WO2019062665A1 - Composé de lieur, conjugué polyéthylène glycol-lieur et dérivé de celui-ci, et conjugué polyéthylène glycol-lieur-médicament - Google Patents

Composé de lieur, conjugué polyéthylène glycol-lieur et dérivé de celui-ci, et conjugué polyéthylène glycol-lieur-médicament Download PDF

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WO2019062665A1
WO2019062665A1 PCT/CN2018/106972 CN2018106972W WO2019062665A1 WO 2019062665 A1 WO2019062665 A1 WO 2019062665A1 CN 2018106972 W CN2018106972 W CN 2018106972W WO 2019062665 A1 WO2019062665 A1 WO 2019062665A1
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group
polyethylene glycol
linker
integer
peg
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PCT/CN2018/106972
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English (en)
Chinese (zh)
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冯泽旺
王庆彬
汪进良
宋艳萍
熊艳丽
王雷敏
杜景辉
赵宣
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天津键凯科技有限公司
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Priority claimed from CN201810186781.6A external-priority patent/CN108727208B/zh
Priority claimed from CN201811043884.3A external-priority patent/CN109589415B/zh
Application filed by 天津键凯科技有限公司 filed Critical 天津键凯科技有限公司
Publication of WO2019062665A1 publication Critical patent/WO2019062665A1/fr
Priority to US16/833,988 priority Critical patent/US11857635B2/en

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    • 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
    • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • 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
    • A61K47/54—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 organic compound
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    • 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
    • A61K47/54—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 organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
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    • 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
    • A61K47/54—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 organic compound
    • A61K47/545—Heterocyclic compounds
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • C08G65/48—Polymers modified by chemical after-treatment

Definitions

  • the present invention relates to the field of medical technology, and in particular to a linker compound, a polyethylene glycol-linker conjugate and a derivative thereof, a polyethylene glycol-linker-drug conjugate, and pharmaceutical compositions and uses thereof.
  • drugs are not suitable for oral administration.
  • they will be destroyed by various proteases, peptidases and other hydrolyzed environments after entering the digestive tract, and the efficacy is reduced or even lost.
  • some drugs are irritating or acid-resistant to the stomach and are easily destroyed by gastric acid.
  • the main route of administration is injection, which is directly injected into human tissues or blood vessels, without passing through the digestive system and liver, and is not affected by digestive juice.
  • the patent document CN200680029849.5 discloses a conjugate comprising an aromatic moiety containing an ionizable hydrogen atom such as a hydrazine, a spacer and a water-soluble polymer.
  • the inventors of the present application have conducted a large number of experiments and studies to obtain a linker compound and a combination thereof with polyethylene glycol and a derivative thereof, which are simple to modify and easy to carry out when the drug is modified, and the reaction yield is obtained. Higher, the scope of application of the modified drug is wider, and the modified drug has an ideal release rate and efficacy in vivo, which can reduce the frequency of administration, and greatly improve the bioavailability of the drug and patient compliance.
  • Another object of the present invention is to provide a combination of polyethylene glycol with the above linker and derivatives thereof.
  • Another object of the invention is to provide a polyethylene glycol-linker-drug combination.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above combination and its pharmaceutically acceptable carrier or additive.
  • a first aspect of the invention provides a compound having the structure:
  • l is an integer from 1 to 5
  • Z is selected from the group consisting of: -H and a hydroxy protecting group
  • A is selected from the group consisting of: amino acid residues, polypeptide residues, One of -(CH 2 ) i -, -NHCO(CH 2 ) i -, -CONH(CH 2 ) i -, -(CH 2 ) i NH- and -CO(CR 15 R 16 ) i NH- Or a combination of multiples, i is an integer from 0-6,
  • the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, proline, aspartic acid, asparagine, glutamic acid, and glutamine.
  • R 1-7 and R 9-11 are independently selected from the group consisting of: -H, -F, -Cl, -Br, -I, C1-6 alkyl, C1-6 alkoxy, C3-6 naphthenic a base, a C1-6 alkenyl group, a C6-12 aryl group, a C6-12 aralkyl group, a C3-12 aromatic or non-aromatic heterocyclic group, a C3-12 heterocycloalkyl group, and -(CH 2 ) l -OZ,
  • R 8 and R 12 are independently selected from a C1-6 alkyl group
  • R 13-16 is independently selected from the group consisting of: -H and C1-6 alkyl groups,
  • B is a linking group -B 1 -B 2 -
  • B 1 is selected from the group consisting of: -(CH 2 ) j -, -NHCO(CH 2 ) j - and -CONH(CH 2 ) j -, and j is an integer from 0 to 6,
  • the l is an integer of from 1 to 5, such as 1, 2, 3, 4, 5, preferably 1, 2 or 3; more preferably 1.
  • said Z is -H.
  • the A is an amino acid residue selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, and serine. , threonine, valine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, arginine, cysteine, methionine, histidine, tryptophan, benzene Alanine and tyrosine, preferably from: glycine, alanine, valine, leucine, isoleucine, aspartic acid, asparagine, glutamic acid, glutamine and lysine More preferably, it is derived from glycine, alanine and valine.
  • the A in the linker compound, is Preferred In a specific embodiment of the invention, the A is
  • the A is -(CH 2 ) i -, -(CH 2 ) i NH- and -CO(CR 15 R 16 ) i NH - a combination of one or more of them.
  • the R 1-7 and R 9-11 are independently selected from the group consisting of: -H, -F, -Cl, -Br, -I, C1-6 alkyl, Alkoxy group of C1-6 and -(CH 2 ) l -OZ; more preferably from: -H, -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 and -(CH 2 ) l -OZ; further preferably from: -H, -F, -Cl, -CH 3 , -OCH 3 and -( CH 2 ) l -OZ.
  • said R 1-4 are both -H.
  • said R 5-7 is -H.
  • said R 9-11 is -H.
  • the R 8 and R 12 are independently selected from a C1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl More preferably, the R 8 and/or R 12 is a methyl group.
  • R 13-16 is independently selected from the group consisting of: -H and C1-3 alkyl groups (such as methyl, ethyl, n-propyl or isopropyl).
  • R 15 is -H
  • R 16 is selected from the group consisting of: -H, methyl, ethyl, n-propyl and isopropyl.
  • said R 13 and/or R 14 is -H.
  • i is an integer of 0-3, such as 0, 1, 2 or 3.
  • j is an integer from 0 to 3, such as 0, 1, 2 or 3.
