CN115197234A - Preparation method of camptothecin derivative intermediate - Google Patents
Preparation method of camptothecin derivative intermediate Download PDFInfo
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- CN115197234A CN115197234A CN202210347568.5A CN202210347568A CN115197234A CN 115197234 A CN115197234 A CN 115197234A CN 202210347568 A CN202210347568 A CN 202210347568A CN 115197234 A CN115197234 A CN 115197234A
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- antibody
- alkyl
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- amino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000003513 alkali Substances 0.000 claims abstract description 5
- -1 alkaline earth metal carbonates Chemical class 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 239000000427 antigen Substances 0.000 claims description 29
- 102000036639 antigens Human genes 0.000 claims description 29
- 108091007433 antigens Proteins 0.000 claims description 29
- 230000027455 binding Effects 0.000 claims description 29
- 239000012634 fragment Substances 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 239000000611 antibody drug conjugate Substances 0.000 claims description 16
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
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- 125000006239 protecting group Chemical group 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
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- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
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- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 claims description 2
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- 150000003839 salts Chemical class 0.000 claims description 2
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- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
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- 125000002950 monocyclic group Chemical group 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
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- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present disclosure relates to a method for preparing camptothecin derivative intermediates. In particular to a preparation method of a compound shown as a formula (II), which comprises the step of reacting a compound shown as a formula (III) with a compound shown as a formula (VII) in the presence of alkali. The method has high yield and mild reaction conditions, and is suitable for industrial production.
Description
Technical Field
The disclosure belongs to the field of medicine, and relates to a preparation method of a camptothecin derivative intermediate.
Background
Antibody Drug Conjugate (ADC) connects monoclonal antibody or antibody fragment with biologically active cytotoxin through stable chemical linker compound, fully utilizes the specificity of antibody for combining normal cell and tumor cell surface antigen and high efficiency of cytotoxin, and avoids the defects of low curative effect of the former and overlarge toxic and side effect of the latter. This means that antibody Drug conjugates bind to tumor cells precisely and have reduced effects on normal cells compared to conventional chemotherapeutic drugs (Mullard a, (2013) Nature Reviews Drug Discovery,12 329-332, dijoseph jf, armallino DC, (2004) Blood, 103.
There are several classes of cytotoxic small molecules for antibody drug conjugates, one of which is camptothecin derivatives, which have anti-tumor effects by inhibiting topoisomerase I. Camptothecine derivative irinotecan (chemical name: (1S, 9S) -1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [ de ] pyrano [3',4':6,7] imidazo [1,2-b ] quinoline-10,13 (9H, 15H) -dione) is reported to be applied to antibody-coupled drugs (ADC) in WO2014057687, WO2020063676, WO2020063673, CN112125915A, and the like.
WO2020063676 discloses an ixitan compound and a process for its preparation, wherein compound C and compound D are important reaction intermediates.
Disclosure of Invention
The purpose of the present disclosure is to provide a novel camptothecin derivative intermediate preparation method.
The disclosure also provides a preparation method of the compound shown as the formula (II), which comprises the step of reacting the compound shown as the formula (III) with the compound shown as the formula (VII) in the presence of alkali,
wherein the base is selected from the group consisting of alkali or alkaline earth metal carbonates, bicarbonates, alkoxides, hydroxides, or hydrides,
R 1 、R 2 each independently selected from hydrogen atom, C 1-6 Alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo, 3-6 membered cycloalkyl, 6-10 membered aryl or C 1 -C 6 Substituted by the substituent of the alkoxy group,
or, R 1 And R 2 Together with the carbon atom to which they are attached form an optionally substituted one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo or C 1 -C 6 3-6 membered cycloalkyl substituted with a substituent of alkoxy;
R 3 、R 4 、R 5 each independently selected from a hydrogen atom or C 1-6 An alkyl group;
R 6 selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said alkyl, aryl, heteroaryl are optionally substituted by one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino and oxo;
R c selected from amino or amino protected by an amino protecting group;
m is an integer of 0 to 4.
The solvent used in the reaction may be a conventional solvent such as one or more of dimethylformamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethylsulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol, water, preferably one or more of tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethylsulfoxide, diethyl ether, isopropyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol. .
