WO2024051794A1 - Conjugué radionucléide-médicament, composition pharmaceutique et leur utilisation - Google Patents

Conjugué radionucléide-médicament, composition pharmaceutique et leur utilisation Download PDF

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WO2024051794A1
WO2024051794A1 PCT/CN2023/117622 CN2023117622W WO2024051794A1 WO 2024051794 A1 WO2024051794 A1 WO 2024051794A1 CN 2023117622 W CN2023117622 W CN 2023117622W WO 2024051794 A1 WO2024051794 A1 WO 2024051794A1
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conjugated drug
formula
drug precursor
radionuclide
targeting ligand
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PCT/CN2023/117622
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Chinese (zh)
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曹锦松
黄保华
王贵涛
陈新
钱刚
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同宜医药（苏州）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of precision diagnosis and treatment, and specifically relates to a radionuclide conjugated drug, a pharmaceutical composition based on the coupled drug, and its application in the medical field.
  • Radiopharmaceuticals refer to a type of special medicine that uses particles or rays released by radionuclides for medical diagnosis and treatment. Radionuclides and their labeled compounds are used to study human physiology, pathology and drug processes in the body. Belongs to the category of radiopharmaceuticals. Radiopharmaceuticals are widely used in tumor diagnosis and treatment, myocardial imaging, early detection of neurodegenerative diseases and inflammatory tissue imaging diagnosis, etc., to achieve fast, non-destructive real-time imaging of physiological and pathological processes, which is an important part of molecular imaging and precision medicine. medicine), providing new means and approaches for early diagnosis and timely treatment in the true sense.
  • RDC uses specific targeting mediated by antibodies, small molecules or peptides to deliver radionuclides used as radiation/imaging factors to the target location, thereby focusing the rays generated by the radionuclides. Targeted at local tissues, it provides efficient and precise diagnosis and treatment while reducing damage to other tissues caused by systemic exposure.
  • RDC Radionuclides loaded by RDC can be used for both diagnosis and treatment.
  • RDC is also slightly different from ADC in structure, requiring the introduction of specific structural fragments for chelating radionuclides. ——Chelates.
  • RDC mainly consists of ligands (such as antibodies, polypeptides or small molecules, etc.), linkers, chelators and radioactive isotopes that mediate the targeting effect. (Radioisotope) composition.
  • ligands such as antibodies, polypeptides or small molecules, etc.
  • linkers such as antibodies, polypeptides or small molecules, etc.
  • chelators such as calcium, calcium, magnesium, calcium, magnesium, magnesium, etc.
  • radioactive isotope composition Depending on the type of ligand, RDC can be divided into antibody-targeted radionuclide antibody conjugates (RAC), radionuclide conjugates based on small molecules (including peptides), etc. Depending on the type of radionuclide, RDC can perform different functions in imaging or treatment, and some nuclides even have both functions.
  • Lutathera Li-177dotatate, or 177Lu-dotatate, used to treat somatostatin receptor-positive gastrointestinal neuroendocrine tumors
  • Pluvicto Li -177 vipivotide tetraxetan, or 177Lu-PSMA-617, for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer
  • Biogen's Zevalin Y-90 ibritumomab tiuxetan, or 90Y -ibritumomab tiuxetan, used to treat non-Hodgkin's lymphoma
  • a few other RDCs there is an urgent need to develop more therapeutic or dual-purpose RDCs to meet the growing demand in the field of precision diagnosis and treatment.
  • the present invention discovered a series of brand-new RDCs, including a variety of dual-ligand RDCs constructed based on dual-targeting technology, which further enriched the range of therapeutic RDCs. Or the type of RDC that is used for both diagnosis and treatment.
  • the invention provides a radionuclide-conjugated drug precursor, which includes a targeting ligand, a chelating agent, an optional linker and an optional spacer.
  • the above-mentioned radionuclide conjugated drug precursor may have a structure shown in formula I,
  • LG represents targeting ligand
  • S represents spacer
  • L represents the linker
  • C represents chelating agent
  • n 1 or 2;
  • n 0 or 1
  • p is 0 or 1
  • LG is directly connected to L or C;
  • the two LGs are the same or different from each other, and the two LGs are connected to S, L, or C at the same time, or the two LGs are connected to each other and then to S, L, or C.
  • the above-mentioned radionuclide-conjugated drug precursor having a structure shown in Formula I may have a structure shown in Formula I-1, LG-LC I-1
  • LG, L and C are as defined in Formula I.
  • the above-mentioned radionuclide-conjugated drug precursor having a structure shown in Formula I may have a structure shown in Formula I-2, LG-C I-2
  • LG and C are as defined in Formula I.
  • the above-mentioned radionuclide-conjugated drug precursor having a structure shown in Formula I may have a structure shown in Formula I-3,
  • LG, S, L and C are as defined in Formula I.
  • the above-mentioned radionuclide-conjugated drug precursor having a structure shown in Formula I may have a structure shown in Formula I-4,
  • LG, S and C are as defined in Formula I.
  • the above-mentioned radionuclide-conjugated drug precursor having a structure shown in Formula I may have a structure shown in Formula I-5,
  • LG, L and C are as defined in Formula I.
  • the above-mentioned radionuclide-conjugated drug precursor having a structure shown in Formula I may have a structure shown in Formula I-6,
  • LG, L and C are as defined in Formula I.
  • the above-mentioned targeting ligand can bind to the following cell surface proteins: PSMA, FORL1, TRPV6, FAPI, C-MET, CAIX, RGD, Hepsin or Sigma.
  • the conjugated drug prodrug including it can bind to the following cell surface proteins: Any one (single target single match), especially PSMA, TRPV6, FAPI, C-MET or CAIX.
  • the conjugated drug prodrugs containing them can bind to any one of the following cell surface protein combinations (single-target double-matching or double-target double-matching), especially PSMA/FORL1, FORL1/TRPV6, PSMA/TRPV6, PSMA/FAPI, PSMA/RGD, PSMA/Hepsin , FAPI/RGD, FAPI/FAPI, FAPI/Hespin, PSMA/Sigma or FAPI/CAIX.
  • the above-mentioned targeting ligand can be formed from a polypeptide, an antibody or a small molecule.
  • Each LG in the precursor can be independently represented by formulas LG-I, LG-II, LG-III, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII, and LG-IX. Any kind of ligand compound is formed,
  • R LG1 is amino
  • R 1 is hydrogen or optionally substituted cycloalkylformyl (e.g., 4-(aminomethyl)cyclohexylformyl, i.e. preferred Or, 4-(6-aminocaproylaminomethyl)cyclohexylformyl, that is preferred
  • cycloalkylformyl e.g., 4-(aminomethyl)cyclohexylformyl, i.e. preferred Or, 4-(6-aminocaproylaminomethyl)cyclohexylformyl, that is preferred
  • R 2 and R 3 are each independently hydrogen or optionally substituted C 6 -C 10 aryl (e.g., phenyl, naphth-1-yl, naphth-2-yl, etc.);
  • R 4 is hydroxyl, optionally substituted C 1 -C 6 alkylamino (e.g., 6-aminohexylamino, i.e. ), an amino acid derivative group (for example, -NH-Asp-COOH) or an oligopeptide derivative group consisting of 2-6 amino acids (for example, -NH-Asp-Asp-Lys-COOH);
  • C 1 -C 6 alkylamino e.g., 6-aminohexylamino, i.e.
