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WO2021233352A1 - Composé présentant une réponse à la libération endocytique de cellules et son utilisation - Google Patents

Composé présentant une réponse à la libération endocytique de cellules et son utilisation Download PDF

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WO2021233352A1
WO2021233352A1 PCT/CN2021/094706 CN2021094706W WO2021233352A1 WO 2021233352 A1 WO2021233352 A1 WO 2021233352A1 CN 2021094706 W CN2021094706 W CN 2021094706W WO 2021233352 A1 WO2021233352 A1 WO 2021233352A1
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lipid
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徐宇虹
梁瑶瑶
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Shanghai Jiao Tong University
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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Definitions

  • the invention belongs to the field of gene therapy, and specifically relates to a compound that responds to endocytosis and release of cells and its application.
  • Gene therapy refers to the introduction of exogenous normal genes into target cells to correct or compensate for diseases caused by defects and abnormal genes, so as to achieve the purpose of treatment. Gene therapy is used to effectively treat congenital and acquired diseases, and has shown great therapeutic potential in the treatment of cancer, X chromosome-related severe immunodeficiency and other diseases.
  • Common gene drugs include small interfering RNA (siRNA), plasmid DNA (pDNA), small hairpin RNA (shRNA), antisense oligonucleotides (ODN), messenger RNA (mRNA), microRNA (miRNA), etc.
  • Plasmid DNA, or pDNA is a type of small circular double-stranded DNA that naturally occurs in bacteria and is sometimes found in archaea and eukaryotic cells. pDNA is often regarded as a replicon, which can replicate autonomously in different host cells. In genetic engineering, artificially constructed plasmids are often used as carriers for special genes.
  • the introduction methods of gene drugs mainly include: physical methods, viral vector-mediated methods and non-viral vector-mediated methods.
  • the physical method is to deliver gene drugs into target cells through electroporation, high pressure injection, magnetic transfection, gene gun and other methods. Most physical methods can efficiently achieve gene drugs directly enter cells and achieve expression, but it is still difficult to enter the clinic due to voltage stimulation, organ damage and other reasons, and it is still limited to the stage of experimental animals.
  • Viral vector-mediated gene delivery mainly includes adenovirus transfection, lentiviral transfection and retroviral transfection. Although virus transfection has the advantages of high efficiency and accuracy, gene delivery using virus as a vector still has major limitations, including potential tumorigenicity, immunogenicity, and extensive tissue tropism, and it is difficult to prepare.
  • the non-viral vector-mediated method refers to the use of liposomes, polymers, inorganic materials and other methods to achieve gene delivery. It can effectively solve the limitations of viral vectors, is far safer than viral vectors and is easy to prepare. It has the advantages of high transfection efficiency, low immunogenicity, easy chemical modification and easy scale-up production.
  • the currently commonly used non-viral vectors still have many problems.
  • the cationic liposome when used for introduction, the cationic lipid/nucleic acid complex will encounter a series of extracellular and intracellular obstacles during the delivery process. Because the complex has a strong positive charge, it is in the extracellular environment. Among them, these complexes will first bind to the negatively charged albumin in the blood to form larger particles. Therefore, they are easily recognized and eliminated by the reticulocytes, and it is difficult to reach the target site.
  • the positive charge on the surface of the cation/nucleic acid complex can easily cause cytotoxicity and cause damage to normal tissues.
  • many researchers try to modify the surface of the complex with PEG to shield more positive charges and prevent aggregation, thereby improving the body fluid stability of the complex and prolonging the circulation time of the complex in the body.
  • the purpose of the present invention is to provide a new compound for introducing genetic drugs (such as nucleic acid) into target cells.