The amino-protecting group may be a protecting group for an amino group commonly used in peptide synthesis, such as a t-butyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, or a benzyloxycarbonyl group. Examples of the other amino-protecting group include alkanoyl groups such as acetyl; alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl; arylmethoxycarbonyl groups such as p-methoxybenzyloxycarbonyl group and p- (or o-) nitrobenzyloxycarbonyl group; arylmethyl groups such as benzyl and triphenylmethyl; aroyl groups such as benzoyl; arylsulfonyl such as 2,4-dinitrobenzenesulfonyl and o-nitrobenzenesulfonyl; preference is given to 9-fluorenylmethyloxycarbonyl.
In certain embodiments, the base is selected from an alkali metal carbonate, bicarbonate, or hydroxide, preferably sodium or potassium carbonate.
In certain embodiments, the molar ratio of the compound of formula (III) to base is 1.1 to 1, preferably 1:1 to 1:5.
In certain embodiments, R 1 Selected from hydrogen atom, C 1-6 Alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo, 3-6 membered cycloalkyl, 6-10 membered aryl or C 1 -C 6 Substituted by the substituent of the alkoxy group,
R 2 selected from hydrogen atoms or C optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo 1 -C 6 An alkyl group, which is a radical of an alkyl group,
or, R 1 And R 2 Together with the carbon atom to which they are attached form an optionally substituted one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo or C 1 -C 6 3-6 membered cycloalkyl substituted by a substituent of alkoxy.
In certain embodiments, R 1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl, 3-6Cycloalkyl-substituted C 1-6 Alkyl, 6-10 membered aryl substituted C 1-6 Alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, R 2 Is a hydrogen atom, or R 1 And R 2 Together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group; preferably R 1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl, 3-6-membered cycloalkyl, R 2 Is a hydrogen atom, or R 1 And R 2 Together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group.
In certain embodiments, R 3 、R 4 、R 5 Are all hydrogen atoms.
In certain embodiments, R 6 Selected from hydrogen atoms, C 1-6 Alkyl, halo C 1-6 Alkyl or hydroxy C 1-6 Alkyl groups, more preferably hydrogen atoms.
In certain embodiments, the method comprises
The disclosure provides a preparation method of a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, which comprises a preparation method of a compound shown as a formula (II) described in the disclosure,
wherein the content of the first and second substances,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 m is as defined above, and n is an integer of 2 to 8.
In certain embodiments, the compound of formula (I) is selected from
The compounds of formula (I) can be prepared from compounds of formula (II) as reactants by methods known in the art, for example, the methods disclosed in WO2014057687, WO2020063676, WO2020063673, CN112125915A, and the like, which are incorporated herein in their entirety.
Alternative schemes include, for example, scheme one:
scheme II:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、m、n、R c As previously described, R d Selected from amino groups or amino groups protected by amino protecting groups.
The present disclosure also provides a method of preparing an antibody-drug conjugate comprising: the method comprises the steps of preparing a compound shown in a formula (I) and obtaining an antibody-drug conjugate shown in a formula (X) through a coupling reaction of Ab reduced and the compound shown in the formula (I),
wherein Ab is an antibody or antigen-binding fragment, k is 1 to 20 (including 1,2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or any number therebetween), R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 M and n are as defined above.
The reducing agent is preferably TCEP, and particularly, it is preferably reducing disulfide bonds on the antibody.
In certain embodiments, the antibody is selected from a chimeric antibody, a humanized antibody, or a fully human antibody; preferably a monoclonal antibody.
In certain embodiments, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of an anti-HER 2 (ErbB 2) antibody, an anti-EGFR antibody, an anti-B7-H3 antibody, an anti-C-Met antibody, an anti-HER 3 (ErbB 3) antibody, an anti-HER 4 (ErbB 4) antibody, an anti-CD 20 antibody, an anti-CD 22 antibody, an anti-CD 30 antibody, an anti-CD 33 antibody, an anti-CD 44 antibody, an anti-CD 56 antibody, an anti-CD 70 antibody, an anti-CD 73 antibody, an anti-CD 105 antibody, an anti-CEA antibody, an anti-a 33 antibody, an anti-Cripto antibody, an anti-EphA 2 antibody, an anti-G250 antibody, an anti-MUCl antibody, an anti-Lewis Y antibody, an anti-VEGFR antibody, an anti-GPNMB antibody, an anti-Integrin antibody, an anti-PSMA antibody, an anti-Tenascin-C antibody, an anti-SLC 44A4 antibody, or an anti-Mesothelin antibody or antigen-binding fragment thereof.
In certain embodiments, the antibody or antigen-binding fragment thereof is selected from Trastuzumab, pertuzumab, nimotuzumab, enobiltuzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, bivatuzumab, lorvotuzumab, cBR96, glemtuzumab, or an antigen-binding fragment thereof.
