WO2023143612A1 - 一种肽脲素衍生物、含其的药物组合物及其应用 - Google Patents

一种肽脲素衍生物、含其的药物组合物及其应用 Download PDF

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WO2023143612A1
WO2023143612A1 PCT/CN2023/073860 CN2023073860W WO2023143612A1 WO 2023143612 A1 WO2023143612 A1 WO 2023143612A1 CN 2023073860 W CN2023073860 W CN 2023073860W WO 2023143612 A1 WO2023143612 A1 WO 2023143612A1
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pharmaceutically acceptable
formula
solvate
acceptable salt
compound
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French (fr)
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王彦军
余海华
王羽
何进秋
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晶核生物医药科技(南京)有限公司
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    • C07—ORGANIC CHEMISTRY
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a peptide urea derivative, a pharmaceutical composition containing it and application thereof.
  • Prostate cancer is the most common disease among men. It is the second most common cancer, after lung cancer.
  • the "2018 Cancer Statistics” report in the United States predicts that the incidence of prostate cancer in American men accounts for about 19% of the incidence of tumors, ranking first.
  • the incidence rate of prostate cancer in Chinese men is 3.25%, ranking sixth, but it has gradually increased in recent years. Therefore, whether in the world or in China, prostate cancer is a high incidence of cancer.
  • Prostate cancer begins in the tissue surrounding the prostate and as it grows, it gradually spreads to other vital organs such as the lungs and bones. In the early stage, there are no obvious symptoms, but as the prostate cancer grows, it can cause problems such as urethral compression and urinary tract obstruction, and further spread to the spine or pelvis.
  • imaging diagnostic methods such as SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography), based on the principle of labeling with radioactive isotopes that emit gamma rays or positrons, have been used.
  • PSMA-targeted polypeptide substances are distributed through the specific targeting of prostate cancer, thereby showing the existence and distribution of tumor cells in tomographic images and three-dimensional images.
  • These diagnostic imaging methods have recently been widely spread due to the dramatic improvement in image quality under the development of SPECT-CT/MRI and PET-CT/MRI that combine CT or MRI.
  • the radiopharmaceuticals currently used for prostate cancer-specific imaging use PSMA ligands as targeting groups, which can bind to the protein PSMA (prostate-specific membrane antigen, prostate-specific membrane antigen) specifically expressed in prostate cancer .
  • PSMA is a type II transmembrane glycoprotein, also known as glutamic acid carboxypeptidase, which is a specific molecular marker of prostate cancer.
  • Typical ligands for PSMA are peptide derivatives such as Glu-urea-Lys (GUL) or Glu-urea-Cys (GUC). Therefore, by labeling radioactive isotopes to ligands containing this peptide, the prepared radiopharmaceuticals can be used for PET or SPECT imaging of prostate cancer, or for the treatment of prostate cancer (MEder, et al., Bioconjugate Chem 2012, 23:688 -697).
  • the radioisotopes used for labeling peptides are mainly ⁇ -ray-emitting radionuclides, ⁇ -ray-emitting radionuclides, ⁇ -ray-emitting radionuclides, and positron beam-emitting radionuclides.
  • radionuclides emitting alpha rays and radionuclides emitting beta rays are used for therapy
  • radionuclides emitting gamma rays and radionuclides emitting positron beams are used for diagnosis by nuclear imaging.
  • radioactive isotope labeling of ligands There are generally two methods for radioactive isotope labeling of ligands: the method of direct binding of the ligand to the radioactive isotope, or the chelation of the ligand by bifunctional chelating agents (BFCA) such as DTPA, DOTA, TETA, HYNIC, N2S2, and MAG3. isotope method.
  • the direct binding method is mainly used for the labeling of various non-metallic radioactive isotopes such as 125I and 131I.
  • the method using bifunctional chelating agent is mainly used for the labeling of various metal radioisotopes, and the type of bifunctional chelating agent (BFCA) can be determined according to the ligand and radioisotope The properties of the elements are selected.
  • the technical problem to be solved by the present invention is that the structure of the existing peptide urea derivatives is single, the uptake of the radiopharmaceutical by non-target organs and the retention of the drug in it for a long time, such as in the kidney, etc. Intratumoral uptake is not high or residence time is not long enough.
  • the present invention provides a peptide urea derivative, a pharmaceutical composition containing it and applications thereof.
  • the derivative can be used for the preoperative imaging diagnosis and grading of PSMA-positive prostate cancer, and can also be used for the treatment of various types and stages of prostate cancer, achieving the integration of diagnosis and treatment, and has broad application prospects.
  • the compound disclosed in the present invention has better selectivity and pharmacokinetics, and the uptake and residence time of the radiopharmaceutical in the targeted tumor are greatly improved.
  • the present invention provides a peptide urea derivative as shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate;
  • R is a group containing radioactive metal ions or a group capable of optical imaging
  • L 1 is a chemical bond
  • R is a group containing radioactive metal ions or a group capable of optical imaging
  • L 1 is a chemical bond
  • L2 is L 3 is
  • the carbonyl end of said L 1 is connected with The carbonyl end of L2 is connected to L1 , and the carbonyl end of L3 is connected to L2 .
  • L 1 is a chemical bond
  • L 3 is The c-terminus of the L1 is connected with connected, the e-terminal in the L2 is connected to L1 , and the g-terminal in the L3 is connected to L2 .
  • L 1 is a chemical bond
  • L2 is L 3 is The c-terminus of the L1 is connected with connected
  • the e-terminal in the L2 is connected to L1
  • the g-terminal in the L3 is connected to L2 .
  • X is The a-end of the X is connected to R, and the two b-terminals of the X are respectively connected to two L 3 .
  • X is The a-end of the X is connected to R, and the two b-terminals of the X are respectively connected to two L 3 .