  • an amino acid derivative group for example, -NH-Asp-COOH
  • an oligopeptide derivative group consisting of 2-6 amino acids for example, -NH-Asp-Asp-Lys-COOH
  • R 5 is optionally substituted C 1 -C 6 alkyl; when substituted, the substituent is amino-substituted C 1 -C 6 alkanoyl, amino-substituted C 6 -C 10 aroyl, or both through amide
  • the acyl group obtained by the reaction for example, 4-(6-aminocaproylaminomethyl)benzoyl);
  • Formula LG-II is pteroic acid or folic acid or an analog thereof; preferably, the analog of folic acid is selected from the group consisting of 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, and methotrexate. rosin, 5,10-methylenetetrahydrofolate, aminopterin, and raltitrexed;
  • Formula LG-III includes all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; preferably, formula LG-III includes 9 to 27 amino acids in the above polypeptide; more preferably, formula LG-III has at least 70% and 75% of the amino acids in the polypeptide KEFLHPSKVDLPR. , 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity;
  • R LG2 is halogen (e.g., bromine), amino,
  • R 8 is hydrogen, in
  • R 8' is carboxyl-substituted C 1 -C 6 alkylamino (for example, 5-amino-5-carboxypentylamino), carboxyl-substituted C 3 -C 8 cycloalkylmethylamino (for example, (trans- 4-carboxycyclohexyl)methylamino) or carboxyl-substituted C 1 -C 2 alkoxy C 1 -C 2 alkoxy C 1 -C 2 alkylamino (for example, 2-(2-(carboxymethoxy )ethoxy)ethylamino);
  • R 8′′ is hydrogen, amino-substituted C 1 -C 6 alkanoyl (for example, 6-aminocaproyl), amino-substituted C 1 -C 2 alkoxy C 1 -C 2 alkoxy C 1 -C 2 Alkanoyl (e.g., 2-(2-(2-aminoethoxy)ethoxy)acetyl), carboxyl-substituted C 1 -C 6 alkanoyl (e.g., 3-carboxypropionyl) or carboxyl-substituted C 1 -C 2 alkoxy C 1 -C 2 alkoxy C 1 -C 2 alkanoyl (e.g., 2-(2-(carboxymethoxy)ethoxy)acetyl);
  • amino-substituted C 1 -C 6 alkanoyl for example, 6-aminocaproyl
  • R 9 is in
  • R 9' is carbonyl or methylene
  • X is a single bond or -(CH 2 CH 2 O) n CH 2 CONH-, where
  • n 0, 1, 2 or 3;
  • R LG3 is hydrogen or in
  • R 10 is a hydroxyl or carboxyl substituted C 1 -C 6 alkylamino group (for example, 5-amino-5-carboxypentylamino);
  • B 1 to B 5 are each independently an amino acid fragment formed from any one of the following amino acids: phenylalanine (Phe), glutamic acid (Glu), arginine (Arg), glycine (Gly), and aspartate Amino acid (Asp); preferably, the formula LG-VI is and
  • an optionally substituted alkanoyl group for example, 3-amino-3-carboxypropionyl
  • an optionally substituted amino group for example, 5-amino -5-carboxypentylamino
  • C 1 to C 4 each independently represent an amino acid fragment, wherein the C terminal of C 1 is connected to a benzothiazolyl group, and the N terminal of C 4 is connected to an acetyl group, and
  • an optionally substituted alkanoyl group e.g., 3-carboxypropionyl
  • an optionally substituted alkanoyl group e.g., 3-carboxypropionyl
  • Y is One end marked with * is connected to the carboxyl group (COOH), and the other end is connected to the ring Z;
  • Ring Z is a C 6 -C 10 aromatic ring (for example, benzene ring, naphthalene ring, etc.) or a 5-9 membered heteroaromatic ring (for example, furan ring, benzofuran ring, etc.);
  • R LG4 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • Formula LG-IX contains the polypeptide Cys a -X1-Cys c -X2-Gly-Pro-Pro-X3-Phe-Glu-Cys d -Trp-Cys b -Tyr-X4-X5-X6, where: X1 is Asn, His or Tyr; X2 is Gly, Ser, Thr or Asn; X3 is Thr or Arg; X4 is Ala, Asp, Glu, Gly or Ser; X5 is Ser or Thr ; Cysteine residue; Preferably, residues Cys a and Cys b and Cys c and Cys d are cyclized respectively to form two independent disulfide bonds; further, the formula LG-IX includes the polypeptide Ala-Gly-Ser- Cys a -Tyr-Cys c -Ser-Gly-Pro-Pro-Arg-Phe-Glu-Cys d -Trp-Cys
  • Each LG in the precursor can independently be a targeting ligand formed from a ligand compound of the formula LG-I or its optical isomer and bound to the cell surface protein PSMA; a ligand compound of the formula LG-II or its optical isomer.
  • the optical isomer forms and binds to the targeting ligand of the cell surface protein FORL1; the targeting ligand formed from the ligand compound of formula LG-III or its optical isomer and binds to the cell surface protein TRPV6; the targeting ligand of the formula LG-IV
  • the body compound or its optical isomer forms and binds the targeting ligand of the cell surface protein FAPI; the formula LG-V ligand compound or its optical isomer forms and binds the targeting ligand of the cell surface protein CAIX; by the formula
  • the LG-VI ligand compound or its optical isomer forms a targeting ligand that binds to the cell surface protein RGD; the LG-VII ligand compound or its optical isomer forms a targeting ligand that binds to the cell surface protein Hepsin.
  • Body formed from a ligand compound of formula LG-VIII or its optical isomer and bound to the target of the cell surface protein Sigma Ligand; or a targeting ligand formed from a ligand compound of the formula LG-IX or an optical isomer thereof and binding to the cell surface protein C-MET.
  • the above-mentioned conjugated drug represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 Each LG in the precursor can be independently formed from any of the following ligand compounds.
  • the LG in the above-mentioned conjugated drug prodrug (monocoupled drug prodrug) represented by Formula I-1 or Formula I-2 can be represented by the formulas LG-I, LG- III, LG-IV, LG-V, LG-IX are formed from any ligand compound (or its optical isomer); preferably, LG can be formed by the formula LG-1, LG-1A, LG-1B, LG-1C, LG-1D, LG-1E, LG-1G, LG-1H, LG-1K, LG-1L, LG-3, LG-4, LG-4A, LG-4B, LG-4C, LG- 4E, LG-4F, LG-11, LG-12, LG-12A, LG-12B, LG-12C, LG-12D, LG-12E, LG-14, LG-5, LG-6, LG-6A, Either ligand compound (or optical isomer thereof) of LG-6B and LG-6C is formed.
  • each LG in the above-mentioned conjugated drug prodrugs (branched double-chain conjugated drug prodrugs) represented by Formula I-3, Formula I-4 or Formula I-6 can be independently composed of formulas LG-I, LG-II, LG-III, LG-IV, LG-V, LG-VI, LG-VII, Any one of the ligand compounds (or optical isomers thereof) in LG-VIII and LG-IX is formed; preferably, each LG can be independently formed by the formulas LG-1, LG-1A, LG-1B, LG -1C, LG-1D, LG-1E, LG-1G, LG-1H, LG-1K, LG-1L, LG-2, LG-3, LG-4, LG-4A, LG-4B, LG-4C , LG-4E, LG-4F, LG-11, LG-12, LG-12A, LG-12B, LG-12C, LG-12D, LG-12E, LG-14, LG-5, LG-6, LG - Any ligand compound (or its optical isomer); more preferably,
  • each LG in the above-mentioned conjugated drug prodrugs (linear dual-coupled drug prodrugs) represented by formula I-5 can be independently composed of formulas LG-I, Any ligand compound in LG-VIII (or its optical isomer) is formed; preferably, each LG can be independently formed by the formula LG-1, LG-1A, LG-1B, LG-1C, LG - Formation of any ligand compound (or its optical isomer) among 1D, LG-1E, LG-1G, LG-1H, LG-1K, LG-1L, LG-9, and LG-10; more preferably Specifically, the two LGs can be formed by ligand compounds of formulas LG-1 and LG-9 (or optical isomers thereof) respectively; further preferably, the two LGs can be formed of ligand compounds of formulas LG-1 and LG-9 respectively. (or its optical isomer) is formed, and LG formed by the formula LG-9 ligand compound (or its optical isomer) is connected to L.
  • the LG formed from the above-mentioned ligand compound can be of various types, and the present invention does not impose any specific limitation on this.
  • it can be a monovalent group (i.e., a secondary amino group) obtained by losing a hydrogen atom from the primary amino group in the structure (preferably the primary amino group located at the end of the main chain), which can be coupled with other structural fragments in the drug precursor.
  • the carboxyl group is connected to form an amide group), or it can be a monovalent group obtained after the carboxyl group in the structure (preferably the carboxyl group located at the end of the main chain) loses the hydroxyl group (i.e., the carboxylic group, which can be coupled with the drug prodrug It can also be a monovalent group (such as an alkoxy group or aromatic group) obtained by losing a hydrogen atom from a hydroxyl group in the structure (preferably the hydroxyl group located at the end of the main chain). Oxygen group, which can be linked to the carboxylic group of other structural segments coupled to the prodrug to form an ester group).