  • said A is -COCH 2 NH-, -COCH(CH 3 )NH-, -COCH(CH(CH 3 ) 2 )NH-.
  • the B 2 is -C(O)O- or -O-.
  • said B is -(CH 2 ) j O-, and j is an integer from 0 to 3, such as 0, 1, 2 or 3.
  • the -BA- is -OCH 2 CH 2 NH-.
  • the linker compound is selected from the group consisting of:
  • Another aspect of the present invention also provides a polyethylene glycol-linker conjugate having the following structure:
  • PEG is a polyethylene glycol residue
  • X is a linking group selected from the group consisting of: -(CH 2 ) a -, -(CH 2 ) a CO-, -(CH 2 ) a OCO-, -(CH 2 ) a NHCO-, -NH(CH 2 ) a CO-, -(CH 2 ) a SO 2 -, -O(CH 2 ) a -, -O(CH 2 ) a CO-, -O(CH 2 ) a OCO-, -O(CH 2 ) a A combination of one or more of NHCO- and -O(CH 2 ) a SO 2 -, a being an integer from 0-10.
  • the polyethylene glycol-linker conjugate has the structure:
  • R 1-12 , 1, A, B, Z and the like have the above definition of the present invention.
  • the X is selected from the group consisting of: -(CH 2 ) a -, -(CH 2 ) a CO-, -(CH 2 ) a one or more of NHCO-, -NH(CH 2 ) a CO-, -O(CH 2 ) a -, -O(CH 2 ) a CO- and -O(CH 2 ) a NHCO- Combinations are preferably -(CH 2 ) a -, -(CH 2 ) a CO- or -(CH 2 ) a NHCO-.
  • a is an integer from 0 to 5, such as 0, 1, 2, 3, 4 or 5.
  • the X is a single bond, -CH 2 -, -CH 2 CH 2 -, -CO-, -CH 2 CO- Or -NHCO-.
  • the PEG is a linear, Y-type, multi-branched polyethylene glycol residue, for example, including monomethoxypolyethylene glycol (mPEG), Linear double-ended PEG, Y-type PEG, 4-arm branched PEG, 6-arm branched PEG or 8-arm branched PEG.
  • mPEG monomethoxypolyethylene glycol
  • Linear double-ended PEG Linear double-ended PEG
  • Y-type PEG 4-arm branched PEG
  • 6-arm branched PEG 6-arm branched PEG or 8-arm branched PEG.
  • the PEG is a linear polyethylene glycol residue having a structure represented by the formula III or IV:
  • p and q are independently selected from an integer of from 1 to 960, preferably from 1 to 480.
  • the PEG is a Y-type polyethylene glycol residue having a structure represented by the formula V or VI:
  • i and h are independently selected from an integer from 1 to 480, preferably from 1 to 420.
  • the PEG is a multi-branched polyethylene glycol residue having a structure represented by the formula VII:
  • k is an integer from 1 to 320, preferably an integer from 1 to 240,
  • j is an integer of 3-8
  • R is a core molecule of a multi-branched polyethylene glycol, and R is selected from the group consisting of: residues of pentaerythritol, oligo-pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerol, and polyglycerol; preferably, R is selected from: Glycerin, hexaglycerol, pentaerythritol, dipentaerythritol and tripolypentaerythritol residues.
  • the multi-branched polyethylene glycol residue contains only one connectable site having the following structure:
  • the multi-branched polyethylene glycol residue has the structure:
  • k is an integer from 1 to 320, preferably an integer from 1 to 240,
  • x is an integer of 1-10 (specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably an integer of 1-6.
  • the multi-branched polyethylene glycol residue has the structure:
  • k is an integer from 1 to 320, preferably an integer from 1 to 240,
  • x is an integer of 1-10 (specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably an integer of 1-6.
  • the multi-branched polyethylene glycol residue has the structure:
  • k is an integer from 1 to 320, preferably an integer from 1 to 240, more preferably an integer from 1 to 120,
  • Y is an integer of 1-10 (specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably an integer of 1-5, and more preferably an integer of 1-3.
  • the multi-branched polyethylene glycol residue has the structure:
  • k is an integer from 1 to 320, preferably an integer from 1 to 240, more preferably an integer from 1 to 120,
  • Y is an integer of 1-10 (specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably an integer of 1-5, and more preferably an integer of 1-3.
  • the PEG may have a molecular weight of 1-100 KDa, such as 1-10 KDa (specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 KDa), 10-50 KDa (specific Can be 10, 15, 20, 25, 30, 35, 40, 45, 50 KDa), 50-100 KDa (specifically 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 KDa) And so on; further preferably from 10 to 50 KDa.
  • 1-10 KDa specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 KDa
  • 10-50 KDa specifically Can be 10, 15, 20, 25, 30, 35, 40, 45, 50 KDa
  • 50-100 KDa specifically 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 KDa
  • the polyethylene glycol-linker conjugate is selected from the group consisting of:
  • the PEG has the structure of the above formula III, V, VI, VII-3 or VII-5 of the present invention
  • the molecular weight of the PEG is 10-50 KDa (specifically, 10, 15, 20, 25, 30, 35, 40, 45 or 50 KDa ).
  • the X is -CH 2 CO-, -CO-, -CH 2 - or -CH 2 CH 2 -.
  • the PEG described herein may be a PEG structure having a linkable site represented by Formula III, V or VI, which is linked to a linker such as PEG having the structure shown in Formula III, and when X is -CO-,
  • the structure of II-d is
  • the PEG can also be a PEG having two or more connectable sites as shown in Formula IV or VII, which can effect ligation of the linker through one or more ligation sites.
  • the PEG when the PEG is a PEG having two or more connectable sites represented by Formula IV or VII, it may be linked to a linker through a linking site, and other connectable sites may be It can be linked to a blocking group (such as methoxy), or can be linked to a linker through a plurality of linking sites, such as the structure shown in Formula VII-1, such as PEG is an eight-arm polyethylene glycol, and X is -CH. 2 CO-, the structure of II-d can be: Also available for Wait.
  • the PEG has the structure of the above III, IV, V, VI, VII-2, VII-3, VII-4 or VII-5 of the present invention, wherein x It is preferably an integer of 1-6, and y is preferably an integer of 1-3.