  • the group containing radioactive metal ions is composed of radioactive metal ions and a group with the function of chelating metal ions, and the group of the radioactive metal ions and the group with the function of chelating metal ions Group chelation.
  • the group with the function of chelating metal ions is
  • the group with the function of chelating metal ions is
  • the group with the function of chelating metal ions is
  • the radioactive metal ion has one or more of the following effects:
  • the radioactive metal ion has one or more of the following effects:
  • the radioactive metal ions are radioactive metal ions releasing alpha, beta or gamma rays.
  • the radioactive metal ions are 68 Ga, 89 Zr, 64 Cu, 86 Y, 99m Tc, 111 In, 90 Y, 67 Ga, 177 Lu, 211 At, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi or 212 Pb.
  • the radioactive metal ions are 68 Ga 3+ , 89 Zr 4+ , 64 Cu 2+ , 86 Y 3+ , 99m Tc 4+ , 111 In 3+ , 90 Y, 67 Ga 3+ , 177 Lu 3+ , 211 At 3+ , 153 Sm 3+ , 186 Re 3+ , 188 Re 3+ , 67 Cu 2+ , 212 Pb 2+ , 225 Ac 3+ , 213 Bi 3+ , 212 Bi or 212 Pb 2+ .
  • the radioactive metal ion is 68 Ga or 177 Lu.
  • the radioactive metal ion is 68 Ga 3+ or 177 Lu 3+ .
  • the group containing radioactive metal ions is any of the following groups:
  • the peptide urea derivative shown in formula I has the following structure:
  • M is a radioactive metal ion; the radioactive metal ion is a trivalent radioactive metal ion, such as 68 Ga 3+ , 86 Y 3+ , 111 In 3+ , 67 Ga 3+ , 177 Lu 3+ , 211 At 3 + , 153 Sm 3+ , 186 Re 3+ , 188 Re 3+ , 225 Ac 3+ or 213 Bi 3+ , preferably 68 Ga 3+ or 177 Lu 3+ .
  • the radioactive metal ion is a trivalent radioactive metal ion, such as 68 Ga 3+ , 86 Y 3+ , 111 In 3+ , 67 Ga 3+ , 177 Lu 3+ , 211 At 3 + , 153 Sm 3+ , 186 Re 3+ , 188 Re 3+ , 225 Ac 3+ or 213 Bi 3+ , preferably 68 Ga 3+ or 177 Lu 3+ .
  • the group capable of optical imaging may be a fluorescent group, such as cy3, cy5 or cy7.
  • the peptide urea derivative shown in formula I is a compound formed by chelating compound A with the radioactive metal ion (such as 68 Ga 3+ or 177 Lu 3+ ), and the The structure of Compound A is either shown below:
  • the peptide urea derivative shown in formula I is a compound formed by chelation of compound A and 177 Lu 3+ , and the structure of compound A is as follows:
  • the peptide urea derivative shown in formula I is a compound formed by chelation of compound A and 68 Ga 3+ , and the structure of compound A is as follows:
  • the present invention also provides a method for preparing the above-mentioned peptide urea derivative shown in formula I, which includes the following steps: chelating radioactive metal ions with the compound shown in formula II;
  • R' is a group with the function of chelating metal ions.
  • the present invention also provides a compound as shown in formula II
  • R' is a group having the function of chelating metal ions, and the definitions of X, L 1 , L 2 and L 3 are as mentioned above.
  • the group having the function of chelating metal ions is not chelated with metal ions.
  • the present invention also provides a compound as shown below:
  • the present invention also provides a pharmaceutical composition, which includes substance X and pharmaceutical excipients; said substance X is the peptide urea derivative shown in formula I above, its pharmaceutically acceptable salt, and its solvent compound or a solvate of a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition can be a pharmaceutical composition for treating or diagnosing prostate cancer.
  • the pharmaceutical composition can be a pharmaceutical composition for imaging prostate cancer.
  • the prostate cancer is castration-resistant prostate cancer.
  • the prostate cancer is metastatic castration-resistant prostate cancer.
  • the prostate cancer is PSMA-positive prostate cancer.
  • said substance X is a therapeutically effective amount of substance X.
  • the present invention also provides the application of a substance X in the preparation of medicine;
  • the substance X is the above-mentioned peptide urea derivative shown in formula I, its pharmaceutically acceptable salt, its solvate or its Solvates of pharmaceutically acceptable salts;
  • the drug is a drug for treating or diagnosing prostate cancer, or the drug is a drug for imaging prostate cancer.
  • the drug is a drug for treating prostate cancer
  • the radioactive metal ion is a radioactive metal ion that releases gamma rays.
  • the drug is a drug for treating prostate cancer
  • the radioactive metal ion is 177 Lu 3+ .
  • the drug is a drug for diagnosing prostate cancer
  • the radioactive metal ion is a radioactive metal ion that releases ⁇ or ⁇ rays.
  • the drug is a drug for diagnosing prostate cancer
  • the radioactive metal ion is 68 Ga 3+ or 64 Cu 2+ .
  • the prostate cancer is castration-resistant prostate cancer.
  • the prostate cancer is metastatic castration-resistant prostate cancer.
  • the prostate cancer is PSMA-positive prostate cancer.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, acetates, trifluoromethylsulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.
  • solvate refers to a substance formed after crystallization of a compound with a solvent (including but not limited to: water, alcohol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base, solvent (including but not limited to: water, alcohol, ethanol, etc. ) combined to form substances, wherein, pharmaceutically acceptable salts
  • solvent including but not limited to: water, alcohol, ethanol, etc.
  • the solvent may be stoichiometric or non-stoichiometric.
  • Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
  • alkyl refers to a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (eg, C 1 -C 6 ).
  • Alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl wait.
