]
+=543.17。
第二步:化合物6b
于50mL单口瓶中加入6a(5g,9.2mmol)及15mL DMF,溶清后,冰水浴下,加入DBU(1.68g,11mmol),反应1h,记为反应液①;
另取50mL单口瓶,加入M4(3.8g,9.2mmol),PyBOP(5.75g,11mmol),HOBt(1.49g,11mmol)及10mL DMF,溶清后,冰水浴下,加入DIPEA(1.82mL,11mmol),继续反应30min,加入反应液①,升至室温反应2h。HPLC监测反应进程,反应完毕后,反应液经高效液相纯化,得制备液。制备液经二氯甲烷萃取、饱和氯化钠溶液洗涤、无水硫酸钠干燥、过滤、浓缩得到6b(4.1)g,收率 62.3%;LC-MS:[M+H]
+=716.25。
第三步:化合物6d
于25mL单口瓶中加入6b(900mg,1.26mmol),15mL DMF溶清后,加入900mg 5%Pd/C,氢化反应2h,反应完毕,过滤,将滤液置于冰水浴中,加入DIPEA(228uL,1.38mmol),再加入M3(712mg,1.26mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到产品6d(525)mg,收率47.9%;LC-MS:[M-H]
-=870.33。
第四步:化合物6e
于50mL单口瓶中加入6d(500mg,0.57mmol),AMCA-4(180mg,0.57mmol),PyBOP(448mg,0.86mmol),HOBt(116mg,0.86mmol)及15mL DMF,冰水浴下加入DIPEA(378uL,2.29mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物6e-1和化合物6e-2的制备液,制备液分别冻干得到210mg化合物6e-1及化合物6e-2,LC-MS:[M+H]
+=1169.46。
第五步:化合物6A
于25mL单口瓶中加入6e-1(100mg,0.085mmol),溴化锌(385mg,1.71mmol)及5mL硝基甲烷,室温下反应1h,HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到化合物6A(50mg),收率59%,LCMS:[M+H]
+=1013.36。
第六步:化合物6B
于25mL单口瓶中加入6e-2(100mg,0.085mmol),溴化锌(385mg,1.71mmol)及5mL硝基甲烷,室温下反应1h,HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到化合物6B(54mg),收率63%,LCMS:[M+H]
+=1013.36。
实施例19
化合物7A和7B的合成:
第一步:化合物7a
于250mL单口瓶中加入M1(10g,27.1mmol),2-环丙基-2-羟基乙酸苄酯(参照专利WO2020244657A1公布的方法制备)(11.2g,54.3mmol),醋酸锌(9.96g,54.3mmol)及100mL甲苯,加热至100℃反应4h。反应完毕,降至室温,过滤除去不溶物,滤液浓缩得粗品。粗品经硅胶柱层析纯化(PE:EA=10:1-5:1-2:1)得到7a(4.97g),收率36%;LC-MS:[M+H]
+=515.2。
第二步:化合物7b
于50mL单口瓶中加入7a(4g,7.8mmol)及10mL DMF,溶清后,冰水浴下,加入DBU(1.42g,9.3mmol),反应1h,记为反应液①;
另取50mL单口瓶,加入M4(3.2g,7.8mmol),PyBOP(4.5g,8.6mmol),HOBt(1.16g,8.6mmol)及10mL DMF,溶清后,冰水浴下,加入DIPEA(1.65mL,10mmol),继续反应30min,加入反应液①,升至室温反应2h。HPLC监测反应进程,反应完毕后,反应液经高效液相纯化,得制备液。制备液经二氯甲烷萃取、饱和氯化钠溶液洗涤、无水硫酸钠干燥、过滤、浓缩得到7b(4.2g),收率78%;LC-MS:[M+H]
+=688.3。
第三步:化合物7d
于25mL单口瓶中加入7b(1000mg,1.45mmol),15mL DMF溶清后,加入1000mg 5%Pd/C,氢化反应2h,反应完毕,过滤,将滤液置于冰水浴中,加入DIPEA(248uL,1.5mmol),再加入M3(720mg,1.45mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到 产品7c(503mg),收率41%;LC-MS:[M-H]
-=842.3。
第四步:化合物7e-1和7e-2
于50mL单口瓶中加入7d(500mg,0.59mmol),AMCA-4(186mg,0.59mmol),PyBOP(339mg,0.65mmol),HOBt(88mg,0.86mmol)及10mL DMF,冰水浴下加入DIPEA(292uL,1.77mmol),升至室温反应2h。HPLC监测反应完毕后,反应液手性柱经高效液相纯化,得化合物7e-1和化合物7e-2的制备液,制备液分别冻干得到化合物7e-1(230mg)及化合物7e-2(211mg),LC-MS:[M+H]
+=1141.5。
第五步:化合物7A
于25mL单口瓶中加入7e-1(100mg,0.087mmol),溴化锌(394mg,1.75mmol)及10mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经手性柱高效液相纯化,得到产品制备液,制备液冻干得到固体7A(61mg),收率72%,LC-MS:[M+H]
+=985.3。
第六步:化合物7B
于25mL单口瓶中加入7e-2(100mg,0.087mmol),溴化锌(394mg,1.75mmol)及10mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经手性柱高效液相纯化,得到产品制备液,制备液冻干得到固体7B(58mg),收率68%,LC-MS:[M+H]
+=985.3。
实施例20
化合物8A和8B的合成:
第一步:化合物8a
于250mL单口瓶中加入M1(10g,27.1mmol),2-羟基-3-环丙基丙酸苄酯(参照专利WO2020063676A公布的方法合成)(12.0g,54.3mmol),醋酸锌(9.96g,54.3mmol)及100mL甲苯,加热至100℃反应4h。反应完毕,降至室温,过滤除去不溶物,滤液浓缩得粗品。粗品经硅胶柱层析纯化(PE:EA=10:1-5:1-2:1)得到目标物8a(5.09g);LC-MS:[M+H]
+=529.2。
第二步:化合物8b
于50mL单口瓶中加入8a(4g,7.6mmol)及10mL DMF,溶清后,冰水浴下,加入DBU(1.39g,9.1mmol),反应1h,记为反应液①;
另取50mL单口瓶,加入M4(3.12g,7.6mmol),PyBOP(4.5g,8.6mmol),HOBt(1.16g,8.6mmol)及10mL DMF,溶清后,冰水浴下,加入DIPEA(1.65mL,10mmol),继续反应30min,加入反应液①,升至室温反应2h。HPLC监测反应进程,反应完毕后,反应液经高效液相纯化,得制备液。制备液经二氯甲烷萃取、饱和氯化钠溶液洗涤、无水硫酸钠干燥、过滤、浓缩得到化合物8b(4.5g),收率84%;LC-MS:[M+H]
+=702.3。
第三步:化合物8d
于25mL单口瓶中加入8b(1000mg,1.42mmol),15mL DMF溶清后,加入1000mg 5%Pd/C,氢化反应2h,反应完毕,过滤,将滤液置于冰水浴中,加入DIPEA(248uL,1.5mmol),再加入M3(708mg,1.42mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到产品8d(443mg),收率36%;LC-MS:[M-H]
-=856.4。
第四步:化合物8e-1和8e-2
于50mL单口瓶中加入8d(400mg,0.47mmol),AMCA-4(148mg,0.47mmol),PyBOP(223mg,0.56mmol),HOBt(83mg,0.56mmol)及10mL DMF,冰水浴下加入DIPEA(248uL,1.5mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物8e-1和化合物8e-2的制备液,制备液分别冻干得到化合物8e-1(163mg)、化合物8e-2(180mg),LC-MS:[M+H]
+=1155.5。
第五步:化合物8A
于25mL单口瓶中加入8e-1(100mg,0.086mmol),溴化锌(389mg,1.73mmol)及10mL硝基甲烷,室温反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到化合物8A(57mg),收率66.2%,LC-MS:[M+H]
+=999.4。
第六步:化合物8B
于25mL单口瓶中加入8e-2(100mg,0.086mmol),溴化锌(389mg,1.73mmol)及10mL硝基甲烷,室温反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到化合物8B(61mg),收率70.9%,LC-MS:[M+H]
+=999.4。
实施例21
化合物9的合成:
第一步:化合物9a
于250mL单口瓶中,加入M1(6g,16.3mmol),100mL THF,对甲苯磺酸一水合物(0.31g,1.63mmol),搅拌冷却至0℃,滴加2-羟基-2-环戊基乙酸苄酯(参照文献Journal of Medicinal Chemistry,2013,56(13),5541-5552.公布的方法合成)(7.2g,32.6mmol),滴毕自然升温至室温反应(反应约2-4h),TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-2:1)得9a(4.6g),收率53%;LC-MS:[M+H]
+=529.5。
第二步:化合物9b
于25mL单口瓶,加入9a(4g,7.6mmol),10mL DMF,0℃搅拌,加入DBU(1.17g,7.8mmol),反应1h,TLC监测Fmoc脱保护完成后,待用;
另取25mL单口瓶中加入M4(3.14g,7.6mmol),PyBOP(4.42g,8.5mmol),HOBt(1.15g,8.5mmol)及10mL DMF,冰水浴下加入DIPEA(1.39mL,0.85mmol),继续搅拌30min,将上述反应液加至反应瓶中,升至室温反应。HPLC监测反应结束后,反应液经制备液相纯化,得到产品制备液,制备液经二氯甲烷萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到9b(2.1g),收率39%;LC-MS:[M+H]
+=702.8。
第三步:化合物9c
于25mL单口瓶中加入9b(1.5g,1.87mmol),25mL DMF溶清后,加入1.5g 5%Pd/C,氢化反应3h,反应完毕,过滤,得滤液,未经纯化直接用于下一步 反应。
第四步:化合物9d
将粗产品9c置于冰水浴中,加入DIPEA(333uL,1.93mmol),再加入化合物M3(1.1g,1.87mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得到制备液,制备液冻干得到9d(519mg);LC-MS:[M-H]
-=856.6。
第五步:化合物9e