  • Another aspect of the present invention also provides a polyethylene glycol-linker conjugate which has the following structure:
  • PEG is a polyethylene glycol residue
  • X is a linking group of PEG and L, and is selected from the group consisting of: -(CH 2 ) a -, -(CH 2 ) a CO-, -(CH 2 ) a OCO-, -(CH 2 ) a NHCO-, -NH (CH 2 ) a CO-, -(CH 2 ) a SO 2 -, -O(CH 2 ) a -, -O(CH 2 ) a CO-, -O(CH 2 ) a OCO-, -O( CH 2 ) a combination of one or more of NHCO- and -O(CH 2 ) a SO 2 -, a being an integer from 0 to 10,
  • P is a linking group of L and a terminal group Q, and is selected from the group consisting of: -(CH 2 ) r -, -(CH 2 ) r O-, -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r SH-, a combination of one or more of the following, r is an integer from 0 to 10,
  • Q is a terminal group selected from the group consisting of: a C1-C6 alkoxy group, a hydroxyl group, an amino group, a carboxyl group, a thiol group, an ester group, a ketone group, an aldehyde group, an o-dithiopyridyl group, an azide group, a hydrazide group, an alkynyl group. Silyl, maleimide and succinimide groups,
  • R 17 and R 18 are independently selected from the group consisting of: -H, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, and a C4-10 alkylene cycloalkyl group.
  • the derivative has the structure:
  • X is a single bond, -CH 2 -, -CH 2 CH 2 -, -CO-, -CH 2 CO- or -NHCO-.
  • R 17 and R 18 are independently selected from the group consisting of: -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 and -OCH 2 CH 2 CH 3 , more preferably from: -H, -CH 3 , -OCH 3 and -OCH 2 CH 3 , in one embodiment of the invention, R 17 is H, and R 18 is -CH 3 , -OCH 3 or -OCH 2 CH 3 , In a preferred embodiment of the invention, R 17 is H and R 18 is -CH 3 .
  • the P is selected from the group consisting of: -(CH 2 ) r -, -(CH 2 ) r CH(CH 3 )-, -(CH 2 ) r O-, -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r SH-, a combination of one or more of them.
  • r is an integer from 0 to 5, such as 0, 1, 2, 3, 4 or 5.
  • the P is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) r O- , -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r SH-,
  • more than one PEG-XL- and more than one Q may be connected, as the P is When the above derivative is Wait.
  • the Q is an ester or ketone group.
  • the ester group is selected from the group consisting of: And -SO 2 CH 2 CF 3 .
  • the ketone group is selected from the group consisting of: -COCH 3 and -COCH 2 CH 3 .
  • the Q is
  • the derivative has the structure:
  • the derivative is selected from the following structures:
  • the PEG has the above formula III, IV, V, VI, VII-2, VII-3, VII-4 or VII of the present invention. -5 structure.
  • the PEG has a molecular weight of 10 to 50 KDa (specifically, 10, 15, 20, 25, 30, 35, 40, 45 or 50 KDa) ).
  • the X is -CH 2 CO-, -CO-, -CH 2 - or -CH 2 CH 2 -.
  • the PEG has the structure of the above III, IV, V, VI, VII-2, VII-3, VII-4 or VII-5 of the present invention, wherein x An integer of 1-6, y is an integer from 1-3.
  • Another aspect of the invention also provides a polyethylene glycol-linker-drug conjugate having the structure:
  • PEG is a polyethylene glycol residue
  • X is a linking group of PEG and L, and is selected from the group consisting of: -(CH 2 ) a -, -(CH 2 ) a CO-, -(CH 2 ) a OCO-, -(CH 2 ) a NHCO-, -NH (CH 2 ) a CO-, -(CH 2 ) a SO 2 -, -O(CH 2 ) a -, -O(CH 2 ) a CO-, -O(CH 2 ) a OCO-, -O( CH 2 ) a combination of one or more of NHCO- and -O(CH 2 ) a SO 2 -, a being an integer from 0 to 10,
  • Y is a linking group of L and D, and is selected from the group consisting of: -(CH 2 ) r -, -(CH 2 ) r O-, -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r SH-, a combination of one or more of the following, r is an integer from 0 to 10,
  • R 17 and R 18 are independently selected from the group consisting of: -H, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, and a C4-10 alkylene cycloalkyl group.
  • L is the above linker of the present invention
  • D is a biologically active agent containing m amine groups, and m is an integer of from 1 to 500,
  • n is an integer and 1 ⁇ n ⁇ m.
  • the n 1 and the formula IX is PEG-X-L-Y-D.
  • the D is an amine group-containing small molecule biologically active agent and a pharmaceutically acceptable salt thereof, and preferably includes: doxorubicin, crizotinib, goserelin, Cytarabine, procaine, benzocaine, chloroprocaine, dimethine, dopamine, norepinephrine, clenbuterol, phenformin, dalapril, propyl sulphur Amine, p-aminosalicylic acid, sulfadiazine, and derivatives thereof.
  • the D is doxorubicin or a derivative thereof, which has the following structure:
  • W 1 is selected from the group consisting of: -H, -OH, -OCH 3 and -OCH 2 CH 3 ; preferably -H or -OCH 3 , more preferably -OCH 3 ;
  • W 2 is selected from the group consisting of: -H, -OH, -OCO(CH 2 ) 5 COOH and -OCO(CH 2 ) 2 NH 2 ; preferably -H or -OH, more preferably -OH;
  • W 3 is selected from the group consisting of: -OH, -OCH 3 and It is preferably -OH.
  • the D is doxorubicin having the following structure:
  • the D is an amine group-containing macromolecular biological active agent such as a polypeptide and a protein drug, such as a cytokine (such as an interleukin, a colony).
  • a cytokine such as an interleukin, a colony
  • the drug molecule is linked to the polyethylene glycol-linker via an amine group, which may be an N-terminal amino group of the peptide chain and/or an amino acid (such as lysine) in the peptide chain. a side chain amino group; more preferably, in the drug conjugate, a polyethylene glycol-linker is formed by reacting an active carbonate group with a primary amine group of a drug molecule Implement the connection.
  • an amine group which may be an N-terminal amino group of the peptide chain and/or an amino acid (such as lysine) in the peptide chain.
  • a side chain amino group more preferably, in the drug conjugate, a polyethylene glycol-linker is formed by reacting an active carbonate group with a primary amine group of a drug molecule Implement the connection.
  • antibody is used in its broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (eg, bispecific antibodies) and antibody fragments, As long as they exhibit the desired biological activity (Miller et al. (2003) Jour. of Immunology, 170: 4854-4861).
  • the antibody can be murine, human, humanized, chimeric, or derived from other species.
