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WO2014114262A1 - Combinaison médicale polymère hydrosoluble-oligopeptide d'acides aminés, procédé de préparation associé, et utilisation associée - Google Patents

Combinaison médicale polymère hydrosoluble-oligopeptide d'acides aminés, procédé de préparation associé, et utilisation associée Download PDF

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Publication number
WO2014114262A1
WO2014114262A1 PCT/CN2014/071395 CN2014071395W WO2014114262A1 WO 2014114262 A1 WO2014114262 A1 WO 2014114262A1 CN 2014071395 W CN2014071395 W CN 2014071395W WO 2014114262 A1 WO2014114262 A1 WO 2014114262A1
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group
cancer
acid
conjugate
tumor
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PCT/CN2014/071395
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English (en)
Chinese (zh)
Inventor
汪进良
赵宣
王振国
冯泽旺
贾健欢
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天津键凯科技有限公司
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Priority claimed from CN201310241907.2A external-priority patent/CN103965458B/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
Priority to US14/764,166 priority Critical patent/US9700633B2/en
Publication of WO2014114262A1 publication Critical patent/WO2014114262A1/fr

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    • 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
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present application provides a water-soluble polymer-amino acid oligopeptide-drug conjugate and a pharmaceutical composition thereof, and a preparation method and use of the conjugate and the pharmaceutical composition.
  • the conjugate increases the therapeutic effect of the drug on the disease by increasing the drug loading of the active drug.
  • the stability of the combination is also greatly improved.
  • the present invention provides a water-soluble polymer-amino acid oligopeptide-drug combination having The structure shown by the following formula (I),
  • P is a water soluble polymer
  • X is a linking group, the linking group linking P and A 1 ;
  • ALA 2 and A 3 are each independently the same or different amino acid or amino acid analog residues
  • Di and D 2 are each independently the same or different drug molecule residues
  • a is 0 or 1
  • b is an integer from 2 to 12;
  • c is an integer from 0 to 7;
  • d is 0 or 1.
  • P is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyglutamic acid, polyaspartic acid, polyvinylpyrrolidone, polyvinyl alcohol, polypropylene morpholine, Dextran, carboxymethylcellulose and analogues or copolymers thereof.
  • P is polyethylene glycol
  • the polyethylene glycol has a molecular weight of 300-60,000.
  • the polyethylene glycol has a molecular weight of 20,000-40. 000.
  • the polyethylene glycol has a molecular weight of 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000.
  • the polyethylene glycol is a linear, Y-branched or multi-branched polyethylene glycol.
  • the polyethylene glycol has a structure represented by the following formula ( ⁇ ),
  • ⁇ is alkyl with 12, 12 D_ embankment heteroaryl group, or aryl alkyl with hydrogen, e is an integer of 10-1,500.
  • P has the structure shown by the following formula ( ⁇ ), (m)
  • R 2 and R 3 are each independently d— 12 fluorenyl, d— 12 heterofluorenyl, hydrogen, aryl fluorenyl;
  • R 4 and R 5 are each independently a C 1-12 fluorenyl group, a C 1-12 fluorenylcarbonyl group;
  • f and g are each independently an integer of from 10 to 1,500.
  • R 2 , R 3 in formula (III) are cyclopropyl, cyclobutyl, cyclohexyl
  • R 2 , R 3 in formula (III) are methyl, F is ethyl, and R 5 is
  • P has the structure shown by formula (IV) below,
  • R 6 is a residue of a hydroxyl group of pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerol or polyglycerol to remove hydrogen; i is 3, 4, 6 or 8; h is 10-1,500 The integer.
  • X is (CH 2 ) n , (CH 2 ) n CO, (CH 2 ) n OCO, (CH 2 ) n NHCO, -S -, -S0 2 -, -SO4 -; n is an integer from 1-12. In certain embodiments, X is CH 2 CO.
  • 1 is an amino acid or amino acid analog residue having at least two carboxylic acid groups and one amino group.
  • R 7 is a Cwo fluorenyl group or a Cwo heterofluorenyl group.
  • R 7 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, Cu embankment group, C 12 embankment Gan Gan ⁇ ⁇ Gan ⁇ Gan ⁇ Gan ⁇ Gan Lane, o ⁇ ⁇ 4 ⁇ Lane, i5 ⁇ lis ⁇ Lane, n ⁇ Lane, lis ⁇ Lane, ⁇ 9 ⁇ Lane, C 20 ⁇ base.
  • the carbonyl group in the formula (V) may be bonded to any one of the carbons of R 7 .
  • R 7 is a linear fluorenyl or heteroindolyl group.
  • R 7 is a branched indenyl or heteroindolyl. In certain embodiments, having the structure shown by the following formula (VI), (VI)
  • R 8 and R 9 are independently hydrogen, d — 12 fluorenyl, d— 12 heterofluorenyl, aryl, heteroaryl, aryl fluorenyl, heteroaryl fluorenyl, and are present in each repeating unit.
  • R 8 and R 9 may be the same or different; j is an integer of 1-10.
  • a 2 and A 3 independently have the structure shown by the following formula (VII), (VII)
  • R 1Q and R u are independently hydrogen, d 6 fluorenyl, d 6 heterofluorenyl, and R 1 ( ) , Ru in each repeating unit may be the same or different; h is 1-10 Integer.
  • R 10 , Ru are independently methyl, ethyl, propyl, butyl, pentyl, hexyl.
  • R 10 , Ru are independently linear fluorenyl or heteroindolyl.
  • R 1Q , Ru are independently branched Sulfhydryl or heteropoly.
  • a 2 , A 3 are independently glycine, alanine, leucine, isoleucine, valine, valine, phenylalanine, methionine, serine, Residues of threonine, cysteine and tyrosine. In certain embodiments, A 2 , A 3 are proline.
  • 0 1 and 1 ⁇ 4 are each independently a residue of an anti-tumor drug.
  • the residues can be antineoplastic agents or A 2 and A 3 form a peptide bond or an ester bond.
  • the anti-tumor drug is capable of forming a peptide bond or an ester bond with 2 or 3 by modification.
  • the anti-tumor drug is dasatinib, rapamycin, irinotecan, imatinib, erlotinib, gefitinib, lapatinib, sorafenib , sunitinib, paclitaxel, camptothecin, scutellaria, glycyrrhetinic acid, sorghum lactone.
  • the anti-tumor drug is dasatinib.
  • the present application provides a conjugate having the structure shown by formula (VIII) below,
  • R 7 is a C ⁇ o fluorenyl group.
  • Ru is independently hydrogen, d 6 fluorenyl and R 1Q , Ru in each repeating unit may be the same or different; h is an integer of 1-10.
  • P, X, a, b, c, d, Di, D 2 are as described above.
  • the present application provides a combination having the structure shown by the following formulas (IX), (X), (XI), c
  • e, f, and g are each independently an integer of from 10 to 1,500. As mentioned above.
  • the present application provides a pharmaceutical composition comprising the above combination and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is a tablet, a capsule, a pill, a granule, a dispersion Agents, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, sprays.
  • the present application provides a medicament for the preparation of an anti-tumor, fungal infection, rheumatoid arthritis, multiple sclerosis, heart stenosis or pneumonia in the above combination and/or pharmaceutical composition. Application in .
  • the anti-tumor drug is applied to the following conditions: leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, myelodysplasia, multiple Myeloma, Hodgkin's disease or non-Hodgkin's disease, small cell or non-small cell lung cancer, gastric cancer, colon cancer, esophageal cancer, colorectal cancer, prostate cancer, ovarian cancer, breast cancer, brain cancer, urinary Cancer, kidney cancer, bladder cancer, malignant melanoma, liver cancer, uterine cancer, pancreatic cancer, myeloma, endometrial cancer, head and neck cancer, pediatric tumor, sarcoma.
  • the present application provides a method of treating a tumor, a fungal infection, rheumatoid arthritis, multiple sclerosis, heart valve restenosis, or pneumonia in a subject, comprising administering to the subject An effective amount of the above combination or pharmaceutical composition.
  • the subject is a mammal. In certain embodiments, the subject is a human.
  • the above-described modes of administration of the combination and/or pharmaceutical composition include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cerebral, vaginal, peritoneal, bladder, Nasal administration.