  • the above-mentioned conjugated drug precursors such as Formula I-3, Formula I-4, Formula I-5 or Formula I-6 are relatively preferred, because the structures of these precursors all contain
  • the two targeting ligands can work in a variety of ways to improve the therapeutic effect and reduce toxic side effects; at the same time, the two targeting molecules enhance the affinity of the coupled compound to target cells and reduce off-target toxicity.
  • the radionuclide chelating agent (i.e., C) contained in the radionuclide conjugated drug precursor of the present invention can complex diagnostic and/or therapeutic radioisotopes, especially therapeutic or dual-purpose radioisotopes.
  • the radionuclide-conjugated drug precursor is chelated with the radioisotope (for example, chelated in an equimolar ratio)
  • the radionuclide-conjugated drug can be obtained. Therefore, the radionuclide-conjugated drug of the present invention includes the radionuclide-conjugated drug precursor of the present invention and the radioactive isotope chelated thereto.
  • radioactive isotopes that can be used for diagnosis (imaging) include, but are not limited to, 45 Ti, 52 Fe, 59 Fe, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 63 Zn, 67 Ga, 68 Ga, 89 Zr, 99m Tc, 111 In , 117m Sn, 153 Sm, 177 Lu, 186 Re, 188 Re, 191m Pt, 193m Pt, 195m Pt, 198 Au, 199 Au, etc.
  • radioactive isotopes examples include, but are not limited to, 58m Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 89 Sr, 90 Y, 103m Rh, 103 Pd, 111 In, 117m Sn, 119 Sb, 153 Sm, 153 Gd, 161 Tb, 161 Ho, 166 Ho, 177 Lu, 186 Re, 188 Re, 193m Pt, 195m Pt, 197 Pt, 198 Au, 199 Au, 201 Tl , 203 Pb, 212 Bi, 213 Bi, 211 At, 223 Ra, 224 Ra, 225 Ac, 227 Th, etc.
  • the above-mentioned conjugated drug represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 C in the precursor can chelate any of the following radionuclides: 47 Sc, 48 Sc, 51 Cr, 55 Fe, 64 Cu, 67 Cu, 69 Zn, 67 Ga, 68 Ga, 72 Ga, 72 As, 72 Se, 89 Sr, 88 Y, 90 Y, 99 Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 In, 119 Sb, 128 Ba, 139 La, 140 La, 142 Pr, 149 Pm, 153 Sm , 159 Gd, 165 Dy, 166 Ho, 169 Er, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 197 Hg, 201 Tl, 202 Pb, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac
  • the above-mentioned conjugated drug represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 C in the precursor can chelate any of the following radionuclides: 64 Cu, 67 Cu, 67 Ga, 68 Ga, 89 Sr, 90 Y, 99m Tc, 111 In, 119 Sb, 153 Sm, 166 Ho, 177 Lu , 186 Re, 188 Re, 198 Au, 199 Au, 201 Tl, 203 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Th, preferably any of the following radionuclides : 64 Cu, 67 Cu, 111 In, 153 Sm, 177 Lu, 186 Re, 188 Re, 198 Au and 199 Au.
  • the above-mentioned conjugated drug represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 C in the precursor can chelate 177 Lu.
  • the chelating agent may contain a variable number of heteroatoms (usually N, O, S or P atoms, especially N, O or S atoms, preferably N or O atoms) to complex radionuclides , and may be cyclic or non-cyclic (especially cyclic).
  • heteroatoms usually N, O, S or P atoms, especially N, O or S atoms, preferably N or O atoms
  • cyclic chelating agents include, but are not limited to, 1,4,7-triazacyclononane; 1,4,7-triazacyclononane-triacetic acid; 1,4,7,10- Tetraazacyclododecane; 1,4,7,10-tetraazacyclotridecane; 1,4,7,11-tetraazacyclotetradecane; 1,4,7,10-tetraaza Heterocyclododecane-1,4,7,10-tetraacetic acid; 2-(1,4,7,10-tetraazacyclododecane-1-yl)acetic acid; 2,2'-(1, 4,7,10-tetraaacyclododecane-1,7-diyl)diacetic acid; 2,2',2′′-(1,4,7,10-tetraaacyclododecane-1 ,4,7-triyl)triacetic acid; 1,4,8,11-tetraaacyclotetradecan
  • acyclic chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (i.e., 2,2',2",2"'-(ethane-1,2-diylbis(nitrilo))) Tetraacetic acid); Diethylenetriaminepentaacetic acid (i.e.
  • the above-mentioned conjugated drug represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 C in the precursor can be formed from any of the following chelating compounds.
  • the above-mentioned conjugated drug represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 C in the precursor may be formed from a chelating agent compound of formula C-1.
  • C formed by the above-mentioned chelating agent compound can be various, and the present invention does not impose any specific limitation on this.
  • it can be a carboxylic acid group obtained by losing the hydroxyl group from the carboxyl group in the structure (preferably the carboxyl group located at the end of the main chain) (which can be connected to the secondary amino group of other structural fragments in the coupled drug precursor to form an amide group).
  • LG and C can be directly connected to form a radionuclide conjugated drug prodrug (i.e., a conjugated drug prodrug as shown in Formula I-2), for example, a targeted formulation
  • a radionuclide conjugated drug prodrug i.e., a conjugated drug prodrug as shown in Formula I-2
  • the linker (i.e., L) in the radionuclide-conjugated drug prodrug of the present invention can be used as an intermediate fragment to connect the chelating agent (C) and the targeting ligand (LG); or, when conjugating the drug before When there is a spacer (S) in the body structure, L can also be used as an intermediate segment to connect C and S.
  • the linker can be either cleavable (or degradable) or non-cleavable (or non-degradable), and the latter is preferred.
  • L in the above-mentioned conjugated drug prodrugs represented by Formula I, Formula I-1, Formula I-3, Formula I-5 or Formula I-6 can be Formula L-I , any one of L-II, L-III, L-IV, L-V,
  • the end marked with * is connected to LG in the conjugated drug precursor or is terminated with a hydroxyl or amino group, and the end marked with ** is connected to LG in the conjugated drug precursor.
  • LG or C is either terminated with hydrogen or an acetyl group;
  • R is absent or is a bivalent structural fragment formed of amino acids; preferably, R is a bivalent structural fragment formed of lysine, tryptophan or valine;
  • the end marked with * is connected to the LG in the conjugated drug precursor or is terminated with a hydroxyl or amino group, and the end marked with ** on the left side is connected to the conjugated drug.
  • C in the precursor, the end marked with ** on the right side is connected to LG in the conjugated drug precursor or is terminated with hydrogen or acetyl group;
  • R does not exist or is a bivalent formed by lysine (Lys) structural fragment;
  • the end marked with *** is connected to S or LG in the conjugated drug precursor, and the end marked with ** is connected to C in the conjugated drug precursor.
  • X does not exist or is NH or O, preferably NH;
  • n is any integer from 1 to 4, preferably 1;
  • the end marked with * is connected to the LG in the conjugated drug precursor or is terminated with a hydroxyl or amino group, and the end marked with ** is connected to the conjugated drug precursor.
  • LG or C in is either terminated with hydrogen or acetyl group; n is any integer from 1 to 6;
  • the end marked by * is terminated with a hydroxyl group, the end marked by ** on the left is connected to C in the conjugated drug precursor, and the end marked by * on the right *The marked end is connected to LG in the conjugated drug precursor; n is 4;
  • the end marked with * is connected to LG in the conjugated drug precursor, and the end marked with ** is connected to C in the conjugated drug precursor;
  • n is any integer from 1 to 5;
  • R 1 does not exist or is -NH-CH 2 -CH 2 -NH-;
  • R 2 does not exist or is One end marked with * is connected to NH in LV, and
  • m is any integer from 1 to 7;
  • the end marked with * is connected to LG in the conjugated drug precursor, and the end marked with ** is connected to C in the conjugated drug precursor; n is 2 or 3; when R 1 does not exist, R 2 does not exist or is One end marked with * is connected to NH in formula LV, and m is 5; or, when R 1 is -NH-CH 2 -CH 2 -NH-, R 2 does not exist.