In certain embodiments, k is from 2 to 8, preferably from 5 to 9. Non-limiting examples include 3, 4, 5, 6, 7.2, 7.5, 8, 8.5, 9.
In certain embodiments, the method comprises
The compounds of formula (I) or the antibodies or antigen-binding fragments thereof can be prepared into antibody-drug conjugates using methods disclosed in the prior art, for example, methods disclosed in WO2014057687, WO2020063676, WO2020063673, CN112125915A, and the like, which are incorporated herein in their entirety.
The "alkyl" groups described in this disclosure are preferably C 1 -C 6 An alkyl group.
The "alkenyl" groups described in this disclosure are preferably C 2 -C 6 An alkenyl group.
The "alkynyl" groups described in this disclosure are preferably C 2 -C 6 Alkynyl.
The "alkylene" groups described in this disclosure are preferably C 1 -C 6 An alkylene group.
The "alkenylene" as described in the present disclosure is preferably C 2 -C 6 An alkenylene group.
"Alkenylene" as described in the present disclosure is preferably C 2 -C 6 Alkynylene radical.
The "alkoxy" groups described in this disclosure are preferably C 1 -C 6 An alkoxy group.
The "alkyl sulfide group" described in the present disclosure is preferably C 1 -C 6 An alkyl thioether group.
The "cycloalkyl" group described in the present disclosure is preferably a3 to 12-membered, more preferably a3 to 6-membered cycloalkyl group.
The "fused cyclic alkyl" groups described in this disclosure are preferably 6 to 14 membered, more preferably 7 to 10 membered fused cyclic alkyl groups.
The "heterocyclic group" described in the present disclosure is preferably a 3-to 12-membered, more preferably a 3-to 6-membered heterocyclic group.
The "fused heterocyclic group" described in the present disclosure is preferably a 6-to 14-membered fused heterocyclic group, more preferably a 7-to 10-membered fused heterocyclic group.
The "aryl" group described in the present disclosure is preferably a 6 to 14-membered, more preferably a 6 to 10-membered aryl group.
The "heteroaryl" group described in the present disclosure is preferably a 5-to 12-membered heteroaryl group, more preferably a 5-to 10-membered heteroaryl group.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "antibody-drug conjugate," means that the antibody is linked to the biologically active drug via a stable linking unit. In the present disclosure, "antibody drug conjugate" (ADC) refers to a monoclonal antibody or antibody fragment linked to a biologically active glucocorticoid by a stable linking unit. Wherein the antibody or antibody fragment can bind to the glucocorticoid molecule comprising the linker through a specific group therein, such as an interchain disulfide bond.
The term "drug loading" refers to the average number of drugs per antibody-drug conjugate molecule in a population of antibody-drug conjugates, and can also be expressed as a ratio of the amount of drug to the amount of antibody. The drug loading may range from 1 to 20, preferably from 1 to 10, glucocorticoids (D) per antibody (Ab) attached. In embodiments of the present disclosure, the drug loading is denoted as k, and may illustratively be 1,2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or an average of any two values. Preferably 1 to 10, more preferably 1 to 8, or2 to 7, or 3 to 8, or 3 to 7, or 3 to 6, or 4 to 7, or 4 to 6, or 4 to 5. The average number of drugs per ADC molecule after the conjugation reaction can be identified by conventional methods such as UV/visible spectroscopy, mass spectrometry, ELISA assays, monoclonal antibody molecule size variant assays (CE-SDS) and HPLC characterization.
The term "antibody" refers to an immunoglobulin, a tetrapeptide chain structure made up of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The constant regions of immunoglobulin heavy chains differ in their amino acid composition and arrangement, and thus in their antigenicity. Accordingly, immunoglobulins can be classified into five classes, otherwise known as the isotype of immunoglobulins, namely IgM, igD, igG, igA and IgE, with their corresponding heavy chains being the μ chain, the δ chain, the γ chain, the α chain, and the ε chain, respectively. The same class of Ig can be divided into different subclasses according to the differences of amino acid composition of the hinge region and the number and position of disulfide bonds of heavy chains, for example, igG can be divided into IgG1, igG2, igG3 and IgG4. Light chains are classified as either kappa or lambda chains by differences in the constant regions. Each of the five classes of Ig may have either a kappa chain or a lambda chain.