  • the present application provides a method of preparing the above-described combination, comprising:
  • Figure 1 shows the degradation of compound DSR1-6 in 0.01 M PBS buffer.
  • DSR-1 is mPEG-dipeptide acid-dasatinib (20 ng
  • DSR-2 is mPEG-dipeptide glycine-dasatinib (20K)
  • DSR-3 is mPEG-dipeptide alanine- Dasatinib (20K)
  • DSR-4 is mPEG-dipeptide valine-dasatinib (20 ⁇ )
  • DSR-5 is ⁇ -PEG-dipeptide valine-dasatinib ( 30K)
  • DSR-6 is mPEG-tripeptide valine-dasatinib (40 ⁇ ).
  • the water-soluble polymer-amino acid oligopeptide-drug combination of the present invention has a structure represented by the following formula (I),
  • P is a water-soluble polymer
  • X is a linking group, and the linking group is bonded to P and
  • a A ; AA 2 and A 3 are each independently the same or different amino acid or amino acid analog residues; and D 2 are each independently the same or different drug molecule residues; a is 0 or 1; b is 2- An integer of 12; c is an integer from 0 to 7; d is 0 or 1.
  • a water-soluble polymer refers to a polymer formed by linking a compound containing a polar or charged functional group, which is soluble in water, that is, hydrophilic.
  • Water-soluble polymers include, but are not limited to: polyethylene glycol, polypropylene glycol, polyglutamic acid, polyaspartic acid, polyvinylpyrrolidone, polyvinyl alcohol, polypropylene morpholine, dextran, carboxymethyl Cellulose and its analogues or copolymers.
  • P is polyethylene glycol
  • the polyethylene glycol has a molecular weight of from 300 to 60,000.
  • the polyethylene glycol has a molecular weight of from 20,000 to 40,000.
  • the polyethylene glycol has a molecular weight of 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000.
  • the polyethylene glycol is a linear, Y-branched or multi-branched polyethylene glycol.
  • the polyethylene glycol has a structure represented by the following formula ( ⁇ ),
  • the 12 fluorenyl group, the 12 hydrazinyl group, the hydrogen or the aryl fluorenyl group, and e is an integer of from 10 to 1,500.
  • e is an integer from 100 to 1,400.
  • e is an integer from 200 to 1,300.
  • e is an integer from 300 to 1,200.
  • e is an integer from 400 to 1,100.
  • e is an integer from 500 to 1,000.
  • e is 600, 700, 800, 900 or 1,000.
  • ⁇ is. ⁇ . ⁇ . More preferably, it is _ 8 fluorenyl. More preferably, it is _ 6 fluorenyl.
  • ⁇ is ⁇ ⁇ base. More preferably, ⁇ is d_ 4 fluorenyl. More preferably, h is the embankment d_ 3-yl. More preferably, R is a Cw fluorenyl group. In certain embodiments, it is methyl, ethyl, propyl, butyl, pentyl.
  • P has a structure represented by the following formula ( ⁇ ), (m)
  • R 2 and R 3 are each independently d— 12 fluorenyl, d— 12 heterofluorenyl, hydrogen, aryl fluorenyl; preferably, R 2 and R 3 are each independently Cw. ⁇ . More preferably, R 2 and R 3 are each independently a d 8 fluorenyl group. More preferably, R 2 and R 3 are each independently a d 6 fluorenyl group. More preferably, R 2 and R 3 are each independently a d 5 fluorenyl group. More preferably, R 2 and R 3 are each independently a d 4 fluorenyl group. More preferably, R 2 and R 3 are each independently a d 3 fluorenyl group. More preferably, R 2 and R 3 are each independently a d 2 fluorenyl group. In certain embodiments, R 2 and R 3 are each independently methyl, ethyl, propyl, butyl, pentyl.
  • R 4 and R 5 are each independently a Cw 2 fluorenyl group and a C 2 fluorenylcarbonyl group.
  • R 4 and R 5 are each independently a Cwo fluorenyl group, a Cwo fluorenylcarbonyl group.
  • R 5 is independently d_ 8 fluorenyl, d 8 fluorenylcarbonyl.
  • R 5 is independently d- 6 fluorenyl, d 6 fluorenylcarbonyl.
  • R 4 and R 5 are each independently a d 5 fluorenyl group, a d 5 fluorenylcarbonyl group.
  • R 4 and R 5 are each independently a d 4 fluorenyl group, a d 4 fluorenylcarbonyl group. More preferably, R 4 and R 5 are each independently a d 3 fluorenyl group, a d 3 fluorenylcarbonyl group. More preferably, R 5 is independently d— 2 fluorenyl, d 2 fluorenylcarbonyl.
  • f and g are each independently an integer of from 10 to 1,500. In certain embodiments, f, g are each independently an integer from 100 to 1,400. In certain embodiments, f, g are each independently an integer from 200 to 1,300. In certain embodiments, f, g are each independently an integer from 300 to 1,200. In some embodiments, f and g are each independently an integer from 400 to 1,100. In certain embodiments, f, g are each independently an integer from 500 to 1,000. In certain embodiments, f, g are each independently 600, 700, 800, 900 or 1,000.
  • R 2 , R 3 in formula (III) are independently cyclopropyl, cyclobutyl, cyclohexyl or benzyl. In certain embodiments, R 2 , R 3 in formula (III) are methyl, ethyl, and R 5 is methylcarbonyl.
  • P has the structure shown by formula (IV) below, Formula (IV)
  • R 6 is a residue at which a hydroxyl group of pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerol or polyglycerol removes hydrogen; i is 3, 4, 6 or 8; h is 10-1,500 Integer.
  • h is an integer from 100 to 1,400.
  • h is an integer from 200 to 1,300.
  • h is an integer from 300 to 1,200.
  • h is an integer from 400 to 1,100.
  • h is an integer from 500 to 1,000.
  • h is 600, 700, 800, 900 or 1,000.
  • the linking group X in the formula (I) means a group which functions as a linking between the hydrophilic polymer and the amino acid oligopeptide. In certain embodiments, the linking group is introduced to modify the hydrophilic polymer to better attach to the amino acid oligopeptide.
  • X is (CH 2 ) n , (CH 2 ) n CO, (CH 2 ) n OCO, (CH 2 ) n NHCO, -S -, -S0 2 -, -S0 4 -; n is an integer from 1-12.
  • n is 1-6.
  • n is 1-3.
  • n is 1-2.
  • X is CH 2 CO.
  • amino acid or amino acid analog residues in formula (I) may comprise at least one amino group and one carboxylic acid group.
  • a 1 is an amino acid or amino acid analog residue having at least two carboxylic acid groups and one amino group.
  • R 7 is d_ 2 . ⁇ base, d_ 2 . Clay base.
  • ⁇ is -1() thiol, Cw. Clay base.
  • R 7 is d- 9 ⁇ , d- 9 heteroalkyl.
  • R 7 is an indenyl, d- 8 heterofluorenyl.
  • R 7 is d- 7 ⁇ , C ⁇ hetero.
  • R 7 is d- 6 fluorenyl, d- 6 heteropoly.
  • R 7 is d — 5 fluorenyl, d — 5 heterofluorenyl.
  • R 7 is d 4 alkyl, d 4 heteroaryl. In certain embodiments, R 7 is d — 3 fluorenyl, d — 3 heterofluorenyl. In certain embodiments, R 7 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, Cu
  • R 7 is a linear fluorenyl or heteroindolyl group. In certain embodiments, R 7 is a branched indenyl or heteroindolyl.
  • R 8 and R 9 are independently hydrogen, d — 12 fluorenyl, d— 12 heterofluorenyl, aryl, heteroaryl, aryl fluorenyl, heteroaryl fluorenyl, and in each repeating unit.
  • R 8 and R 9 may be the same or different; j is an integer of 1-10. In certain embodiments, j is an integer from 1 to 10. In certain embodiments, j is an integer from 1-9. In certain embodiments, j is an integer from 1-8. In certain embodiments, j is an integer from 1-7. In certain embodiments, j is an integer from 1 to 6. In certain embodiments, j is an integer from 1 to 5. In certain embodiments, j is an integer from 1 to 4. In certain embodiments, j is an integer from 1 to 3. In certain embodiments, j is an integer from 1 to 2.