  • cycloalkyl or “carbocycle” refers to a saturated cyclic group with a specified number of carbon atoms (such as C 3 to C 6 ), composed only of carbon atoms, which is a monocyclic, bridged ring or Spiral. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl or "aromatic ring” refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (such as C 6 to C 10 ), which is a single ring or a condensed ring, and at least one The ring is aromatic (according to Huckel's rule).
  • the aryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, wait.
  • pharmaceutical excipients refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except for active ingredients. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
  • therapeutically effective amount refers to the amount of a compound administered to a patient sufficient to effectively treat the disease.
  • the therapeutically effective amount will vary according to the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
  • patient refers to any animal, preferably a mammal, most preferably a human, who has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
  • treating refers to any of the following: (1) amelioration of one or more biological manifestations of disease; (2) interference with one or more points in the biological cascade leading to disease; (3) slowing of disease The development of one or more biological manifestations.
  • prevention refers to reducing the risk of developing a disease.
  • DMF stands for N,N-dimethylformamide.
  • DMAP stands for 4-dimethylaminopyridine.
  • Fmoc represents a 9-fluorenylmethoxycarbonyl protecting group.
  • H-Glu(OtBu)-OH represents L-glutamic acid-5-tert-butyl ester.
  • Lys represents L-lysine
  • ivDde represents 1-(4,4-dimethyl-2,6-dioxcyclohexylene)ethyl.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the derivative can be used for the preoperative imaging diagnosis and grading of PSMA-positive prostate cancer, and can also be used for the treatment of various types and stages of prostate cancer, achieving the integration of diagnosis and treatment, and has a wide range of applications. Application prospect.
  • Figure 1 is the Micro-SPECT/CT imaging images of DB-01 at different times in the mouse 1.
  • Figure 2 is the Micro-SPECT/CT imaging images of DB-01 at different times in the mouse 2.
  • Fig. 3 shows the uptake of intratumoral samples of mice after administration of different DB compounds in effect example 4 for 24 hours.
  • Fig. 4 shows the uptake amount of liver samples of mice after administration of different DB compounds in effect example 4 for 24 hours.
  • Fig. 5 shows the uptake amount of the kidney samples of the mice after administration of different DB compounds in the effect example 4 for 24 hours.
  • Fig. 6 shows the uptake amount of blood samples of mice after administration of different DB compounds in effect example 4 for 24 hours.
  • Fig. 7 shows the uptake of intramuscular samples of mice after administration of different DB compounds in effect example 4 for 24 hours.
  • Figure 8 shows the competitive binding of DB and reference compounds on PSMA expressing cells.
  • Figure 9 is the killing experiment of DB and reference compounds on LNCaP cells.
  • Fig. 10 is the fat-water partition coefficient of DB and reference compound.
  • Figure 11 is the albumin binding rate of DB and reference compounds in rat plasma.
  • Fig. 12 is the drug effect (tumor volume change) of DB and the reference compound on the 22RV1 tumor-bearing mouse animal model.
  • Fig. 13 is the drug effect (body weight change) of DB and the reference compound on the 22RV1 tumor-bearing mouse animal model.
  • This method is a general synthesis method for compound M1, wherein L is any group at the corresponding position in DB-01-DB-10.
  • the target polypeptide was cleaved from the compound M3 resin and the side chain protecting group was removed (cleavage at 30°C for 3 hours).
  • the filtrate was added to a large amount of cold anhydrous ether to precipitate the polypeptide and centrifuged. After washing several times with ether and drying, the crude polypeptide M3 was obtained.
  • This method is a general synthesis method for compound M3, wherein X is any group at the corresponding position in DB-01-DB-10.
  • DB-01 is prepared from M5 and M2a according to general synthesis method D, MS (ESI): 1844 (M+1) + .
  • DB-02 is prepared from M5 and M3a according to general synthesis method D, MS(ESI): 1844(M+1) + .
  • DB-03 is prepared from M11 and M3a according to general synthesis method E. MS (ESI): 1923 (M+1) + .
  • Compound DB-04 is first prepared M15 from lysine derivatives and M2a according to Synthesis Method E according to the following synthetic route, TFA removes the Boc protection on the nitrogen atom of M15 and then prepares M16 with DOTA derivatives according to Synthesis Method E, and on M16 After the Fmoc protecting group was taken out, it was coupled with M3d, and then the Boc protecting group on DOTA was removed by TFA to obtain the crude product of DB-04, which was purified by preparative liquid phase and lyophilized to obtain the pure product of DB-04. MS (ESI): 1909 (M+1) + .
  • DB-05 is prepared by coupling M13 and M3b. MS (ESI): 2105 (M+1) + .
  • DB-06 is prepared from M14 and M3c according to general synthesis method F. MS (ESI): 2173 (M+1) + .
  • DB-07 is prepared by coupling M12 and M3d. MS (ESI): 2097 (M+1) + .
  • DB-08 is prepared by the method of synthesizing DB-07. MS (ESI): 2098 (M+1) + .
  • DB-09 was synthesized by the same method as DB-08: MS (ESI): 1703 (M+1) + .
  • DB-10 is prepared by the method of synthesizing DB-04. MS (ESI): 1949 (M+1) + .
  • Embodiment 21 metal complex 177 Lu-DB-01 is synthesized:
  • Cover with a rubber stopper take out the silica gel plate when the developing agent expands to 9-10cm, and blow dry.
  • the gamma scanner scans the silica gel plate, compares the 177 LuCl3 solution and the solution after the reaction, and calculates the radiochemical purity and labeling rate through the peak area.
  • the labeled compound 177 Lu-DB-01 can only develop to the bottom of the silica gel plate in the developer, its radiochemical purity is 99.1%, and the labeling rate is also 100%.
  • DB-12 was synthesized using the following general method.