  • the antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA) and classes (e.g., IgGl, IgG2, IgG3, IgG4, IgA1, and IgA2), wherein IgM contains about 450 free amino groups.
  • the D is a cytokine; in one embodiment of the invention, the cytokine is an interleukin, preferably an interleukin 2 (IL-2), more preferably a recombinant human interleukin 2 (rhIL-2).
  • IL-2 interleukin 2
  • rhIL-2 recombinant human interleukin 2
  • the cytokine is a colony stimulating factor, preferably a granulocyte colony stimulating factor, more preferably a recombinant human granulocyte colony stimulating factor.
  • the D is an antibody.
  • the antibody is a monoclonal antibody, such as an anti-HER2 monoclonal antibody, preferably a recombinant anti-HER2 humanized monoclonal antibody.
  • the D is human hemoglobin.
  • the D is an enzyme and a coenzyme, preferably from: pancreatic ribonuclease, superoxide dismutase, and asparaginase.
  • the D is a protein hormone, preferably insulin.
  • n is an integer from 1 to 500 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500), if the drug is interleukin 2, n can Is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; when the drug is a recombinant anti-HER2 humanized monoclonal antibody, n may be an integer from 1 to 90; When the drug is IgM, n may be an integer from 1 to 450.
  • the Y is selected from the group consisting of: -(CH 2 ) r -, -(CH 2 ) r CH(CH 3 )-, -(CH 2 ) r O-, -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r SH-, a combination of one or more of them.
  • r is an integer from 0 to 5, such as 0, 1, 2, 3, 4 or 5.
  • the Y is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) r O- , -(CH 2 ) r CO-, -(CH 2 ) r CONH-, -(CH 2 ) r NH-, -(CH 2 ) r SH-,
  • Y is -(CH 2 ) r CO- and a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH (CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )- , -(CH 2 ) r O-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r NH-, -(CH 2 ) r SH-, a combination of one or more of them.
  • the polyethylene glycol - linker - drug conjugate the Y is - (CH 2) r CO-.
  • the Y is -CO-.
  • the Y has more than two linking sites, more than one PEG-XL- and D may be connected, as the Y is
  • the polyethylene glycol-linker-drug conjugate can be
  • the polyethylene glycol-linker-drug conjugate has the structure:
  • R 1-4 is all -H.
  • the R 5-7 is -H.
  • the R 9-11 is -H.
  • the R 8 and/or R 12 is a methyl group.
  • the l is 1.
  • the A is -COCH 2 NH-, -COCH(CH 3 )NH- or -COCH(CH(CH 3 ) 2 )NH-.
  • the -BA- is -OCH 2 CH 2 NH-.
  • the X is a single bond, -CH 2 -, -CH 2 CH 2 -, -CO-, -CH 2 CO- or - NHCO-.
  • the D is a polypeptide and a protein drug, preferably a cytokine, more preferably IL-2 (such as rhIL-2), PEG has the structure of the above III, V, VI, VII-3 or VII-5 of the present invention; preferably, wherein x is an integer from 1 to 6, and y is an integer from 1 to 3.
  • a protein drug preferably a cytokine, more preferably IL-2 (such as rhIL-2)
  • PEG has the structure of the above III, V, VI, VII-3 or VII-5 of the present invention; preferably, wherein x is an integer from 1 to 6, and y is an integer from 1 to 3.
  • the D is doxorubicin or a derivative thereof, and has the structure represented by the above formula X of the present invention, preferably doxorubicin, Having the structure represented by the above formula X-1 of the present invention, the PEG having the structure of the above III, IV, V, VI, VII-2 or VII-4 of the present invention; preferably, wherein x is an integer of 1-6 , y is an integer from 1-3.
  • the PEG has a molecular weight of 10 to 50 KDa (specifically, 10, 15, 20, 25, 30, 35, 40, 45 or 50KDa).
  • the D is a polypeptide and a protein drug, preferably a cytokine, more preferably IL-2, and the PEG has the above III of the present invention.
  • PEG is a structure of the formula V, VI, VII-3 or VII-5, the steric hindrance effect can be increased to regulate the drug release rate.
  • the D in the above formulas IX-a to IX-e, is doxorubicin or a derivative thereof, and has the structure represented by the above formula X of the present invention; preferably, the D is Doxorubicin having the structure represented by the above formula X-1 of the present invention, wherein n is 1.
  • the molecular weight of the PEG is 10-50 KDa (specifically, 10, 15, 20, 25, 30, 35, 40, 45 or 50 KDa ).
  • the X is -CH 2 CO-, -CO-, -CH 2 - or -CH 2 CH 2 -.
  • the D is IL-2, preferably rhIL-2, and the n is an integer of 1-12, preferably 1-7 An integer, such as 1, 2, 3, 4, 5, 6, or 7.
  • the drug is a polypeptide and a proteinaceous drug, preferably a cytokine, more preferably IL-2 (such as rhIL-2), the polyethylene glycol-linker-
  • IL-2 such as rhIL-2
  • the IL-2 conjugate has the following structure:
  • x is an integer from 1 to 6, preferably x is 6.
  • n is an integer from 1 to 12, preferably an integer from 1 to 7, specifically such as 1, 2, 3, 4, 5, 6, or 7.
  • the IL-2 is rhIL-2.
  • the drug is doxorubicin or a derivative thereof, having the structure represented by the above formula X of the present invention; preferably, the D is doxorubicin, which has the present invention
  • the structure represented by the above formula X-1, the polyethylene glycol-linker-doxorubicin conjugate has the following structure:
  • the y is an integer from 1 to 5, such as 1, 2, 3, 4 or 5.
  • Another aspect of the present invention provides a method for producing the above polyethylene glycol-linker-drug conjugate, comprising the step of reacting the above polyethylene glycol-linker conjugate of the present invention with a drug.
  • the derivative is an active ester, and more preferably, the reactive group of the derivative is an active carbonate group.
  • the derivative has the structure of the above formulae VIII-a to VIII-e.
  • the reactive group of the drug is an amine group, and more preferably a primary amino group.
  • the medicament is a polypeptide and a proteinaceous drug, preferably IL-2, more preferably rhIL-2.
  • the drug is doxorubicin or a derivative thereof, and has the structure of the above formula X of the present invention, preferably doxorubicin, which has the above formula X-1 of the present invention. structure.