  • 1 is a residue of aspartic acid or glutamic acid.
  • a 2 and A 3 in the formula (I) may independently be any amino acid or amino acid analog residue, and the amino acid or amino acid analog residue contains at least one amino group and one carboxylic acid group.
  • a 2 and A 3 independently have the structure shown by the following formula (VII), Formula (VII)
  • R 1Q and R u are independently hydrogen, d 6 fluorenyl, d 6 heterofluorenyl, and R 1 ( ) , Ru in each repeating unit may be the same or different; h is 1-10 Integer.
  • R 10 , Ru are independently methyl, ethyl, propyl, butyl, pentyl, hexyl.
  • R 10 , Ru are independently linear fluorenyl or heteroindolyl.
  • R 1Q , Ru is independently branched fluorenyl or heterofluorenyl.
  • h is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.
  • a 2 , A 3 are independently glycine, alanine, leucine, isoleucine, valine, valine, phenylalanine, methionine, serine, Residues of threonine, cysteine and tyrosine.
  • the pharmaceutical compound in the water-soluble polymer-amino acid oligopeptide-drug conjugate of the present invention includes any drug molecule which can bind to an amino acid or an amino acid analog.
  • a drug molecule that can bind to an amino acid or amino acid analog comprises a functional group such as an amino group, a hydroxyl group, a phenol group, a thio group or a thiol group.
  • Examples of drug molecules containing an amino group, a hydroxyl group, a phenol group, a thiol group or a thiol group include, but are not limited to, acetaminophen, acyclovir ⁇ 2-amino-1,9-dihydro-9-[(2- Hydroxyethoxy)methyl] 6H-indol-6-one ⁇ , allopurinol, adenosine (6-amino-9-i3-D-furonucleoside nitrosourea-9-H-indole), dehydrocortic (retained) alcohol, prednisone, triamcinolone acetonide, cortisone (hydrocortisone), adenosine (6-amino-9- ⁇ -indole-furan nitrosourea-9-H- ⁇ ), Pine, estradiol, estrogen, estriol, 16-hydroxyestrene, equine estradiol, equine estrone,
  • a drug molecule that can bind to an amino acid or amino acid analog comprises a carboxyl group or a phosphate group/phosphonic acid group.
  • drug molecules containing a carboxyl group include, but are not limited to, mesalic acid, aminosalicylic acid, mesalic acid, aminosalicylic acid, baclofen, carbidopa, levodopa, aminobenzoic acid, bumami Tani, captopril [l-[(2S)-3-mercapto-2-methylpropionyl]-L-valine], cilastatin [(2)-7-[[( 3 ) -2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxamide]-2-heptanoic acid], levothyroxine [D-3, 5, 3', 5'-tetraiodothyronine], amphotericin B, etret
  • 0 1 and 126 are each independently a residue of an anti-tumor drug.
  • the residues can be antineoplastic agents or A 2 and A 3 form a peptide bond or an ester bond.
  • the antitumor agent can be modified by a peptide bond or an ester bond with A 2 or A 3 is formed.
  • the anti-tumor drug is dasatinib, rapamycin, irinotecan, imatinib, erlotinib, gefitinib, lapatinib, sorafenib , sunitinib, paclitaxel, camptothecin, scutellaria, glycyrrhetinic acid, sorghum lactone.
  • the present application provides a conjugate having the structure shown by formula (VIII) below,
  • R 1( ) , R u are independently hydrogen, d 6 fluorenyl and R 10 , Rii in each repeating unit may be the same or different; h is an integer from 1 to 10.
  • R 7 , P, X, a, b, c, d, D 2 are as described above.
  • the present application provides a combination having the structure shown by the following formulas (IX), (X), (XI), Formula (IX)
  • e, f, and g are each independently an integer of from 10 to 1,500.
  • e, f, g are each independently an integer from 100 to 1,400.
  • e, f, g are each independently an integer from 200 to 1,300.
  • e, f, g are each independently an integer from 300 to 1,200.
  • e, f, g are each independently an integer from 400 to 1,100.
  • e, f, g are each independently an integer from 500 to 1,000.
  • e, f, g are each independently 600, 700, 800, 900 or 1,000. As mentioned above. In one embodiment, it is dasatinib.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a _ b ) fluorenyl group means any fluorenyl group containing "a" to "b" carbon atoms.
  • (d_ 6 ) fluorenyl refers to a fluorenyl group containing from one to six carbon atoms.
  • the thiol group is branched or linear.
  • Negoxy refers to a straight or branched, monovalent, saturated aliphatic chain bonded to an oxygen atom, including but not limited to, for example, methoxy, ethoxy, propoxy, Butoxy, isobutoxy, tert-butoxy and other similar groups.
  • Mercapto refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Pentyl, isopentyl, hexyl and the like.
  • Heteropoly means that one or more carbon atoms in the above fluorenyl group have been replaced by a hetero atom such as nitrogen, oxygen or sulfur. If the heterocyclic group contains more than one heteroatom, these heteroatoms may be the same or different.
  • Alkenyl means a straight or branched hydrocarbon bearing one or more double bonds including, but not limited to, vinyl, propenyl, and the like.
  • Aryl means a cyclic aromatic hydrocarbon including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl and the like.
  • Cycloalkyl refers to a saturated monocyclic or polycyclic indenyl group, possibly fused to an aromatic hydrocarbon group. Cyclodecyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
  • Aryl fluorenyl means a group to which the above aryl group is covalently bonded to the above thiol group, such as, but not limited to, phenylmethyl, phenylethyl, phenylpropyl.
  • Heteroaryl means a monocyclic or polycyclic aromatic hydrocarbon in which one or more carbon atoms have been replaced by a hetero atom such as nitrogen, oxygen or sulfur. If a heteroaryl contains more than one heteroatom, these heteroatoms may be the same or different.
  • Heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furyl, imidazolyl, oxazolyl, Pyridazinyl, fluorenyl, isobenzofuranyl, isodecyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, Pyridazinyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b]decyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizine A quinolyl group, a quinolyl group, a
  • One cyclic group can be bonded to another group in a variety of ways. If the bonding method is not explicitly defined, it means that all possible ways are included. For example, “pyridyl” includes 2-, 3-, or 4-pyridyl, and “thienyl” includes 2- or 3-thienyl.
  • amino acid analog means an organic compound having a structure similar to that of an amino acid containing at least one amino group and at least one carboxyl group.
  • conjugates of the present invention can be synthesized according to the following scheme. This procedure is illustrative only and not limiting of other ways in which the combination may be made. In addition, the steps in the scheme are only for better description of the preparation method of the combination of the present invention, and the steps can be modified without departing from the scope of the invention described herein.
  • a method of preparing a water soluble polymer-amino acid oligopeptide-drug conjugate comprising:
  • the hydrophilic polymer P is linked to an amino acid via a linking group X to obtain a conjugate
  • the drug compound 0 1 is reacted with the amino acid A 2 to give the conjugate DA 2 .
  • drug compound 02 is reacted with an amino acid A 3 was obtained in conjunction with D 2 -A 3.
  • the hydrophilic polymer can be modified to introduce a reactive functional group that is bonded to the amino acid oligopeptide.
  • the introduction of a reactive functional group is achieved by a linking group X.
  • the reactive functional group introduced is a carboxylic acid group.
  • the conjugates can be formed DA 2 and / or D 2 -A 3 with an active functional group on the drug compound with an amino acid A 3 or A 2 reaction.
  • the reactive functional group on the drug compound can be a hydroxyl group, an amino group.
  • the drug compound and the amino acid are esterified or amidated.
  • the amides Di-As and I or D 2 -A 3 are amidated with the compound P_ ⁇ X ⁇ A1 to give a compound of formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a water-soluble polymer-amino acid oligopeptide-drug complex and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or potting.
  • a pharmaceutically acceptable substance such as a liquid or solid filler, diluent, excipient, solvent or potting.
  • the pharmaceutically acceptable carrier can be a medium, diluent, excipient or other material which is not excessively toxic or side effects and which can be used to contact animal tissues.