于50mL单口瓶中加入9d(400mg,0.47mmol),AMCA-4(148mg,0.48mmol),PyBOP(250mg,0.48mmol),HOBt(103mg,48mmol)及15mL DMF,冰水浴下加入DIPEA(330uL,2.0mmol),升至室温反应4h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物9e的制备液,制备液冻干得到9e(287mg),收率53%,LC-MS:[M+H]
+=1155.5。
第六步:化合物9
于25mL单口瓶中加入9e(100mg,0.086mmol),溴化锌(389mg,1.73mmol)及10mL硝基甲烷,40℃室温反应1h。反应完毕后,水泵45℃减压浓缩除去溶剂,得粗品。粗品经过高效液相纯化,得到产品制备液,制备液冻干得到固体化合物9(49mg),收率57.2%,LC-MS:[M+H]
+=999.6。
实施例22
化合物10的合成:
第一步:化合物10a
于25mL单口瓶中加入M1(1.5g,4.0mmol,1.0eq),对甲苯磺酸一水合物 (77mg,0.4mmol,0.1eq)及15mL THF,搅拌均匀后,降至0℃,再缓慢加入(S)-2-甲基-3-羟基丙酸苄酯(2.32g,12.0mmol,3eq),加完后升至室温反应。TLC监控,反应结束后,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,无水硫酸钠干燥,过滤,浓缩,残余物经反相柱纯化得10a(1.12g),收率55%,LC-MS:[M+NH
4]
+=520.2。
第二步:化合物10b
于25mL单口瓶中加入化合物10a(1g,1.99mmol)和8mL DMF,搅拌均匀后,降至0℃,再缓慢加入DBU(363mg,2.39mmol),加完后升至室温反应。TLC监控,反应结束,记为反应液①;
另取25mL单口瓶中加入M4(823mg,1.99mmol),PyBOP(1.24g,2.39mmol)和6mL DMF,室温搅拌5分钟,加入反应液①,室温反应,HPLC监测。反应完毕,反应液经高效液相纯化得化合物10b(882mg),收率65.6%,LC-MS:[M+H]
+=676.2。
第三步:化合物10c
于100mL单口瓶中加入10b(800mg,1.18mmol,1.0eq),DMF(15mL)溶解,再加入5%Pd/C(800mg),室温氢化反应2h(采用HPLC监测反应进程)。过滤Pd/C,滤液未经浓缩,直接用于下一步。
第四步:化合物10d
将上步所得10c的DMF溶液置于冰水浴中,加入DIPEA(194uL,1.18mmol),再加入化合物M3(668mg,1.18mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到10d(502mg),收率51%,LC-MS:[M-H]
-=830.3。
第五步:化合物10e
于100mL单口瓶中加入10d(500mg,0.6mmol),AMCA-4(189mg,0.6mmol),PyBOP(469m g,0.9mmol),HOBt(122g,0.9mmol)及DMF(10mL),冰水浴下加入DIPEA(148uL,0.9mmol),升至室温反应2h(采用HPLC监测)。反应液直接经制备纯化,制备液水泵减压水浴35℃浓缩除去乙腈,冻干得到化合物10e(461mg),收率68.1%,LC-MS:[M+H]
+=1129.5。
第六步:化合物10
于50mL单口瓶中加入化合物10e(250mg,0.22mmol),10mL硝基甲烷,溶解 后再加入溴化锌(996mg,4.42mmol),室温反应1h,采用HPLC监测。反应完毕后水泵减压水浴45℃浓缩除去硝基甲烷,得粉色残余物固体。经酸法制备,得到产品制备液,冻干得到化合物10(140mg),收率65%,LC-MS:[M+H]
+=973.3。
实施例23
化合物11的合成:
参照实施例22的合成方法,将(R)-2甲基-3-羟基丙酸苄酯替代(S)-2-甲基-3-羟基丙酸苄酯,得化合物11,LC-MS:[M+H]
+=973.3。
实施例24
化合物12的合成:
第一步:化合物12a
于250mL单口瓶中,加入M1(6g,16.3mmol),100mL THF,对甲苯磺酸一水合物(0.31g,1.63mmol),搅拌冷却至0℃,滴加2-羟基-2-环丁基乙酸苄酯(7.2g,32.6mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-2:1)得12a(5.3g),收率62%;LC-MS:[M+H]
+=529.2。
第二步:化合物12b
于25mL单口瓶,加入12a(4g,7.5mmol),10mL DMF,0℃搅拌,加入DBU(1.38g,9.0mmol),反应1h,TLC监测Fmoc脱保护完成后,待用;
另取25mL单口瓶中加入M4(3.0g,8.0mmol),PyBOP(4.72g,9.0mmol),HOBt(1.22g,9.0mmol)及10mL DMF,冰水浴下加入DIPEA(1.87mL,11.3mmol),继续搅拌40min,将上述反应液加至反应瓶中,升至室温反应。HPLC监测反应结束后,反应液经制备液相纯化,得到产品制备液,制备液经二氯甲烷萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到12b(2.3g),收率42%,LC-MS:[M+H]
+=702.3。
第三步:化合物12c
于25mL单口瓶中加入12b(1.0g,1.4mmol),25mL DMF溶清后,加入1.0g 5%Pd/C,氢化反应4h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第四步:化合物12d
将上述12c的DMF溶液置于冰水浴中,加入DIPEA(352uL,2.13mmol),再加入化合物M3(966mg,1.7mmol),加毕升至室温反应2h。HPLC监测反应完毕,反应液经高效液相纯化,得到制备液,制备液冻干得到12d(623mg),收率51%,LC-MS:[M-H]
-=856.3。
第五步:化合物12e
于50mL单口瓶中加入12d(200mg,0.23mmol),AMCA-4(74mg,0.23mmol),PyBOP(145mg,0.28mmol),HOBt(38mg,0.28mmol)及30mL DMF,冰水浴下加入DIPEA(58uL,0.35mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得产品制备液,制备液冻干得到12e(168mg),收率62.5%,LC-MS:[M+H]
+=1155.5。
第六步:化合物12
于25mL单口瓶中加入12e(100mg,0.087mmol),溴化锌(394mg,1.75mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物12(61mg),收率71%,LC-MS:[M+H]
+=999.4。
实施例25
化合物M6的合成:
第一步:化合物M5的合成
于500mL单口瓶中加入氨基-八聚乙二醇-羧基(10g,22.7mmol),20mLDMF溶清,加入McOSu(8.38g,27.2mmol),DIEA(5.6mL,3.4mmol),室温反应2h,TLC监测。反应结束后,将反应液倒入100mL水中,用二氯甲烷萃取三次,合并有机相,用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥。过滤,45℃减压浓缩得粗品。粗品经过硅胶柱层析纯化(DCM:MeOH=30:1-10:1),收集产品洗脱液,浓缩得到化合物M5(12.1g),收率84.5%,LCMS:[M-H]
+=633.3。
第二步:化合物M6的合成
于500mL单口瓶,加入化合物M5(12.0g,18.9mmol)、五氟苯酚(3.83g,20.8mmol)、DCC(4.28g,20.8mmol)及THF(50mL),室温反应1h,TLC监测。反应结束后,过滤滤去不溶物。滤液水泵减压45℃浓缩除去溶剂得残余物。残余物经过硅胶柱层析纯化(PE:EA=5:1-2:1),收集产品洗脱液,浓缩得到化合物M6(13.8g),收率91.5%,LCMS:[M+H]
+=801.3。
实施例26
化合物13的合成:
第一步:化合物13a的合成
向化合物1c(220mg,0.5mmol)中加入10mL DMF,冰水浴加入M6(500mg,0.6mmol)冷却至0℃,加入化合物DIPEA(124uL,0.75mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物13a(430mg),收率83%,LCMS:[M-H]
+=1038.5。
第二步:化合物13的合成
于25mL单口瓶中加入13(100mg,0.096mmol),AMCA-4(30mg,0.096mmol),PyBOP(60mg,0.11mmol),HOBt(15.6mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(24uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得制备液,制备液冻干得到化合物13(95mg),收率73.8%,LC-MS:[M+H]
+=1337.6。
实施例27
化合物14的合成:
第一步:化合物14a的合成
向化合物3c(200mg,0.45mmol)中加入10mL DMF,冰水浴加入M6(439mg,0.55mmol)冷却至0℃,加入化合物DIPEA(113uL,0.68mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物14a(419mg),收率87%,LCMS:[M-H]
+=1052.5。
第二步:化合物14的合成
于25mL单口瓶中加入14a(100mg,0.094mmol),AMCA-4(29.8mg,0.094mmol),PyBOP(60mg,0.11mmol),HOBt(15.6mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(24uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得产品制备液,制备液冻干得到化合物14(90mg),收率70.8%,LC-MS:[M+H]
+=1351.6。
实施例28
化合物15的合成:
按照实施例27的合成方法,将化合物5c替代3c,得到化合物15,LC-MS:[M+H]
+=1351.6。
实施例29
化合物16A和16B的合成:
第一步:化合物16a的合成
向6c(200mg,0.4mmol)中加入10mL DMF,冰水浴加入M6(391mg,0.48mmol)冷却至0℃,加入化合物DIPEA(100uL,0.61mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制 备液,制备液减压除去乙腈以后,冻干,得到化合物16a(368mg),收率81.7%,LCMS:[M-H]
+=1106.4。
第二步:化合物16A和16B的合成
于25mL单口瓶中加入16a(100mg,0.09mmol),AMCA-4(28.4mg,0.09mmol),PyBOP(56mg,0.10mmol),HOBt(14.6mg,0.10mmol)及5mL DMF,冰水浴下加入DIPEA(22uL,0.13mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得制备液,制备液冻干得到化合物16A(45mg),化合物16B(54mg),LC-MS:[M+H]