  • L in the above-mentioned conjugated drug prodrugs represented by Formula I, Formula I-1, Formula I-3, Formula I-5 or Formula I-6 can be the following structure Any of the fragments, in which the end marked by * is connected to LG in the conjugated drug precursor, the end marked by ** is connected to LG or C in the conjugated drug precursor, and the end marked by *** is connected Conjugate S or LG in the prodrug.
  • L in the above-mentioned conjugated drug prodrugs represented by Formula I, Formula I-1, Formula I-3, Formula I-5 or Formula I-6 can be Formula L -1, one of L-2, L-3, L-10, L-11, L-12, L-13, L-14, L-15.
  • L in the above-mentioned conjugated drug prodrugs represented by Formula I-1 or Formula 1-5 can be one of Formulas L-I, L-III, L-IV, and L-V; preferably Land, L can be one of the formulas L-3, L-3A, L-3B, L-10, L-11, L-12, L-13, L-14, and L-15.
  • L in the above-mentioned conjugated drug prodrug as shown in formula I-3 can be formula L-II, L-III; preferably, L can be formula L-2, L -3.
  • L in the above-mentioned conjugated drug prodrug represented by formula I-6 can be one of formulas L-1 and L-1A.
  • the above-mentioned L can be connected with LG, C and optional S.
  • they are connected to each other through a condensation reaction between amino groups and carboxyl groups; specifically, it can be a condensation reaction between the primary amino group in the linker compound (preferably the primary amino group located at the end of the main chain) and the carboxyl group in other compounds to form an amide.
  • the group can also be a carboxyl group in the linker compound (preferably the carboxyl group located at the end of the main chain) and a primary amino group in other compounds to form an amide group through a condensation reaction.
  • L when only one LG is contained, L can connect LG and C to form a radionuclide conjugated drug prodrug (i.e., a conjugated drug prodrug as shown in Formula I-1 ), for example, the targeting ligand is connected to the carboxyl group of the linker through its secondary amino group, and at the same time, the linker is connected to the carboxyl group of the chelating agent through its secondary amino group to form an amide group respectively.
  • a radionuclide conjugated drug prodrug i.e., a conjugated drug prodrug as shown in Formula I-1
  • L when two LGs are contained, L can connect one of the LGs (which is also connected to the other LG) with C to form a radionuclide conjugated drug precursor (i.e., as Coupled drug prodrugs represented by formula I-5), for example, the first targeting ligand is connected to the carboxylic group of the second targeting ligand through its secondary amino group, and the second targeting ligand is connected to the carboxylic acid group of the second targeting ligand through its secondary amino group.
  • the carboxyl group of the linker is connected, and at the same time, the linker is connected to the carboxyl group of the chelating agent through its secondary amino group to form an amide group respectively.
  • L when two LGs are contained, L can simultaneously connect two LGs (which are not connected to each other) and C to form a radionuclide conjugated drug precursor (i.e., as shown in Formula I
  • the coupled drug precursor shown in -6 for example, the first targeting ligand and the second targeting ligand are each independently connected to the carboxylic acid group or secondary amino group of the linker through its secondary amino group or carboxylic acid group, At the same time, the linker is connected to the carboxylic acid group of the chelating agent through its secondary amino group to form an amide group.
  • the radionuclide-conjugated drug precursor of the present invention contains two targeting ligands (LG)
  • a spacer i.e., S
  • S can be used as an intermediate segment to connect the chelating agent (C) and the targeting ligand. body (LG); alternatively, when there is a linker (L) in the conjugate structure, S can also be used as an intermediate segment to connect L and LG.
  • the spacer may be either cleavable (or degradable) or non-cleavable (or non-degradable), and the latter is preferred.
  • S in the above-mentioned conjugated drug prodrug as shown in Formula I, Formula I-3 or Formula I-4 can be in Formula S-I, S-II or S-III. any kind,
  • one end marked by * is connected to one LG in the conjugated drug precursor, one end marked by ** is connected to the other LG in the conjugated drug precursor, and **The other end marked is connected to L or C in the conjugated drug prodrug;
  • the end marked with * is connected to one LG of the conjugated drug precursor, and the end marked with ** above is connected to the other end of the conjugated drug precursor.
  • LG, the end marked with ** below is connected to L or C in the conjugated drug precursor;
  • a 1 -A 2 -A 3 is -Asp-Asp-Lys;
  • m is 4,
  • n is 4;
  • one end marked with * is connected to one LG in the conjugated drug precursor, and one end marked with ** is connected to the other LG in the conjugated drug precursor. , the other end marked by ** is connected to L or C in the conjugated drug precursor;
  • n is any integer from 2 to 6, preferably n is 4;
  • n is any integer from 1 to 5, preferably n is 1 or 2.
  • S in the above-mentioned conjugated drug prodrug as shown in Formula I, Formula I-3 or Formula I-4 can be any one of the following structural fragments, wherein * The end marked by *** is connected to one LG in the conjugated drug precursor, the end marked by ** is connected to the other LG in the conjugated drug precursor, and the end marked by *** is connected to the LG in the conjugated drug precursor.
  • * The end marked by *** is connected to one LG in the conjugated drug precursor
  • the end marked by ** is connected to the other LG in the conjugated drug precursor
  • the end marked by *** is connected to the LG in the conjugated drug precursor.
  • S in the above-mentioned conjugated drug prodrug as shown in Formula I, Formula I-3 or Formula I-4 can be Formula S-6, S-9, S-13 , one of S-18.
  • S in the above-mentioned conjugated drug prodrug as shown in formula I-3 can be one of the formulas S-II and S-III; preferably, S can be the formula S- 13.
  • S in the above-mentioned conjugated drug prodrug as shown in formula I-4 can be one of formulas S-I and S-II; preferably, S can be formula S-6, One of S-9 and S-13.
  • the above-mentioned S can be connected with LG, C and optional L.
  • they are connected to each other through a condensation reaction between amino groups and carboxyl groups; specifically, it can be a condensation reaction between a primary amino group in a spacer compound (preferably a primary amino group located at the end of the main chain) and a carboxyl group in other compounds to form an amide.
  • the group can also be a carboxyl group in the spacer compound (preferably the carboxyl group located at the end of the main chain) and a primary amino group in other compounds to form an amide group through a condensation reaction.
  • S can simultaneously connect two LGs (which are not connected to each other) and C to form a radionuclide conjugated drug precursor (i.e., a conjugated drug as shown in Formula I-4 Precursor), for example, the first targeting ligand and the second targeting ligand are each independently connected to the carboxyl group or secondary amino group of the spacer through its secondary amino group or carboxyl group, and at the same time, the spacer is connected through its secondary amino group Connected to the carboxylic acid group of the chelating agent to form an amide group respectively.
  • a radionuclide conjugated drug precursor i.e., a conjugated drug as shown in Formula I-4 Precursor
  • S can simultaneously connect two LG (which are not connected to each other) and L, and then connect C through L to form a radionuclide conjugated drug precursor (ie, as shown in Formula I-
  • the coupled drug prodrug shown in 3) for example, the first targeting ligand and the second targeting ligand are each independently connected to the carboxyl group or secondary amino group of the spacer through its secondary amino group or carboxyl group, and the spacer
  • the linker is connected to the carboxyl group of the linker through its secondary amino group, and at the same time, the linker is connected to the carboxyl group of the chelating agent through its secondary amino group to form an amide group respectively.
  • LG can be formed from any of the ligand compounds (or optical isomers thereof) in the formulas LG-I, LG-IV, and LG-V; preferably, it can be formed from the formulas LG-1B, LG-1D, and LG-1E. , any one of the ligand compounds (or optical isomers thereof) in LG-4 and LG-6 is formed;
  • L can be one of the formulas L-I, L-IV, L-V (or its optical isomer); preferably, it can be L-10, L-11, L-12, L-13, L-14, L-15 One (or its optical isomer);
  • C can be formed from a chelating compound of formula C-1.
  • LG can be formed by any ligand compound (or its optical isomer) in the formula LG-I, LG-III or LG-5; preferably, it can be formed by the formula LG-1D, LG-3, LG-5 Any one of the ligand compounds (or its optical isomers) is formed;
  • C can be formed from a chelating compound of formula C-1.
