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WO2025016441A1 - Nouveau fragment d'administration ciblée de galnac, sa préparation et son utilisation - Google Patents

Nouveau fragment d'administration ciblée de galnac, sa préparation et son utilisation Download PDF

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Publication number
WO2025016441A1
WO2025016441A1 PCT/CN2024/106233 CN2024106233W WO2025016441A1 WO 2025016441 A1 WO2025016441 A1 WO 2025016441A1 CN 2024106233 W CN2024106233 W CN 2024106233W WO 2025016441 A1 WO2025016441 A1 WO 2025016441A1
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Prior art keywords
group
compound
galnac
unsubstituted
substituted
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English (en)
Chinese (zh)
Inventor
卢涔宾
唐国志
周云隆
刘永福
阙日明
马大为
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Shanghai Visonpharma Co Ltd
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Shanghai Visonpharma Co Ltd
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    • 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
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to the field of medicine, and in particular, provides a novel GalNAc targeted delivery fragment and its preparation and application.
  • Hepatitis B virus belongs to the Hepaciviridae family of small, enveloped, primarily hepatotropic viruses with a partially double-stranded DNA genome of approximately 3.2 kb in size. HBV infection remains a major public health problem. Despite the availability of safe and effective preventive HBV vaccines, it is estimated that approximately 250 million people worldwide are chronically infected with HBV. Chronic HBV infection places patients at high risk for cirrhosis and liver cancer, and it is estimated that more than 686,000 people die each year from complications of HBV. (WHO.Global hepatitis report 2017)
  • nucleoside (nucleotide) analogs often require prolonged or potentially lifelong treatment, and some have resistance, low efficacy, and tolerability issues. Therefore, there is still a huge medical need to discover and develop effective and safe anti-HBV drugs with novel mechanisms of action to improve disease cure rates.
  • GalNAc-mediated liver-targeted delivery of small interfering RNA drugs can inhibit the expression of target genes at the basic level of mRNA translation into protein, and has recently been used to treat a variety of liver-related diseases.
  • GalNAc-siRNA molecules have the characteristics of strong efficacy, high liver targeting specificity, and good safety, so they have unique advantages in the field of anti-hepatitis B, but current experimental drugs cannot effectively reduce HBsAg content and cannot achieve a high level of clinical cure rate. Therefore, it is necessary to optimize this type of molecule, focusing on the structural modification of the targeted delivery fragment containing GalNAc to improve delivery efficiency and drug properties.
  • the object of the present invention is to provide a GalNAc-siRNA molecule and a nucleic acid delivery pharmaceutical composition prepared using the same.
  • GalNAc delivery molecule as shown in the following formula (I), or a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof:
  • Ax is a substituted or unsubstituted 4-12-membered saturated or partially unsaturated nitrogen-containing heterocyclic group, or a substituted or unsubstituted 4-12-membered nitrogen-containing heteroaryl group;
  • R1 is selected from the group consisting of H, DMTr, phosphate, phosphorothioate, phosphorothioate-siRNA conjugate, or phosphate-siRNA conjugate;
  • Linker is a divalent linking group
  • Q is selected from the group consisting of a chemical bond, -NH-C(O)-, -C(O)-;
  • r is 0, 1, 2, 3, 4, 5 or 6;
  • R2 is a GalNAc target head portion and has a structure selected from the group consisting of:
  • L 1 and L 2 are each independently a trivalent linking group
  • L 3 is a divalent linking group
  • R 3 , R 4 and R 5 are each independently a substituted or unsubstituted sugar group, preferably a group formed by a substituted or unsubstituted N-acetylgalactosamine molecule
  • substitution refers to that one or more hydrogen atoms on the group are replaced by substituents selected from the following groups: C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C3-8 aryl, 5- to 7-membered heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, amino, C1-8 alkoxy, C1-10 sulfonyl; or two substituents located on adjacent ring atoms can form a group selected from the following group together with the connected ring atoms: 5-7 membered carbocyclic or heterocyclic ring, benzene ring, or 5-7 membered heteroaromatic ring.