+=1405.6。
实施例30
化合物17A和17B的合成:
第一步:化合物17a的合成
向化合物7c(200mg,0.43mmol)中加入10mL DMF,冰水浴加入M6(413mg,0.51mmol)冷却至0℃,加入化合物DIPEA(106uL,0.65mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物17a(366mg),收率78.7%,LCMS:[M-H]
+=1078.5。
第二步:化合物17A和17B的合成
于25mL单口瓶中加入化合物17a(100mg,0.092mmol),AMCA-4(29mg, 0.092mmol),PyBOP(58mg,0.11mmol),HOBt(15mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(23uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得制备液,制备液冻干得到化合物17A(47mg),化合物17B(53mg),LC-MS:[M+H]+=1377.6。
实施例31
化合物18A和18B的合成:
第一步:化合物18a的合成
向化合物8c(200mg,0.42mmol)中加入10mL DMF,冰水浴加入M6(402mg,0.5mmol)冷却至0℃,加入化合物DIPEA(104uL,0.63mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物18a(362mg),收率79.1%,LCMS:[M-H]
+=1092.5。
第二步:化合物18A和18B的合成
于25mL单口瓶中加入化合物18a(100mg,0.091mmol),AMCA-4(29mg,0.091mmol),PyBOP(58mg,0.11mmol),HOBt(15mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(23uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得制备液,制备液冻干得到化合物18A(50mg),化合物18B(56mg),LC-MS:[M+H]+=1391.7。
实施例32
化合物19的合成:
第一步:化合物19a的合成
向化合物9c(200mg,0.42mmol)中加入10mL DMF,冰水浴加入M6(402mg,0.5mmol)冷却至0℃,加入化合物DIPEA(104uL,0.63mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物19a(355mg),收率77.4%,LCMS:[M-H]
+=1092.5。
第二步:化合物19的合成
于25mL单口瓶中加入化合物19a(100mg,0.091mmol),AMCA-4(29mg,0.091mmol),PyBOP(58mg,0.11mmol),HOBt(15mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(23uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得制备液,制备液冻干得到化合物19(95mg),收率75%,LC-MS:[M+H]
+=1391.7。
实施例33
化合物20的合成:
第一步:化合物20a的合成
向化合物10c(200mg,0.44mmol)中加入10mL DMF,冰水浴加入M6(425mg,0.53mmol)冷却至0℃,加入化合物DIPEA(110uL,0.66mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物20a(357mg),收率75.4%,LCMS:[M-H]
+=1066.5。
第二步:化合物20的合成
于25mL单口瓶中加入化合物20(100mg,0.094mmol),AMCA-4(30mg,0.094mmol),PyBOP(58mg,0.11mmol),HOBt(15mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(23uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得制备液,制备液冻干得到化合物20(92mg),收率72%,LC-MS:[M+H]
+=1365.7。
实施例34
化合物21的合成:
按照实施例33的合成方法,将化合物11c替代10c,得到化合物21,LC-MS:[M+H]
+=1365.7。
实施例35
化合物22的合成:
第一步:化合物22a的合成
向化合物12c(200mg,0.42mmol)中加入10mL DMF,冰水浴加入M6(402mg,0.5mmol)冷却至0℃,加入化合物DIPEA(104uL,0.63mmol),室温反应1h,HPLC监测反应。反应完毕后,反应液经制备级高效液相色谱法纯化得到产品制备液,制备液减压除去乙腈以后,冻干,得到化合物22a(363mg),收率79.4%,LCMS:[M-H]
+=1092.5。
第二步:化合物22的合成
于25mL单口瓶中加入化合物22a(100mg,0.091mmol),AMCA-4(29mg,0.091mmol),PyBOP(58mg,0.11mmol),HOBt(15mg,0.11mmol)及5mL DMF,冰水浴下加入DIPEA(23uL,0.14mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得制备液,制备液冻干得到化合物22(92mg),收率72%,LC-MS:[M+H]
+=1391.7。
实施例36
化合物M7的合成:
参照实施例1的合成方法,于5L单口瓶中加入N-苄氧羰基-缬氨酰-丙氨酰-甘氨酸(SM-3,100g,263mmol,1.0eq),四乙酸铅(163g,369mmol,1.4eq),2L干燥四氢呋喃和670mL甲苯,搅拌均匀,氮气保护,加热至85℃反应3h。TLC监控,原料反应完后,冷却至室温,过滤,滤液减压浓缩,残余物经柱色谱纯化 (PE:EA=5:1-2:1),得化合物M7(74g),收率71%,LC-MS:[M+NH
4]
+=411.1。
实施例37
化合物M8的合成:
参照实施例1的合成方法,于5L单口瓶中加入N-苄氧羰基-缬氨酰-赖氨酰-甘氨酸(SM-4,100g,215mmol,1.0eq),四乙酸铅(133g,300mmol,1.4eq),2L干燥四氢呋喃和670mL甲苯,搅拌均匀,氮气保护,加热至85℃反应3h。TLC监控,原料反应完后,冷却至室温,过滤,滤液减压浓缩,残余物经柱色谱纯化(PE:EA=5:1-2:1),得化合物M8(77g),收率75%,LC-MS:[M+H]
+=480.2。
实施例38
化合物23的合成:
第一步:化合物23a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加羟乙酸苄酯(2.53g,15mmol),滴毕自然升温至室温反应3h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物23a(1.32g),收率52%;LC-MS:[M+H]
+=500.2。
第二步:化合物23b
于25mL单口瓶中加入23a(200mg,0.4mmol),15mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物23c
将上述所得化合物23b的DMF溶液置于冰水浴中,加入DIPEA(99uL,0.6mmol),再加入化合物M3(271mg,0.48mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物23c(134mg),收率51%,LC-MS:[M-H]
+=654.3。
第四步:化合物23d
于50mL单口瓶中加入23c(200mg,0.3mmol),AMCA-4(96mg,0.3mmol),PyBOP(190mg,0.36mmol),HOBt(49mg,0.36mmol)及10mL DMF,冰水浴下加入DIPEA(75uL,0.45mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物23d的制备液,制备液冻干得到化合物23d(197mg),收率69.1%,LC-MS:[M+H]
+=953.4。
第五步:化合物23
于25mL单口瓶中加入化合物23d(100mg,0.104mmol),溴化锌(472mg,2.09mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物23(57mg),收率68%,LC-MS:[M+H]
+=797.3。
实施例39
化合物24的合成:
参照实施例38的合成方法,将化合物ent-M3替代化合物M3,得到化合物24,LC-MS:[M+H]+=797.3。
实施例40
化合物25的合成:
第一步:化合物25a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加L-乳酸苄酯(2.7g,15mmol),滴毕自然升温至室温反应3h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物25a(1.43g),收率56%;LC-MS:[M+H]
+=514.2。
第二步:化合物25b
于25mL单口瓶中加入25a(200mg,0.39mmol),15mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物25c
将上述所得化合物25b的DMF溶液置于冰水浴中,加入DIPEA(99uL,0.6mmol),再加入化合物M3(264mg,0.46mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物25c(140mg),收率54%,LC-MS:[M-H]
+=668.3。
第四步:化合物25d
于50mL单口瓶中加入25c(200mg,0.298mmol),AMCA-4(94mg,0.298mmol),PyBOP(187mg,0.358mmol),HOBt(48mg,0.358mmol)及10mL DMF,冰水浴下加入DIPEA(75uL,0.45mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得产品制备液,制备液冻干得到化合物 25d(188mg),收率65.1%,LC-MS:[M+H]
+=967.4。
第五步:化合物25
于25mL单口瓶中加入化合物25d(100mg,0.104mmol),溴化锌(472mg,2.09mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物25(54.5mg),收率65%,LC-MS:[M+H]
+=811.3。
实施例41
化合物26的合成:
参照实施例40的合成方法,将D-乳酸苄酯替代L-乳酸苄酯,得到化合物26,LC-MS:[M+H]+=811.3。
实施例42
化合物27A和27B的合成:
第一步:化合物27a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加3,3,3-三氟乳酸苄酯(3.51g,15mmol),滴毕自然升温至室温反应3h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物27a(1.44g),收率51%;LC-MS:[M+H]
+=568.2。
第二步:化合物27b
于25mL单口瓶中加入27a(400mg,0.7mmol),15mL DMF溶清后,加入400mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物27c
将上述所得化合物27b的DMF溶液置于冰水浴中,加入DIPEA(174uL,1.06mmol),再加入化合物M3(474mg,0.84mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物27c(284mg),收率56%,LC-MS:[M-H]
+=722.3。
第四步:化合物27d-1和27d-2
于50mL单口瓶中加入27c(250mg,0.34mmol),AMCA-4(109mg,0.34mmol),PyBOP(215mg,0.41mmol),HOBt(56mg,0.41mmol)及10mL DMF,冰水浴下加入DIPEA(85uL,0.52mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物27d-1和27d-2的制备液,分别冻干得到化合物27d-1(103mg)、化合物27d-2(111mg),LC-MS:[M+H]
+=1021.4。
第五步:化合物27A
于25mL单口瓶中加入化合物27d-1(100mg,0.097mmol),溴化锌(440mg,1.95mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物27A(52mg),收率62%,LC-MS:[M+H]
+=865.3。
第六步:化合物27B
于25mL单口瓶中加入化合物27d-2(100mg,0.097mmol),溴化锌(440mg,1.95mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到 固体化合物27A(57mg),收率67%,LC-MS:[M+H]
+=865.3。
实施例43
化合物28A和28B的合成:
第一步:化合物28a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加2-环丙基-2-羟基乙酸苄酯(3g,15mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物28a(1.56g),收率58%;LC-MS:[M+H]
+=540.2。
第二步:化合物28b
于25mL单口瓶中加入28a(500mg,0.93mmol),15mL DMF溶清后,加入500mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物28c
将上述所得化合物28b的DMF溶液置于冰水浴中,加入DIPEA(229uL,1.39mmol),再加入化合物M3(629mg,1.11mol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物28c(335mg),收率52%,LC-MS:[M-H]
+=694.3。
第四步:化合物28d-1和28d-2
于50mL单口瓶中加入28c(250mg,0.36mmol),AMCA-4(113mg,0.36mmol),PyBOP(225mg,0.43mmol),HOBt(58mg,0.43mmol)及10mL DMF,冰水 浴下加入DIPEA(89uL,0.54mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物28d-1和28d-2的制备液,分别冻干得到化合物28d-1(109mg)、化合物28d-2(116mg),LC-MS:[M+H]
+=993.4。
第五步:化合物28A
于25mL单口瓶中加入化合物28d-1(100mg,0.1mmol),溴化锌(454mg,2mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物28A(52mg),收率62%,LC-MS:[M+H]
+=837.3。
第六步:化合物28B
于25mL单口瓶中加入化合物28d-2(100mg,0.1mmol),溴化锌(454mg,2mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物28B(56mg),收率67%,LC-MS:[M+H]
+=837.3。
实施例44
化合物29A和29B的合成:
第一步:化合物29a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水 合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加2-羟基-环丙基丙酸苄酯(3.3g,15mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物29a(1.55g),收率56%;LC-MS:[M+H]
+=554.2。
第二步:化合物29b
于25mL单口瓶中加入29a(500mg,0.9mmol),10mL DMF溶清后,加入500mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物29c
将上述所得化合物29b的DMF溶液置于冰水浴中,加入DIPEA(223uL,1.35mmol),再加入化合物M3(613mg,1.08mol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物29c(325mg),收率51%,LC-MS:[M-H]
+=708.3。
第四步:化合物29d-1和29d-2
于50mL单口瓶中加入29c(250mg,0.35mmol),AMCA-4(111mg,0.35mmol),PyBOP(220mg,0.42mmol),HOBt(57mg,0.42mmol)及10mL DMF,冰水浴下加入DIPEA(87uL,0.53mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物29d-1和29d-2的制备液,分别冻干得到化合物29d-1(109mg)、化合物29d-2(116mg),LC-MS:[M+H]
+=1007.5。
第五步:化合物29A
于25mL单口瓶中加入化合物29d-1(100mg,0.099mmol),溴化锌(446mg,1.98mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物29A(55mg),收率65%,LC-MS:[M+H]
+=851.3。
第六步:化合物29B
于25mL单口瓶中加入化合物29d-2(100mg,0.1mmol),溴化锌(454mg,2mmol)及8mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物29B(56mg),收率66%,LC-MS:[M+H]
+=851.3。
实施例45
化合物30的合成:
第一步:化合物30a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加(S)-2-甲基-3-羟基-丙酸苄酯(2.91g,15mmol),滴毕自然升温至室温反应3h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物30a(1.2g),收率55%;LC-MS:[M+H]
+=438.2。
第二步:化合物30b
于25mL单口瓶中加入30a(200mg,0.45mmol),10mLDMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物30c
将上述所得化合物30b的DMF溶液置于冰水浴中,加入DIPEA(113uL,0.68mmol),再加入化合物M3(367mg,0.68mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物30c(148mg),收率50%,LC-MS:[M-H]
+=680.3。
第四步:化合物30d
于50mL单口瓶中加入30c(100mg,0.15mmol),AMCA-4(46mg,0.15mmol),PyBOP(92mg,0.18mmol),HOBt(24mg,0.18mmol)及5mL DMF,冰水浴下加入DIPEA(36uL,0.22mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物30d的制备液,制备液冻干得到化合物30d(98mg),收率68.1%,LC-MS:[M+H]
+=981.4。
第五步:化合物30
于25mL单口瓶中加入化合物30d(50mg,0.05mmol),溴化锌(225mg,1.0mmol)及5mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物30(30mg),收率71%,LC-MS:[M+H]
+=825.3。
实施例46
化合物31的合成:
按照实施例45的合成方法,将(R)-2-甲基-3-羟基丙酸苄酯替代(S)-2-甲基-3-羟基丙酸苄酯,得到化合物31,LC-MS:[M+H]+=825.3。
实施例47
化合物32的合成:
第一步:化合物32a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加3-羟基-2-环丁基乙酸苄酯(3.3g g,15mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物32a(1.47g),收率53%;LC-MS:[M+H]
+=554.2。
第二步:化合物32b
于25mL单口瓶中加入32a(200mg,0.36mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物32c
将上述所得化合物32b的DMF溶液置于冰水浴中,加入DIPEA(89uL,0.54mmol),再加入化合物M3(245mg,0.43mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物32c(156mg),收率61%,LC-MS:[M-H]
+=708.3。
第四步:化合物32d
于50mL单口瓶中加入32c(100mg,0.14mmol),AMCA-4(45mg,0.14mmol),PyBOP(90mg,0.17mmol),HOBt(23mg,0.17mmol)及10mL DMF,冰水浴下加入DIPEA(36uL,0.22mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物32d的制备液,制备液冻干得到化合物32d(97mg),收 率68.3%,LC-MS:[M+H]
+=1007.5。
第五步:化合物32
于25mL单口瓶中加入化合物32(50mg,0.05mmol),溴化锌225mg,1.0mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物32(28.5mg),收率67.5%,LC-MS:[M+H]