  • the two LGs can be respectively formed by any one of the ligand compounds (or optical isomers thereof) in the formulas LG-I, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII; preferably Ground, can be represented by the formula LG-I and LG-IV, LG-I and LG-VI, LG-I and LG-VII, LG-I and LG-VIII, LG-IV and LG-IV, LG-IV and LG -V, LG-IV and LG-VI or LG-IV and LG-VII ligand compounds (or optical isomers thereof) are formed; more preferably, they can be formed by formulas LG-1 and LG-11, LG-1B and LG-4, LG-1B and LG-7, LG-1B and LG-8A, LG-1B and LG-10, LG-4A and LG-4B, LG-4A and LG-6C, LG-4A and LG-7A or LG-4A and LG-8B ligand compounds (or optical isomers thereof) Formed; further preferably, can be formed by formulas LG-1B and LG
  • S can be one of the formulas S-II and S-III (or its optical isomer); preferably, it can be one of the formulas S-13 and S-18 (or its optical isomer); more preferably, It can be formula S-13 (or its optical isomer);
  • L can be one of the formulas L-II and L-III (or its optical isomer); preferably, it can be one of the formulas L-2 and L-3; more preferably, L can be the formula L-2;
  • C can be formed from a chelating compound of formula C-1.
  • the two LGs can be formed by any ligand compound (or its optical isomer) in the formulas LG-I, LG-II, and LG-III respectively; preferably, they can be formed by the formulas LG-I and LG-II, LG-I and LG-III or LG-II and LG-III ligand compounds (or optical isomers thereof) are formed; more preferably, they can be formed by formulas LG-1 and LG-2, LG-1E and LG-3 or the formation of LG-2 and LG-3 ligand compounds (or optical isomers thereof);
  • S can be one of the formulas S-I and S-II (or its optical isomer); preferably, it can be one of the formulas S-6, S-9 and S-13 (or its optical isomer);
  • C can be formed from a chelating compound of formula C-1.
  • the two LGs can be formed by ligand compounds of formulas LG-I and LG-VIII (or optical isomers thereof) respectively; preferably, they can be formed by ligand compounds of formulas LG-1 and LG-9 (or optical isomers thereof). ) is formed, and LG formed by the ligand compound of formula LG-9 (or its optical isomer) is connected to L;
  • L can be formula L-III (or its optical isomer); preferably, it can be formula L-3 (or its optical isomer);
  • C can be formed from a chelating compound of formula C-1.
  • the two LGs can be formed by any ligand compound (or its optical isomer) in the formulas LG-I, LG-II, and LG-III respectively; preferably, they can be formed by the formulas LG-I and LG-II, LG-I and LG-III or LG-II and LG-III ligand compounds (or optical isomers thereof) are formed; more preferably, they can be formed by formulas LG-1E and LG-3, LG-1L and LG-2 or the formation of LG-2 and LG-3 ligand compounds (or optical isomers thereof);
  • L can be formula L-I (or its optical isomer); preferably, it can be one of formula L-1 and L-1A (or its optical isomer);
  • C can be formed from a chelating compound of formula C-1.
  • different structural fragments used to construct radionuclide-conjugated drug prodrugs can be connected to each other in series through amide groups, and the amide groups can in turn be connected through primary amino groups (for example, to form linkers, spacers or targeting It is formed by the condensation reaction of the terminal amino group in the compound of the ligand) and the carboxyl group (for example, multiple carboxyl groups in the compound that forms the chelating agent).
  • the above-mentioned condensation reaction can be carried out in the presence of a coupling reagent in order to activate the carboxylic acid into a better electrophile, thereby promoting the forward progress of the reaction.
  • Exemplary coupling reagents include, but are not limited to, EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), HOBt (1 -hydroxybenzotriazole), HATU (O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate), etc.
  • amide bond formation can also be achieved by activating carboxylic acids with N-hydroxysuccinimide (NHS) to form succinimide esters, which can be combined with amines without any other coupling reagents. further reaction.
  • NHS N-hydroxysuccinimide
  • the present invention provides the following specific presentation forms of radionuclide conjugated drug precursors.
  • the present invention provides the following specific presentation forms of radionuclide-conjugated drug precursors.
  • the present invention also provides a dual-ligand compound, which can be directly connected or indirectly connected to a chelating agent through a connecting fragment, thereby obtaining the radionuclide-conjugated drug precursor of the present invention.
  • the above-mentioned dual-ligand compound may be in the following specific presentation forms.
  • the present invention provides a radionuclide-conjugated drug, which includes the radionuclide-conjugated drug precursor described in the ⁇ first aspect> or the ⁇ second aspect>, and a radioactive isotope chelated thereto.
  • the radioactive isotope in the above-mentioned radionuclide conjugated drug is selected from 47 Sc, 48 Sc, 51 Cr, 55 Fe, 64 Cu, 67 Cu, 69 Zn, 67 Ga, 68 Ga, 72 Ga, 72 As, 72 Se, 89 Sr, 88 Y, 90 Y, 99 Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 In, 119 Sb, 128 Ba, 139 La, 140 La, 142 Pr , 149 Pm, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Er, 175 Yb, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 197 Hg, 201 Tl, 202 Pb, 203 Pb, 212 Any of Pb, 212 Bi, 213 Bi, 225 Ac and 227 Th.
  • the radioactive isotope in the above-mentioned radionuclide conjugated drug is selected from 64 Cu, 67 Cu , 67 Ga, 68 Ga, 89 Sr, 90 Y, 99m Tc , 111 In , 119 Sb, Any one of 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 201 Tl, 203 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Th, preferably 64 Cu, 67 Cu , any one of 111 In, 153 Sm, 177 Lu, 186 Re, 188 Re, 198 Au and 199 Au.
  • the radioisotope in the above-mentioned radionuclide conjugated drug is 177 Lu.
  • the present invention provides a pharmaceutical composition, which contains the radionuclide conjugated drug precursor described in the ⁇ first aspect> or the ⁇ second aspect> or the radionuclide conjugated drug precursor described in the ⁇ third aspect>. combined drugs.
  • the pharmaceutical composition further contains at least one pharmaceutically acceptable excipient.
  • the present invention provides the radionuclide-conjugated drug precursor described in the ⁇ first aspect> or the ⁇ second aspect> or the radionuclide-conjugated drug described in the ⁇ third aspect> or the ⁇ fourth aspect> Use of the pharmaceutical composition described in for the preparation of medicaments for the prevention and/or treatment of diseases or conditions.
  • the present invention provides the radionuclide-conjugated drug precursor described in the ⁇ first aspect> or the ⁇ second aspect> or the radionuclide-conjugated drug described in the ⁇ third aspect> or the ⁇ fourth aspect>
  • the pharmaceutical composition described in is used to prevent and/or treat diseases or conditions.
  • the present invention provides a method for preventing and/or treating a disease or condition, comprising:
  • the pharmaceutical composition described in ⁇ Fourth Aspect> is administered to an individual in need thereof.
  • the disease or condition is cancer, preferably prostate cancer, breast cancer, liver cancer, pancreatic cancer, ovarian cancer, gastric cancer or Lung cancer.
  • the radionuclide conjugated drug of the present invention can specifically deliver radionuclides to target cells.
  • the conjugated drug contains one targeting ligand (LG)
  • it can specifically deliver radionuclides to target cells
  • the conjugated drug contains two targeting ligands (LG)
  • LG targeting ligands
  • Figure 1 is the HPLC spectrum of compound 1’.
  • Figure 2 is the LC-MS spectrum of compound 1’.
  • Figure 3 is the HPLC spectrum of compound 2’.
  • Figure 4 is the LC-MS spectrum of compound 2'.
  • Figure 5 is the HPLC spectrum of compound 4'.
  • Figure 6 is the LC-MS spectrum of compound 4'.
  • Figure 7 is the HPLC spectrum of compound 17'.
  • Figure 8 is the LC-MS spectrum of compound 17'.
  • Figure 9 is the HPLC spectrum of compound 21'.
  • Figure 10 is the LC-MS spectrum of compound 21'.
  • Figure 11 is the HPLC spectrum of compound 24'.