  • HPLC: 95.58%, RT: 10.963; MS: [M/2+H] + 1109.90.
  • Dissociation constants were determined by Biacore 8K (GE Healthcare) following the manufacturer's instructions for the instrument. Briefly, PSMA-bio protein diluted in PBS pH7.4, 1 mM TCEP, 0.05% Tween20, 2% DMSO buffer was immobilized on the flow cell of the SA sensor chip. Using PBS pH7.4, 1mM TCEP, 0.05% Tween20, 2% DMSO as the running buffer, five serial dilutions of candidate molecules targeting PSMA were injected into the flow cell at 30 ⁇ L/min, and the binding time was 90s . Buffer flow was maintained for dissociation for 1800s. The KD value of the interaction between candidate small molecules and PSMA protein was evaluated using Biacore 8K evaluation software 1.0 and 1:1 binding fitting model.
  • Human prostate cancer cell line 22RV1 cells were subcutaneously injected into the axilla of nude mice to establish a prostate cancer tumor model. by approx. 3.7MBq (100 ⁇ Ci/200 ⁇ L) intravenous injection of the 177Lu labeled compound [ 177Lu ]DB-01 of the present invention, used at the 3rd, 5th, 24th, 72nd, 120th and 168th hour after injection
  • U-SPECT+/CT MI Labs
  • Table 4 shows the uptake of [ 177 Lu]DB-01 at the 3rd hour, the 5th hour, the 24th hour, the 72nd hour, the 120th hour and the 168th hour after the injection of each organ of the mouse, that is, the injection in quantitative % Micro-SPECT/CT quantitative analysis results expressed in dose (ID)/g.
  • Effect example 3 uses Biacore to test the affinity of DB compound to PSMA protein
  • Biacore 8K (Cytiva) instrument was used to detect ligand binding of PSMA protein (Sino biological). Capture of PSMA protein on SA chip. Before immobilizing the ligand (flow path 1, 2, flow rate 10 ⁇ L/min), immobilize PSMA protein (10 ⁇ g/ml, flow rate 5 ⁇ L/min, injection time 600 s) on flow path 2 with flow buffer, at 50 mM Three consecutive injections of 1M NaCl in NaOH were used to condition the sensor surface. After each ligand injection, include an additional wash with isopropanol in 1M NaCl and 50 mM NaOH (flow path 1, 2, flow rate 10 ⁇ L/min, injection time 60 s).
  • KD the binding of the compound to PSMA protein measured by Biacore force.
  • KD(M) Kd(1/s)/Ka(1/Ms).
  • tumor-bearing animals purchased from Shanghai Alamo Pharmaceutical Technology Co., Ltd.
  • subcutaneously inoculated 3x10 6 22rv1 cells in 50% Matrigel, Corning
  • inject 177 Lu radioactively labeled DB compound from the tail vein of the mouse about 1.85MBq-3.7MBq/mouse, specific activity: 22423.82KBq/ ⁇ g
  • Animals were euthanized by carbon dioxide inhalation, and animal blood and organs (blood, liver, kidney, muscle, tumor) were collected after euthanasia.
  • 177Lu -labeled DB compounds were quickly distributed to various organs of tumor-bearing mice, and the uptake in non-targeted organs was always low and quickly metabolized out of the body, and the clearance rate in the blood was relatively fast , and is mainly excreted through renal metabolism.
  • the uptake of Lu-177-labeled compounds on the tumor remained at a high level, especially DB-12 and DB-19 had abnormally high uptake in PSMA-positive 22RV1 tumor cells.
  • the 22Rv1 cells in the logarithmic growth phase were made into a cell suspension, and the cell density was adjusted to 1 ⁇ 104/mL to inoculate 1 mL into a 24-well cell culture plate. Incubate overnight in a 37°C incubator.
  • PPB [(upper counts-background counts)]/(lower clear counts+upper counts-2*background counts)]*100%.
  • mice were inoculated subcutaneously with 3x106 cells of 22rv1 (in 50% Matrigel, Corning) on the right shoulder blade of the animals.
  • the animals are randomly assigned to 11 experimental groups according to the tumor volume, with 5 animals in each group, and the body weight and tumor size of the animals are measured.