The sequences of the antibody heavy and light chains, near the N-terminus, are widely varied by about 110 amino acids, the variable region (Fv region); the remaining amino acid sequence near the C-terminus is relatively stable and is a constant region. The variable regions include 3 hypervariable regions (HVRs) and 4 Framework Regions (FRs) which are relatively sequence-conserved. The 3 hypervariable regions determine the specificity of the antibody, also known as Complementarity Determining Regions (CDRs). Each Light Chain Variable Region (LCVR) and Heavy Chain Variable Region (HCVR) is composed of 3 CDR regions and 4 FR regions, arranged sequentially from amino terminus to carboxy terminus in the order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2 and HCDR3.
Antibodies of the present disclosure include murine, chimeric, humanized and fully human antibodies, preferably humanized and fully human antibodies.
The term "murine antibody" is used in this disclosure to prepare antibodies from mice according to the knowledge and skill in the art. Preparation is accomplished by injecting a subject with a particular antigen and then isolating hybridomas that express antibodies having the desired sequence or functional properties.
The term "chimeric antibody" refers to an antibody obtained by fusing a variable region of a murine antibody to a constant region of a human antibody, and can reduce an immune response induced by the murine antibody. The chimeric antibody is established by firstly establishing hybridoma secreting mouse-derived specific monoclonal antibody, then cloning variable region gene from mouse hybridoma cell, cloning constant region gene of human antibody according to the need, connecting mouse variable region gene and human constant region gene into chimeric gene, inserting into expression vector, and finally expressing chimeric antibody molecule in eukaryotic system or prokaryotic system.
The term "humanized antibody", also known as CDR-grafted antibody (CDR-grafted antibody), refers to an antibody produced by grafting murine CDR sequences into a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. Can overcome the heterogenous reaction induced by the chimeric antibody carrying a large amount of murine protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. Germline DNA Sequences of genes such as the human heavy and light chain variable regions can be found in the "VBase" human germline sequence database (available at the Internet www.mrccpe.com.ac.uk/VBase), and in Kabat, E.A. et al, 1991Sequences of Proteins of Immunological Interest, 5 th edition. To avoid reduced immunogenicity and reduced activity, the human antibody variable region framework sequences may be minimally back-mutated or back-mutated to retain activity. The humanized antibodies of the present disclosure also include humanized antibodies after further affinity maturation of the CDRs by phage display. Further literature describing methods involved in humanizing usable mouse antibodies include, for example, queen et al, proc., natl.Acad.Sci.USA,88, 2869, 1991 and Winter and co-workers' methods [ Jones et al, nature,321, 522 (1986), riechmann, et al, nature,332, 323-327 (1988), verhoeyen, et al, science,239, 1534 (1988) ].
The terms "fully human antibody", "fully human antibody" or "fully human antibody", also known as "fully human monoclonal antibody", have both the variable and constant regions of the antibody being of human origin, eliminating immunogenicity and toxic side effects. Monoclonal antibodies have progressed through four stages, respectively: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully human monoclonal antibodies. The present disclosure is fully human monoclonal antibodies. The related technologies for preparing fully human antibodies mainly include: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology (phage display), transgenic mouse antibody preparation technology (transgenic mouse), single B cell antibody preparation technology, and the like.
The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used to perform the antigen-binding function of the antibody. Examples of binding fragments encompassed within "antigen-binding fragments" include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F (ab') 2 A fragment comprising a bivalent fragment of two Fab fragments connected by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) (ii) an Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) Single domain or dAb fragments (Ward et al, (1989) Nature341: 544-546), which consist of a VH domain; and (vi) an isolated Complementarity Determining Region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined by a synthetic linker using recombinant methods, enabling them to produce a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., bird et al (1988) Science242:423-426; and Huston et al (1988) Proc. Natl. Acad. Sci USA85: 5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody. Obtained using conventional techniques known to those skilled in the artSuch antibody fragments, and fragments are screened for utility in the same manner as for intact antibodies. Antigen binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins. The antibodies can be of different isotypes, e.g., igG (e.g., igG1, igG2, igG3, or IgG4 subtypes), igA1, igA2, igD, igE, or IgM antibodies.
Fab is an antibody fragment having a molecular weight of about 50,000 and having an antigen binding activity among fragments obtained by treating an IgG antibody molecule with protease papain (which cleaves the amino acid residue at position 224 of the H chain), in which about half of the N-terminal side of the H chain and the entire L chain are bonded together by a disulfide bond.
F (ab') 2 is an antibody fragment having a molecular weight of about 100,000 and having antigen binding activity and comprising two Fab regions joined at the hinge position obtained by digestion of the lower part of the two disulfide bonds in the IgG hinge region with the enzyme pepsin.