+=851.4。
实施例48
化合物33的合成:
参照实施例47的合成方法,将化合物ent-M3替代M3,得化合物33,LC-MS:[M+H]
+=851.4。
实施例49
化合物34的合成:
第一步:化合物34a
于100mL单口瓶中,加入M7(2g,5mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.5mmol),搅拌冷却至0℃,滴加2-羟基-2-环丁基乙酸苄酯(3.0g g,15mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物34a(1.47g),收率 53%;LC-MS:[M+H]
+=554.2。
第二步:化合物34b
于25mL单口瓶中加入34a(200mg,0.36mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物34c
将上述所得化合物34b的DMF溶液置于冰水浴中,加入DIPEA(89uL,0.54mmol),再加入化合物M3(244mg,0.43mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物34c(156mg),收率61%,LC-MS:[M-H]
+=708.3。
第四步:化合物34d
于50mL单口瓶中加入34c(100mg,0.14mmol),AMCA-4(45mg,0.14mmol),PyBOP(90mg,0.17mmol),HOBt(23mg,0.17mmol)及10mL DMF,冰水浴下加入DIPEA(36uL,0.22mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物34d的制备液,制备液冻干得到化合物34d(92mg),收率65.3%,LC-MS:[M+H]
+=1007.5。
第五步:化合物34
于25mL单口瓶中加入化合物34d(50mg,0.05mmol),溴化锌225mg,1.0mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物34(26.5mg),收率62.5%,LC-MS:[M+H]
+=851.4。
实施例50
化合物35的合成:
参照实施例49的合成方法,将化合物ent-M3替代M3,得化合物35,LC-MS:[M+H]
+=851.4。
实施例51
化合物36的合成:
第一步:化合物36a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(79mg,0.42mmol),搅拌冷却至0℃,滴加2-羟基乙酸苄酯(2.0g,12.5mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物36a(1.37g),收率56%;LC-MS:[M+H]
+=586.2。
第二步:化合物36b
于25mL单口瓶中加入36a(200mg,0.34mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物36c
将上述所得化合物36b的DMF溶液置于冰水浴中,加入DIPEA(84.5uL,0.51mmol),再加入化合物M3(231mg,0.41mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物36c(160mg),收率63%,LC-MS:[M-H]
+=740.3。
第四步:化合物36d
于50mL单口瓶中加入36c(100mg,0.13mmol),AMCA-4(42mg,0.13mmol),PyBOP(84mg,0.16mmol),HOBt(22mg,0.16mmol)及10mL DMF,冰水浴下加入DIPEA(33uL,0.2mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物36d的制备液,制备液冻干得到化合物36d(92mg),收 率65.8%,LC-MS:[M+H]
+=1039.5。
第五步:化合物36
于25mL单口瓶中加入化合物36d(50mg,0.048mmol),溴化锌216mg,0.96mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物36(29mg),收率68.5%,LC-MS:[M+H]
+=883.4。
实施例52
化合物37的合成:
参照实施例51的合成方法,将化合物ent-M3替代M3,得化合物37,LC-MS:[M+H]
+=883.4。
实施例53
化合物38的合成:
第一步:化合物38a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(79mg,0.42mmol),搅拌冷却至0℃,滴加L-乳酸苄酯(2.25g,12.5mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物 经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物38a(1.37g),收率52%;LC-MS:[M+H]
+=600.3。
第二步:化合物38b
于25mL单口瓶中加入38a(200mg,0.33mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物38c
将上述所得化合物38b的DMF溶液置于冰水浴中,加入DIPEA(82.5uL,0.5mmol),再加入化合物M3(226mg,0.4mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物38c(164mg),收率65%,LC-MS:[M-H]
+=754.3。
第四步:化合物38d
于50mL单口瓶中加入38c(100mg,0.13mmol),AMCA-4(42mg,0.13mmol),PyBOP(84mg,0.16mmol),HOBt(22mg,0.16mmol)及10mL DMF,冰水浴下加入DIPEA(33uL,0.2mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物38d的制备液,制备液冻干得到化合物38d(93mg),收率66.5%,LC-MS:[M+H]
+=1053.5。
第五步:化合物38
于25mL单口瓶中加入化合物38d(50mg,0.047mmol),溴化锌214mg,0.95mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物38(28.6mg),收率67.2%,LC-MS:[M+H]
+=897.4。
实施例54
化合物39的合成:
参照实施例53的合成方法,将化合物D-乳酸苄酯替代L-乳酸苄酯,得化合物39,LC-MS:[M+H]
+=897.4。
实施例55
化合物40A和40B的合成:
第一步:化合物40a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.42mmol),搅拌冷却至0℃,滴加3,3,3-三氟乳酸苄酯(2.94g,12.5mmol),滴毕自然升温至室温反应3h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物40a(1.48g),收率54%;LC-MS:[M+H]
+=654.3。
第二步:化合物40b
于25mL单口瓶中加入40a(400mg,0.61mmol),10mL DMF溶清后,加入400mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物40c
将上述所得化合物40b的DMF溶液置于冰水浴中,加入DIPEA(151uL,1.06mmol),再加入化合物M3(415mg,0.73mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物40c(286mg),收率58%,LC-MS:[M-H]
+=808.3。
第四步:化合物40d-1和40d-2
于50mL单口瓶中加入40c(250mg,0.3mmol),AMCA-4(97mg,0.3mmol),PyBOP(193mg,0.37mmol),HOBt(50mg,0.37mmol)及10mL DMF,冰水浴下加入DIPEA(76uL,0.46mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物40d-1和40d-2的制备液,分别冻干得到化合物40d-1(93mg)、化合物40d-2(101mg),LC-MS:[M+H]
+=1107.5。
第五步:化合物40A
于25mL单口瓶中加入化合物40d-1(50mg,0.045mmol),溴化锌(203mg,0.90mmol)及5mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物40A(29mg),收率68%,LC-MS:[M+H]
+=951.4。
第六步:化合物40B
于25mL单口瓶中加入化合物40d-2(50mg,0.045mmol),溴化锌(203mg,0.90mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物40B(26mg),收率61%,LC-MS:[M+H]
+=951.4。
实施例56
化合物41A和41B的合成:
第一步:化合物41a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.42mmol),搅拌冷却至0℃,滴加2-羟基-2-环丙基乙酸苄酯(2.57g,12.5mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物41a(1.55g),收率59%;LC-MS:[M+H]
+=626.3。
第二步:化合物41b
于25mL单口瓶中加入41a(500mg,0.8mmol),10mL DMF溶清后,加入500mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物41c
将上述所得化合物41b的DMF溶液置于冰水浴中,加入DIPEA(198uL,1.2mmol),再加入化合物M3(542mg,0.96mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物41c(350mg),收率56%,LC-MS:[M-H]
+=780.4。
第四步:化合物41d-1和41d-2
于50mL单口瓶中加入41c(300mg,0.38mmol),AMCA-4(121mg,0.38mmol),PyBOP(239mg,0.46mmol),HOBt(62mg,0.46mmol)及10mL DMF,冰水浴下加入DIPEA(95uL,0.57mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物41d-1和41d-2的制备液,分别冻干得 到化合物41d-1(113mg)、化合物41d-2(121mg),LC-MS:[M+H]
+=1079.5。
第五步:化合物41A
于25mL单口瓶中加入化合物41d-1(50mg,0.046mmol),溴化锌(208mg,0.92mmol)及5mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物41A(26mg),收率61%,LC-MS:[M+H]