  • the control group (normal saline), group 1 ( 177 Lu-DB-130.15mCi/piece), Group 2 ( 177 Lu-DB-13 0.45mCi/piece), Group 3 ( 177 Lu-DB-13 0.05mCi/piece), Group 4 ( 177 Lu-B- 11 0.05mCi/piece), Group 5 ( 177 Lu-DB-11 0.15mCi/piece), Group 6 ( 177 Lu-DB-11 0.45mCi/piece), Group 7 ( 177 Lu-PSMA-617 0.15mCi/piece ), Group 8 ( 177 Lu-PSMA-617 0.45mCi/piece), Group 9 ( 177 Lu-DB-19 0.05mCi/piece), Group 10 ( 177 Lu-DB-19 0.15mCi/piece), Group 11 ( 177 Lu-DB-19 0.45mCi/only) began to be administered, general health and appearance observations were carried out every day after the experiment started, and the animal body weight and tumor size were measured before each sample sampling time point. Any anomalous observations made throughout the

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Abstract

公开了一种肽脲素衍生物、其药物组合物及其应用。该衍生物如式I所示，其中，R为含有放射性金属离子的基团或能够光学成像的基团。该衍生物既可以用于PSMA阳性前列腺癌的手术前显影诊断及分级，也可以用于各个分型和分期的前列腺癌的治疗，达到诊疗一体化，具有广泛的应用前景。

Description

一种肽脲素衍生物、含其的药物组合物及其应用
本申请要求申请日为2022年1月30日的中国专利申请202210116230.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种肽脲素衍生物、含其的药物组合物及其应用。
背景技术
根据美国癌症学会官方期刊《临床医师癌症杂志》在线发表的“2018年全球癌症统计数据”报告，对185个国家中的36种癌症发病率和死亡率的评估结果发现：前列腺癌是男性中发病率第二高的癌症，仅次于肺癌。美国的“2018年癌症统计”报告中预测美国男性的前列腺癌发病率约占肿瘤发生率的19％，高居第一。中国国家癌症中心发布的2014年全国癌症统计数据显示前列腺癌在中国男性中的发病率为3.25％，居第六位，但是在近年来有逐步升高的趋势。所以无论在世界范围还是中国国内，前列腺癌都是一个高发的癌种。
前列腺癌的早期影像诊断和治疗在中国乃至整个世界都已成为一个需要迫切解决的问题。前列腺癌开始在前列腺周围的组织中发生，随着其生长，逐渐转移至其他重要器官例如肺部和骨骼部位。在早期，没有比较明显的症状，但随着前列腺癌的生长，会引起例如尿道压迫和尿路梗阻等问题，并进一步转移至脊柱或盆骨。对于前列腺癌的诊断，目前已经在使用SPECT(单光子发射计算机断层术)和PET(正电子发射断层照相术)等的成像诊断方法，其原理是通过使用发射γ射线或正电子的放射性同位素标记PSMA靶向的多肽物质，通过前列腺癌特异性靶向分布从而在断层图像和三维图像中显示出肿瘤细胞的存在和分布。这些成像诊断方法最近由于在组合了CT或MRI的SPECT-CT/MRI和PET-CT/MRI的发展下，图像质量有了大幅度提高从而得到极大推广。目前用于前列腺癌特异显影的放射性药物是以PSMA配体为靶向基团的，该配体可以与前列腺癌中特异性表达的蛋白质PSMA(前列腺特异性膜抗原，prostate-specific membrane antigen)结合。PSMA是一种Ⅱ型跨膜糖蛋白，又称谷氨酸羧肽酶，是前列腺癌特异性分子标志，在肾、小肠、脑组织有极少量表达，肿瘤组织中的表达水平远高于正常组织中的表达。PSMA的代表性的配体是例如Glu-脲-Lys(GUL)或Glu-脲-Cys(GUC)等的肽衍生物。因此，通过将放射性同位素标记到含有这种肽配体上来，制备的放射性药物可以用于PET或SPECT的前列腺癌成像、或用于治疗前列腺癌(MEder,等人,Bioconjugate Chem 2012,23:688-697)。用于标记肽的放射性同位素主要是发射α射线的放射性核素、发射β射线的放射性核素、发射γ射线的放射性核素、和发射正电子束的放射性核素。其中，发射α射线的放射性核素和发射β射线的放射性核素用于治疗，发射γ射线的放射性核素和发射正电子束的放射性核素用于通过核成像诊断。放射性同位素标记配体的方法一般有以下两种：配体与放射性同位素直接结合的方法，或配体通过DTPA、DOTA、TETA、HYNIC、N2S2、和MAG3等双官能螯合剂(BFCA)螯合放射性同位素的方法。直接结合方法主要用于各种非金属放射性同位素如125I、131I等的标记。而使用双官能螯合剂(BFCA)的方法主要用于各种金属放射性同位素的标记，双官能螯合剂(BFCA)的种类可以根据配体和放射性同位 素的性质进行选择。
目前去势手术、抗雄激素去势方法以及雄激素受体抑制剂是前列腺癌症的主流治疗方案。虽然这些治疗方案在初始阶段是非常有效的，但是有很大一部分患者会发展成去势抵抗的前列腺癌(Castration Resistant Prostate Cancer，简称CRPC)，甚至是转移性去势抵抗的前列腺癌(Metastatic Castration Resistant Prostate Cancer，mCRPC)。mCRPC是一种治疗选择有限且存在重大未满足医疗需求的疾病，所以以PSMA为靶点的放射性药物成为近年来的研究热点。