  • R 1 is the lipophilic head
  • R 8 is a hydrophilic chain (preferably, PEG);
  • X is selected from the following group: O, S, NR a ;
  • Y is selected from the following group: O, S;
  • R 7 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl (preferably, phenyl); in R 7 , the substitution refers to the group One or more hydrogens of is replaced by one or more (preferably, 1-3) substituents selected from the following group: deuterium, halogen (F, Cl, Br, I), cyano, nitro, N(R a ) 2 , C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5 to 12 membered heteroaryl, 5 to 10 membered heterocyclic group;
  • L is selected from the following group: none, O, S, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene;
  • R 9 is selected from the group: none, C1-C6 alkylene, substituted or unsubstituted C6-C12 aryl (preferably, C6-C10 aryl; more preferably, phenyl), substituted or unsubstituted 5 to 12 membered heteroaryl (preferably, 5 to 10 membered heteroaryl; more preferably, 5 to 6 membered heteroaryl), substituted or unsubstituted C3-C12 cycloalkylene, substituted or unsubstituted Substituted 5- to 10-membered heterocyclic group;
  • W is selected from the following group: none, -O-, -S-, -R'C(O)R"-, -R'C(O)OR"-, -R'OC(O)R”-, R'S (O)R”-, -R'S(O) 2 R”-, -R'N(R a )R”-, -R'C(O)N(R a )R”-, -R'C( O)ON(R a )R”-, -R'OC(O)N(R a )R”-, -R'S(O)N(R a )R”-, -R'S(O) 2 N(R a )R”-, -R'N(R a )C(O)R”-, -R'N(R a )OC(O)R”-, -R'N(R a )C(O) OR”-, -R'N(R
  • R'and R" are each independently selected from the following group: none, unsubstituted or C1-C6 alkylene substituted with 1-3 R b ;
  • R b is a substituted or unsubstituted group selected from the following group : Deuterium, C1-C6 alkyl, phenyl, benzyl, heteroaryl, C3-C6 cycloalkyl, 4 to 7 membered heterocyclic group;
  • R 3 is selected from the following group: substituted or unsubstituted C3-C12 cycloalkyl (preferably, C5-C7 cycloalkyl), substituted or unsubstituted 5 to 12 membered heterocyclic group, substituted or unsubstituted C6 -C12 aryl (preferably, C6-C10 aryl; more preferably, phenyl), substituted or unsubstituted 5 to 12 membered heteroaryl (preferably, 5 to 10 membered heteroaryl; more preferably ⁇ , 5- to 6-membered heteroaryl);
  • R a is a substituted or unsubstituted group selected from the following group: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl (preferably phenyl) , 5 to 12 membered heteroaryl (preferably 5 or 6 membered heteroaryl), C3-C12 cycloalkyl (preferably C3-C6 cycloalkyl), 4 to 12 membered heterocyclic group (preferably 4- to 7-membered heterocyclic group); or, two adjacent Ra and connected with them together form a substituted or unsubstituted 5- to 12-membered heteroaryl group (preferably a 5- or 6-membered heteroaryl group) or a substituted or Unsubstituted 4 to 12 membered heterocyclic group (preferably 4 to 7 membered heterocyclic group);
  • substitution means that one or more (preferably 1-3) hydrogens on the group are replaced by a substituent selected from the following group: deuterium, halogen (preferably F, Cl, Br) , Cyano, hydroxyl, nitro, N(R d ) 2 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6- C12 aryl (preferably phenyl), 5 to 12 membered heteroaryl (preferably 5 or 6 membered heteroaryl), C3-C12 cycloalkyl (preferably C3-C6 cycloalkyl), 4 To 12-membered heterocyclic group (preferably 4 to 7-membered heteroaryl), C1-C6 alkoxy, -C(O)OR d , -OC(O)R d , -SO 2 R d , -C (O)
  • Each R d is independently selected from the group consisting of H, deuterium, and C1-C6 alkyl.
  • the lipophilic head includes a lipophilic end derived from a lipid (preferably, a neutral lipid) or a C10-C20 saturated or unsaturated hydrocarbon group; and the lipophilic end passes through The linking group is connected to X or directly connected to X.
  • the C10-C20 saturated or unsaturated hydrocarbon group contains 0, 1, 2, 3, 4 or 5 double bonds or triple bonds.
  • the C10-C20 saturated or unsaturated hydrocarbon group is a linear or branched hydrocarbon group.
  • the neutral lipids include: sterol lipids, phosphatidylcholine lipids, phosphatidylethanolamine lipids, sphingosine phospholipid lipids, or a combination thereof.
  • the sterol lipid includes: cholesterol (Chol).
  • the phosphatidylcholine (PC) lipids include: DPPC (1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine), DMPC (1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine) Myristoylphosphatidylcholine), DDPC (1,2-Didecanoyl-sn-glycerol-3-phosphorylcholine), DSPC (distearoylphosphatidylcholine), DOPC (dioleoylphosphatidylcholine) Choline), or a combination thereof.
  • DPPC 1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine
  • DMPC 1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine
  • Myristoylphosphatidylcholine Myristoylphosphatidylcholine
  • DDPC 1,2-Didecanoyl-sn-glycerol
  • the phosphatidylethanolamine (PE) lipids include: DSPE (distearoyl-phosphatidylethanolamine), DPPE (dipalmitoylphosphatidylethanolamine), DOPE (dioleoylphosphatidylethanolamine) ), DLPE (Dilauroylphosphatidylethanolamine), or a combination thereof.