Fab 'is an antibody fragment having a molecular weight of about 50,000 and having an antigen-binding activity, which is obtained by cleaving the disulfide bond in the hinge region of the above-mentioned F (ab') 2.
In addition, the Fab ' may be produced by inserting DNA encoding the Fab ' fragment of the antibody into a prokaryotic expression vector or a eukaryotic expression vector and introducing the vector into a prokaryote or a eukaryote to express the Fab '.
The term "single chain antibody", "single chain Fv" or "scFv" means a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) joined by a linker. Such scFv molecules can have the general structure: NH (NH) 2 -VL-linker-VH-COOH or NH 2 -VH-linker-VL-COOH. Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof, e.g. using 1-4 repeated variants (Holliger et al (1993), proc.natl.acad.sci.usa90: 6444-6448). Other linkers useful in the present disclosure are made by Alfthan et al (1995), protein Eng.8:725-731, choi et al (2001), eur.J. Immuno l.31:94-106, hu et al (1996), cancer Res.56:3055-3061, kipriyanov et al (1999), J.mol.biol.293:41-56 and Rovers et al (2)001 Cancer immunol.
The term "CDR" refers to one of the 6 hypervariable regions within the variable domain of an antibody which primarily contributes to antigen binding. One of the most common definitions of the 6 CDRs is provided by Kabat e.a. et al, (1991) Sequences of proteins of immunological interest, nih Publication 91-3242). As used herein, the Kabat definition of CDRs applies only to CDR1, CDR2 and CDR3 of the light chain variable domain (CDR L1, CDR L2, CDR L3 or L1, L2, L3), and CDR2 and CDR3 of the heavy chain variable domain (CDR H2, CDR H3 or H2, H3). Typically, there are three CDRs (HCDR 1, HCDR2, HCDR 3) per heavy chain variable region and three CDRs (LCDR 1, LCDR2, LCDR 3) per light chain variable region. Any of a variety of well-known protocols can be used to determine the amino acid sequence boundaries of the CDRs, including the "Kabat" numbering convention (see Kabat et Al (1991), "Sequences of Proteins of Immunological Interest", 5 th edition, public Health Service, national Institutes of Health, bethesda, MD), "Chothia" numbering convention (see Al-Lazikani et Al, (1997) JMB 273 927-948), and ImmunoGenTics (IMGT) numbering convention (see Lefranc M.P., immunological, 7, 132-136 (1999); lefranc, M.P. et Al, dev.Comp.Microl., 27, 55-77 (2003)), among others. For example, for the classical format, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR 1), 50-65 (HCDR 2), and 95-102 (HCDR 3), following Kabat rules; CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR 1), 50-56 (LCDR 2) and 89-97 (LCDR 3). Following the Chothia rule, CDR amino acids in VH are numbered 26-32 (HCDR 1), 52-56 (HCDR 2), and 95-102 (HCDR 3); and amino acid residues in VL are numbered 26-32 (LCDR 1), 50-52 (LCDR 2) and 91-96 (LCDR 3). By combining the CDR definitions of both Kabat and Chothia, the CDRs are made up of amino acid residues 26-35 (HCDR 1), 50-65 (HCDR 2) and 95-102 (HCDR 3) in the human VH and amino acid residues 24-34 (LCDR 1), 50-56 (LCDR 2) and 89-97 (LCDR 3) in the human VL. Following the rules of IMGT, the CDR amino acid residue numbers in VH are approximately 26-35 (CDR 1), 51-57 (CDR 2), and 93-102 (CDR 3), and the CDR amino acid residue numbers in VL are approximately 27-32 (CDR 1), 50-52 (CDR 2), and 89-97 (CDR 3). Following the IMGT rules, the CDR regions of the antibody can be determined using the program IMGT/DomainGap alignment.
The term "antibody framework" refers to a portion of a variable domain, VL or VH, that serves as a scaffold for the antigen binding loops (CDRs) of that variable domain. It is essentially a variable domain without CDRs.
The term "epitope" or "antigenic determinant" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds. Epitopes typically comprise at least 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14 or 15 contiguous or non-contiguous amino acids in a unique spatial conformation (see, e.g., epitopic Mapping Protocols in Methods in Molecular B biology, vol 66, g.e.morris, ed. (1996)).
The terms "specific binding," "selective binding," "selectively binds," and "specifically binds" refer to the binding of an antibody to an epitope on a predetermined antigen. Typically, the antibody is administered at a rate of about less than 10 -7 M, for example: less than about 10 -8 M、10 - 9 M or 10 -10 M or less affinity (KD) binding.