  • substituents selected from the following groups: C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3
  • R' is selected from the following group: H or C 1-8 alkyl
  • p 1, 2, 3, 4, 5 or 6.
  • the siRNA is selected from the following group: siRNA that inhibits the expression of hepatitis B virus (HBV) gene, siRNA that inhibits the expression of apolipoprotein C3 (APOC3) gene, siRNA that inhibits the expression of PCSK9 gene, siRNA that inhibits the expression of CCR4 gene, and siRNA that inhibits the expression of thyroxine transporter (TTR) gene.
  • HBV hepatitis B virus
  • APOC3 apolipoprotein C3
  • PCSK9 siRNA that inhibits the expression of PCSK9 gene
  • CCR4 thyroxine transporter
  • the Linker has a structure selected from the following group:
  • n, n3 and m are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n1 and n2 are each independently selected from the following group: 0 or 1;
  • Z is selected from the following group: a single bond, a substituted or unsubstituted C 1-8 alkylene group, a substituted or unsubstituted 7-12-membered fused bicyclic ring, a substituted or unsubstituted 7-15-membered spirocyclic ring, a substituted or unsubstituted 5-15-membered bridged ring, a -NH-substituted or unsubstituted 7-12-membered fused bicyclic ring, a -NH-substituted or unsubstituted 7-15-membered spirocyclic ring, a -NH-substituted or unsubstituted 5-15-membered bridged ring, a -NH-substituted or unsubstituted 7-12-membered fused bicyclic ring-NH-, -NH-substituted or unsubstituted 7-12-member
  • substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, C 1-8 alkoxy, C 1-10 sulfonyl; or two substituents located on adjacent ring atoms can form a group selected from the group consisting of a 5-7-membered carbocyclic or heterocyclic ring, a benzene ring, or a 5-7-membered heteroaromatic ring together with the connected ring atoms;
  • Z has a structure selected from the group consisting of:
  • s1, s2, s3, s4, s5 and s6 are each independently selected from the following group: 0, 1 or 2;
  • s7 is selected from the group consisting of 1, 2, 3, 4, 5 or 6;
  • Each of M 1 , M 2 , M 3 and M 4 is independently selected from the group consisting of CHR, C(R)R, C(O), O, S, NR;
  • M5 and M6 are each independently selected from the group consisting of (CHR) s6 , C(R)R, C(O), (CHR) s6 -C(O), O, S, NR;
  • R is selected from the following group: H, halogen, methyl; or two R located on adjacent reducing atoms and the carbon atom to which they are connected together constitute a substituted or unsubstituted C 3-8 saturated or partially unsaturated carbocyclic ring, a 4-8 membered saturated or partially unsaturated heterocyclic ring, a C 6-10 aromatic ring or a 5-12 membered heteroaromatic ring.
  • the Z has a structure selected from the following group:
  • L 1 , L 2 and L 3 are each independently a structure shown in the following formula:
  • the L3 is a structure shown in the following formula:
  • R 11 is selected from the following group: H or C 1-4 alkyl
  • Each u, v and w is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
  • Glu is an unmodified or modified 5-6-membered sugar group;
  • X1 is selected from the group consisting of a substituted or unsubstituted C4-10 saturated or partially unsaturated carbocyclic group, a substituted or unsubstituted 4-10 membered saturated or partially unsaturated heterocyclic group (preferably a nitrogen-containing heterocyclic group), a substituted or unsubstituted C6-10 phenyl group, or a substituted or unsubstituted 5-10 membered heteroaryl group;
  • X2 is selected from the following group: -NH-( C1 - C6 alkyl)-NH-, -NH-( C3 - C8 cycloalkyl)-NH-, -NH-(4-10 membered heterocyclyl)-NH-, substituted or unsubstituted C4-10 saturated or partially unsaturated carbocyclyl, substituted or unsubstituted 4-10 membered saturated or partially unsaturated heterocyclyl (preferably nitrogen-containing heterocyclyl), substituted or unsubstituted C6-10 phenyl, or substituted or unsubstituted 5-10 membered heteroaryl;
  • the carbocyclic group and heterocyclic group may be a single ring, a condensed ring, a bridged ring or a spiro ring.