  • the sphingosine phospholipid lipid includes: ceramide.
  • the lipophilic end is a group derived from a lipid selected from the group consisting of Chol, DSPE, and ceramide.
  • R 1 is a group represented by formula IA,
  • R 1a is a group derived from a neutral lipid, or a C10-C20 saturated or unsaturated hydrocarbon group
  • W a is selected from the group consisting of: none, -O -, - S -, - R'C (O) R “-, - R'C (O) OR" -, - R'OC (O) R “-, R'S(O)R”-, -R'S(O) 2 R”-, -R'N(R a )R”-, -R'C(O)N(R a )R”-, -R'C (O)ON(R a )R”-, -R'OC(O)N(R a )R”-, -R'S(O)N(R a )R”-, -R'S(O) 2 N( R a )R”-, -R'N(R a )C(O)R”-, -R'N(R a )OC(O)R”-, -R'N(R a )C(O )OR”-
  • L a is - (Z) n -; wherein, Z is independently selected from the group: C (R c) 2, C3-C6 cycloalkyl group, O, S, NR a;
  • n is an integer of 2-20
  • R c is each independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl (preferably, C1-C4 alkyl; more preferably, selected from: methyl, ethyl );
  • Ra , R'and R" are the same as before.
  • Z is CH 2 .
  • R 1a is a group derived from lipids selected from the group consisting of cholesterol, DOPC, DOPE, DDPC, DDPE, DLPC, DLPE, DMPC, DMPE, DPPC, DPPE, DSPC, DSPE, DPhyPE, sheath Phospholipids, ceramides, diglycerides, sphingosine; or R 1a is a C10-C20 saturated or unsaturated hydrocarbon group.
  • R 1a is a group derived from the group of lipids selected from the group consisting of Chol, DSPE (1,2-distearoyl-sn-glyceryl-3-phosphocholine), ceramide (ceramide ), DOPE, DSPC; or R 1a is a C10-C20 saturated or unsaturated hydrocarbon group.
  • L a is - (CH 2) n -;
  • L a is - (CH 2) 2-8 -; more preferably, L a is - (CH 2) 2-6 -.
  • R'and R" are none.
  • W a is selected from the group consisting of: none, -O -, - C (O ) NH -, - OC (O) NH-.
  • W a is selected from the group consisting of: none, -O -, - C (O ) NH 2 -.
  • R 1a is selected from the group consisting of Chol, DSPE, and ceramide; preferably, R 1a is Chol.
  • R 1 is Chol-OC(O)-NH-(CH 2 ) 2-5 -, Chol-C(O)-NH-(CH 2 ) 2-5 -or Chol-O- (CH 2 ) 5-8 -; More preferably, R 1 is Chol-OC(O)-NH-(CH 2 ) 3 -or Chol-O-(CH 2 ) 6 -.
  • R 1 is Chol-C(O)-NH-(CH 2 ) 2-5 -or Chol-O-(CH 2 ) 5-8 -; more preferably, R 1 is Chol- OC(O)-NH-(CH 2 ) 3 -or Chol-O-(CH 2 ) 6 -.
  • R 3 is selected from the following group: substituted or unsubstituted C3-C12 cycloalkyl (preferably, C3-C7 cycloalkyl), substituted or unsubstituted C6-C12 aryl (more Preferably, C6-C8 aryl).
  • the said substitution means that one or two hydrogens in the group are substituted by a group selected from the following group: hydroxyl, C1-C6 alkoxy.
  • R 3 is a substituted or unsubstituted C6-C8 aryl group, and the said substitution means that one hydrogen in the group is replaced by a group selected from the following group: hydroxyl, C1-C3 alkane Oxy.
  • R 3 is selected from the group: phenyl, hydroxyphenyl, C1-C3 alkoxy, phenyl, cyclohexyl group; preferably, R3 is phenyl.
  • R 3 is a group derived from a compound selected from the following group of compounds:
  • R3 is
  • R 7 is a benzene ring or a C1-C6 alkylene group.
  • L is selected from the following group: none, O.
  • R 9 is selected from the following group: none, C1-C6 alkylene (preferably (CH 2 ) 1-2 ), C6-C12 aryl (preferably phenyl).
  • W is selected from the following group: none, C(O)NH.