+=923.4。
第六步:化合物41B
于25mL单口瓶中加入化合物41d-2(50mg,0.046mmol),溴化锌(208mg,0.92mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物41B(27mg),收率63%,LC-MS:[M+H]
+=923.4。
实施例57
化合物42A和42B的合成:
第一步:化合物42a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(96.5mg,0.42mmol),搅拌冷却至0℃,滴加2-羟基-3-环丙基丙酸苄酯(2.75g,12.5mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物42a(1.54g),收率57.2%;LC-MS:[M+H]
+=640.3。
第二步:化合物42b
于25mL单口瓶中加入42a(500mg,0.78mmol),10mL DMF溶清后,加入500mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物42c
将上述所得化合物42b的DMF溶液置于冰水浴中,加入DIPEA(193uL,1.17mmol),再加入化合物M3(530mg,0.94mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物42c(342mg),收率55%,LC-MS:[M-H]
+=794.4。
第四步:化合物42d-1和42d-2
于50mL单口瓶中加入42c(300mg,0.37mmol),AMCA-4(17mg,0.37mmol),PyBOP(230mg,0.44mmol),HOBt(60mg,0.44mmol)及10mL DMF,冰水浴下加入DIPEA(91uL,0.55mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经手性柱高效液相纯化,得化合物42d-1和42d-2的制备液,分别冻干得到化合物42d-1(105mg)、化合物42d-2(116mg),LC-MS:[M+H]
+=1093.5。
第五步:化合物42A
于25mL单口瓶中加入化合物42d-1(50mg,0.045mmol),溴化锌(206mg,0.90mmol)及5mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物42A(28.7mg),收率67%,LC-MS:[M+H]
+=937.4。
第六步:化合物42B
于25mL单口瓶中加入化合物42d-2(50mg,0.045mmol),溴化锌(208mg,0.90mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物42B(27mg),收率63%,LC-MS:[M+H]
+=937.4。
实施例58
化合物43的合成:
第一步:化合物43a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(79mg,0.42mmol),搅拌冷却至0℃,滴加(S)-2-甲基-3-羟基丙酸苄酯(2.43g,12.5mmol),滴毕自然升温至室温反5h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物43a(1.31g),收率51%;LC-MS:[M+H]
+=614.3。
第二步:化合物43b
于25mL单口瓶中加入43a(200mg,0.33mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物43c
将上述所得化合物43b的DMF溶液置于冰水浴中,加入DIPEA(82.5uL,0.5mmol),再加入化合物M3(226mg,0.4mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物43c(158mg),收率63%,LC-MS:[M-H]
+=768.3。
第四步:化合物43d
于50mL单口瓶中加入43c(100mg,0.13mmol),AMCA-4(42mg,0.13mmol),PyBOP(84mg,0.16mmol),HOBt(22mg,0.16mmol)及10mL DMF,冰水浴下加入DIPEA(33uL,0.2mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物43d的制备液,制备液冻干得到化合物43d(87mg),收率62.5%,LC-MS:[M+H]
+=1067.5。
第五步:化合物43
于25mL单口瓶中加入化合物43d(50mg,0.047mmol),溴化锌214mg,0.95mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物43(26.5mg),收率62.2%,LC-MS:[M+H]
+=911.4。
实施例59
化合物44的合成:
参照实施例58的合成方法,将化合物(R)-2-甲基-3-羟基丙酸苄酯替代(S)-2-甲基-3-羟基丙酸苄酯,得化合物44,LC-MS:[M+H]
+=911.4。
实施例60
化合物45的合成:
第一步:化合物45a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(79mg,0.42mmol),搅拌冷却至0℃,滴加2-环丁基-3-羟基丙酸苄酯(2.75g,12.5mmol),滴毕自然升温至室温反4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物45a(1.55g),收率58%;LC-MS:[M+H]
+=640.3。
第二步:化合物45b
于25mL单口瓶中加入45a(200mg,0.31mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物45c
将上述所得化合物45b的DMF溶液置于冰水浴中,加入DIPEA(77uL,0.47mmol),再加入化合物M3(210mg,0.47mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物45c(150mg),收率61%,LC-MS:[M-H]
+=794.4。
第四步:化合物45d
于50mL单口瓶中加入45c(100mg,0.125mmol),AMCA-4(40mg,0.125mmol),PyBOP(78mg,0.15mmol),HOBt(20mg,0.15mmol)及5mL DMF,冰水浴下加入DIPEA(31uL,0.19mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物45d的制备液,制备液冻干 得到化合物45d(99mg),收率72.5%,LC-MS:[M+H]
+=1093.5。
第五步:化合物45
于25mL单口瓶中加入化合物45d(50mg,0.045mmol),溴化锌205mg,0.90mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物45(27mg),收率63%,LC-MS:[M+H]
+=937.4。
实施例61
化合物46的合成:
参照实施例60的合成方法,将化合物ent-M3替代M3,得化合物46,LC-MS:[M+H]
+=937.4。
实施例62
化合物47的合成:
第一步:化合物47a
于100mL单口瓶中,加入M8(2g,4.2mmol),20mL THF,对甲苯磺酸一水合物(79mg,0.42mmol),搅拌冷却至0℃,滴加2-环戊基-2-羟基乙酸苄酯(2.75g,12.5mmol),滴毕自然升温至室温反应4h,TLC监控。反应结束,加入饱和NaHCO
3溶液,用乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤, 浓缩,残余物经硅胶柱纯化(PE:EA=10:1-5:1-1:1)得化合物47a(1.47g),收率55%;LC-MS:[M+H]
+=640.3。
第二步:化合物47b
于25mL单口瓶中加入47a(200mg,0.31mmol),10mL DMF溶清后,加入200mg 5%Pd/C,氢化反应2h,反应完毕,过滤,得滤液,未经纯化直接用于下一步反应。
第三步:化合物47c
将上述所得化合物47b的DMF溶液置于冰水浴中,加入DIPEA(77uL,0.47mmol),再加入化合物M3(212mg,0.37mmol),加毕升至室温反应1h。HPLC监测反应完毕,反应液经高效液相纯化,得制备液,制备液冻干得到化合物47c(248mg),收率60%,LC-MS:[M-H]
+=794.4。
第四步:化合物47d
于50mL单口瓶中加入47c(100mg,0.125mmol),AMCA-4(40mg,0.125mmol),PyBOP(78mg,0.15mmol),HOBt(20mg,0.15mmol)及5mL DMF,冰水浴下加入DIPEA(31uL,0.19mmol),升至室温反应2h。HPLC监测反应完毕后,反应液经高效液相纯化,得化合物47d的制备液,制备液冻干得到化合物47d(84mg),收率61.8%,LC-MS:[M+H]
+=1093.5。
第五步:化合物47
于25mL单口瓶中加入化合物47d(50mg,0.046mmol),溴化锌225mg,0.92mmol)及6mL硝基甲烷,室温下反应1h。HPLC监测反应完毕后,减压浓缩除去溶剂,得粗品。粗品经高效液相纯化,得到产品制备液,制备液冻干得到固体化合物47(29mg),收率62.5%,LC-MS:[M+H]
+=937.4。
实施例63
化合物48的合成:
参照实施例62的合成方法,将化合物ent-M3替代M3,得化合物48,LC-MS:[M+H]
+=937.4。
实施例64(对照例)
化合物49的合成:
化合物49参照专利“CN112209990A”的实施例1-(8)化合物70的合成”提供的方法合成。
实施例65
以下为Trastuzumab的序列:
轻链
重链
配体-药物偶联物的制备:
1)通用偶联方法
将通过初步的纯化后单体率大于95%的抗体分子,使用超滤离心管换液至磷酸盐缓冲液中,浓度10mg/mL。加入20倍于抗体摩尔分子数的TCEP,室温下反应4h以打开抗体链间二硫键。加入20倍于抗体摩尔分子数的连接子-药物化合物(payload),室温下反应2h。反应结束后,使用截留分子量为30KDa的超滤离心管换液至PBS中,并去除未偶联的payload。换液后的ADC样品使用0.22微米除菌过滤器过滤后备用。
2)配体-药物偶联物DAR值的测定
单体率检测条件:
样品14000rpm离心5分钟,取上清液进样分析;
仪器:Waters e2695(2489UV/Vis);
色谱柱:TSKgel G3000SWXL(7.8×300mm,5μm);
流动相:A:50mM PB,300mM NaCl,200mM Arg,5%IPA,pH为6.5;
流动相A等度洗脱30min,流速:0.714mL/min,柱温25℃,检测波长:280nm。
DAR检测条件:
样品14000rpm离心5分钟,取上清液进样分析;
仪器:Waters H-class(TUV);
色谱柱:Proteomix HIC Butyl-NP5(4.6×35mm,5μm);
流动相:A:1.5M硫酸铵,0.025M无水磷酸钠,pH为7.0,B:0.025M无水磷酸钠,25%IPA,pH为7.0;