The term "nucleic acid molecule" refers to both DNA molecules and RNA molecules. The nucleic acid molecule may be single-stranded or double-stranded, but is preferably double-stranded DNA. A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence.
The term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. In one embodiment, the vector is a "plasmid," which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. In another embodiment, the vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. The vectors disclosed herein are capable of autonomous replication in a host cell into which they have been introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors) or can be integrated into the genome of a host cell upon introduction into the host cell so as to be replicated along with the host genome (e.g., non-episomal mammalian vectors).
Methods for producing and purifying antibodies and antigen-binding fragments are well known in the art, such as the Cold spring harbor antibody protocols, chapters 5-8 and 15. Antigen-binding fragments can likewise be prepared by conventional methods. The antibody or antigen binding fragment of the invention is genetically engineered to add one or more human FR regions to the CDR regions of non-human origin. Human FR germline sequences can be obtained from the website http:// IMGT. Circles. FR of Imminogenetics (IMGT) or from the immunoglobulin journal, 2001ISBN012441351 by aligning the IMGT human antibody variable region germline gene database with the MOE software.
The term "host cell" refers to a cell into which an expression vector has been introduced. Host cells may include bacterial, microbial, plant or animal cells. Bacteria susceptible to transformation include members of the enterobacteriaceae family (enterobacteriaceae), such as strains of Escherichia coli (Escherichia coli) or Salmonella (Salmonella); bacillaceae (Bacillus) such as Bacillus subtilis; pneumococcus (Pneumococcus); streptococcus (Streptococcus) and Haemophilus influenzae (Haemophilus influenzae). Suitable microorganisms include Saccharomyces cerevisiae and Pichia pastoris. Suitable animal host cell lines include CHO (chinese hamster ovary cell line) and NS0 cells.
Engineered antibodies or antigen-binding fragments of the present disclosure can be prepared and purified using conventional methods. For example, cDNA sequences encoding the heavy and light chains can be cloned and recombined into a GS expression vector. Recombinant immunoglobulin expression vectors can stably transfect CHO cells. As a more recommended prior art, mammalian expression systems result in glycosylation of antibodies, particularly at the highly conserved N-terminal site of the Fc region. Positive clones were expanded in bioreactor serum-free medium to produce antibodies. The antibody-secreting culture medium can be purified by conventional techniques. For example, purification is carried out using an A or G Sepharose FF column containing a buffer adjusted. Non-specifically bound fractions are washed away. And eluting the bound antibody by using a pH gradient method, detecting antibody fragments by using SDS-PAGE, and collecting. The antibody can be concentrated by filtration by a conventional method. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves, ion exchange. The resulting product is either immediately frozen, e.g., -70 ℃, or lyophilized.
Amino acid sequence "identity" refers to the percentage of amino acid residues in a first sequence that are identical to amino acid residues in a second sequence, when the amino acid sequences are aligned and gaps are introduced, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. For the purpose of determining percent amino acid sequence identity, alignments can be accomplished in a variety of ways that are within the skill in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN-2, or Megalign (DNASTAR) software. One skilled in the art can determine parameters suitable for measuring alignment, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared.
The term "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. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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-methylhexyl, 5-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and the like 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched chain isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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, and the like. Alkyl groups may be substituted or unsubstituted and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "carbocyclic" refers to a ring system in a cycloalkyl group.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "heterocycle" refers to the ring system of a heterocyclyl.
The term "aryl" refers to a 6 to 14 membered, all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. "aromatic ring" refers to a ring system in an aryl group. Non-limiting examples of aryl groups include:
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate, preferably phenyl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. "heteroaryl ring" refers to a ring system in a heteroaryl group. Non-limiting examples of heteroaryl groups include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"carboxyl protecting Groups" are suitable Groups known in the art for carboxyl protection, see the literature ("Protective Groups in Organic Synthesis", 5) Th Ed.T.W.Greene&P.g.m.wuts), the carboxyl protecting group may be, for example, a substituted or unsubstituted C 1-10 Straight or branched alkyl, substituted or unsubstituted C 2-10 Straight or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 With a cyclic alkyl group, substituted or unsubstituted C 5-10 Aryl or heteroaryl of (A), or (C) 1-8 Alkyl or aryl) 3 Silane groups, and the like.