  • R 2 is selected from the following group: none, -phenyl-C(O)NH-, -phenyl-O-(CH 2 ) 1-2 -C(O)NH-, -benzene -O-phenyl-C(O)NH-, -phenyl-phenyl-C(O)NH-, -(CH 2 ) 1-2 -O-(CH 2 ) 1-2 -C(O ) NH-(-C(O)NH- is connected to the hydrophilic chain).
  • R 8 is PEG (polyethylene glycol).
  • R 8 is PEG with an average molecular weight of 190-22,000 (ie, PEG 200-20000 ).
  • R 8 is PEG with an average molecular weight of 1800-2200 (ie PEG 2000 ).
  • the compound is represented by formula II,
  • R 4 , R 5 and R 6 are the same as the definition of R e in claim 1;
  • R 1 , R 2 , R 3 , R 8 , X and Y are the same as those defined in claim 1.
  • R 4 , R 5 and R 6 are each independently selected from the following group: H, deuterium, C1-C6 alkoxy, hydroxyl, N(R a ) 2 , C1-C6 amide, C1 -C6 acyloxy, C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5 to 12 membered heteroaryl, substituted or unsubstituted C6-C12 cycloalkylene, substituted Or an unsubstituted 5- to 10-membered heterocyclic group.
  • R 4 , R 5 and R 6 are each independently selected from the following group: H, deuterium, C1-C6 alkoxy; preferably, R 4 , R 5 and R 6 are each independently H or deuterium.
  • the compound is represented by formula III-A,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are the same as those defined in claim 1.
  • the compound is represented by formula III-B,
  • R 1a is a group derived from a neutral lipid, or a C10-C20 saturated or unsaturated hydrocarbon group
  • W a is selected from the group consisting of: -O -, - S-, C (O) -, - C (O) O -, - OC (O) -, S (O) -, - S (O) 2 -, -NH-, -C(O)NH-, -C(O)ONH-, -OC(O)NH-, -S(O)NH-, -S(O) 2 NH-, -NHC(O) -, - NHOC (O) - , - NHC (O) O -, - NHS (O) -, - NHS (O) 2 -; preferably, W a is selected from the group: -O -, - OC ( O)NH-, -NHC(O)O-;
  • R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are the same as those defined in claim 1.
  • R 1a is as defined above.
  • n 5, 6, 7, or 8.
  • Wa is -OC(O)NH- or -NHC(O)O-
  • n 2, 3, 4 or 5.
  • the compound is represented by formula III-C or formula III-D,
  • R 1a, R 3, R 4, R 5, R 6, R 9, Y, L, W a, W, m and n are as defined above.
  • each group in each formula has the same definitions as those in the compounds in Table 1. Group.
  • the compound is selected from the compounds in Table 1.
  • an intermediate I is provided.
  • the intermediate I is represented by formula IV,
  • R 1 , R 3 , R 4 , R 5 , R 6 , X and Y are the same as those defined in the first aspect.
  • the intermediate I is represented by formula IV-A,
  • R 1a, W a, R 3, R 4, R 5, R 6, Y and n are as defined above.
  • an intermediate II is provided, and the intermediate is represented by formula V,
  • W b is an active linking group
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 9 , L, X and Y are the same as those defined in the first aspect.
  • W b is selected from the group consisting of -R'COOH, -R'C(O)H, -R'OH, -R'N(R a )H, -R'SO 3 H, -R'SO 2 H; wherein the definitions of R'and Ra are as described above.
  • W b is -R'COOH; preferably, W b is -COOH.
  • the intermediate II is represented by formula V-A,
  • R 1a, W a, R 3 , R 4, R 5, R 6, Y, L, R 9, W b and n are as defined above.
  • W b is selected from the group consisting of -COOH, -OH, and -NH 2 .
  • a method for preparing the compound according to the first aspect is provided, and the compound is prepared by method one or method two;
  • W b and W c are each independently the same or different active groups; the intermediate I is an intermediate as shown in formula IV, and the intermediate II is an intermediate as shown in formula V; R 2 and The definition of R 8 is the same as that in claim 1.
  • the active group W b and the active group W c can react to form the group W.
  • Intermediate I is an intermediate represented by Formula IV-A.
  • Intermediate I is an intermediate as shown in Formula IV-A and Intermediate II is an intermediate as shown in Formula V-A.
  • W b is selected from the group consisting of -R'COOH, -R'C(O)H, -R'OH, -R'N(R a )H, -R'SO 3 H, -R'SO 2 H; wherein the definitions of R'and Ra are as described above; preferably, W b is -R'COOH.
  • W c is selected from the following group: -R"COOH, -R"C(O)H, -R"OH, -R"N(R a )H, -R"SO 3 H, -R "SO 2 H; wherein, R" and R a is as previously defined; preferably, W c is -R "NH 2.