  • Figure 12 is the LC-MS spectrum of compound 24'.
  • Figure 13 is a SPECT dynamic image of a double-formed radionuclide conjugated drug prepared from compound 17'.
  • Figure 14 is a quantitative organ enrichment diagram of a double-formed radionuclide conjugated drug prepared from compound 17'.
  • Figure 15 is a SPECT dynamic image of a double-formed radionuclide conjugated drug prepared from compound 21'.
  • Figure 16 is a quantitative organ enrichment diagram of a double-formed radionuclide conjugated drug prepared from compound 21'.
  • Figure 17 is a SPECT dynamic image of a single radionuclide conjugated drug prepared from compound 1'.
  • Figure 18 is a quantitative organ enrichment diagram of a monoparticulate radionuclide conjugated drug prepared from compound 1'.
  • Figure 19 is a SPECT dynamic image of a single radionuclide conjugated drug prepared from compound 2'.
  • Figure 20 is a quantitative diagram of organ enrichment of monoparticulate radionuclide conjugated drugs prepared from compound 2'.
  • Figure 21 is a SPECT dynamic image of a single radionuclide conjugated drug prepared from compound 4'.
  • Figure 22 is a quantitative graph of organ enrichment of monoparticulate radionuclide conjugated drugs prepared from compound 4'.
  • target refers to the binding site between drugs and biological macromolecules in the body, mainly involving receptors, enzymes, ion channels, transporters, immune systems, genes, etc.
  • drugs target receptors, and receptors have become the main and most important targets; more than 20% of drugs target enzymes, especially enzyme inhibitors. It has a special status in clinical application; about 6% of drugs target ion channels; 3% of drugs target nucleic acids; the targets of 20% of drugs still need further research.
  • certain medical treatments such as radiotherapy
  • radiation is irradiated from different directions and concentrated on the lesion, and the lesion is also a target.
  • radioactive nuclide or “radioactive isotope” refers to an unstable element that can release rays (or radiation) during the decay process. Includes both naturally occurring elements and elements primarily produced during nuclear fission or fusion processes. According to the different rays released during the decay process of radionuclides, they can be roughly divided into three categories: ⁇ , ⁇ , and ⁇ .
  • conjugated drug refers to fragments with different functions connected to each other through optional connecting fragments.
  • Pharmaceutical compounds formed and able to exert corresponding activities such as antibody drug conjugates (ADC), peptide drug conjugates (PDC), small molecule drug conjugates (SMDC), radionuclide drug conjugates (RDC), etc.
  • radionuclide conjugated drug or “radionuclide drug conjugate” refers to fragments such as chelating agents containing radionuclides and targeting ligands (Ligand) for at least one target through A pharmaceutically acceptable compound formed by connecting optional linkers and spacers to each other and capable of exerting targeted radiotherapy activity.
  • the chelator part is used to complex radioisotopes and targeting ligands.
  • the linker part and the spacer part are used to connect the chelator part and the targeting ligand part to each other to form a radionuclide couple.
  • the complete structure of the combined drug means that the chelating agent part in the radionuclide conjugate drug has not yet complexed with the radionuclide. precursor form.
  • targeting ligand refers to any molecule or part capable of targeting to a target site, target tissue, target organ, target cell, or region within a target cell.
  • the targeting ligand causes the moiety linked to the targeting ligand to be present in the target site, target tissue, or in the non-target tissue as compared to the non-target site, non-target tissue, non-target organ, non-target cell, or non-target intracellular region.
  • the target organ, the target cell or the area within the target cell is allocated more, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more. higher.
  • a conjugate compound or agent with a targeting ligand distributes more to the target site, target tissue, target organ, target cell, or region within the target cell than without the targeting ligand. , for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more.
  • the targeting ligand can trigger or promote the specific binding of the conjugate compound containing such targeting ligand to the target molecule, trigger or promote the endocytosis of the conjugate compound by the target cell, trigger or Promote the concentration of the conjugate compound around the target cells and/or enter the target cells.
  • ligand may include a variety of chemical molecules or polypeptides that have specific binding affinity for a selected target, which may be a cell surface protein (for example, cell surface receptors or cell surface antigens), specific proteins, cells, tissues, organs, etc.
  • a ligand can specifically bind to a cell surface receptor.
  • a ligand can specifically bind to a cell surface antigen.
  • a ligand may specifically bind to a specific protein that may be responsible for a disease.
  • overexpression of the particular protein causes disease or the particular protein is a mutant protein that causes disease.
  • the ligands of the present application bind to the target with an affinity of 10 -6 to 10 -11 M (K d value). In some embodiments, ligands of the present application bind to the target with an affinity of at least 10 -6 , at least 10 -7 , at least 10 -8 or at least 10 -9 M (K d value).
  • the ligands of the present application bind to the target with a certain affinity, which refers to binding to a non-target (for example, other cell surface receptors, cell surface antigens or specific Compared with the affinity of protein, etc.), the affinity of the ligand for the target is at least two times, three times, four times, five times, six times, eight times, ten times, twenty times, fifty times, A hundred times or more.
  • the expression of cell surface receptors, cell surface antigens, and specific proteins of the present application on the surface of target cells (for example, cancer cells or cells with physiological abnormality) or within target cells is significantly higher than the expression in normal cells. .
  • the term "significant" as used in this application refers to a statistically significant difference, or a significant difference that can be recognized by a person skilled in the art.
  • folate receptor 1 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that binds folate with nanomolar affinity, thereby promoting receptor-mediated endocytosis. effect. Rapidly growing solid malignancies, including ovarian and lung cancers, depend on folate for metabolism and nucleic acid synthesis.
  • GPI glycosylphosphatidylinositol
  • TRPV6 transient receptor potential cation channel subfamily V member 6 (transient receptor potential cation channel subfamily V member 6), which is a highly selective calcium ion transmembrane transport channel that mediates calcium ions from cells. Active transport from the outside into the cell. TRPV6 is expressed in normal human kidneys, gastrointestinal tract, pancreas, mammary gland, salivary glands, etc., but is mainly expressed in intestinal epithelial cells, where it is involved in the transport of calcium ions into cells. Therefore, when the number or function of TRPV6 channels changes, , can cause changes in calcium ion regulation, further leading to structural or functional abnormalities in related tissues and organs.
  • TRPV6 Compared with normal tissues, the expression of TRPV6 is significantly higher in malignant tumors such as breast cancer, cholangiocarcinoma, ovarian cancer, lung squamous cell carcinoma, and prostate cancer. Its abnormal expression may be related to the formation and progression of tumors.
  • PSMA prostate-specific membrane antigen
  • prostate-specific membrane antigen refers to a type II transmembrane glycoprotein present in the prostate epithelial cell membrane. It consists of 750 amino acids, which has 19 intracellular amino acids, 24 transmembrane amino acids in the membrane region and 707 amino acids in the extracellular region.
  • Prostate-specific membrane antigen is expressed in normal prostate epithelial cells, but its expression levels are much higher in prostate cancer cells.
  • prostate-specific membrane antigen is a more sensitive and specific prostate cancer tumor marker. It is especially highly expressed in hormone-refractory prostate cancer and prostate cancer metastases. High sensitivity and specificity in distinguishing prostate cancer from other types of malignancies.
  • prostate-specific membrane antigen is also highly specifically expressed on tumor vascular endothelial cells.
  • C-MET is a protein product encoded by the C-MET proto-oncogene. It is a receptor for hepatocyte growth factor (HGF), has tyrosine kinase activity, and interacts with various oncogene products. Related to regulatory proteins, it participates in the regulation of cell information transmission and cytoskeleton rearrangement, and is an important factor in cell proliferation, differentiation and movement. C-MET is closely related to the occurrence and metastasis of various cancers. Studies have shown that many tumor patients have C-MET overexpression and gene amplification during the occurrence and metastasis of their tumors.
  • HGF hepatocyte growth factor
  • C-MET acts on different substrates in different cells and at different stages of differentiation, it can exhibit multiple functions under specific conditions, such as promoting the division of hepatocytes, endothelial cells and melanocytes, and causing the dispersion and induction of epithelial cells. Cell morphological changes.
  • pharmaceutical composition refers to a pharmaceutically acceptable composition, which contains small molecule drugs as active pharmaceutical ingredients (API), polypeptides, antibodies (or antibody ligands) or conjugates thereof, and other components (such as pharmaceutically acceptable excipients).