  • Typical pharmaceutically acceptable carriers include sugars, starches, cellulosics, maltose, tragacanth, gelatin, Ringer's solution, alginic acid, physiological saline, buffers and the like.
  • Each pharmaceutically acceptable carrier should be compatible with the other ingredients, for example, with the conjugates provided herein, without excessive toxicity, irritation, allergic response, immunogen to biological living tissue or organs. Sexual or other problems or complications, and a reasonable ratio of benefits to risks.
  • Some pharmaceutically acceptable carrier materials include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives, such as Sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; (4) scutellaria powder; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa Fats and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols, such as Glycerin, sorbitol, mannitol and polyethylene glycol; (12) lipids such as ethyl oleate, ethyl laurate; (13) agarose; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) starches
  • the pharmaceutical composition may include pharmaceutically acceptable excipients to mimic physiological conditions such as pH adjustment and buffering agents, toxicity modulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate Wait.
  • pharmaceutically acceptable excipients to mimic physiological conditions such as pH adjustment and buffering agents, toxicity modulators, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate Wait.
  • the pharmaceutical ingredient can be formulated into any suitable dosage form, such as a solid dosage form (e.g., tablets, capsules, powders, granules, etc.) and a liquid dosage form (e.g., aqueous solution, emulsion, elixirs, syrup, etc.).
  • a solid dosage form e.g., tablets, capsules, powders, granules, etc.
  • a liquid dosage form e.g., aqueous solution, emulsion, elixirs, syrup, etc.
  • Processes for the preparation of pharmaceutical compositions are well known and can be prepared according to conventional procedures, such as those found in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).
  • the compounds or pharmaceutical compositions provided herein can be formulated into a dosage form suitable for drug delivery, such as subcutaneous, intravenous, intramuscular, arterial, sheath, vesicles.
  • a dosage form suitable for drug delivery such as subcutaneous, intravenous, intramuscular, arterial, sheath, vesicles.
  • non-injectable routes eg, oral, intestinal, oral, nasal, intranasal, mucosal, epidermal, plaster, dermis, eye drops, lungs, tongue Subcutaneous, rectal, vaginal or epidermal administration).
  • Suitable dosage forms include, but are not limited to, dosage forms for injection use such as emulsions, solutions and suspensions, and dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, topical or topical Formulations for skin absorption such as sprays, ointments, pastes, creams, lotions, gels, solutions, drug patches and inhalants, vaginal or rectal administration such as suppositories.
  • These dosage forms can be prepared according to the compound and suitable excipients under suitable conditions, and are well known, for example, by Remington: in The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000) ) provided.
  • One aspect of the invention is to increase the water solubility of a drug molecule by modification of a hydrophilic polymer, thereby prolonging the half-life of the drug.
  • the pharmaceutically active amount of the conjugate is increased as compared to the unmodified drug molecule, the drug loading, drug activity, stability, and water solubility.
  • Another aspect of the invention is to increase the stability of a drug conjugate by an amino acid oligopeptide, thereby reducing toxic side effects.
  • the increase in stability of the drug conjugate is achieved by selection of a suitable amino acid oligopeptide.
  • the pharmaceutical composition to increase the stability of the binding by selecting a suitable amino acid residue in combination with a pharmaceutical compound, i.e., the amino acid of formula A (I) 2 A 3, or implemented.
  • the amino acid residue bound to the drug compound is a proline residue.
  • the toxicity of the combination is reduced.
  • the conjugate further enhances the clinical effectiveness of the drug.
  • each hydrophilic polymer can be linked to a plurality of drug compounds by an amino acid oligopeptide, thereby greatly increasing the drug loading rate.
  • each hydrophilic polymer can be attached to at least two pharmaceutical compounds.
  • each The hydrophilic polymer can be attached to at least three drug compounds.
  • each hydrophilic polymer can be attached to at least four pharmaceutical compounds.
  • Another aspect of the invention provides the use of the above conjugates and/or pharmaceutical compositions for the preparation of a medicament and for the treatment of a disease.
  • the present invention provides a medicament for the preparation of an antitumor, fungal infection, rheumatoid arthritis, multiple sclerosis, heart stenosis or pneumonia in the above conjugate and/or pharmaceutical composition.
  • a medicament for the preparation of an antitumor, fungal infection, rheumatoid arthritis, multiple sclerosis, heart stenosis or pneumonia in the above conjugate and/or pharmaceutical composition.
  • the anti-tumor drug is applied to the following conditions: leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphocytic leukemia, myelodysplasia, multiple Myeloma, Hodgkin's disease or non-Hodgkin's disease, small cell or non-small cell lung cancer, gastric cancer, colon cancer, esophageal cancer, colorectal cancer, prostate cancer, ovarian cancer, breast cancer, brain cancer, urinary Cancer, kidney cancer, bladder cancer, malignant melanoma, liver cancer, uterine cancer, pancreatic cancer, myeloma, endometrial cancer, head and neck cancer, pediatric tumor, sarcoma.
  • the present application provides a method of treating a tumor, a fungal infection, rheumatoid arthritis, multiple sclerosis, heart valve restenosis, or pneumonia in a subject, comprising administering to the subject An effective amount of the above combination or pharmaceutical composition.
  • the subject is a mammal.
  • the subject is a human, animal or pet.
  • the conjugate or pharmaceutical composition of the present invention may be administered to a living organism by any suitable route, such as by oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal or subcutaneous routes.
  • the present invention relates to a method of administration of a combination or pharmaceutical composition comprising oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cerebral, vaginal, peritoneal, bladder, nasal Dosing.
  • the conjugates or pharmaceutical compositions of the present invention can be administered concurrently with a second active substance, such that a synergistic or even synergistic effect can be achieved in the organism.
  • a second active substance such that a synergistic or even synergistic effect can be achieved in the organism.
  • the compounds of the invention may be combined with the second active substance into a pharmaceutical composition, or may be administered simultaneously in separate compositions, or sequentially in separate compositions.
  • Second active substances which can be administered simultaneously with the compounds of the invention for the treatment of cancer include, but are not limited to: fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprolide, goserelin, fluoro Hemet, Nilemet, Finasteride, Dexamethasone, Amlodipine, Ampicillin, Anastrozole, Asparaginase, BCG, Bicalutamide, Bleomycin, Clinical, Busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, colchicine, cyclophosphamide, drug, cyproterone, a Cytosine, dacarbazine, actinomycin d, gentamicin, diethestrol, diethylstilbestrol, docetaxel, doxorubicin, doxorubicin, epirubicin, estradio
  • the conjugates provided herein can be used in conjunction with non-chemical methods for cancer treatment. In certain embodiments, the conjugates provided herein can be performed concurrently with radiation therapy. In certain embodiments, the conjugates provided herein can be used in combination with surgery, tumor heat therapy, ultrasound focus therapy, cryotherapy, or several of the above.
  • the conjugates provided herein can be used concurrently with steroids.
  • Suitable steroids include, but are not limited to: Anxis, beclomethasone, betamethasone, budesonide, chlorinated Nisson, clobetasol, corticosterone, cortisone, hydroxyprednisolone, deshydroxymetasone, dexamethasone, diflurazon, difluoromethasone, difluprednate, glycyrrhetinic acid, fluza Fluke, flumetasone, flunisolide, flucline acetonide, acetonide acetate, fluocinolone acetonide, flubutylbutabutyl ester, fluconazole, acetonide, fluphene acetate, fluphene acetate Nitinidine, fluprednisolone, fluorohydrogenated, propionic acid fluoride, aldehyde-based shrinkage
  • the compounds provided herein can be used concurrently with an immunotherapeutic agent.
  • immunotherapeutic agents include: tumor cell multidrug resistance reversal agents (such as verapamil), rapamycin, mycophenolate mofetil, thalidomide, cyclophosphamide, cyclosporine, and Cloning of antibodies.
  • the beneficial effects of the conjugates described herein 1) The water soluble polymer-amino acid oligopeptide-drug conjugates described herein have a better therapeutic effect than drugs. At the same dosage, the conjugates described herein exhibit better anti-tumor and anti-cancer activities; 2) The water-soluble polymer-amino acid described in the present application can bind more drugs and increase the drug loading of the conjugate. , while the sustained release of drug can be avoided to achieve the sustained effective blood concentration administered to a patient repeatedly; 3) the conjugate reduces the toxicity of the drug; 4) by using the a and eight amino acid 2, the The stability of the drug conjugate is improved, facilitating the preparation, storage and administration of the drug.