  • the polyethylene glycol-linker-drug conjugate is a polyethylene glycol-linker-IL-2 conjugate, and the preparation method thereof comprises the above polyethylene glycol of the present invention. a step of the ligation of the linker conjugate derivative with IL-2.
  • the molar ratio of the polyethylene glycol-linker conjugate derivative to IL-2 is 1-50:1 ( Specifically, it is 1:1, 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1 or 50:1), more preferably 10-30:1.
  • the reaction pH is 6.0-10.0 (specifically, such as 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5). Or 10.0).
  • the reaction temperature is 20-30 ° C, more preferably room temperature.
  • the reaction is carried out in a buffer, and a person skilled in the art can select a suitable buffer type according to the reaction pH used.
  • a suitable buffer type according to the reaction pH used.
  • the phosphate buffer solution, the borate buffer solution or the sodium hydrogencarbonate buffer solution is not specifically limited in the present invention.
  • the method for preparing the polyethylene glycol-linker-IL-2 conjugate further comprises the step of terminating the reaction, and more preferably, the terminating reaction step comprises adding a glycine solution having a concentration of 0.5- 2M (specifically 0.5, 1.0, 1.5 or 2.0M).
  • the terminating reaction step comprises adding a glycine solution having a concentration of 0.5- 2M (specifically 0.5, 1.0, 1.5 or 2.0M).
  • the method for preparing the polyethylene glycol-linker-IL-2 conjugate further comprises the step of isolating and purifying the reaction product.
  • the separation and purification method may employ a combination of one or more of methods commonly used in the art, such as ion exchange column chromatography, reversed-phase high performance liquid chromatography separation, and gel permeation chromatography separation, etc. No specific limitation.
  • the present invention provides a composition of the above polyethylene glycol-linker-drug conjugate comprising at least two polyethylene glycol-linkers of the present invention having different n values. Drug conjugate.
  • At least three of the above-described polyethylene glycol-linker-drug conjugates having different n values of the invention are included in the above composition.
  • the drug in the above composition is a polypeptide and a proteinaceous drug, preferably a cytokine, more preferably IL-2 (such as rhIL-2).
  • the polyethylene glycol-linker-drug conjugate polyethylene glycol-linker-IL-2 conjugate.
  • the composition comprises a polyethylene glycol-linker-IL-2 conjugate having an n value of from 1 to 7.
  • the composition comprises a polyethylene glycol-linker-IL-2 conjugate having an n value of 1-3.
  • the composition comprises a polyethylene glycol-linker-IL-2 conjugate having an n value of 3-5.
  • the composition comprises a polyethylene glycol-linker-IL-2 conjugate having an n value of 4-7.
  • Another aspect of the invention also provides a pharmaceutically acceptable salt, isomer, prodrug or solvate of the above polyethylene glycol-linker-drug conjugate.
  • Another aspect of the present invention provides a polyethylene glycol-linker-drug conjugate as described above, and a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and a pharmaceutically acceptable carrier or additive Pharmaceutical composition.
  • the term "pharmaceutically acceptable” refers to an allergic or similar reaction that is physiologically compatible after administration to a human and does not cause a gastrointestinal disorder, such as dizziness.
  • the additive may be any one of an excipient, a disintegrant, a binder, a lubricant, a suspending agent, a stabilizer, and the like.
  • the excipient include lactose, mannitol, isomalt, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, and the like.
  • the disintegrant include low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, croscarmellose sodium, starch, and the like.
  • binder examples include hydroxypropylcellulose, hypromellose, povidone, copovidone, pregelatinized starch, and the like.
  • lubricant examples include stearic acid, magnesium stearate, sodium fumarate, and the like; examples of the wetting agent include polyoxyethylene sorbitan fatty acid ester, poloxamer, polyoxyethylene hydrazine Sesame oil derivatives and so on.
  • suspending agents include hypromellose, hydroxypropylcellulose, povidone, copovidone, sodium carboxymethylcellulose, methylcellulose, and the like.
  • stabilizer examples include citric acid, fumaric acid, succinic acid, and the like.
  • the pharmaceutical composition of the present invention may further comprise any one of an anti-coagulant, a flavor enhancer, an emulsifier, a preservative, and the like.
  • the pharmaceutical composition of the present invention may be a tablet (including a sugar-coated tablet, a film-coated tablet, a sublingual tablet, an orally disintegrating tablet, an oral tablet, etc.), a pill, a powder, a granule, a capsule.
  • an oral disintegrating film for example, an oral mucosa-adhesive film agent, an injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), an intravenous drip, a transdermal absorption preparation, an ointment, a wash Agent, adhesive preparation, suppository (for example, rectal suppository, vaginal suppository), small pill, nasal preparation, lung preparation (inhalation), eye drops, etc., oral or parenteral preparation (for example, intravenous, intramuscular) , subcutaneous, intra-organ, intranasal, intradermal, instillation, intracerebral, intrarectal, etc., administered to the vicinity of the tumor and directly administered to the lesion).
  • an oral disintegrating film for example, an oral mucosa-adhesive film agent, an injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), an intravenous drip, a transdermal absorption
  • the pharmaceutically acceptable excipients of the present invention are preferably pharmaceutically acceptable injectable excipients, such as isotonic sterile saline solutions (sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, potassium chloride, chlorination). Calcium, magnesium chloride, or the like, or a mixture of the above salts, or the pharmaceutical composition is a dry, for example, freeze-dried composition, which is suitably formed into an injectable solute by the addition of sterile water or physiological saline.
  • injectable excipients such as isotonic sterile saline solutions (sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, potassium chloride, chlorination). Calcium, magnesium chloride, or the like, or a mixture of the above salts, or the pharmaceutical composition is a dry, for example, freeze-dried composition, which is suitably formed into an injectable solute by the addition of sterile water or physiological saline.
  • Another aspect of the present invention also provides the use of the above linker compound, polyethylene glycol-linker conjugate, in the preparation of a polyethylene glycol-linker conjugate derivative.
  • the derivative is an active ester, more preferably an activated carbonate.
  • Another aspect of the present invention also provides the use of the above-described linker compound, polyethylene glycol-linker conjugate and derivatives thereof in modifying a medicament.
  • the use is for the preparation of a polyethylene glycol-linker-drug conjugate; the medicament having the above definition of the invention.
  • the present invention provides a linker compound, a polyethylene glycol-linker conjugate and a derivative thereof, a polyethylene glycol-linker-drug conjugate, a pharmaceutically acceptable salt thereof, and a heterogeneous Use of a body, prodrug or solvate, pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of a disease.