流动相A平衡色谱柱,流动相A和B梯度洗脱,流速0.8mL/min;柱温25℃,检测波长:214nm。
实施例66
按照实施例65的通用偶联方法制备得到ADC-1:
实施例67
按照实施例65的通用偶联方法制备得到ADC-2:
实施例68
按照实施例65的通用偶联方法制备得到ADC-3:
实施例69
按照实施例65的通用偶联方法制备得到ADC-4:
实施例70
按照实施例65的通用偶联方法制备得到ADC-5:
实施例71
按照实施例65的通用偶联方法制备得到ADC-6:
实施例72
按照实施例65的通用偶联方法制备得到ADC-7:
实施例73
按照实施例65的通用偶联方法制备得到ADC-8:
实施例74
按照实施例65的通用偶联方法制备得到ADC-9:
实施例75
按照实施例65的通用偶联方法制备得到ADC-10:
实施例76
按照实施例65的通用偶联方法制备得到ADC-11:
实施例77
按照实施例65的通用偶联方法制备得到ADC-12:
实施例78
按照实施例65的通用偶联方法制备得到ADC-13:
实施例79
按照实施例65的通用偶联方法制备得到ADC-14:
实施例80
按照实施例65的通用偶联方法制备得到ADC-15:
实施例81
按照实施例65的通用偶联方法制备得到ADC-16:
实施例82
按照实施例65的通用偶联方法制备得到ADC-17:
实施例83
按照实施例65的通用偶联方法制备得到ADC-18:
实施例84
按照实施例65的通用偶联方法制备得到ADC-19:
实施例85
按照实施例65的通用偶联方法制备得到ADC-20:
实施例86
按照实施例65的通用偶联方法制备得到ADC-21:
实施例87
按照实施例65的通用偶联方法制备得到ADC-22:
实施例88
按照实施例65的通用偶联方法制备得到ADC-23:
实施例89
按照实施例65的通用偶联方法制备得到ADC-24:
实施例90
按照实施例65的通用偶联方法制备得到ADC-25:
实施例91
按照实施例65的通用偶联方法制备得到ADC-26:
实施例92
按照实施例65的通用偶联方法制备得到ADC-27:
实施例93
按照实施例65的通用偶联方法制备得到ADC-28:
实施例94
按照实施例65的通用偶联方法制备得到ADC-29:
实施例95
按照实施例65的通用偶联方法制备得到ADC-30:
实施例96
按照实施例65的通用偶联方法制备得到ADC-31:
实施例97
按照实施例65的通用偶联方法制备得到ADC-32:
实施例98
按照实施例65的通用偶联方法制备得到ADC-33:
实施例99
按照实施例65的通用偶联方法制备得到ADC-34:
实施例100
按照实施例65的通用偶联方法制备得到ADC-35:
实施例101
按照实施例65的通用偶联方法制备得到ADC-36:
实施例102
按照实施例65的通用偶联方法制备得到ADC-37:
实施例103
按照实施例65的通用偶联方法制备得到ADC-38:
实施例104
按照实施例65的通用偶联方法制备得到ADC-39:
实施例105
按照实施例65的通用偶联方法制备得到ADC-40:
实施例106
按照实施例65的通用偶联方法制备得到ADC-41:
实施例107
按照实施例65的通用偶联方法制备得到ADC-42:
实施例108
按照实施例65的通用偶联方法制备得到ADC-43:
实施例109
按照实施例65的通用偶联方法制备得到ADC-44:
实施例110
按照实施例65的通用偶联方法制备得到ADC-45:
实施例111
按照实施例65的通用偶联方法制备得到ADC-46:
实施例112
按照实施例65的通用偶联方法制备得到ADC-47:
实施例113
按照实施例65的通用偶联方法制备得到ADC-48:
实施例114
按照实施例65的通用偶联方法制备得到ADC-49:
实施例115
按照实施例65的通用偶联方法制备得到ADC-50:
实施例116
按照实施例65的通用偶联方法制备得到ADC-51:
实施例117
按照实施例65的通用偶联方法制备得到ADC-52:
实施例118
按照实施例65的通用偶联方法制备得到ADC-53:
实施例119
按照实施例65的通用偶联方法制备得到ADC-54:
实施例120
按照实施例65的通用偶联方法制备得到ADC-55:
实施例121
按照实施例65的通用偶联方法制备得到ADC-56:
实施例122
按照实施例65的通用偶联方法制备得到ADC-57:
实施例123
按照实施例65的通用偶联方法制备得到ADC-58:
实施例124
按照实施例65的通用偶联方法制备得到ADC-59:
实施例125
按照实施例65的通用偶联方法制备得到ADC-60:
实施例126
按照实施例65的通用偶联方法制备得到ADC-61(对照例):
实施例127:血浆稳定性
1)操作
取一定量的ADC样品,加入到已去除人IgG的人血浆中,每种ADC重复三管,放置37℃水浴中孵,分别孵育72h、144h后,取出ADC样品,每管加入ProteinA resin(MabSelect SuReTM LX Lot:#10221479GE,用取PBS洗涤过的)100uL,垂直混合仪晃动吸附2h,经过洗涤洗脱步骤,获得孵育后的ADC。对孵育特定时间的ADC样品进行RP-HPLC检测。
2)结果
表1.本发明公开配体-药物偶联物(ADC)DAR值及单体率数据。
表2.本发明公开配体-药物偶联物(ADC)血浆稳定性数据。
3)结论
如表1所示,本发明公开的ADC具有DAR值(>7.5)及单体率(>97%)高的优异性质。
如表2所示,本发明公开的ADC血浆中孵育7天后DAR值仍可以保持较高水平,证明本发明的ADC在血浆中具有优异的稳定性。
实施例128:体外活性测试
1)实验材料
细胞:来源于中国科学院细胞库;
肿瘤细胞培养基:Gibco;
FBS:BIOWEST;
2)培养基的配制
生长培养基(with 10%FBS,Penicillin/streptomycin(100U/mL);
检测培养基(with 1%FBS,Penicillin/streptomycin(100U/mL);
3)操作
提前30min开启生物安全柜紫外灯照射,后通风3min。将生长培养基、检测培养基、D-PBS和胰酶放入37℃恒温水浴锅预热,之后用酒精对表面进行消毒,放入生物安全柜中。选择汇合度在~80%的细胞(对数生长期),放于生物安全柜中,吸掉旧培养基,用D-PBS润洗,吸弃,用胰酶消化2~3min,后加入生长培养基终止胰酶,500×g离心5min。吸去离心上清液,用4mL检测培养基混匀,取100uL计数(其中取出50uL细胞液,加入50μL0.4%Trypan Blue Stain并混匀,混匀后计数)。按照之前设置好的细胞数铺板,80uL/孔铺于96孔板中,孔E11、F11、G11只加80uL检测培养基,边缘孔加入200uL的DPBS封边。待铺板细胞完全贴壁后(通常至少需要4小时),进行受试样品配置与稀释:用检测培养基配置1.0mL,2.5μM(5×Top Dose)的受试样品,分装于V型96孔板第一列,每孔200μL;后面第2至8列分别加入180μL的检测培养基,从第一列中取30μL加入到第二列,用排枪上下混匀10次,弃枪头,剩余检测浓度点依次操作,进行7倍梯度浓度稀释。将梯度浓度的受试样品按照每孔20uL的量加入细胞中,同时第11列只加入20uL的检测培养基,每个浓度设置3个复孔,随后将96孔板放入5%CO
2,37℃细胞培养箱,培养5天。
4)检测
受试样品作用5天后取出MTS试剂,常温避光解冻后,充分涡旋混匀后,在生物安全柜中,沿孔侧壁按每100μL细胞培养体积加入20μL Cell Titer One Solution Reagen MTS试剂,轻轻拍动板面,使MTS溶液混合均匀,放于细胞培养箱中5%CO
2,37℃避光静置孵育2h。反应结束后,取出96孔板,于酶标仪中检测OD490nm吸光值,并进行数据记录、整理、存储。
5)结果
表3:抗体药物偶联物及毒素对N87肿瘤细胞的体外增值抑制的IC50值。
Sample | IC50(nM) |
Trastuzumab | >500 |
CA4 | 4.24 |
AMCA-4 | 4.51 |
D-1 | 0.57 |
D-2 | 0.54 |
D-4 | 0.26 |
D-6 | 0.45 |
D-8 | 0.11 |
ADC-1 | 0.1 |
ADC-16 | 0.41 |
ADC-29 | 0.72 |
ADC-29 | 0.52 |
ADC-61(对照) | 9.54 |
表4:抗体药物偶联物及毒素对SK-BR-3肿瘤细胞的体外增值抑制的IC50值。
Sample | IC50(nM) |
Trastuzumab | >500 |
CA4 | 6.04 |
AMCA-4 | 7.56 |
D-1 | 0.62 |
D-2 | 0.85 |
D-4 | 2.79 |
D-6 | 1.07 |
D-8 | 0.89 |
ADC-1 | 0.22 |
ADC-16 | 0.58 |
ADC-29 | 2.26 |
ADC-29 | 2.58 |
ADC-61(对照) | 16.54 |
6)讨论
如表3所示,本发明针对HER2靶标的配体-药物偶联物对HER2阳性细胞N87具有明显的体外增值抑制活性,明显优于裸抗(Trastuzumab)、对照组ADC-61。
如表4所示,与裸抗(Trastuzumab)及对照组ADC对比,本发明公开的ADC及单药对HER2阳性的细胞SK-BR-3也具有明显的体外增值抑制活性。
实施例129:体内活性测试
1)实验材料
细胞:来源于中国科学院细胞库;
肿瘤细胞培养基:Gibco;
Balb/c-nu裸鼠:雌性,5-7周(肿瘤细胞接种时的小鼠周龄),体重18.0-24.0g,170只(110只加60只富余小鼠)。购自北京维通利华实验动物技术有限公司;
供试品和对照品:
供试品:ADC-61、ADC-1由成都多特抗体药物有限责任公司提供。
Histidine缓冲液,由成都多特抗体药物有限责任公司提供。
0.9%氯化钠注射液:科伦药业有限责任公司。
2)细胞培养
NCI-H1975(人非小细胞肺癌腺癌细胞)培养在RPMI1640培养基中。收集指数生长期的NCI-H1975细胞,RPMI1640培养基重悬至适合浓度后用于小鼠皮下肿瘤接种。
NCI-N87(人胃癌细胞)培养在RPMI1640培养基中。收集指数生长期的NCI-N87细胞,RPMI1640培养基重悬至适合浓度后用于小鼠皮下肿瘤接种。
3)动物造模和随机分组
85只雌性裸鼠右肩侧皮下接种5×10
7个NCI-H1975细胞。待肿瘤平均体积 170mm
3左右时,根据肿瘤大小随机分组。选取55只肿瘤体积合适的荷瘤小鼠,随机分组并开始给药(尾静脉注射,给药体积按0.1ml/10g)。分组当天定义为第0天。
85只雌性裸鼠右肩侧皮下接种5×10
7个NCI-N87细胞。待肿瘤平均体积170mm
3左右时,根据肿瘤大小随机分组。选取55只肿瘤体积合适的荷瘤小鼠,随机分组并开始给药(尾静脉注射,给药体积按0.1ml/10g)。分组当天定义为第0天。
4)供试品和对照品的配制
表5.在NCI-H1975(人非小细胞肺癌腺癌细胞)和NCI-N87(人胃癌细胞)裸鼠皮下移植瘤模型中抗肿瘤作用研究的供试品和对照品溶液的配制。
注:使用前混匀,确保制剂是均一的。
5)实验观察和数据收集
本实验过程中,动物实验操作均根据抗肿瘤药物体内筛选试验标准操作规程的要求。肿瘤接种后,常规监测包括了肿瘤生长(肿瘤每周测量2次)及治疗对动物正常行为的影响,具体内容有实验动物的活动性,摄食和饮水情况,体重增加或降低(体重每周测量2次)情况,眼睛、被毛及其它异常情况。实验过程中观察到的临床症状均记录在原始数据中。肿瘤体积计算公式:肿瘤体积(mm