"amino-protecting Groups" are suitable Groups for amino protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5) Th .Ed.T.W.Greene&M.wuts), preferably, the amino protecting group may be (C) 1-10 Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl and the like; may be (C) 1-6 Alkyl or C 6-10 Aryl) sulfonyl; or (C) 1-6 Alkoxy or C 6-10 Aryloxy) carbonyl, for example: boc or Cbz; and may also be substituted or unsubstituted alkyl groups, such as: trityl (Tr), 2,4-Dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
In the chemical structure of the compounds described in the present disclosure, a bond
No configuration is specified, i.e. if configurational isomerism is present in the chemical structure, the bond
Can be that
Or at the same time contain
Two configurations. In the chemical structure of the compounds described in this disclosure, a bond
The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated.
Detailed Description
The present disclosure will be explained in detail with reference to specific examples below so that those skilled in the art can more fully understand that the specific examples of the present disclosure are merely illustrative of the technical solutions of the present disclosure and do not limit the present disclosure in any way.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) at 10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: thermo, model: finnigan LCQ advantage MAX).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC assay using Agilent 1260DAD HPLC.
High performance liquid chromatography preparative chromatographs were used, including Waters 2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson-281.
Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.
Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan ChemBiotech (Accela ChemBio Inc), darril Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
The hydrogenation reaction is usually carried out by vacuum pumping, hydrogen filling and repeated operation for 3 times.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
Example 1
To a reaction flask was added compound A (105 g), compound B (100.6 g, prepared according to the method disclosed in WO 2020063676), dichloromethane (3.15L), methanol (1.05L), cooled to 0 deg.C, and DMTMM (87.3 g), anhydrous potassium carbonate (81.9 g) was added and the reaction was stirred with constant temperature. After the reaction was completed, purified water (1.0L) was added thereto and stirred. Dichloromethane (3.1L) was then added and stirred, allowed to stand and the organic phase collected. The organic phase was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane: methanol (40). The purity was 99.5% by HPLC.
Example 2
Compound C (10mg, 11.88umol) was placed in a reaction flask, and DCM (2 mL), diethylamine (870ug, 11.88umol) and argon atmosphere were added to stir the reaction at room temperature. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was washed with n-hexane, and the clear solution was removed by suction, and the residue was concentrated under reduced pressure to give a total of 7.4mg of Compound D, which was directly subjected to the next reaction without purification.
Example 3
Compound D (10.5mg, 16.9454umol) was placed in a reaction flask, DMF was added, cooling was performed in ice bath, compound E (8mg, 16.9316umol) was added under ice bath, warmed to room temperature, and stirred for reaction. After the reaction, the product was purified by HPLC (separation conditions: preparative column ACQUITY UPLC BEHC 18.7um 2.1 x 50mm, mobile phase: A-water (5 mmol NH) 4 OAc), B-acetonitrile) to yield a total of 2.7mg of compound I-1.
Example 4
According to the procedure of example 1, compound A (105 g) was charged and anhydrous potassium carbonate was changed to triethylamine (81.9 g), to obtain compound C (142.7 g, yield 85.8%). The purity was 98.24% by HPLC.
Example 5: stability study of C samples obtained by different processes
Samples of C obtained in example 1 and example 4 were taken, left at room temperature, and sampled for 0,7, 15 and 30 days, respectively, for HPLC analysis of the relevant substances, and the results are shown in the following table:
TABLE 1 stability study of samples C obtained by different procedures
Since the present disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the present disclosure.
Claims (18)
1. A preparation method of a compound shown as a formula (II) comprises the step of reacting a compound shown as a formula (III) with a compound shown as a formula (VII) in the presence of alkali,
wherein the base is selected from the group consisting of alkali or alkaline earth metal carbonates, bicarbonates, alkoxides, hydroxides or hydrides,
R 1 、R 2 each independently selected from hydrogen atom, C 1-6 Alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo, 3-to 6-membered cycloalkyl, 6-to 10-membered aryl or C 1 -C 6 Substituted by the substituent of the alkoxy group,
or, R 1 And R 2 Together with the carbon atom to which they are attached form an optionally substituted C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo or C 1 -C 6 3-6 membered cycloalkyl substituted with a substituent of alkoxy;
R 3 、R 4 、R 5 each independently selected from a hydrogen atom or C 1-6 An alkyl group;
R 6 selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said alkyl, aryl, heteroaryl are optionally substituted by one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino and oxo;
R c selected from amino or amino protected by an amino protecting group, preferably amino protected by 9-fluorenylmethyloxycarbonyl;
m is an integer of 0 to 4.