  • Dasatinib used in the present embodiment was purchased from Nanjing Ange Pharmaceutical Chemical Co., Ltd., and L-(+)-glutamic acid was purchased from Beijing Chemical Reagent Co., Ltd., p-toluenesulfonic acid, benzyl alcohol and two Cyclohexylcarbodiimide (DCC) was purchased from Sinopharm Chemical Reagent Co., Ltd., 4-dimethylaminopyridine (DMAP) and 1-hydroxybenzotriazole (HOBt) were purchased from Shanghai Covalent Chemical Technology Co., Ltd.
  • DMAP 4-dimethylaminopyridine
  • HOBt 1-hydroxybenzotriazole
  • N,tert-butoxycarbonylglycine, N-tert-butoxycarbonylalanine, N-tert-butoxycarbonylproline and N-tert-butoxycarbonyl-L-glutamate-5-benzyl ester from Sichuan Acrylic Amino Acid Co., Ltd., monooxypolyethylene glycol acetate (20K), Y-type polyethylene glycol acetic acid (40 ⁇ ) is supplied by Beijing Keykai Technology Co., Ltd., and the rest are commercially available reagents (
  • Example 1 monomethoxy polyethylene glycol glutamic acid dipeptide acid (number average molecular weight 20000)
  • L-(+)-glutamic acid dibenzyl ester p-toluenesulfonate (Compound 1) 61go [00137] L-(+)-glutamic acid dibenzyl ester p-toluenesulfonate (compound 1) 30 g (0.06 mol) was dissolved in 500 mL of dichloromethane, and tert-butoxycarbonyl-L-glutamic acid was added. 5-benzyl ester 20.86 g (0.062 mol), DMAP 7.55 g (0.062 mol), HOBt 8.35 g (0.07 mol), a solution of 14.3 g of dichloromethane was added under nitrogen.
  • Example 2 Monomethoxypolyethylene glycol glutamic acid dipeptide glycine (number average molecular weight 20000) Preparation of a dasatinib conjugate (DSR-2)
  • N-tert-butoxycarbonyl glycine dasatinib (Compound 6) 1 g (1.6 mmol), dichloromethane (50 mL) was added to the reaction flask, then 25 mL of trifluoroacetic acid was added, and the reaction was stirred. After 3 hours, the solvent was evaporated under reduced pressure. dichloromethane was evaporated and evaporated to dryness, and then evaporated to dryness.
  • Example 3 Preparation of monomethoxypolyethylene glycol glutamic acid dipeptide alanine (number average molecular weight 20000) - Dasatinib conjugate (DSR-3).
  • N-tert-Butoxycarbonylalanine dasatinib (Compound 8) 1 g (1.6 mmol), dichloromethane (50 mL) was added to the reaction flask, then 25 mL of trifluoroacetic acid was added. After stirring for 3 hours, the solvent was evaporated under reduced pressure, dichloromethane was added to the residue, and evaporated to dryness under reduced pressure, and then repeated three times to obtain dasatinib alanine.
  • Trifluoroacetate (Compound 9) 1.3 g, directly reacted downward.
  • reaction solution was concentrated the next day, and the residue was recrystallized from isopropyl alcohol to give monomethoxy polyethylene glycol glutamic acid dipeptide alanine (20K) - dasatinib conjugate (DSR-3) 0.39 g .
  • Example 4 Monomethoxypolyethylene glycol glutamate dipeptide proline (number average molecular weight 20000) Preparation of a dasatinib conjugate (DSR-4).
  • valine dasatinib trifluoroacetate 140 mg (0.15 mmol), HOBt (3.4 mg, 0.025 mmo) and DMAP 24.4 mg (0.2 mmol) were added to the reaction flask. Dissolve in a mixed solvent of methylene chloride and N,N-dimethylformamide, cool in an ice bath under nitrogen atmosphere, and then add DCC 36.1 mg (0.175 mmol) in a solution of dichloromethane. The reaction was overnight. The reaction solution was concentrated the next day, and the residue was recrystallized from isopropanol to obtain monomethoxy polyethylene glycol glutamic acid dipeptide proline.
  • Example 5 Y-type polyethylene glycol glutamic acid dipeptide proline (number average molecular weight 40000)
  • N-tert-Butoxycarbonylglutamic acid benzyl ester dipeptide (Compound 2) 0.78 g (Example 1) Dissolved in 7 mL of dichloromethane, 3 mL of trifluoroacetic acid, and reacted at room temperature for 2 h. The solvent was removed, 100 mL of dichloromethane was added, and the pH was adjusted to 7-8 with a 5% sodium hydrogen carbonate solution. The extract was separated and the organic phase was washed twice with 5% sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate.
  • valine dasatinib trifluoroacetate (Compound 11) was prepared according to the method described in Example 4.
  • Y-type polyethylene glycol glutamic acid dipeptide acid (Compound 13) (40K, 0.6g, 0.02mmol)
  • Dasatinib triacetate valine 112mg (0.12mmol)
  • HOBt 2.7 Mg, 0.02mmo
  • DMAP 24.4 mg (0.2mmol)
  • Example 6 Preparation of monomethoxypolyethylene glycol glutamic acid tripeptide valine (number average molecular weight 20000) - Dasatinib conjugate (DSR-6) [00159] N-tert-Butoxycarbonyl glutamic acid benzyl ester dipeptide (Compound 2) 6.47 g (0.1 mol) was dissolved in 15 mL of dichloromethane, 6 mL of trifluoroacetic acid was added, and reacted at room temperature for 2 h. The solvent was removed, 100 mL of dichloromethane was added, and the pH was adjusted to 7-8 with a 5% sodium hydrogen carbonate solution.
  • Compound 2 N-tert-Butoxycarbonyl glutamic acid benzyl ester dipeptide
  • the extract was separated and the organic phase was washed twice with 5% sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Filtration, the filtrate was directly added to the reaction flask, under the protection of nitrogen, tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester 3.37g (O.Olmol), DMAP 1.22g (O.Olmol), HOBt l. 35 g (O.Olmol), after completely dissolved, a solution of 2.39 g (O.Ol.lmol) of dichloromethane was added dropwise. After the dropwise addition, the closed system was reacted overnight. The reaction was monitored by TLC.
  • valine dasatinib trifluoroacetate (Compound 11) was prepared according to the method described in Example 4. Monomethoxy polyethylene glycol glutamic acid tripeptide (Compound 17) (20K, 0.6 g, 0.03 mmol), Valine dasatinib trifluoroacetate (compound ll) 224 mg (0.24 mmol), HOBt (4 mg, 0.03 mmol) and hydrazine DMAP 29.3 mg (0.24 mmol) were added to the reaction flask with dichloro Methyl hydrazine and N,N-dimethylformamide were dissolved in a mixed solvent, cooled in an ice bath under nitrogen protection, and then dropped into DCC 43.3 mg.
  • Example 8 Antitumor effects of different polyethylene glycol dasatinib conjugates in a K562 human chronic myeloid leukemia subcutaneous tumor model. [00166] Experimental method:
  • K562 cells were subcutaneously inoculated into the right side of NOD/SCID mice to establish a subcutaneous model of human chronic myeloid leukemia xenograft animals. When the average tumor volume reached 130 mm3, the experimental mice were divided into groups of 8 and administered intravenously twice a week. The efficacy was evaluated based on the relative tumor growth rate (T/C%).
  • K562 cell line is supplemented with 10% fetal bovine serum, L-glutamine (2 mM)
  • RPMI-1640 medium culture in vitro at 37 ° C in the presence of 5% CO 2 in air. Tumor cells were routinely passaged twice a week. Tumor cells in the exponential growth phase were collected and suspended in an equal volume of PBS: Matrigel mixture and placed on ice for tumor inoculation.
  • mice were subcutaneously inoculated with 5 x 106 K562 cells on the right side of the right side, and tumor growth was periodically observed. When the tumors were grown to an average of 130 mm3, the tumor size and the body weight of the mice were randomly grouped and treatment was started.