  • the R 2 has a structure as shown below:
  • the X 1 is a substituted or unsubstituted structure selected from the following group:
  • s1, s2, s, s4, s5 and s6 are each independently selected from the following group: 0, 1 or 2;
  • s7 is selected from the group consisting of 1, 2, 3, 4, 5 or 6;
  • Each of M 1 , M 2 , M 3 and M 4 is independently selected from the group consisting of CHR, C(R)R, C(O), O, S, NR;
  • M5 and M6 are each independently selected from the group consisting of (CHR) s6 , C(R)R, C(O), (CHR) s6 -C(O), O, S, NR;
  • R is selected from the following group: H, halogen, methyl; or two R located on adjacent reducing atoms and the carbon atom to which they are connected together form a substituted or unsubstituted 4-8 membered carbocyclic or heterocyclic ring (including saturated, unsaturated or aromatic ring).
  • the X2 is a substituted or unsubstituted structure selected from the following group:
  • the sugar group has a structure as shown in Formula III below:
  • the R 15 is selected from the following group: -NH(C 2 -C 6 acyl), -NH(halogenated C 2 -C 6 acyl), -NH(C 2 -C 6 sulfonyl), -NH(halogenated C 2 -C 6 sulfonyl);
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of H or C 1 -C 6 acyl.
  • R 15 is selected from the group consisting of -NH (C 2 -C 4 acyl); R 12 , R 13 and R 14 are each independently selected from the group consisting of H or C 1 -C 4 acyl.
  • R 15 is -NHAc; R 12 , R 13 and R 14 are each independently selected from the following group: H or Ac.
  • the GalNAc delivery molecule has a structure selected from the group consisting of:
  • the GalNAc delivery molecule has a structure selected from the group consisting of:
  • a pharmaceutical composition comprising: one or more of the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and/or diluents.
  • the composition is used to prepare a pharmaceutical composition for treating or preventing tumors or infections caused by viruses.
  • a disease or condition selected from the group consisting of: Diseases or conditions caused by hepatitis B virus, diseases or conditions caused by abnormal expression of ANGPTL3 gene, diseases or conditions caused by abnormal expression of TTR gene, diseases or conditions caused by abnormal expression of hepatocyte genes, or other liver diseases or conditions.
  • GalNAc delivery molecule linker as shown in formula (Ia), or a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof:
  • the part shown in formula (Ia) has a structure selected from the group consisting of
  • the inventors Based on long-term and in-depth research, the inventors have prepared a novel type of GalNAc targeted drug delivery fragment with a novel structure.
  • the drug or drug composition composed of the GalNAc targeted delivery fragment has good targeted delivery effect, good efficacy and higher safety. Based on the above findings, the inventors have completed the present invention.
  • the halogen is F, Cl, Br or I.
  • C 1 -C 6 alkyl refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C 1 -C 6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
  • C 3 -C 7 cycloalkyl refers to a cyclic alkyl group having 3 to 7 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • C 5 -C 6 cycloalkyl and “C 3 -C 6 cycloalkyl” have similar meanings.
  • aromatic ring or “aryl” has the same meaning, preferably "aryl” is “C 6 -C 12 aryl” or “C 6 -C 10 aryl”.
  • aryl is “C 6 -C 12 aryl” or “C 6 -C 10 aryl”.
  • C 6 -C 12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.
  • C 6 -C 10 aryl has a similar meaning.
  • the term "aromatic heterocycle” or “heteroaryl” has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms.
  • the heteroatoms referred to here include oxygen, sulfur and nitrogen.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • 3-9 membered carbocyclic group refers to a saturated or unsaturated (non-aromatic ring, including monocyclic, cyclic, spirocyclic, bridged ring, etc.) 3-9 membered cyclic group, whose ring skeleton structure only includes carbon atoms, such as cyclopentyl, cyclohexyl, etc.
  • 3-9 membered heterocyclic group refers to a 3-9 membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which is saturated or unsaturated (non-aromatic ring, including monocyclic, cyclic, spirocyclic, bridged, etc.), such as dioxolanyl, etc.