  • step (1.1) the molar ratio of intermediate I to NH 2 -R 8 is (0.8 to 1.2):1.
  • step (2.1) the molar ratio of intermediate I to NH 2 -R 2 -W b is (0.8 to 1.2):1.
  • step (2.2) the molar ratio of intermediate II to W c -R 8 is (0.8 to 1.2):1.
  • reaction temperature in step (1.1) is 20 to 150°C; preferably, 20 to 100°C.
  • reaction time of step (1.1) is 2 to 48 hours; preferably, 10 to 48 hours.
  • reaction temperature in step (2.1) is 20 to 150°C; preferably, 20 to 100°C.
  • reaction time of step (2.1) is 2 to 48 hours; preferably, 10 to 48 hours.
  • reaction temperature in step (2.2) is 0-100°C; preferably, 10-50°C; more preferably, 15-40°C.
  • reaction time in step (2.2) is 10 to 48 hours; preferably, 20 to 30 hours; more preferably, 24 hours.
  • the first inert solvent is selected from the group consisting of methanol, ethanol, toluene, dichloromethane, or a combination thereof.
  • the second inert solvent is selected from the group consisting of dichloromethane, methanol, ethanol, or a combination thereof.
  • the modified liposomes and/or lipid-drug complexes have endocytosis and release response functions.
  • the lipid-drug complex is a lipid-drug complex formed by complexing liposomes and drugs.
  • the drug is a gene drug.
  • the gene medicine is a nucleic acid.
  • the genetic medicine is selected from the group consisting of RNA (siRNA), plasmid DNA (pDNA), small hairpin RNA (shRNA), antisense oligonucleotide (ODN), messenger RNA (mRNA), Micro RNA (miRNA).
  • RNA siRNA
  • pDNA plasmid DNA
  • shRNA small hairpin RNA
  • ODN antisense oligonucleotide
  • mRNA messenger RNA
  • miRNA Micro RNA
  • the liposomes include cationic lipids and optional auxiliary lipids.
  • the cationic lipid includes: DOTAP (N-[1-(2,3-bisoleoyloxy)propyl]-N,N,N-trimethylammonium salt), DODAC (N,N-Dioleyl-N,N-Dimethylammonium Chloride), DDAB (N,N-Distearyl-N,N-Dimethylammonium Bromide), DODAP(1,2 -Dioleyl-3-dimethylammonium-propane), DOTMA (N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride ), DOCDAP (1,2-dioleoylcarbamoyl-3-dimethylammonium-propane), DLINDAP (1,2-dilinoleyl-3-dimethylammonium-propane), DLTAP (dilaurel (C12:0) trimethylammonium propane), DOGS
  • the cationic lipid includes: DOTAP, DOTAM, DOSPA, DOGS, or a combination thereof.
  • the auxiliary lipids include: sterol lipids, phosphatidylcholine lipids, phosphatidylethanolamine lipids, sphingosine phospholipid lipids, or a combination thereof; preferably ,
  • the auxiliary lipid is a sterol lipid; more preferably, the lipid is cholesterol (Chol).
  • the sterol lipid includes: cholesterol (Chol).
  • the phosphatidylcholine (PC) lipids include: DPPC (1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine), DMPC (1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine) Myristoylphosphatidylcholine), DDPC (1,2-Didecanoyl-sn-glycerol-3-phosphorylcholine), DSPC (distearoylphosphatidylcholine), DOPC (dioleoylphosphatidylcholine) Choline), or a combination thereof.
  • DPPC 1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine
  • DMPC 1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine
  • Myristoylphosphatidylcholine Myristoylphosphatidylcholine
  • DDPC 1,2-Didecanoyl-sn-glycerol
  • the phosphatidylethanolamine (PE) lipids include: DSPE (distearoyl-phosphatidylethanolamine), DPPE (dipalmitoylphosphatidylethanolamine), DOPE (dioleoylphosphatidylethanolamine) ), DLPE (Dilauroylphosphatidylethanolamine), or a combination thereof.
  • the sphingosine phospholipid lipid includes: ceramide.
  • lipid-drug complex that is responsive to endocytosis and release, and the lipid-drug complex is a lipid-modified compound as described in the first aspect.
  • Drug complexes are provided.
  • the lipid-drug complex is formed by complexing liposomes and drugs.
  • the lipid-drug complex is a lipid-gene drug complex (that is, a lipid-drug complex formed by complexing liposomes and a gene drug).