  • the disease is a tumor, an autoimmune disease, a viral disease or a bacterial disease.
  • the tumor disease comprises renal cell carcinoma, melanoma, malignant vascular endothelial cell tumor, cutaneous T cell tumor, ovarian cancer, breast cancer, bladder cancer, lung cancer, glioma, neuroblastoma, liver cancer, hair Cell leukemia, myeloid leukemia, colon cancer, cancerous pleural effusion or non-Hodgkin's lymphoma.
  • the autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome.
  • the virus comprises hepatitis virus, papillomavirus, HSV, HIV, EBv, coronavirus and influenza virus, etc., more preferably hepatitis virus such as HBV or HCV.
  • the bacterial disease is leprosy, tuberculosis or the like.
  • the application is the use of the polyethylene glycol-linker-IL-2 conjugate of the present invention in the preparation of a medicament for enhancing the immune function of a tumor patient after surgery, radiation therapy or chemotherapy.
  • Another aspect of the invention also provides a method of administering the above pharmaceutical composition to an individual.
  • the linker compound provided by the invention and the combination thereof with polyethylene glycol and the derivative thereof can be used for modifying a drug, and the modification reaction is simple, easy to carry out, the reaction yield is high, and the modified drug has a wide application range.
  • the polypeptide and protein drug provided by the invention can be combined with a polyethylene glycol by a non-peptide linker, especially an interleukin (such as interleukin 2), and the drug can be combined with a polyethylene glycol. Degradation and separation from the structure of the conjugate can achieve sustained release and controlled release, reduce the frequency of administration, and greatly improve the bioavailability of the drug and patient compliance.
  • the inventors of the present invention conducted a more in-depth study on the degree of coupling of the conjugate, and obtained a conjugate having a well-coupled degree or a mixture thereof, which is advantageous for optimization of subsequent effects and pharmacological studies.
  • Fig. 1 is a RP-HPLC chromatogram of mPEG-L5-rhIL-2 (20K) prepared in each reaction group of Example 8, and the detection wavelength was 214 nm. From top to bottom are: 1-reaction 1 group, 2-reaction 2 group, 3-reaction 3 group, 4-reaction 4 group, 5-reaction 5 group, 6-reaction group 6 group.
  • Figure 2 is a SEC-MALS spectrum of mPEG-L5-rhIL-2 (20K) prepared in the reaction group 3 of Example 8.
  • Figure 3 is a chromatogram of mPEG-L5-rhIL-2 (20K) prepared by the reaction of Group 3 in Example 8 after cation exchange chromatography.
  • Figure 4 is a RP-HPLC chromatogram of the purified peak of the mPEG-L5-rhIL-2 (20K) prepared in the reaction group 3 of Example 8 and the conjugates collected in each fraction. From top to bottom are: 1-penetration, 2-A8, 3-A7, 4-A6, 5-A5, 6-A4, 7-A3.
  • Figure 5 shows the results of the pharmacodynamic study obtained in Example 14.
  • Figure 6 shows the results of a pharmacodynamic study obtained in Example 23.
  • polypeptide and protein drugs means for prevention, treatment, and Diagnosed polypeptides and proteinaceous materials, wherein the polypeptide is a compound formed by linking alpha-amino acids with peptide bonds, or may be an intermediate product of protein hydrolysis; N polypeptide chains are entangled into a protein according to a certain spatial structure.
  • Peptides and protein drugs can be classified according to their drug structure: amino acids and their derivatives, peptides and protein drugs, enzymes and coenzymes, nucleic acids and their degradants and derivatives, sugars, lipids. Drugs, cell growth factors and other biological products.
  • the IL-2 described in the present invention may be a natural, recombinant protein (e.g., recombinant human interleukin 2) or a mutant having the same function as a native IL-2 (e.g., "recombinant human interleukin-2 (IL-2) mutant clone. And expression and purification in the Pichia pastoris system", Liu Wei, Ph.D. thesis, "IL-2-C125A/L18M/L19S”), also includes tissue culture, protein synthesis, cells Products obtained by culturing (natural, recombinant cells or mutants) methods. Methods for the extraction and isolation of natural, recombinant IL-2 or mutants are well known to those skilled in the art.
  • IL-2 interleukin 2
  • rhIL-2 recombinant human interleukin 2
  • HSV simple herpesvirus
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • EBv human herpesvirus Type 4.
  • the starting materials of the compounds used in the present invention are either commercially available or can be prepared according to the disclosed preparation methods without limiting the scope of the invention.
  • the polyethylene glycol and its derivatives used in the examples were supplied by Beijing Key Kai Technology Co., Ltd., and unless otherwise specified, the molecular weight was 20K. Others are commercially available reagents.
  • Example 2 Synthesis of a combination of monomethoxypolyethylene glycol acetic acid and a linking chain (mPEG-L-40K)
  • the synthetic route of the link L5 is as follows:
  • Example 4 Synthesis of a combination of monomethoxypolyethylene glycol acetic acid and a linking chain (mPEG-L5-NHS-20K)
  • the compound mPEG-L5 (1 g, 0.05 mmol) was added to a reaction flask, dissolved in dichloromethane (6 mL), cooled under N 2 and then succinimide carbonate (19.0 mg, 0.075 mmol) Further, DIPEA (12.9 mg, 0.1 mmol) was added, and after cooling, the cold bath was removed and allowed to react at room temperature overnight. The reaction solution was concentrated, and the residue was crystallized from isopropyl alcohol to give the product mPEG-L5-NHS.
  • Example 4 The preparation method is referred to Example 4.
  • Example 4 The preparation method is referred to Example 4.
  • Example 4 The preparation method is referred to Example 4.
  • mPEG-L5-NHS (20K, prepared in Example 4) stored at -20 ° C was warmed to room temperature under a nitrogen purge.
  • Prepare mPEG-L5-NHS (20K) stock solution (200mg/mL) in DMSO and add it to rhIL-2 solution (reaction grouping, reaction conditions such as reactant mPEG-L5-NHS:rhIL-2 molar ratio (hereinafter referred to as PEG: rhIL-2 molar ratio) and specific reaction pH are shown in Table 1.
  • the final concentration of rhIL-2 in the mixture was 0.5 mg/mL.
  • Sodium bicarbonate buffer (1 M, pH 9.0) was added to the mixture separately to reach a final concentration of 20 mM, and reacted at room temperature for 2 h to provide a conjugate. After 2 h, 1 M glycine (pH 6.0) was added to a final concentration of 100 mM to terminate the reaction.