  • API active pharmaceutical ingredients
  • Pharmaceutical compositions may be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding and/or lyophilizing processes.
  • auxiliary materials refer to auxiliary materials widely used in the field of pharmaceutical production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has specific functionality, and also to provide a method so that after the drug is administered to the subject, the active ingredient can be used in the desired manner. rate dissolution, or promote effective absorption of the active ingredient in the subject to whom it is administered.
  • Pharmaceutically acceptable excipients may be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients in the composition).
  • “pharmaceutically acceptable excipients” include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, Glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.
  • the starting materials used in the present invention can be synthesized by methods known in the art, or purchased through conventional commercial means.
  • the isolation and purification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to column chromatography (CC), high-performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC), etc. .
  • the structural identification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), etc.
  • step 1
  • PSMA-002 (6.00g, 3.0eq) reacted with wang resin (1.0eq), HOBt (3.0eq), DIC (3.8eq) and DMAP (0.6eq) in DMF (7V) system for 1h, sampling, ninhydrin Color development was performed to confirm that the reaction was complete and the product PSMA-003 was obtained.
  • a lysis solution equivalent to 7V of crude resin i.e. CB6-003 weight (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), pre-cooled at 0-5°C Then pour the crude resin into the lysis solution, raise it to 25°C, protect it with nitrogen, stir and cleave for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the lysis solution.
  • a lysis solution (formula: 30% TFE/DCM) equivalent to 7V of the crude resin (i.e., intermediate 1-4), pre-cool the lysis solution at 0-5°C, add the crude resin to the lysis solution, and raise it to 25°C. Under nitrogen protection, stir and lyse for 3 hours. After the control reaction is complete, the resin is removed by suction filtration to obtain a lysis solution. Concentrate under reduced pressure at 30°C to remove DCM in the lysate. Pre-cool the lysate concentrate in MTBE with a volume of 10V to 0°C, slowly drop the lysate concentrate into it, stir to precipitate the solid, and centrifuge to settle to obtain crude intermediate 1-5.
  • intermediate 2-3 (1.7g, 1.6eq), intermediate 1-7 (1.0g, 1.0eq) and DMF (20ml)
  • TEA 1.2ml
  • the reaction solution is added dropwise to MTBE (200 ml) to make a slurry, and filtered to obtain 2.7 g of white solid, namely DOTA-Met-Val-Lys(Mal)-OH, with a purity of 92%.
  • Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.
  • a lysis solution equivalent to 7V of crude resin i.e., intermediate 3-3) weight (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), 0-5°C
  • Pre-cool the pyrolysis solution then pour the crude resin into the pyrolysis solution, raise it to 25°C, protect it with nitrogen, stir and pyrolyze it for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the pyrolysis solution.
  • Step 15 is similar to step 20 in Example 1, but Cys-108 is used instead of CB6-004.
  • the reaction solution is purified by preparative chromatography to obtain 137 mg of white solid, namely compound 3', with a purity of 96.62%.
  • step 1
  • a lysis solution equivalent to 7V of crude resin i.e. intermediate 4-3) weight (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), 0-5°C
  • Pre-cool the pyrolysis solution then pour the crude resin into the pyrolysis solution, raise it to 25°C, protect it with nitrogen, stir and pyrolyze it for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the pyrolysis solution.
  • Steps 1-6 were similar to steps 1-6 in Example 2 to obtain CB2-002.
  • a lysis solution equivalent to 7V of crude resin i.e. CB2-003 weight (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), pre-cooled at 0-5°C Then pour the crude resin into the lysis solution, raise it to 25°C, protect it with nitrogen, stir and cleave for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the lysis solution.
  • Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.
  • step 1
  • a lysis solution equivalent to 7V of crude resin i.e., intermediate 8-1 weight (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), 0-5°C
  • Pre-cool the pyrolysis solution then pour the crude resin into the pyrolysis solution, raise it to 25°C, protect it with nitrogen, stir and pyrolyze it for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the pyrolysis solution.
  • Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.
  • the resin is lysed with lysis solution, it is filtered, and the lysis solution is poured into MTBE to precipitate the solid, which is washed with MTBE to obtain a crude product.
  • the crude product is prepared by Pre-HPLC to obtain CB10-001.
  • step 1
  • a lysis solution equivalent to 7V of crude resin i.e. intermediate 10-1 weight (formula: 92.5% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), 0-5°C
  • Pre-cool the pyrolysis solution then pour the crude resin into the pyrolysis solution, raise it to 25°C, protect it with nitrogen, stir and pyrolyze it for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the pyrolysis solution.
  • Steps 3-13 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.
  • step 1
  • a lysis solution equivalent to 7V of crude resin i.e., intermediate 11-3) weight (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-cresolthiophenol, 2.5% TIPS), 0-5°C
  • Pre-cool the pyrolysis solution then pour the crude resin into the pyrolysis solution, raise it to 25°C, protect it with nitrogen, stir and pyrolyze it for 3 hours, and after the reaction is complete, remove the resin by suction filtration to obtain the pyrolysis solution.
  • Slowly drop into 0°C pre-cooled MTBE (the volume of MTBE is 10V of the volume of the lysis solution), stir to precipitate the solid, and centrifuge to settle to obtain the crude product.
  • 222.2 mg of the pure product is obtained, namely compound 11', with a purity of 93.975%.
  • step 1
  • intermediate 12-2 (1.06g, 1.0eq), N-Boc-ethylenediamine (0.2990g, 1.5eq), DMF (10ml), HATU (0.7095g, 1.5eq) and DIEA (0.4823g, 3.0eq), after nitrogen replacement three times, the reaction was stirred at 25°C for 2 hours. After the reaction is monitored by HPLC, pour the reaction solution into water (100ml), and then extract with DCM (100mL*3).
  • Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.
  • step 1
  • intermediate 15-1 (100.0 mg, 1.0 eq) into a 100 ml single-neck bottle, then add DOTA-OSu (276.0 mg, 1.5 eq) and acetonitrile (10 ml). After stirring and dissolving, add DIEA (150 ⁇ l) dropwise in an ice bath. ), control the pH to 9, remove the ice bath, and stir at room temperature overnight. Add 5% citric acid aqueous solution to quench the reaction, and then add DCM for extraction. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.272 mg of a transparent oil, which is intermediate 15-2.
  • Steps 1-3 are similar to steps 16-18 in Example 1 to obtain intermediate 2-3.
  • Steps 1-6 are similar to steps 1-6 in Example 1 to obtain CB6-002.
  • a pyrolysis solution (formula: 90% TFA/DCM) equivalent to 10V of the weight of the crude resin (i.e., intermediate 17-3), pre-cool the pyrolysis solution at 0-5°C, add the crude resin to the pyrolysis solution, and raise it to 25°C. Under nitrogen protection, stir and lyse for 3 hours. After the control reaction is complete, the resin is removed by suction filtration to obtain a lysis solution. Concentrate under reduced pressure at 30°C to remove DCM in the lysate.
  • step 1
  • intermediate 18-2 (100.0mg, 1.0eq) and intermediate 17-4 (169.3mg, 1.0eq) to a 25ml single-neck bottle, then add DMF (5ml) to dissolve, stir magnetically at room temperature, add DIEA dropwise to complete the reaction The pH of the liquid was adjusted to 9, and the reaction was carried out overnight. HPLC monitors that the reaction is complete, and the reaction solution is added dropwise to MTBE. After the solid is precipitated, the supernatant is removed by centrifugation, and the solid is dried to obtain 245.3 mg of the product, which is intermediate 18-3.
  • step 1
  • intermediate 19-1 (279.1mg, 2.0eq) and intermediate 17-4 (169.3mg, 1.0eq) to a 25ml single-neck bottle, then add DMF (5ml) to dissolve, stir magnetically at room temperature, and then add DIEA dropwise. The pH of the reaction solution was adjusted to 9, and the reaction was carried out overnight. LCMS was used to control the complete reaction of the raw materials. The reaction solution was added dropwise to MTBE. After the solid precipitated, the supernatant was removed by centrifugation and the solid was dried to obtain 273 mg of the product, namely intermediate 19-2.