2. The process according to claim 1, wherein the base is selected from the group consisting of alkali metal carbonates, bicarbonates or hydroxides, preferably sodium or potassium carbonate.
3. The process according to claim 1 or2, wherein the molar ratio of the compound of formula (III) to the base is 1.
4. The production method according to any one of claims 1 to 3, wherein R is 1 Selected from hydrogen atoms, C 1-6 Alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with one or more groups selected from C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo, 3-6 membered cycloalkyl, 6-10 membered aryl or C 1 -C 6 Substituted by the substituent of the alkoxy group,
R 2 selected from hydrogen atoms or C optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo 1 -C 6 An alkyl group, a carboxyl group,
or, R 1 And R 2 Together with the carbon atom to which they are attached form an optionally substituted C 1 -C 6 Alkyl, halogen, hydroxy, amino, oxo or C 1 -C 6 3-6 membered cycloalkyl substituted by a substituent of alkoxy.
5. The process according to any one of claims 1 to 4, wherein R is 1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl, 3-6-membered cycloalkyl substituted C 1-6 Alkyl, 6-10 membered aryl substituted C 1-6 Alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, R 2 Is a hydrogen atom, or R 1 And R 2 Together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl group; preferably R 1 Is selected from C 1-6 Alkyl radical, C 1-6 Haloalkyl, 3-6-membered cycloalkyl, R 2 Is a hydrogen atom, or R 1 And R 2 Together with the carbon atoms to which they are attached form a 3-6 membered cycloalkyl group.
6. The method according to any one of claims 1 to 5, wherein R is 3 、R 4 、R 5 Are all hydrogen atoms.
7. The production method according to any one of claims 1 to 6, whereinR 6 Selected from hydrogen atoms, C 1-6 Alkyl, halo C 1-6 Alkyl or hydroxy C 1-6 Alkyl groups, more preferably hydrogen atoms.
8. The production method according to any one of claims 1 to 7, wherein the method comprises
9. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula (II) according to any one of claims 1 to 8,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 M is as defined in claim 1, and n is an integer of 2 to 8.
10. The method of manufacturing according to claim 9, wherein the method further comprises:
11. the method of making as defined in claim 10, wherein the method further comprises:
12. the process according to claim 9, wherein the compound of formula (I) is selected from
13. A method for preparing an antibody-drug conjugate, comprising the steps of preparing a compound represented by the formula (I) according to any one of claims 9 to 12, and performing a coupling reaction with the compound represented by the formula (I) after Ab is reduced to obtain an antibody-drug conjugate represented by the formula (X),
wherein Ab is an antibody or antigen-binding fragment, k is 1 to 20 1 、R 2 、R 3 、R 4 、R 5 、R 6 M is as defined in claim 1, and n is an integer of 2 to 8.
14. The production method according to claim 13, wherein the antibody is selected from a chimeric antibody, a humanized antibody or a fully human antibody; preferably a monoclonal antibody.
15. The preparation method of claim 13 or 14, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of an anti-HER 2 (ErbB 2) antibody, an anti-EGFR antibody, an anti-B7-H3 antibody, an anti-C-Met antibody, an anti-HER 3 (ErbB 3) antibody, an anti-HER 4 (ErbB 4) antibody, an anti-CD 20 antibody, an anti-CD 22 antibody, an anti-CD 30 antibody, an anti-CD 33 antibody, an anti-CD 44 antibody, an anti-CD 56 antibody, an anti-CD 70 antibody, an anti-CD 73 antibody, an anti-CD 105 antibody, an anti-CEA antibody, an anti-a 33 antibody, an anti-Cripto antibody, an anti-EphA 2 antibody, an anti-G250 antibody, an anti-cl antibody, an anti-Lewis Y antibody, an anti-VEGFR antibody, an anti-GPNMB antibody, an anti-Integrin antibody, an anti PSMA antibody, an anti-Tenascin-C antibody, an anti-SLC 44A4 antibody or an anti-solaclin antibody or an antigen-binding fragment thereof.
16. The method of any one of claims 13-15, wherein the antibody or antigen-binding fragment thereof is selected from Trastuzumab, pertuzumab, nimotuzumab, enobiltituzumab, emibetuzumab, inotuzumab, pinatuzumab, brentuximab, gemtuzumab, bivatuzumab, lorvotuzumab, cBR96, glemtuzumab, or an antigen-binding fragment thereof.
17. The process according to any one of claims 13 to 16, wherein k is from 2 to 8, preferably from 5 to 9.
18. The method of any one of claims 13-17, wherein the method comprises
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