  • RTV refers to the relative tumor volume.
  • the T/C ratio is the percentage of the tumor volume relative to the treatment group and the control group at some point after the end of treatment, reflecting the antitumor efficacy of the different treatment groups.
  • the positive drug dasatinib 5mg/kg was statistically significantly different from the solvent control group (p ⁇ 0.001), and the average tumor volume was 311mm 3 , the relative tumor proliferation rate. (T/C%) was 12.4%; the drug effects of the test drugs DSR-4, DSR-5 and DSR-6 (5mg/kg) were statistically significantly different from the solvent control group (p ⁇ 0.001).
  • mean tumor volume were 39.2 mm 3, 178.6 mm 3, and 137mm 3, the relative tumor proliferation rate (T / C%) was 1.6%, 7.3% and 5.8%.
  • the average tumor volume of the dasatinib (5 mg/kg) group was 391 mm 3
  • the test drugs DSR-4, DSR-5 and DSR-6 were effective. in contrast there were significant differences (p ⁇ 0.001) statistically, the mean tumor volume were 176 mm 3, 203mm 3 and 258mm 3, the relative tumor proliferation rate (T / C%) were 45%, 52 % and 66%.
  • Relative tumor proliferation rate of the positive drug dasatinib (5 mg/kg), test drug DSR-4, DSR-5 and DSR-6 (5 mg/kg) compared with the solvent control group (T/ C%) were 12.4%, 1.6%, 7.3%, and 5.8%, respectively, indicating that all compounds had significant anti-K562 tumor growth effects (p ⁇ 0.001).
  • dasatinib 5 mg/kg
  • the antitumor effects of the same doses of DSR-4, DSR-5 and DSR-6 were all significantly more ⁇ 0.001).
  • Example 9 Pharmacodynamic study of different polyethylene glycol dasatinib conjugates on a PC-3 human prostate cancer subcutaneous tumor model.
  • the PC-3 cell line was cultured in vitro in Ham's F12K medium supplemented with 10% fetal calf serum, L-glutamine (2 mM) at 37 ° C in air containing 5% CO 2 . Tumor cells were routinely passaged twice a week. Tumor cells in the exponential growth phase were collected, suspended in an equal volume of PBS: Matrigel mixture, placed on ice for tumor inoculation.
  • mice were subcutaneously inoculated with 5 ⁇ 10 6 PC-3 cells on the right side of the right side, and tumor growth was observed periodically, and when the tumors were grown to an average of 160 mm 3 , the tumor size and the body weight of the mice were randomly grouped and treatment was started.
  • the body weight and tumor size of the mice were measured twice a week throughout the experiment.
  • Tumor size calculation formula: tumor volume (mm 3 ) 0.5 x (tumor long diameter X tumor short diameter 2 ).
  • the RTV and T/C ratios were calculated based on the tumor volume of the experimental and control groups.
  • RTV refers to the relative tumor volume.
  • T/C The ratio refers to the percentage of tumor volume in the treatment group and the control group at a certain point after the end of treatment, reflecting the antitumor efficacy of different treatment groups.
  • the tumors were recorded in the following two ways: 1. After each group of animals was euthanized by co 2 , the tumor-bearing side was facing upwards and photographed separately according to the group; 2. After the tumor was removed, weighed first. Tumor weight, T/C (% of the tumor weight of the treatment group and the control group) was calculated, and then the tumors of each group were simultaneously placed and photographed in order.
  • the drug efficacy of the positive drug dasatinib (10mg/kg) was statistically significantly different from the solvent control group (p ⁇ 0.01), and the average tumor volume was 1752mm 3 , the relative tumor proliferation rate. (T/C%) was 73%; the drug effects of the test drugs DSR-4, DSR-5 and DSR-6 (10 mg/kg) were statistically significantly different from the solvent control group (p ⁇ 0.001).
  • the average tumor volume of the dasatinib (10 mg/kg) group was 1868 mm 3
  • the test drugs DSR-4, DSR-5 and DSR-6 (10 mg/kg) were effective. were compared statistically significant difference (p ⁇ 0.05, p ⁇ 0.05 and p ⁇ 0.01), mean tumor volumes were 1200 mm 3 1406mm 3 and 1449mm 3, relative tumor proliferation rate, (T / C %) are 61%, 75% and 72% respectively.
  • Relative tumor growth rate (T/C%) of the positive drug dasatinib (10 mg/kg), test drugs DSR-4, DSR-5 and DSR-6 (10 mg/kg) compared to the solvent control ) were 73%, 47%, 57%, and 56%, respectively, indicating that all compounds had statistically significant anti-PC-3 tumor growth effects (p ⁇ 0.01).
  • the antitumor effects of the same doses of DSR-4, DSR-5 and DSR-6 (10 mg/kg) were more significant (p ⁇ 0.05) compared with dasatinib (10 mg/kg).
  • rapamycin used in the examples was purchased from Wuhan Yuancheng Co-creation Technology Co., Ltd., and t-butyl bromoacetate and triphenylphosphine were purchased from Sinopharm Chemical Reagent Co., Ltd.
  • Example 10 Preparation of monomethoxypolyethylene glycol glycine acetate (number average molecular weight 20000) - rapamycin conjugate (LPR-1)
  • tert-Butyl bromoacetate (5.82 g, 30 mmol) was added to a reaction flask, dissolved in acetone (80 mL), then sodium azide (4.55 g, 70 mmol) dissolved in water (40 mL) The solution was heated to reflux overnight. The reaction mixture was evaporated to dryness. EtOAc was evaporated. This liquid was dissolved in methanol (90 mL), then 1N sodium hydroxide solution (90 mL) was added, stirred and heated to reflux for 3 h. After cooling, the methanol was evaporated under reduced pressure, and the mixture was cooled with ice-cooled overnight.
  • Azidoacetic acid (Compound 18) (253 mg, 2.5 mmoL) and rapamycin (2.28 g, 2.5) mmoL) was added to the reaction flask, dissolved in dichloromethane, cooled in an ice bath, and then added with 4-dimethylaminopyridine (DMAP, 611 mg, 5 mmoL) and N,N-dicyclohexylcarbimide ( DCC, 1.03 g, 5 mmoL) was added to the reaction flask and stirring was continued at room temperature overnight. After the reaction mixture was concentrated, the residue was purified by column chromatography to give the titled product of the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the
  • Azoxyacetic acid rapamycin ester (Compound 19) (0.7 g, 0.7 mmoL) and triphenylphosphine (0.37 g, 1.4 mmoL) were added to the reaction flask, followed by a mixture of tetrahydrofuran and water ( 5:1, 180 mL), heated to 50 ° C overnight, and the residue was concentrated with ethyl acetate. The extract was washed with saturated brine and dried. After concentration under reduced pressure, the residue was purified by column chromatography to yield EtOAc (yield: 20), yield: 70%, MS m/z: 994 [M+Na]+.
  • Example 1 Monomethoxypolyethylene glycol glutamic acid dipeptide glycine (number average molecular weight)
  • Monomethoxypolyethylene glycol glutamic acid dipeptide acid (Compound 5) was prepared according to the method described in Example 1.
  • Example 12 Y-type polyethylene glycol glutamic acid dipeptide glycine (number average molecular weight 40000) Preparation of a rapamycin conjugate (LPR-3)
  • Y-type polyethylene glycol glutamic acid dipeptide acid (Compound 13) was prepared as described in the above examples.
  • Y-type polyethylene glycol glutamic acid dipeptide acid (Compound 13) (40K, 0.5g, 0.0125mmol), glycine rapamycin ester (Compound 20) 24.3 mg (0.025mmol), HOBt (1.7 Mg, 0.0125mmo) and DMAP 3 mg (0.025mmol) were added to the reaction flask, dissolved in dichloromethane, cooled in ice bath, and then added dropwise to DCC 4.1 mg (0.02 mmol) in dichloromethane solution. After that, it naturally rose to room temperature and reacted overnight.
  • reaction solution was concentrated the next day, and the residue was crystallized from isopropanol to obtain Y-type polyethylene glycol glutamic acid dipeptide glycine (number average molecular weight: 40000) - rapamycin conjugate (LPR-3) 0.44 g.