用PSMA作为靶点的放射性药物来治疗mCRPC病人已进行了一系列临床研究，虽然177Lu-PSMA-617和177Lu-PSMA I&T等放射性药物的初步临床结果令人鼓舞，但也存在一些问题，比如有近30％的病人对此治疗方法并无响应，一种可能的解释是由于不理想的药代导致没有足够的放射性药物被输送到肿瘤病灶，另一个值得关注的是177Lu-PSMA-617等放射性药物在肾脏，唾液腺等器官内的长时间累计。因此，一个以PSMA为靶点的高活性，高选择性，同时具有更好药代动力学的放射性药物是在治疗及诊断mCRPC领域的持续热点。
发明内容
本发明所要解决的技术问题是现有的肽脲素衍生物的结构单一，非靶向器官对于放射性药剂的摄取及药剂在其内长时间滞留，如在肾脏等，而在所期望的靶向肿瘤内摄取量不高或滞留时间不够长。为此，本发明提供了一种肽脲素衍生物、含其的药物组合物及其应用。该衍生物既可以用于PSMA阳性前列腺癌的手术前显影诊断及分级，也可以用于各个分型和分期的前列腺癌的治疗，达到诊疗一体化，具有广泛的应用前景。与参照化合物PSMA-617相比，本发明所披露的化合物具有更好的选择性及药代动力学，放射性药剂在靶向肿瘤内的摄取及滞留时间均有极大地提高。
本发明提供了一种如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
其中，X为
R为含有放射性金属离子的基团或能够光学成像的基团；
L1为化学键、
L2为
L3为
在某一方案中，所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物里，某些基团的定义如下所述，其余基团的定义其他任一方案所述(以下简称为“在某一方案中”)：
X为
R为含有放射性金属离子的基团或能够光学成像的基团；
L1为化学键、 L2为 L3为
在某一方案中，所述L1中羰基端与相连，所述L2羰基端与L1相连，所述L3羰基端与L2相连。
在某一方案中，L1为化学键、
L2为
L3为 所述L1中的c端与相连，所述L2中的e端与L1相连，所述L3中的g端与L2相连。
在某一方案中，L1为化学键、 L2为 L3为 所述L1中的c端与相连，所述L2中的e端与L1相连，所述L3中的g端与L2相连。
在某一方案中，X为 所述X的a端与R相连，所述X的两个b端与分别与两个L3相连。
在某一方案中，X为 所述X的a端与R相连，所述X的两个b端与分别与两个L3相连。
在某一方案中，所述的含有放射性金属离子的基团由放射性金属离子与具有螯合金属离子功能的基团组成，所述的放射性金属离子与所述的具有螯合金属离子功能的基团螯合。
在某一方案中，所述的具有螯合金属离子功能的基团为
在某一方案中，所述的具有螯合金属离子功能的基团为
在某一方案中，所述的具有螯合金属离子功能的基团为
在某一方案中，所述的放射性金属离子具有下述作用中的一个或多个：
(1)PET成像；
(2)SPECT成像；
(3)放射性治疗。
在某一方案中，所述的放射性金属离子具有下述作用中的一个或多个：
(1)示踪；
(2)递送；
(3)成像；
(4)治疗。
在某一方案中，所述的放射性金属离子为释放α、β或γ射线的放射性金属离子。
在某一方案中，所述的放射性金属离子为68Ga、89Zr、64Cu、86Y、99mTc、111In、90Y、67Ga、177Lu、211At、153Sm、186Re、188Re、67Cu、212Pb、225Ac、213Bi、212Bi或212Pb。
在某一方案中，所述的放射性金属离子为68Ga3+、89Zr4+、64Cu2+、86Y3+、99mTc4+、111In3+、90Y、67Ga3+、177Lu3+、211At3+、153Sm3+、186Re3+、188Re3+、67Cu2+、212Pb2+、225Ac3+、213Bi3+、212Bi或212Pb2+。
在某一方案中，所述的放射性金属离子为68Ga或177Lu。
在某一方案中，所述的放射性金属离子为68Ga3+或177Lu3+。
在某一方案中，所述的含有放射性金属离子的基团为以下任一基团：
在某一方案中，所述的如式I所示的肽脲素衍生物具有如下结构：
其中，M为放射性金属离子；所述放射性金属离子为3价的放射性金属离子，例如68Ga3+、86Y3+、111In3+、67Ga3+、177Lu3+、211At3+、153Sm3+、186Re3+、188Re3+、225Ac3+或213Bi3+，优选68Ga3+或177Lu3+。
在某一方案中，所述的能够光学成像的基团可为具有荧光性的基团，例如cy3、cy5或cy7。
在某一方案中，所述的如式I所示的肽脲素衍生物为化合物A与所述的放射性金属离子(例如68Ga3+或177Lu3+)螯合形成的化合物，所述的化合物A的结构如下任一所示：





在某一方案中，所述的如式I所示的肽脲素衍生物为化合物A与177Lu3+螯合形成的化合物，所述的化合物A的结构如下任一所示：






在某一方案中，所述的如式I所示的肽脲素衍生物为化合物A与68Ga3+螯合形成的化合物，所述的化合物A的结构如下任一所示：





本发明还提供了一种上述的如式I所示的肽脲素衍生物的制备方法，其包括下述步骤：将放射性金属离子与如式II所示的化合物进行螯合，即可；
所述的如式II所示的化合物中，R’为具有螯合金属离子功能的基团。
本发明还提供了一种如式II所示的化合物
其中，R’为具有螯合金属离子功能的基团，X、L1、L2和L3的定义如前所述。
所述的如式II所示的化合物中，所述的具有螯合金属离子功能的基团的定义可如前所述。
所述的如式II所示的化合物中，所述的具有螯合金属离子功能的基团未与金属离子螯合。
所述的如式II所示的化合物的结构可如下任一所示：





本发明还提供了一种如下所示的化合物：



本发明还提供了一种药物组合物，其包括物质X和药用辅料；所述的物质X为上述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某一方案中，所述的药物组合物可为治疗或诊断前列腺癌的药物组合物。
在某一方案中，所述的药物组合物可为使前列腺癌成像的药物组合物。
在某一方案中，所述的前列腺癌为去势抵抗的前列腺癌。
在某一方案中，所述的前列腺癌为转移性去势抵抗的前列腺癌。