  • the term “3-7 membered heterocyclic group” has a similar meaning.
  • substituted refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent.
  • the specific substituent is a substituent described above or a substituent appearing in the examples.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl may be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, two rings having There is a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically feasible.
  • the substituents include, but are not limited to, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, alkoxy, C 1-10 sulfonyl, etc.
  • substituents are designated by their conventional chemical formula (written from left to right), they equivalently include chemically identical substituents resulting from the structure written from right to left, e.g., -NH-C(O)- is intended to include -C(O)-NH-, and -COO- is intended to include -OCO-.
  • composition containing active ingredients
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 0.01-99.99% by weight of the compound of the present invention/dose, and more preferably, contains 0.1-99.9% by weight of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • compositions of the present invention include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings. and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If necessary, the active compound may also be in microcapsule form with one or more of the above excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, anti-HBV agents).
  • other pharmaceutically acceptable compounds eg, anti-HBV agents.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds.
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention to prevent and/or treat related diseases or conditions.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when applied is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the dosage when applied is a pharmaceutically effective dosage.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health status, which are all within the skill of a skilled physician.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shift ( ⁇ ) is given in units of 10 -6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • SHIMADZU LC system chromatographic column: CSH TM Prep-C18, 19*150mm, liquid Analyzer LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution).
  • LC/MS spectra of the compounds were obtained using LC/MS (Agilent Technologies 1200 Series). The LC/MS conditions were as follows (run time was 10 min):
  • Acidic conditions A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;
  • intermediates and final compounds were purified by silica gel column chromatography or by using Purification was performed by preparative HPLC on a CSH TM Prep-C18 (5 ⁇ m, OBD TM 19*150 mm) column or using an XBridgeTM Prep Phenyl (5 ⁇ m, OBD TM 30*100 mm) column on a reverse phase column.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography (TLC) silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography detection products are 0.15mm ⁇ 0.2mm, and the specifications used in thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • NaIO 4 sodium periodate
  • RuCl 3 ruthenium trichloride
  • BnBr benzyl bromide
  • K 2 CO 3 potassium carbonate
  • DIEPA (DIEA) N,N-diisopropylethylamine
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • TEA triethylamine
  • HATU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • CbzCl benzyl chloroformate
  • NaOH sodium hydroxide
  • DMSO dimethyl sulfoxide
  • HOBt 1-hydroxybenzotriazole
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMF N,N-dimethylformamide
  • reaction mixture was diluted with ethyl acetate and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified to obtain a yellow oil compound A3-4 (16 g).
  • reaction mixture of compound A3-4 (16 g) in dichloromethane (100 ml) and trifluoroacetic acid (20 ml) was stirred at 20°C for 12 hours; the reaction mixture was then concentrated to obtain a yellow oil compound A3-5 (20 g), which was used directly in the next step without purification.
  • Step 4 Preparation of Compound A12-4
  • a DMF (10 ml) solution of tert-butyl (3-aminopropyl)carbamate (3.07 g, 17.63 mmol), DIEA (1.898 g, 14.69 mmol), Compound A12-3 (4 g, 2.94 mmol) and HATU (4.47 g, 11.75 mmol) was stirred at 20°C for 40 hours; the reaction mixture was then concentrated to obtain a crude product, which was purified to obtain a yellow oily compound A12-4 (630 mg, 16.7%).
  • Step 4 Preparation of Compound A13-6 Synthesis of Compound A13-6
  • Compound A13-6 was prepared by using Compound A13-3 instead of 1-(tert-butyl) 2-methyl (S)-pyrrolidine-1,2-dicarboxylate.
  • aminogalactose compound connected to the solid phase carrier disclosed in the present invention is synthesized by methods well known to those skilled in the art or by methods described in detail in the prior art.
  • WO2015006740A2 describes in detail the preparation method of the aminogalactose compound connected to the solid phase carrier.
  • the synthesis of the aminogalactose compound III-LA13-CPG linked to the solid phase support was based on the synthesis of the aminogalactose compound III-LA15-CPG linked to the solid phase support.