  • step 1
  • Fmoc-Lys(Dde)-OH, Fmoc-aminocaproic acid, DOTA-COOH and Fmoc-tranexamic acid were sequentially connected to Fmoc-Lys(Boc)-OH.
  • the resin was washed three times with DCM (100 ml) to remove residual DMF, washed twice with methanol (100 ml), and dried. Soak the dried resin in 20% trifluoroethanol/DCM solution (200 ml), react with magnetic stirring at room temperature for 3 hours, and remove the condensed amino acid fragments from the resin. HPLC monitored that the reaction was complete. The reaction solution was filtered to remove the resin. The organic phase was concentrated under reduced pressure to nearly dryness and purified by preparative chromatography to obtain 7.47g of a white solid, which was intermediate 20-1.
  • intermediate 20-2 (1.63g) to a 50ml single-neck bottle, add an equal volume of mixed TFA/DCM solution (20ml), and add TES (0.2ml), and react at room temperature for 2h. After LC-MS monitors that the reaction is complete, the reaction solution is concentrated under reduced pressure to nearly dryness and added dropwise to MTBE. After solid precipitation, the supernatant is removed. The solid is purified by preparative chromatography to obtain 545 mg of the product, which is intermediate 20-3.
  • intermediate 20-5 (100.0mg, 1.0eq) and intermediate 20-4 (134.0mg, 1.0eq) to a 25ml single-neck bottle, then add DMF (5ml) to dissolve, stir magnetically at room temperature, add DIEA dropwise to complete the reaction The pH of the liquid was adjusted to 9, and the reaction was carried out overnight. HPLC monitors the completeness of the reaction.
  • the reaction solution is added dropwise to MTBE. After the solid is precipitated, the supernatant is removed by centrifugation and the solid is dried to obtain 206.7 mg of the product, which is intermediate 20-6.
  • Step 1-3 was similar to step 1-3 in Example 19, and 545 mg of white solid, namely intermediate 20-3, was obtained.
  • step 1
  • intermediate 19-1 (279.1mg, 2.0eq) and intermediate 20-3 (134.0mg, 1.0eq) to a 25ml single-neck bottle, then add DMF (5ml) to dissolve, stir magnetically at room temperature, add DIEA dropwise to complete the reaction The pH of the liquid was adjusted to 9, and the reaction was carried out overnight. LC-MS monitors that the reaction is complete. The reaction solution is added dropwise to MTBE. After the solid is precipitated, the supernatant is removed by centrifugation and the solid is dried to obtain 216 mg of product, namely intermediate 22-1.
  • step 1
  • intermediate 23-2 (213mg, 1.0eq) and intermediate 23-4 (140mg, 1.0eq) into a 25ml single-neck bottle, then add THF (5ml) to dissolve, stir magnetically for 5 minutes, add DIEA (138mg, 3.0eq) ), stir the reaction at room temperature for 2 h. HPLC monitored the reaction to be complete, and the reaction solution was purified by preparative chromatography to obtain 79 mg of product, namely intermediate 23-5.
  • step 1
  • Steps 1-3 were similar to steps 1-3 in Example 19, and 545 mg of product, namely intermediate 20-3, was obtained.
  • the actual dosage of the precursor is about one thousandth of its theoretical molecular weight
  • take 100 ⁇ l and add to 900 ⁇ l acetic acid solution (pH 4.5, 0.4M)
  • then add 30 ⁇ l of acetic acid solution heat at 60°C for 30 minutes, cool to room temperature after the reaction is completed, and obtain radionuclide coupling drug.
  • compound 7' its actual dosage is 2.5 mg, and the chelation is completed in 177 LuCl 3 solution Finally, the corresponding 177 Lu conjugated drug was obtained.
  • 293T-F/P high expression of FOLR1 receptor and PSMA receptor
  • cell preparation transfect FOLR receptor and PSMA receptor plasmids into 293T cells to obtain 293T cells with high expression of FOLR1 receptor and PSMA receptor, that is, 293T-F/P cells.
  • Relevant tests have shown that the cells can also highly express FAPI receptors and can therefore be used to screen radionuclide-conjugated drugs targeting FAPI receptors. This experiment uses the above-mentioned 293T-F/P cells to test compound activity.
  • Model construction Inoculate the prepared 293T-F/P cells into the subcutaneous skin of the right limb of BALB/c nude mice (5 weeks old, 18-20g, female). When the tumor grows and expands to 300-500mm3 , the model The build is complete.
  • Grouping After the tumors grow to an average length of about 300-500mm , they are divided into groups, and a model control group (BALB/c nude mice inoculated with 293T cells) and different drug administration groups are set up.
  • a model control group BALB/c nude mice inoculated with 293T cells
  • the conjugate prepared from precursor 17' is highly enriched in tumors, enriched quickly, and has a long retention time (the drug is still enriched in tumors after 72 hours); renal metabolism is rapid ( Basic metabolism is completed in 8 hours), and the enrichment in other organs is low.
  • the above results show that the conjugate and its precursor have good specificity for binding to PSMA/FAP, low toxicity to kidneys and other organs, high safety, and can be used for the treatment or diagnosis of tumors.
  • the conjugate prepared from precursor 21' is highly enriched in tumors, and the enrichment is rapid, with a long retention time (a certain amount of drug is still enriched in tumors after 72 hours), and rapid renal metabolism (2 hours Basic metabolism is completed), other organs have low enrichment, and metabolism is fast.
  • the above results show that the conjugate and its precursor have good specificity for binding to FAP/FAP, have low toxicity to other organs and are highly safe, and can be used for the treatment or diagnosis of tumors.
  • the conjugate prepared from precursor 1' is highly enriched in tumors, and the enrichment is rapid, the retention time is long (a certain amount of drug is still enriched in tumors after 72 hours), and the kidney metabolism is rapid ( Basic metabolism is completed in 24 hours), other organs have low enrichment and fast metabolism.
  • the above results show that the conjugate and its precursor have good specificity for binding to PSMA, low toxicity, and high safety, and can be used for the treatment or diagnosis of tumors.
  • the conjugate prepared from precursor 2' is highly enriched in tumors, and the enrichment is rapid, the retention time is long (more than 8 hours), and the kidney metabolism is rapid (basic metabolism is completed in 8 hours). Organ enrichment is low.
  • the above results show that the conjugate and its precursor have good specificity for binding to PSMA, low nephrotoxicity, high safety, and can be used for the treatment or diagnosis of tumors.
  • the conjugate prepared from precursor 4' is highly enriched in tumors, and the enrichment is rapid, the residence time is long (more than 8 hours), and the kidney metabolism is rapid (basic metabolism is completed in 8 hours). Organ enrichment is low.
  • the above results show that the conjugate and its precursor have good specificity for binding to PSMA, low nephrotoxicity, high safety, and can be used for the treatment or diagnosis of tumors.
  • the precursor of the present invention has good tumor targeting properties, and the radionuclide conjugated drug prepared therefrom is rapidly enriched in tumors and has a long treatment time, while it is enriched in other organs (especially kidneys). It has low concentration, fast metabolism and low toxicity, and can be used for the treatment or diagnosis of tumors.

Abstract

L'invention concerne un conjugué radionucléide-médicament et une composition pharmaceutique et leur utilisation. De manière spécifique, un précurseur du conjugué radionucléide-médicament a une structure représentée par la formule I, LG représentant un ligand de ciblage; S représente un espaceur; L représente un lieur; et C représente un agent chélatant capable de contenir un radionucléide. Le conjugué radionucléide-médicament peut spécifiquement administrer le radionucléide à une cellule cible. Lorsqu'elle contient un ligand LG, le conjugué médicamenteux peut administrer spécifiquement le radionucléide à la cellule cible. Lorsqu'il contient deux ligands LG, le conjugué de médicamenteux peut fonctionner de diverses manières pour améliorer les effets thérapeutiques et réduire les effets toxiques et secondaires. D'autre part, la présence de deux ligands LG améliore également l'affinité du conjugué médicamenteux pour la cellule cible, réduisant la toxicité hors cible.
PCT/CN2023/117622 2022-09-09 2023-09-08 Conjugué radionucléide-médicament, composition pharmaceutique et leur utilisation WO2024051794A1 (fr)

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