在某一方案中，所述的前列腺癌为PSMA阳性前列腺癌。在某一方案中，所述的物质X为治疗有效量的物质X。
本发明还提供了一种物质X在制备药物中的应用；所述的物质X为上述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
所述的药物为治疗或诊断前列腺癌的药物，或者，所述的药物为使前列腺癌成像的药物。
在某一方案中，所述的药物为治疗前列腺癌的药物，所述的放射性金属离子为释放γ射线的放射性金属离子。
在某一方案中，所述的药物为治疗前列腺癌的药物，所述的放射性金属离子为177Lu3+。
在某一方案中，所述的药物为诊断前列腺癌的药物，所述的放射性金属离子为释放α或β射线的放射性金属离子。
在某一方案中，所述的药物为诊断前列腺癌的药物，所述的放射性金属离子为68Ga3+或64Cu2+。
在某一方案中，所述的前列腺癌为去势抵抗的前列腺癌。
在某一方案中，所述的前列腺癌为转移性去势抵抗的前列腺癌。
在某一方案中，所述的前列腺癌为PSMA阳性前列腺癌。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括但不限于盐酸盐、硫酸盐、甲磺酸盐，醋酸盐，三氟甲基磺酸盐等。具体参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,2002)。
术语“溶剂合物”是指化合物与溶剂(包括但不限于：水、、乙醇等)结晶后形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱、溶剂(包括但不限于：水、、乙醇等)结合形成的物质，其中，药学上可接受的盐 与上文术语“药学上可接受的盐”的含义相同，溶剂为化学计量的或非化学计量的。药学上可接受的盐的溶剂合物包括但不限于盐酸盐一水合物。
术语“烷基”是指具有指定的碳原子数(例如C1～C6)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。
术语“环烷基”或“碳环”是指具有指定的碳原子数(例如C3～C6)的、仅由碳原子组成的、饱和的环状基团，其为单环、桥环或螺环。环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“芳基”或“芳环”是指具有指定的碳原子数(例如C6～C10)的、仅由碳原子组成的环状基团，其为单环或稠环，且至少一个环具有芳香性(符合休克尔规则)。芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。芳基包括但不限于苯基、萘基、等。
结构片段中的是指该结构片段通过该位点与分子中的其他片段连接。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
术语“患者”是指已经或即将接受治疗的任何动物，优选哺乳动物，最优选人类。哺乳动物包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
术语“治疗”是指下述任一情形：(1)缓解疾病的一种或多种生物学表现；(2)干扰引发疾病的生物级联中的一个或多个点；(3)减缓疾病的一种或多种生物学表现发展。
术语“预防”是指降低发生疾病的风险。
本发明采用以下缩略词：
DMF表示N,N-二甲基甲酰胺。
DMAP表示4-二甲基氨基吡啶。
Fmoc表示9-芴基甲氧基羰基保护基。
H-Glu(OtBu)-OH表示L-谷氨酸-5-叔丁基酯。
Lys表示L-赖氨酸。
ivDde表示1-(4,4-二甲基-2，6-二氧环亚己基)乙基。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：该衍生物既可以用于PSMA阳性前列腺癌的手术前显影诊断及分级，也可以用于各个分型和分期的前列腺癌的治疗，达到诊疗一体化，具有广泛的应用前景。
附图说明
图1为在小鼠1体内，DB-01在不同时间内Micro-SPECT/CT的成像图像。
图2为在小鼠2体内，DB-01在不同时间内Micro-SPECT/CT的成像图像。
图3为效果实施例4中，将小鼠给药不同DB化合物24h后，小鼠的肿瘤内样本的摄取量。
图4为效果实施例4中，将小鼠给药不同DB化合物24h后，小鼠的肝脏内样本的摄取量。
图5为效果实施例4中，将小鼠给药不同DB化合物24h后，小鼠的肾脏内样本的摄取量。
图6为效果实施例4中，将小鼠给药不同DB化合物24h后，小鼠的血液内样本的摄取量。
图7为效果实施例4中，将小鼠给药不同DB化合物24h后，小鼠的肌肉内样本的摄取量。
图8为DB及参比化合物在PSMA表达细胞上的竞争结合。
图9为DB及参比化合物对LNCaP细胞的杀伤实验。
图10为DB及参比化合物的脂水分配系数。
图11为DB及参比化合物在大鼠血浆中的白蛋白结合率。
图12为DB及参比化合物在22RV1荷瘤小鼠动物模型上的药效(肿瘤体积变化)。
图13为DB及参比化合物在22RV1荷瘤小鼠动物模型上的药效(体重变化)。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1化合物M1的合成
通用合成方法A：以Fmoc-Lys(ivDde)-Wang resin(0.3mmol/g)为起始原料，加入至反应容器中，再加入25％六氢吡啶/DMF(体积比)，搅拌30min，以茚三酮检测显示深蓝色，抽干过滤反应液，用DMF洗涤5次，去除N端Fmoc保护基使N端成为自由氨基；以DMF为溶剂，按比例(1：2：2)投入N,N二琥珀酰亚胺基碳酸酯(1当量)，N,N-二异丙基乙胺DIPEA(2当量)和4-二甲氨基吡啶DMAP(2当量)，在氮气保护下，反应1h，再加入H-Glu(OtBu)-OH(1.1当量)，搅拌24小时。用2％水合肼/DMF溶液去除Lys的侧链Dde保护基后，加入Fmoc-2-Nal-OH/HOBt/DIC(3当量)与树脂进行接枝引入2-Nal氨基酸残基。随后再次用25％六氢吡啶/DMF(体积比)去除Fmoc保护基使2-Nal的N端成为自由氨基后，加入Fmoc-L-COOH/HOBt/N，N-二异丙基二亚胺(DIC)(3当量)与树脂进行接枝引入L氨基酸残基。随后再次用25％六氢吡啶/DMF(体积比)去除Fmoc保护基使L的N端成为自由氨基，合成得到产物M1。