  • siRNA targeting mouse TTR gene mRNA (Nucleic Acids Res. 2020 Dec 2; 48(21): 11827-11844) is as follows, the aminogalactose molecule cluster M is covalently linked to the 3' end of the SS chain,
  • siRNA conjugates disclosed herein are synthesized by methods well known to those skilled in the art or by methods described in detail in the prior art.
  • WO2015006740A2 describes in detail the preparation methods of various siRNA conjugates.
  • S-L96 was purchased from Jima Gene; C, G, A, U or c, g, a, u represent the base composition of nucleotides.
  • the uppercase and lowercase letters represent monomers modified with 2′-deoxy-2′-fluoro (2′-F) and 2′-O-methyl (2′-OMe), respectively.
  • ⁇ represents thio
  • L represents N-acetylgalactosamine ligand.
  • siRNA conjugate After the preparation of the siRNA conjugate disclosed above is completed, it is freeze-dried into solid powder using standard means and stored for later use. When in use, it can be redissolved into a solution of desired concentration using, for example, water for injection, physiological saline, phosphate buffer or phosphate buffer.
  • the test compound and GalNAc-Cy5 compete with the ASGPR receptor on the surface of monkey primary cells (PCMH, purchased from Miaoshun Biotechnology Co., Ltd.).
  • the fluorescence intensity of Cy5 detected by flow cytometry can reflect the affinity of the test compound to ASGPR. The weaker the Cy5 fluorescence intensity, the stronger the affinity of the test compound to ASGPR, and vice versa.
  • mice 6-8 week old C57/BL6 mice were randomly divided into 3 groups, 3 mice in each group, and 1 group received no treatment.
  • the positive control group (S-L96) and drug treatment group (S-LA13, S-LA15) were injected subcutaneously with 0.3 mg/kg, 1 mg/kg and 3 mg/kg of GalNac-siRNA.
  • Blood was collected from the eye sockets to separate serum before administration (day 0), 3 days after administration (day 3), 7 days after administration (day 7), 14 days after administration (day 14) and 21 days after administration (day 21), and mice were killed on day 21 to obtain liver samples.
  • the TTR levels in mouse serum and liver samples were detected using the Mouse Prealbumin ELISA Kit (cat#ALPCO(41-PALMS-E01)), and the results are as follows:

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Abstract

La présente invention divulgue une molécule d'administration de GalNAc telle que représentée dans la formule (I), ou un stéréoisomère, un énantiomère ou un sel pharmaceutiquement acceptable de celle-ci, les définitions des groupes étant telles que décrites dans la description.
PCT/CN2024/106233 2023-07-19 2024-07-18 Nouveau fragment d'administration ciblée de galnac, sa préparation et son utilisation Pending WO2025016441A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015006740A2 (fr) * 2013-07-11 2015-01-15 Alnylam Pharmaceuticals, Inc. Conjugués ligands d'oligonucléotides et procédé pour leur préparation
CN104717982A (zh) * 2012-08-06 2015-06-17 阿尔尼拉姆医药品有限公司 碳水化合物共轭物及其制备改进工艺
CN111973618A (zh) * 2019-05-23 2020-11-24 苏州瑞博生物技术股份有限公司 核酸、药物组合物与siRNA缀合物及制备方法和用途
CN114621954A (zh) * 2021-04-13 2022-06-14 厦门甘宝利生物医药有限公司 一种抑制乙型肝炎病毒基因表达的rna抑制剂及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104717982A (zh) * 2012-08-06 2015-06-17 阿尔尼拉姆医药品有限公司 碳水化合物共轭物及其制备改进工艺
WO2015006740A2 (fr) * 2013-07-11 2015-01-15 Alnylam Pharmaceuticals, Inc. Conjugués ligands d'oligonucléotides et procédé pour leur préparation
CN111973618A (zh) * 2019-05-23 2020-11-24 苏州瑞博生物技术股份有限公司 核酸、药物组合物与siRNA缀合物及制备方法和用途
CN114621954A (zh) * 2021-04-13 2022-06-14 厦门甘宝利生物医药有限公司 一种抑制乙型肝炎病毒基因表达的rna抑制剂及其应用

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