  • lipid-drug complex responsive to endocytosis, dilution and release.
  • the lipid-drug complex is composed of liposomes, drugs (preferably, gene drugs) and The compound is compounded as described in the first aspect, and the liposome includes: cationic lipid and optional auxiliary lipid.
  • the molar ratio of the cationic lipid to the compound as described in the first aspect is 1:(0.1-10); preferably, it is 1:( 0.2 ⁇ 5); more preferably, 1:(1 ⁇ 0.2).
  • the molar ratio of the cationic lipid, the compound as described in the first aspect and the auxiliary lipid is 1:(0.1-10):(0.1-10) ); Preferably, it is 1:(0.2 ⁇ 5):(0.2 ⁇ 5); more preferably, it is 1:(1 ⁇ 0.2):(1 ⁇ 0.2).
  • the cationic lipid is as defined in the fifth aspect.
  • the auxiliary lipid is as defined in the fifth aspect.
  • the preparation comprises the lipid-drug complex as described in the sixth or seventh aspect.
  • kits comprising: the compound as described in the first aspect, a cationic lipid, and optional auxiliary lipids.
  • the kit also includes drugs (preferably, genetic drugs).
  • the definition of the cationic lipid, auxiliary lipid and/or drug is the same as that in the fifth aspect.
  • a method for introducing a drug into a cell including the step of contacting a subject with the drug complex according to the seventh aspect or the drug complex according to the eighth aspect, thereby Import drugs.
  • the drug is a gene drug.
  • the definition of the cationic lipid, auxiliary lipid and/or drug is the same as that in the fifth aspect.
  • the method is non-therapeutic in vitro.
  • the object is a cell.
  • the method includes the step of culturing the drug complex according to the seventh aspect or the drug complex according to the eighth aspect together with cells, so as to introduce the drug into the cells.
  • a method for cell transfection including the step of contacting a subject (preferably, a cell) with a lipid-gene drug complex modified by the compound described in the first aspect , So as to carry out transfection.
  • the gene medicine is DNA.
  • the method is non-therapeutic in vitro.
  • the lipid-gene drug complex is cultured with the cell, thereby introducing the gene drug into the cell.
  • the method includes the step of: modifying the compound as described in the first aspect
  • a method of gene therapy including the step of administering the lipid-drug complex as described in the seventh aspect or the lipid-drug complex as described in the eighth aspect to a subject ⁇ or formulation as described in the eighth aspect.
  • the drug is a gene drug.
  • Figures 1A and B respectively show the degradation under in vitro conditions.
  • FIG. 1 shows the transfection of different compounds.
  • Cationic liposomes modified with such compounds or cationic liposomes containing such compounds can be used to deliver genetic drug compounds and provide excellent cell transfection efficiency.
  • Such compounds include a lipophilic head, a hydrophilic chain (such as a long PEG chain), and an intermediate group with a special core structure that has a pH response function.
  • Cationic liposomes modified by the compounds of the present invention or complexes of cationic liposomes containing the compounds of the present invention and genetic drugs are not easy to aggregate and bind to albumin to form large particles in an extracellular environment, and are not easily reticulated Epithelial cells are recognized and eliminated, so that they can reach the target site smoothly.
  • the compound modified by the compound of the present invention or the complex containing the compound of the present invention can be rapidly degraded in the environment of the intracellular solvent medium (that is, the compound of the present invention is broken due to pH response), thereby exposing cationic lipids and genetic drugs (such as nucleic acids)
  • the positive charge of the complex and then realize the lysosome escape of nucleic acid, release the nucleic acid into the cytoplasm, enter the nucleus, and realize the efficient transfection of nucleic acid.
  • the inventor completed the present invention.
  • halogen refers to F, Cl, Br, and I. More preferably, the halogen atom is selected from F, Cl and Br.
  • C10-C20 saturated or unsaturated hydrocarbon group includes alkyl groups, unsaturated hydrocarbon groups containing one or more (such as 1, 2, 3, 4, or 5) double bonds and/or triple bonds.
  • the C10-C20 saturated or unsaturated hydrocarbon group is a straight or branched chain hydrocarbon group (for example, containing 1, 2 or 3 straight chain hydrocarbon groups).
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 represents 1-6 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.
  • C1-C6 alkoxy includes linear or branched alkoxy groups of 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, or the like.
  • cycloalkyl refers to a hydrocarbon ring that has the specified number of ring atoms (eg, C3-C8 cycloalkyl) and is fully saturated or has no more than one double bond between the ring tops.
  • Cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like.
  • heterocycloalkyl refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • the heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system.
  • Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, Piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc.
  • the heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom.
  • cycloalkylalkyl and heterocycloalkylalkyl it is meant that the cycloalkyl or heterocycloalkyl is connected to the rest of the molecule through an alkyl or alkylene linker.
  • cyclobutylmethyl- is a cyclobutyl ring attached to the methylene linker of the rest of the molecule.
  • aryl means a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized . Heteroaryl groups can be attached to the rest of the molecule through heteroatoms.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, Quinoxalinyl, quinazolinyl, cinnoline, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benziso Oxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzene And thiazolyl, benzofuranyl, benzothienyl, indolyl, quinoliny
  • aryl when used in combination with other terms (eg, aryloxy, arylthio, aralkyl), it includes aryl and heteroaryl rings as defined above. Therefore, the term “aralkyl” is meant to include those groups in which the aryl group is attached to an alkyl group attached to the rest of the molecule (e.g., benzyl, phenethyl, pyridylmethyl, etc.).
  • heteroatom is meant to include oxygen (O), nitrogen (N), and sulfur (S).
  • derived from a compound or lipid refers to a corresponding group formed by reacting an active group (such as an amino group, a hydroxyl group, a carboxyl group, etc.) in the compound or lipid with another compound or a compound.
  • an active group such as an amino group, a hydroxyl group, a carboxyl group, etc.
  • Liposomes are microvesicles formed by encapsulating drugs in a lipid bilayer.
  • the main components are phospholipids and cholesterol.
  • Lipid membrane has a structure similar to biological membrane, so it has good biocompatibility. After encapsulating the drug, it enters the cell in the form of endocytosis and fusion, thereby delivering the drug to the target cell.
  • Cationic liposomes are liposomes composed of positively charged cationic lipids and neutral auxiliary lipids. Cationic liposomes have the advantages of strong ability to load macromolecular gene drugs and high transfection efficiency in vitro. They are widely used in in vivo and in vitro research, and they are also one of the most used non-viral vectors at present. Cationic lipids are composed of a positively charged hydrophilic head, a hydrophobic tail, and a connecting chain connecting the head to the tail. Cationic liposomes are generally composed of cationic lipids and auxiliary lipids.
  • the head of cationic lipids is positively charged and can be combined with negatively charged nucleic acid substances through electrostatic interaction; auxiliary lipids are generally uncharged and have stable lipid bimolecules
  • the layer may help the lipid membrane to fuse with the endosomal membrane.
  • Common cationic lipids include DOTAP, DOTAM, DOSPA, etc.
  • the positive charge of different lipid heads is different, which determines the amount of nucleic acid loaded in liposomes and the toxicity;
  • common neutral lipids mainly include Chol, DOPE, DPPC, etc.
  • the gene delivery mechanism of the cationic lipid/nucleic acid complex is: the cationic liposome and the negatively charged nucleic acid are tightly combined through electrostatic interaction to form a lipid/nucleic acid complex of uniform size and small particle size.
  • the positively charged lipid/nucleic acid complex is easily adsorbed to the surface of the negatively charged cell membrane and enters the cell through the mechanism of endocytosis or membrane fusion.
  • the endocytosed lipid/nucleic acid complex escapes through the lysosome and releases nucleic acid and DNA After the drug-like endosomes escape, they are released into the cytoplasm, and then further penetrate the nuclear membrane and enter the nucleus to play a role.
  • the pH-responsive chemical bonds in the compound will partially or All of them are broken, thereby releasing the hydrophilic chains (such as hydrophilic long-chain PEG) and exposing the positive charge properties of cationic liposomes (such as DOTAP), so that the lipid/nucleic acid complexes expose more positive charges.
  • the hydrophilic chains such as hydrophilic long-chain PEG
  • cationic liposomes such as DOTAP
  • the compound of the present invention includes a lipophilic head for insertion into liposomes (or complexes), a hydrophilic chain, and a responsive group connecting the lipophilic head and the hydrophilic chain, wherein the The response group has a pH response function.
  • the intermediate chain remains stable when the pH is greater than 7 (for example, 7.35 to 7.45), and breaks when the pH is lower than 6 (for example, about 5), thereby releasing the hydrophilic group.
  • the compound modified by the compound of the present invention (for example, a lipid-nucleic acid complex) is stable in the extracellular environment, is not easy to aggregate, is not easy to be eliminated, and can smoothly reach the target site.
  • the compound modified by the compound of the present invention can be rapidly degraded in the intracellular environment (generally within 2 hours), exposing the complex of cationic lipid and gene drug (such as nucleic acid) to realize lysosome escape.