  • RP-HPLC was used to determine the coupling of different reaction groups after the termination of the reaction system.
  • the coupling efficiency and coupling degree were evaluated according to the migration of the conjugate (the left shift represents the high coupling degree).
  • RP-HPLC spectrum As shown in Fig. 1, it can be seen from Fig. 1 that the coupling degree and the coupling efficiency are all three groups of reactions: 4 groups of reactions > 5 groups of reactions > 2 groups of reactions > 6 groups of reactions > 1 group of reactions. Further, three groups of SEC+MALS analysis reactions were carried out, and the coupling degree was evaluated. The results are shown in Fig. 2.
  • Reaction group 1 Reaction 2 Reaction 3 groups Reaction 4 groups Reaction 5 groups Reaction 6 groups Feeding molar ratio 10:1 20:1 30:1 30:1 30:1 30:1 Reaction pH 9.8 9.8 9.8 8.0 7.2 6.0 Coupling degree 1,2,3 1,2,3 4 ⁇ 7 3 ⁇ 5 1,2,3 1,2,3 proportion ⁇ 90% ⁇ 90% ⁇ 90% ⁇ 70% ⁇ 80%
  • the products obtained in the above table can be divided into three categories: mPEG-L5-rhIL-2 with a coupling degree of 4-7, mPEG-L5-rhIL-2 with a coupling degree of 3-5, and a coupling degree of 1-3.
  • the optimal content of mPEG-L5-rhIL-2 can be controlled to be greater than 90%.
  • reaction-terminated mixture was then separately diluted with purified water to provide a conductivity of less than 0.5 mS/cm (25 ° C).
  • the pH was adjusted to 4.0 using glacial acetic acid and then purified by column chromatography as shown in FIG.
  • PEG was enriched in the breakthrough peak
  • mPEG-L5-rhIL-2 was eluted in 0-50% B (0-0.5 M NaCl gradient). Peaks (A3 to A8) were observed to have a high to low distribution.
  • Example 8 The preparation method is referred to in Example 8.
  • Example 8 The preparation method is referred to in Example 8.
  • Example 8 The preparation method is referred to in Example 8.
  • Example 8 The preparation method is referred to in Example 8.
  • the final concentration of rhIL-2 in the mixture was 0.5 mg/mL.
  • Example 14 Pharmacodynamic study of IL-2 modified by the present invention
  • the PEG was coupled with rIL-2 using the reaction 3 conditions of Example 8.
  • the coupled mixture was purified by ion exchange chromatography, and the conjugate of PEG and rIL-2 was isolated for pharmacodynamic experiments.
  • the tumor suppressing effect of mPEG-L5-rhIL-2 conjugate (hereinafter abbreviated as PEG-rhIL-2) was evaluated using a subcutaneous melanoma B16 model of C57BL/6 mice.
  • the experimental procedure was as follows: Each 5-6 week old C57BL/6 mouse was implanted with 10 6 B16 cells in the middle of the back.
  • mice After tumor growth to measurable size, experimental animals were randomized into groups of 6 rats, and test compounds were administered to mice at different dose concentrations and dosage regimens: rhIL-2, PEG-rhIL-2, and solvent control. Body weight and tumor volume were measured every other day. The pharmacodynamic experiment grouping is shown in Table 2, and the experimental results are shown in Table 3 and Figure 5.
  • the administration day 9 compared to the vehicle control group Tumor volume (1260mm 3), according to the present invention by a modified rhIL-2 group tumor volume (310mm 3) greatly reduced, unmodified rhIL-2 group Compared with the tumor volume (650 mm 3 ), the anti-tumor effect of the mPEG-L5-rhIL-2 group modified by the present invention was increased by 27%, and the frequency of administration was greatly reduced, and the anti-tumor drug has a reduced frequency of administration, Greatly improve the bioavailability of drugs and the advantages of patient compliance.
  • the compound was added to 4arm-PEG-L3 (2g, 0.1mmol, prepared in Example 18) the reaction flask, was dissolved with dichloromethane (40 mL), cooled under N 2, was added succinimidyl carbonate (1.02 g of, 0.4 mmol), after stirring and stirring, triethylamine (60.6 mg, 0.6 mmol) was added. After the addition, the cold bath was removed and allowed to react at room temperature overnight. The reaction solution was concentrated, and the residue was crystallized from isopropyl alcohol to give the product 4arm-PEG-L3-NHS (20K) 1.8 g, yield 90.0%.
  • 8-arm-PEG-N 3 (20K, 2g, 0.1mmol), compound L4 (prepared by the method described in Chinese patent application CN201510354709.6, 220mg, 1mmol), vitamin C (440mg, 2.5mmol), added to N, In N-dimethylformamide (20 mL), it was dissolved by rapid stirring, then an aqueous solution of copper sulfate pentahydrate (250 mg, 1 mmol) (4.4 mL, 2.2 mL/g PEG) was added and allowed to react overnight at room temperature with isopropanol. The precipitate gave 1.8 g of product.
  • the compound was cooled under 8arm-PEG-L4-NHS ( 20K, 1.5g, 0.075mmol, prepared in Example 20) was dissolved in dichloromethane (30mL) in, N 2 protection, was added diisopropylethyl amine (77.5 mg , 0.6 mmol), after stirring evenly, doxorubicin hydrochloride (261 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was crystallised from isopropyl alcohol, filtered, and dried to give a red solid product of 8 ⁇ / RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ RTIgt;
  • the compound 4arm PEG-NHS (1 g, 0.05 mmol, obtained in the above step) was added to a reaction flask, dissolved in dichloromethane (20 mL), cooled under N 2 and added to diisopropylethylamine. Further, doxorubicin hydrochloride (348.8 mg, 0.3 mmol) was added, and the reaction was allowed to proceed overnight at room temperature after the addition. The reaction mixture was concentrated, and the residue was crystallised from isopropyl alcohol, filtered, and dried to give a brown brown solid product 4arm PEG-L5-Dox (0.84 g, 84%).
  • Example 23 Tumor growth inhibition study in a mouse model of HCT116 tumor ectopic transplantation
  • the tumor growth inhibition effect of the drug on the HCT116 tumor ectopic transplantation mouse model was examined.
  • G2 positive drug doxorubicin (commercially available).
  • G3 4arm PEG-L5-Dox (prepared in Example 22).
  • HCT116 cells (commercially available)
  • the original culture solution was aspirated, and 10 mL of fresh culture solution was added.