  • Plc/prf/5 cells were cultured in vitro in a single layer in a MEM medium supplemented with 10% heat-inactivated fetal bovine serum and cultured in an incubator containing 5% CO2 air at 37 °C. Digestion was performed twice with trypsin-EDTA twice a week. When cells are exponentially growing, cells are harvested, counted, and vaccinated.
  • LPR1, 2, 3 anti-tumor efficacy evaluation indexes of plc/prf/5 subcutaneous xenograft model are shown in Table 8. Evaluation of anti-tumor effect of each treatment group
  • LPR-1 and LPR-2 use polyethylene glycol of the same structure and the same number average molecular weight, except that polyethylene glycol of LPR-1 is only bonded to rapamycin via glycine, polyethylene glycol molecule One end group is only bonded to one rapamycin molecule; and the polyethylene glycol of LPR-2 is bonded to rapamycin through glutamic acid dipeptide and glycine, and one terminal group of the polyethylene glycol molecule can be bonded Combine three rapamycin molecules.
  • the drug loading rate of LPR-2 is three times that of LPR-1, and its antitumor activity is also significantly higher than that of LPR-1.
  • the irinotecan hydrochloride used in the examples was purchased from Shanghai Longxiang Biomedical Development Co., Ltd.
  • Example 14 monomethoxy polyethylene glycol glutamic acid dipeptide glycine (number average molecular weight 20000)
  • Monomethoxypolyethylene glycol glutamic acid dipeptide acid (Compound 5) was prepared according to the method described in Example 1.
  • Monomethoxypolyethylene glycol glutamic acid dipeptide acid (Compound 5) (molecular weight: 20,000) 5.0 g, enonotecan glycine (Compound 22) 1.02 g, N-hydroxysuccinimide (NHS) 115 mg , 4-dimethylaminopyridine (DMAP) 153mg dissolved in 50mL anhydrous dichloromethane, under the protection of nitrogen, add two Cyclohexylcarbodiimide (DCC) 309 mg. The reaction was stirred at room temperature overnight.
  • Example 15 Y-type polyethylene glycol glutamic acid dipeptide glycine (number average molecular weight 40000) - Preparation of INOTECK conjugate (YNR-2)
  • Y-type polyethylene glycol glutamic acid dipeptide acid (compound 13) (molecular weight: 40,000) was prepared according to the method described in the above examples.
  • Y-type polyethylene glycol glutamic acid dipeptide acid (compound 13) (molecular weight 40,000) 10 g, quinolidine glycine (compound 22) 1.02 g, N-hydroxysuccinimide (NHS) 115 mg, 4- Dimethylaminopyridine (DMAP) 153 mg was dissolved in 50 mL of anhydrous dichloromethane, and 309 mg of dicyclohexylcarbodiimide (DCC) was added under nitrogen. The reaction was stirred at room temperature overnight.
  • DCC dicyclohexylcarbodiimide
  • Example 16 Monomethoxypolyethylene glycol glutamic acid tripeptide glycine (number average molecular weight 20000)
  • Monomethoxypolyethylene glycol glutamic acid tripeptide acid (molecular weight: 20,000) was prepared according to the method described in the above examples.
  • Monomethoxy polyethylene glycol glutamic acid tripeptide acid (compound 17) (molecular weight 20000) 5.0 g, ennotecan glycine ester (compound 22) 1.36 g, N-hydroxyl
  • <RTI ID 0.0>> Monomethoxypolyethylene glycol glutamic acid tripeptide glycine (number average molecular weight - INOTECO conjugate (YNR-3) 4 -NMR (DMSO-d6): .84.89 (m, 8H), 1.24(m, 9H),, 1.71-1.74(m, 23H), 2.12(m, 16H), 2.95-2.99(m, 19H), 3.50(m, 1800H), 4.22(m, 18H), 5.45(m 5H), 5.49 (m, 5H), 7.07 (m, 2H), 7.55-7.60 (m, 3H), 7.89 (m, 3H), 8.1 l (m, 4H), 8.20 (m, 3H).
  • Example 17 Growth Inhibition of Human Intestinal Carcinoma HCT-1 16 Nude Mice Transplanted with Polyethylene Glycosin Inocomb Conjugate
  • test substance YNR-1 is a monomethoxypolyethylene glycol acetate glycine-inonotecan conjugate.
  • CPT-1 1 Positive control drug enonotecan hydrochloride injection (CPT-1 1 ), 40mg/2ml, batch number is 8UL002-B, manufactured by Aventis Pharma (Dagenham). Dilute with physiological saline to the desired concentration at the time of use.
  • YNR-1 dose was set to 45 mg / kg (calculated according to the amount of INOTECK), administered intravenously, once a week for three weeks; CPT-1 1 dose was 45 mg / kg, weekly Administered once intravenously; and 15 mg/kg, administered intravenously three times a week for three consecutive weeks.
  • Animals BALB/cA nude mice, male, 5-6 weeks old, weighing 19 ⁇ 2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production certificate number: SCXK (Shanghai) 2008-0017.
  • the number of animals in each group 12 in the negative control group and 6 in the drug-administered group.
  • Human intestinal cancer HCT-1 16 cell line was purchased from ATCC. The cell strain was inoculated subcutaneously into the right axillary fossa of the nude mice, and the inoculation amount was 5 ⁇ 106/head, and the transplanted tumor was formed and then used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into about 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm 3 .
  • YNR-1 was administered in the 45 mg/kg dose group and the control group was given the same amount of normal saline once a week for three consecutive weeks.
  • CPT-1 1 (15 mg/kg) was used as a positive control drug, administered intravenously three times a week for three weeks. After the end of the administration, continue to observe for one week.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V0 is the measured tumor volume at the time of sub-cage administration (i.e., d0)
  • Vt is the tumor volume at each measurement.
  • the experimental results are shown in Table 9.
  • YNR-1 45 mg/kg was administered intravenously once a week for three weeks, and the growth of subcutaneous xenografts of human intestinal cancer HCT-116 nude mice was significantly inhibited.
  • the percentage of T/C was 27.60%.
  • the effect is better than the same dose of CPT-1145mg/kg of the same dosage regimen.
  • the same treatment scheme CPT-11 can also inhibit the growth of HCT-116 subcutaneous xenografts to a certain extent, but the percentage of T/C is only 63.56%.
  • the positive control CPT-11 (15mg/kg) was administered intravenously three times a week for three weeks, which also significantly inhibited the growth of HCT-116 subcutaneous xenografts.
  • the T/C value was 39.84%.
  • the body weight of the mice decreased. Compared with the solvent control group, the weight loss of the nude mice in the CPT-11 45 mg/kg group was slightly stronger than that in the
  • Example 18 Growth Inhibition of Human Intestinal Carcinoma HT-29 Nude Mice Transplanted Tumor by Polyethylene Glycosin Integate Conjugate
  • test substance YNR-1 is a monomethoxy polyethylene glycol glutamic acid dipeptide glycine-inonotecan complex.
  • YNR-1 dose is set to 45mg / kg (calculated according to the amount of INOTEC), intravenous administration, once a week for three weeks; CPT-11 dose is 45mg / kg, weekly vein The drug was administered once; and 15 mg/kg, administered intravenously three times a week for three consecutive weeks.
  • BALB/cA nude mice male, 5-6 weeks old, weighing 18 ⁇ 2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production certificate number: SCXK (Shanghai) 2008-0017.
  • the number of animals in each group 12 in the negative control group and 6 in the drug-administered group.
  • Human intestinal cancer HT-29 cell line was purchased from ATCC. The cell strain was used to inoculate the right axilla of the nude mice subcutaneously, and the inoculation amount of the cells was 5 ⁇ 106/head, and the transplanted tumor was formed and then used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm 3 .
  • YNR-1 and CPT-11 were given the same amount of normal saline in the 45 mg/kg dose group and the control group, intravenously once a week for three weeks.
  • CPT-11 (15 mg/kg) was administered as a positive control drug three times a week for three weeks. After the end of the administration, continue to observe for one week.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V0 is the measured tumor volume at the time of sub-cage administration (ie, d0)
  • vt is the tumor volume at each measurement.