  • the transfection efficiency of the compound modified by the compound of the present invention is high.
  • the transfection under serum-free condition is slightly higher than that of non-modified cationic liposome, and the transfection efficiency under serum-containing condition can generally reach 10-20 of that of unmodified cationic liposome. Times.
  • the present invention synthesizes the compound Cpd7 which has a pH-responsive group but cannot achieve effective transfection of intracellular genes.
  • the present invention investigates the degradation rate of the synthesized compound with different structures under different buffer system conditions and at different time points.
  • Preparation of cationic blank liposomes take an appropriate amount of DOTAP/Chol chloroform stock solution in a 25ml eggplant-shaped bottle, so that the molar ratio of DOTAP/Chol is 1:1, the total lipid concentration is 2mg/ml, and the total lipid is 4mg Rotate and evaporate under reduced pressure on a rotary evaporator for 30 minutes, dry the residual chloroform with N 2 , add 2 ml of 10 mM Hepes buffer salt solution, and sonicate for 30 minutes to obtain a cationic blank liposome.
  • Malvern laser particle size analyzer measured its particle size as 153.2nm, polydispersity coefficient as 0.212, and potential as 50.4mV.
  • the Cpd8 modified negative control group (DOTAP+Cpd8) has a transfection ⁇ 1000, which is consistent with the untreated group (untreated group), and it is considered untransfected;
  • the transfection result of the unmodified cationic lipid group (DOTAP group, namely the cationic lipid/nucleic acid complex prepared in 2.1) was 1 ⁇ 10 6
  • the transfection result of the Cpd2 modified lipid complex group (DOTAP+Cpd2 group) was 4 ⁇ 10 6
  • the transfection result of DOTAP+Cpd2 group was about 4 times that of DOTAP group.
  • 20% FBS is to simulate the internal environment of body fluid circulation.
  • the negative control group DOTAP+Cpd8 is still not transfected, while the transfection efficiency of the unmodified cationic DOTAP group is greatly reduced, only 6 ⁇ 10 3 , but the transfection result of the Cpd2 modified lipid complex DOTAP+Cpd2 group was 1.2 ⁇ 10 5 , and the transfection result of the DOTAP+Cpd2 group was about 20 times that of the DOTAP group.

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Abstract

La présente invention concerne un composé présentant une réponse à la libération endocytique de cellules et son utilisation. En particulier, la présente invention concerne un composé présentant une réponse à l'endocytose, qui est composé d'une tête lipophile, d'une chaîne hydrophile, et d'un groupement présentant une réponse au pH au milieu, et qui est tel que représenté par la formule I. Le complexe modifié au moyen du composé selon la présente invention est stable en termes de circulation de fluides corporels, et possède également une grande efficacité de transfection.
PCT/CN2021/094706 2020-05-19 2021-05-19 Composé présentant une réponse à la libération endocytique de cellules et son utilisation Ceased WO2021233352A1 (fr)

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Citations (4)

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CN106754912A (zh) * 2016-11-16 2017-05-31 上海交通大学 一类定向清除肝细胞中HBVccc的DNA、质粒及制剂
CN107441506A (zh) * 2016-05-30 2017-12-08 上海交通大学 基因输送载体及其制备与应用

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EP3721943A1 (fr) * 2009-12-23 2020-10-14 Novartis AG Lipides, compositions de lipides et leurs procédés d'utilisation
CN102351852B (zh) * 2011-08-23 2014-06-18 上海交通大学 苯并呋喃类化合物及其制备方法、用途
WO2015153345A1 (fr) * 2014-04-03 2015-10-08 Invictus Oncology Pvt. Ltd. Agents thérapeutiques combinatoires supramoléculaires
CN104478836B (zh) * 2014-12-09 2017-06-13 上海交通大学 苯并呋喃类化合物及其制备、用途
CN108743953B (zh) * 2018-06-13 2021-06-01 四川大学 一种双重脑肿瘤靶向脂质材料及其应用

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WO1997013764A1 (fr) * 1995-10-12 1997-04-17 Eli Lilly And Company Benzothiofenes lipophiles
US20130261168A1 (en) * 2012-03-30 2013-10-03 Purdue Research Foundation Nucleic acid complexes
CN107441506A (zh) * 2016-05-30 2017-12-08 上海交通大学 基因输送载体及其制备与应用
CN106754912A (zh) * 2016-11-16 2017-05-31 上海交通大学 一类定向清除肝细胞中HBVccc的DNA、质粒及制剂

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