  • Cells were harvested and passaged when the cells reached ⁇ 90% confluence.
  • After removing the culture solution add 10 mL EDTA/PBS solution, leave it at room temperature for 5 min, aspirate the EDTA/PBS solution, and mix 3 mL of 0.25 c/o trypsin (37 ° C) on the cell surface, then immediately aspirate and no
  • the culture flask of the medium was placed in the incubator until the cells were separated from the wall of the culture flask (5 min).
  • the cells were counted by counting plates and diluted with 10% FBS in DMEM, and 40 mL of the cell suspension was transferred to a 150 mm cell culture dish, which was then placed in an incubator. Change the liquid every other day, when the cells reach ⁇ 80% confluence and pass the passage, the subculture method is the same as above.
  • the cells were examined to reach ⁇ 80% confluence and the cells were changed in advance. After 3 hours, remove the culture solution with a pipette, add 20 mL of EDTA/PBS solution to each dish, leave it at room temperature for 5 min, aspirate EDTA/PBS solution, and mix 3 mL of 0.25 c/o trypsin (37 ° C) on the cells. The surface was then immediately aspirated and the medium-free flask was placed in the incubator until the cells were separated from the flask wall (5 min). Add 20 mL of DMEM containing 10% FBS and gently pipette to mix the cells. Transfer the cell suspension. Centrifuge the tube at room temperature for 5 min.
  • HCT116 cells were inoculated subcutaneously into the right anterior humerus, and each animal was inoculated with 200 ⁇ L of PBS cell suspension. A total of 30 animals were inoculated. The tumor volume was measured twice a week after inoculation. When the average tumor volume reached 100-200 mm 3 , 18 tumors were selected to be close in size. Animals were randomly divided into 3 groups of 6 animals each. Dosing was started within 24 hours after grouping, and the body weight of the animals was weighed before each administration to adjust the dose. The animals were continuously observed after the last administration, and the body weight and tumor size were measured twice a week.
  • the average volume of tumors in a certain group of animals was greater than 2000 mm 3 , that is, the animals were sacrificed. Differences in tumor size between groups will be compared using the t test, and P ⁇ 0.05 will be considered as a statistically significant difference.
  • the experimental results are shown in Figure 6.
  • the positive drug doxorubicin and the compound 4armPEG-L5-Dox have significant anti-tumor effects, and the compound 4arm PEG-L5-Dox is better than doxorubicin, and with the administration The time is prolonged, and the effect gap is gradually increased. This is likely to be related to the compound 4arm PEG-L5-Dox, which uses polyethylene glycol as a carrier to allow the drug to stay in the tumor for a longer period of time and achieve sustained release and controlled release. related.
  • the weight loss of the animal during administration is acceptable and the compound has further research value.
  • the "degree of coupling” as used in the examples of the present invention means the number of PEG molecules coupled on each IL-2 molecule (i.e., the value of n described in the formula IX in the present invention), for example, the degree of coupling is 4 mPEG-L5-rhIL-2 refers to the coupling of 4 mPEG-L5 segments on each rhIL-2 molecule; mPEG-L5-rhIL-2 with a coupling degree of 4-7, which means coupling mPEG-L5-rhIL-2 with degree 4, mPEG-L5-rhIL-2 with coupling degree of 5, mPEG-L5-rhIL-2 with coupling degree of 6, and mPEG-L5- with coupling degree of 7 a mixture of rhIL-2.

Abstract

La présente invention concerne un composé de lieur, un conjugué polyéthylène glycol-lieur et un dérivé de celui-ci, et un conjugué polyéthylène glycol-lieur-médicament. Le composé de lieur et le conjugué polyéthylène glycol et un dérivé de celui-ci peuvent être utilisés pour une modification de médicament, et la réaction de modification est simple et facile à mettre en oeuvre et a un rendement de réaction élevé, et les médicaments modifiés ont une large gamme d'applications. Les médicaments modifiés se dégradent progressivement à partir d'une chaîne conjuguée dans le corps, et peuvent rester dans une lésion (telle qu'un site cancéreux) pendant une plus longue période de temps, ce qui permet d'obtenir une libération prolongée et contrôlée, de réduire la fréquence d'administration, et d'améliorer considérablement la biodisponibilité des médicaments et l'observance médicamenteuse des patients.
PCT/CN2018/106972 2017-09-30 2018-09-21 Composé de lieur, conjugué polyéthylène glycol-lieur et dérivé de celui-ci, et conjugué polyéthylène glycol-lieur-médicament WO2019062665A1 (fr)

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CN201810186781.6 2018-03-07
CN201811043884.3A CN109589415B (zh) 2017-09-30 2018-09-07 一种聚乙二醇-多肽和蛋白类药物的结合物
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CN101104077A (zh) * 2006-07-12 2008-01-16 北京紫辰医药生物技术研究所 重组人白介素-2与聚乙二醇的偶合物
CN101104078A (zh) * 2006-07-11 2008-01-16 北京美倍他药物研究有限公司 多肽及蛋白药物的聚乙二醇偶合物
CN102448494A (zh) * 2009-02-13 2012-05-09 免疫医疗公司 具有胞内可裂解的键的免疫共轭物
CN103083680A (zh) * 2011-11-07 2013-05-08 北京键凯科技有限公司 聚乙二醇-氨基酸寡肽-依诺替康药物结合物及其药物组合物

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US6180095B1 (en) * 1997-12-17 2001-01-30 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
WO2006116948A1 (fr) * 2005-04-30 2006-11-09 Chengdu Institute Of Biological Products Conjugue de polyethylene glycol et d’interleukine-6 et son procede de preparation et son utilisation
CN103965458B (zh) * 2013-01-28 2017-02-15 天津键凯科技有限公司 聚乙二醇‑氨基酸寡肽‑达沙替尼结合物及其药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101104078A (zh) * 2006-07-11 2008-01-16 北京美倍他药物研究有限公司 多肽及蛋白药物的聚乙二醇偶合物
CN101104077A (zh) * 2006-07-12 2008-01-16 北京紫辰医药生物技术研究所 重组人白介素-2与聚乙二醇的偶合物
CN102448494A (zh) * 2009-02-13 2012-05-09 免疫医疗公司 具有胞内可裂解的键的免疫共轭物
CN103083680A (zh) * 2011-11-07 2013-05-08 北京键凯科技有限公司 聚乙二醇-氨基酸寡肽-依诺替康药物结合物及其药物组合物

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