3)=1/2× (a×b
2)(其中a表示长径,b表示短径)。实验中采用人工记录数据,包括肿瘤的长短径的测量和动物体重的称量。
6)疗效评价标准
相对肿瘤增殖率,T/C%,即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下:
T/C%=TRTV/CRTV×100%(TRTV:治疗组平均RTV;CRTV:溶媒对照组平均RTV;RTV=Vt/V0,V0为分组时该动物的瘤体积,Vt为治疗后该动物的瘤体积);或T/C%=TTW/CTW×100%(TTW:治疗组实验终结时平均瘤重;CTW:溶媒对照组实验终结时平均瘤重)。
相对肿瘤抑制率,TGI(%),计算公式如下:TGI%=(1-T/C)×100%。[T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)或瘤重(TW)]。
7)结果
表6:给药抗体药物偶联物对NCI-H1975移植瘤的体内疗效。
表7:给药抗体药物偶联物对NCI-N87移植瘤的体内疗效。
表8:给药抗体药物偶联物(3.75mg/kg)对NCI-H1975移植瘤小鼠体重影响情况。
NCI-H1975\分组信息\平均体重(g) | D0 | D3 | D7 | D10 | D14 | D17 | D21 | D24 | D28 | D31 |
Vehicle | 19.83 | 20.52 | 20.13 | 19.79 | 20.42 | 19.83 | 19.57 | 20.45 | 18.21 | 19.79 |
ADC-1((3.75mg/kg) | 19.89 | 20.56 | 19.30 | 20.26 | 20.45 | 19.69 | 20.58 | 19.69 | 20.62 | 20.79 |
8)讨论
如表6所示,本发明公开ADC-1在低剂量对照组(3.75mg/Kg)对荷瘤小鼠NCI-H1975体内药效明显优于对照组ADC-61及裸抗。
如表7所示,在相同剂量下(3.75mg/Kg)本发明公开ADC-1对荷瘤小鼠NCI-N87体内药效明显优于对照组ADC-61。
如表8所示,本发明公开ADC-1对NCI-H1975荷瘤小鼠的体重影响明显小,即便在该高剂量组下,未出现小鼠死亡,证明本发明所述的ADC药物在安全性方面具有显著的优势。
Claims (22)
- 一种如通式D所示的CA4衍生物,或其药学上可接受的盐或溶剂化物;其中:R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;X选自-C(O)-CR aR b-(CR 1R 2) m-O-、-C(O)-CR aR b-(CR 1R 2) m-NH-或-C(O)-CR aR b-(CR 1R 2) m-S-;R a选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;R b选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;或者,R a、R b及其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基;R 1、R 2相同或者不同,且分别独立地为氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基;或者,R 1、R 2及其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基;m选自0-4的整数。
- 一种包括权利要求1-4任一所述CA4衍生物的连接子-药物偶联物或其药学上可接受的盐或溶剂化物:其中:R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;X选自-C(O)-CR aR b-(CR 1R 2) m-O-、-C(O)-CR aR b-(CR 1R 2) m-NH-或-C(O)-CR aR b-(CR 1R 2) m-S-;R a选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;R b选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;或者,R a、R b及其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基;R 1、R 2相同或者不同,且分别独立地为氢原子、氘原子、卤素、烷基、卤代烷基、氘代烷基、烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基;或者,R 1、R 2及其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基;m选自0-4的整数;L为-L 1-L 2-L 3-L 4-。
- 根据权利要求5所述的连接子-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:-L-为-L 1-L 2-L 3-L 4-,其中L 1端与配体Ab相连,L 4端与X相连。
- 根据权利要求5或6中所述的连接子-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:L 2选自:-NC(R 3R 4)C(O)、-NR 5(CH 2) oC(O)-、-NR 5(CH 2CH 2O) oCH 2C(O)-、-S(CH 2) pC(O)-或者化学键,其中o选自0-20的整数;p选自0-20的整数;R 3、R 4相同或者不同,且各自独立地选自氢原子、氘原子、烷基、取代烷基、氘代烷基、杂烷基、羧基、氨基、取代氨基;R 5选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;L 1与L 2共用N原子。
- 根据权利要求5或6所述的连接子-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:L 3选自由氨基酸构成的肽残基,其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、羧基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代;优选由一个、两个或者多个选自苯丙氨酸(F)、甘氨酸(G)、缬氨酸(V)、赖氨酸(K)、瓜氨酸、丝氨酸(S)、谷氨酸(E)或者天冬氨酸(D)中的氨基酸形成的肽残基。
- 根据权利要求5或6所述的连接子-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:L 4选自:-NR 6(CR 7R 8) q-、-C(O)NR 6-、-C(O)NR 6(CH 2) q-或者化学键,q选自0-6的整数;R 6、R 7和R 8相同或者不同,且各自独立地选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
- 一种包括权利要求5-12任一所述连接子-药物偶联物的配体-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:所述配体-药物偶联物包含式Ⅰ所示的结构:其中:R选自氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、环烷基烷基、烷氧基烷基、芳基、取代芳基或杂芳基;X选自-C(O)-CR aR b-(CR 1R 2) m-O-、-C(O)-CR aR b-(CR 1R 2) m-NH-或-C(O)-CR aR b-(CR 1R 2) m-S-;R a选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;R b选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基;或者,R a、R b及其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基;R 1、R 2相同或者不同,且分别独立地为氢原子、氘原子、卤素、烷基、取代烷基、氘代烷基、烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基;或者,R 1、R 2及其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基;Ab为配体单元,选自抗体、抗体片段、靶向蛋白、Fc-融合蛋白等;L为与Ab连接单元;X为药物部分修饰单元;m选自0-4的整数;n选自1-20的整数或小数。
- 根据权利要求13所述的配体-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:Ab为抗体,可通过其杂原子与连接单元形成连接键,所述抗体选自鼠源抗体、嵌合抗体、人源化抗体、全人源抗体、抗体片段、双特异性抗体或多特异性抗体。
- 根据权利要求14所述的配体-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于,所述的抗体或其抗原结合片段,非限制性地选自:抗EGFRvIII抗体、抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin 18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin 4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗Integrin Av抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin 6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD47抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体。
- 如权利要求1-18中任一项所述的CA4衍生物、连接子-药物偶联物或配体-药物偶联物或其药学上可接受的盐或溶剂化物,其特征在于:所述药学上可接受的盐包括与结构式中酸性官能团形成的钠盐、钾盐、钙盐或镁盐等;或与结构中碱性官能团形成的醋酸盐、三氟乙酸盐、柠檬酸盐、草酸盐、酒石酸盐、苹 果酸盐、硝酸盐、氯化物、溴化物、碘化物、硫酸盐、硫酸氢盐、磷酸盐、乳酸盐、油酸盐、抗坏血酸盐、水杨酸盐、甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐。
- 一种药物组合物,其含有治疗有效量的权利要求1-19中任一项所述的CA4衍生物、连接子-药物偶联物或配体-药物偶联物或其药学上可接受的盐或溶剂化物,以及药学上可接受的载体、稀释剂或赋形剂。
- 一种包括权利要求1-19中任一项所述的CA4衍生物、连接子-药物偶联物或配体-药物偶联物或其药学上可接受的盐或溶剂化合物,以及药学上可接受的载体、稀释剂或者赋形剂,在制备用于治疗或预防肿瘤的药物中的用途。
- 根据权利要求21所述的用途,其特征在于:所述的肿瘤为乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤和白血病等实体瘤或血液瘤。
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