  • T/C (%) (TRTV/CRTV) X100%, TRTV: treatment group RTV; CRTV: negative control group RTV.
  • mice in the experimental results were shown in Table 10.
  • YNR-1 45 mg/kg was administered intravenously once a week for three weeks, and the growth of subcutaneous xenografts of human intestinal cancer HT-29 nude mice was significantly inhibited.
  • mice in the experimental treatment group The increase in tumor volume is slowed down.
  • T/C the percentage of T/C was 41.08%.
  • the positive control CPT-1 1 (15 mg/kg) was administered intravenously three times a week for three consecutive weeks, which also significantly inhibited the growth of HT-29 subcutaneous xenografts with a T/C value of 27.27%.
  • the nude mice in each group grew well, and only the two different dose groups of CPT-1 1 had a decrease in body weight.
  • test substance YNR-1 is a monomethoxy polyethylene glycol glutamic acid dipeptide glycine-inonotecan complex.
  • CPT-1 1 The positive control drug inonotecan hydrochloride (CPT-1 1 ) 40 mg/2 ml, lot number 8UL002-B, was manufactured by Aventis Pharma (Dagenham). When used, it is diluted with physiological saline to the desired concentration. [00280] Dose setting
  • YNR-1 dose was set to 45 mg / kg (calculated according to the amount of INOTECK), administered intravenously, once a week for three weeks; CPT-1 1 dose was 45 mg / kg, weekly Intravenous administration And 15 mg/kg, administered intravenously three times a week for three consecutive weeks.
  • BALB/cA nude mice female, 5-6 weeks old, weighing 18 ⁇ 2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production certificate number: SCXK (Shanghai) 2008-0017.
  • the number of animals in each group 12 in the negative control group and 6 in the drug-administered group.
  • Human lung cancer A549 cell line was purchased from ATCC. The cell strain was used to inoculate the right axilla of the nude mice, and the inoculation amount was 5 ⁇ 106/head. After the transplanted tumor was formed, it was used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm 3 .
  • YNR-1 and CPT-11 were given the same amount of normal saline in the 45 mg/kg dose group and the control group, intravenously once a week for three weeks.
  • CPT-11 (15 mg/kg) was administered as a positive control drug three times a week for three weeks. After the end of the administration, continue to observe for one week.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • T/C (%) (TRTV/CRTV) X100%
  • TRTV treatment group RTV
  • CRTV negative control group RTV.
  • YNR-1 and CPT-11 (45 mg/kg) were administered intravenously once a week for three weeks, which significantly inhibited the growth of subcutaneous xenografts in human lung cancer A549 nude mice.
  • the T/C percentage is 20.62%.
  • the anti-tumor effect of YNR-1 is much better than that of CPT-11 of the same dosage regimen.
  • the growth of subcutaneous xenografts in tumor-bearing mice was slowed after one week of YNR-1 treatment.
  • the positive control CPT-11 (15 mg/kg) was administered intravenously three times a week for three consecutive weeks, which also significantly inhibited the growth of A549 subcutaneous xenografts with a T/C value of 53.26%.
  • the nude mice in each treatment group grew well, and the weight gain was slightly slower than the solvent control group.
  • Example 20 Growth inhibition of ectopic conjugates of polyethylene glycol on human ovarian cancer SKOV-3 nude mice
  • test substance YNR-1 is a monomethoxy polyethylene glycol glutamic acid dipeptide glycine-inonotecan complex.
  • YNR-1 dose was set to 45 mg / kg (calculated according to the amount of INOTECK), administered intravenously, once a week for three weeks; CPT-11 dose was 45 mg / kg, weekly vein The drug was administered once; and 15 mg/kg, administered intravenously three times a week for three consecutive weeks. [00296] animals
  • BALB/cA nude mice female, 5-6 weeks old, weighing 19 ⁇ 2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production certificate number: SCXK (Shanghai) 2008-0017.
  • the number of animals in each group 12 in the negative control group and 6 in the drug-administered group.
  • Human ovarian cancer SKOV-3 cell strain was purchased from ATCC. The cell strain was inoculated subcutaneously into the right axilla of the nude mice, and the inoculation amount was 5 ⁇ 106/piece, and the transplanted tumor was formed and then used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm3.
  • YNR-1 and CPT-11 were given the same amount of normal saline in the 45 mg/kg dose group and the control group, intravenously once a week for three weeks.
  • CPT-11 (15 mg/kg) was administered as a positive control drug three times a week for three weeks. After the end of the administration, continue to observe for one week.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • T/C (%) (TRTV/CRTV) X100%
  • TRTV treatment group RTV
  • CRTV negative control group RTV.
  • CPT-1 1 (15 mg/kg) was administered intravenously three times a week for three consecutive weeks, which also significantly inhibited the growth of SKOV-3 subcutaneous xenografts with a T/C value of 55.69%.
  • the weight of mice in the solvent control group and CPT-1 1 treatment group decreased slightly; while the YNR-1 experimental treatment group had good growth and weight gain.
  • Example 21 Inhibition of growth of human intestinal cancer SW-620 nude mice xenografts by different formulations of irinotecan
  • test substance YNR-1 is a monomethoxy polyethylene glycol glutamic acid dipeptide glycine-inonotecan complex.
  • CPT-1 1 The positive control drug inonotecan hydrochloride (CPT-1 1 ) 40 mg / 2 ml, batch number 8UL002-B, manufactured by Aventis Pharma (Dagenham). Dilute with physiological saline to the desired concentration at the time of use. [00308] Dose setting
  • YNR-1 dose was set to 45 mg / kg (calculated according to the amount of INOTECK), administered intravenously, once a week for three weeks; CPT-11 dose was 45 mg / kg, weekly vein The drug was administered once; and 15 mg/kg, administered intravenously three times a week for three consecutive weeks.
  • BALB/cA nude mice male, 4-6 weeks old, weighing 19 ⁇ 2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production certificate number: SCXK (Shanghai) 2008-0017.
  • the number of animals in each group 12 in the negative control group and 6 in the drug-administered group.
  • Human intestinal cancer SW-620 cell line was purchased from ATCC. The cell strain was inoculated subcutaneously into the right axillary fossa of the nude mice, and the inoculation amount was 5 ⁇ 106/head, and the transplanted tumor was formed and then used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm 3 .
  • YNR-1 and CPT-11 were given the same amount of normal saline in the 45 mg/kg dose group and the control group, intravenously once a week for three weeks.
  • CPT-11 (15 mg/kg) was administered as a positive control drug three times a week for three weeks. After the end of the administration, continue to observe for one week.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • YNR-1 and CPT-1 1 were administered intravenously once a week for three weeks, which significantly inhibited the growth of subcutaneous xenografts in human intestinal cancer SW-620 nude mice, and YNR-1.
  • the anti-tumor effect was better than the same dose of CPT-1 1 in the same dosage regimen.
  • two tumor-bearing mice in the YNR-1 treatment group had complete tumors. Regressed, there was no rebound after one week of withdrawal.
  • the positive control CPT-1 1 (15 mg/kg) was administered intravenously three times a week for three consecutive weeks, which also significantly inhibited the growth of SW-620 subcutaneous xenografts.
  • the T/C value was

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Abstract

La présente invention concerne une combinaison médicale polymère hydrosoluble-oligopeptide d'acides aminés telle que présentée dans la formule (I), et une composition médicale comprenant la combinaison. Dans la combinaison, P et un polymère hydrosoluble ; X est un groupe de liaison qui lie P et A1 ; A1, A2, et A3 sont des résidus indépendants d'acides aminés identiques ou différents ou d'analogues d'acides aminés ; D1 et D2 sont des résidus indépendants de molécules médicales identiques ou différentes ; a vaut 0 ou 1 ; b est un nombre entier compris entre 2 et 12 ; c est un nombre entier compris entre 0 et 7 ; d est 0 ou 1 ; la combinaison peut améliorer le taux de chargement du médicament, la solubilité dans l'eau, la stabilité, et l'activité du médicament.
PCT/CN2014/071395 2013-01-28 2014-01-24 Combinaison médicale polymère hydrosoluble-oligopeptide d'acides aminés, procédé de préparation associé, et utilisation associée WO2014114262A1 (fr)

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