该方法为化合物M1通用合成方法，其中L为任意的DB-01～DB-10中相应位置的基团。
实施例2化合物M2的合成
通用合成方法B：以M1为起始原料，使用切割试剂(三氟乙酸：H2O：三异丙基硅烷＝90:5:5，v/v)将目标多肽从化合物M2树脂上裂解下来并除去侧链保护基(30℃下切割3小时)。滤液加入到大量冷的无水乙醚中使多肽沉淀析出，离心。用乙醚洗涤数次后干燥，即得到多肽产物M2。
实施例3化合物M3的合成
通用合成方法C:以M1为原料，使用通用合成方法A，偶合氨基酸FmocNHXCOOH，去除Fmoc保护基使X的N端成为自由氨基，随后使用切割试剂(三氟乙酸：H2O：三异丙基硅烷＝90:5:5，v/v)将目标多肽从化合物M3树脂上裂解下来并除去侧链保护基(30℃下切割3小时)。滤液加入到大量冷的无水乙醚中使多肽沉淀析出，离心。用乙醚洗涤数次后干燥，即得到多肽粗品M3。
该方法为化合物M3通用合成方法，其中X为任意的DB-01～DB-10中相应位置的基团。
实施例4化合物M5的合成
通用合成方法D：3，5-二羧基苯胺(1.0当量)溶于DMF(50mL),加入DIPEA(1.5当量)， 随后加入NHS活化的DOTA酯(1.1当量)，反应在室温下搅拌过夜，反应液倒入水中，用乙酸乙酯(3x 30mL)萃取，混和的萃取液用饱和NaCl溶液洗涤(30mL),干燥(Na2SO4)，过滤，浓缩去除溶剂后，柱层析纯化(SiO2,5-10％MeOH/DCM)得到M4(0.8当量，80％)。将M4(0.5当量),DMAP(0.1当量)，N-羟基丁二酰亚胺(1.1当量)溶于DMF(20mL)，反应过夜，用乙酸乙酯(100mL)稀释，NaHCO3饱和溶液(35mL)洗涤，有机相用饱和NaCl溶液洗涤，干燥(Na2SO4)，过滤，浓缩后得到M5，MS(ESI)：916。M5粗品直接用于下一步反应。
实施例5化合物M6的合成
通用合成方法E：将M5(0.01当量)，M3(0.02当量)，DIPEA(0.025当量)溶于DMF(10mL),反应过夜，溶剂在真空下除去，残留物用切割试剂(三氟乙酸：H2O：三异丙基硅烷＝90:5:5，v/v)在30℃搅拌3小时，倒入大量冷的无水乙醚中，沉淀物过滤，用冷无水乙醚洗涤，干燥，用制备液相进行纯化(C18柱，A:100％水/0.1％TFA，B:100％乙腈/0.1％TFA)，含有目标产物的馏分混合，冷冻干燥得产物M6。
实施例6化合物M11的合成
化合物M11的合成
将N-Boc甘氨酸(1.0当量)，DCC(1.3当量)加入THF(100mL),室温搅拌30分钟，加入1,3,5-triazinane(1.1当量)，搅拌过夜，浓缩，残留液经柱层析纯化(SiO2,5-10％MeOH/DCM)得到M7(0.8当量)，MS(ESI)：245(M+1)+。
将M7(1.0当量)，2-溴乙酸叔丁酯(2.1当量)，三乙胺(2.5当量)溶于DMF(100mL),反应液在室温下搅拌过夜，浓缩，残留液用柱层析纯化(SiO2,5-10％MeOH/DCM)得到M8(0.75当量)，MS(ESI)：473(M+1)+。
M8(1.0当量)与TAF的DCM混合液(TFA：DCM：TIS＝9：1:0.1)混合，在室温下搅拌6小时，浓缩，用无水乙醚洗涤，过滤，固体(M9)经真空干燥直接用于下一步反应。
M9(0.5当量)，DIPEA(0.5当量)，NHS活化的DOTA酯(0.55当量)溶于DMF(50mL)，使用通用合成方法D得到M10(0.5当量)。MS(ESI)：816(M+1)+。
将M10(0.5当量)，DMAP(0.1当量)，N-羟基丁二酰亚胺(1.05当量)溶于DMF(20mL),使用通用合称方法D得到M11(0.48当量)。MS(ESI)：1010(M+1)+。
实施例7化合物M12的合成
3,5-双-BOC-氨基苯甲酸(0.5当量)，DCC(0.55当量)和DMAP(0.1当量)溶于DMF(100mL)并在室温下搅拌30分钟，随后将DOTA衍生物(0.5当量)加入，反应液在室温下搅拌过夜，浓缩，过滤，滤液浓缩，残留物用TAF的DCM混合液(TFA：DCM：TIS＝9：1:0.1)混合，在室温下搅拌2小时，浓缩，用无水乙醚洗涤，过滤，固体(M12)经真空干燥得M12，MS(ESI)：581(M+1)+。M12未经纯化直接用于下一步反应。即DB-07的制备。
实施例8化合物M13的合成
将DOTA衍生物(0.15当量)，DCC(0.15当量)DMAP(0.05当量)溶于DMF(20mL)并搅拌30分钟，随后加入三(2-氨基乙基)胺(0.5当量)，反应液搅拌过夜，浓缩，用DCM稀释，过滤，浓缩得M13粗品，该粗品直接用与下一步反应。MS(ESI)：701(M+1)+。
实施例9化合物M14的合成(通用合成方法F)：
1，3，5-三丙烯酰基六氢-1，3，5-三嗪(0.5当量)与M3c(0.15当量)在DMF中搅拌过夜，浓缩，残留液用冷乙醚稀释，沉淀过滤，用冷乙醚洗涤，干燥得到M14。MS(ESI)：882(M+1)+。
实施例10化合物的合成
M2a的合成：
使用通用合成方法A和B得到化合物M2a,MS(ESI):656(M+1)+。
M3a的合成：
使用通用合成方法A和C得到化合物M3a,MS(ESI):713(M+1)+。
M3b的合成：
使用通用合成方法A和相应的C得到化合物M3b,MS(ESI):804(M+1)+。
M3c的合成：
使用通用合成方法A和C得到化合物M3c,MS(ESI):730(M+1)+。
M3d的合成：
使用通用合成方法A和C得到化合物M3d,MS(ESI):776(M+1)+。
M3e的合成：
使用通用合成方法A和C得到化合物M3e,MS(ESI):579(M+1)+。
M3f的合成：
使用通用合成方法A和B得到化合物M3f,MS(ESI):676(M+1)+。
实施例11 DB-01的合成：
DB-01是M5与M2a按通用合成方法D制得,MS(ESI):1844(M+1)+。
实施例12 DB-02的合成：
DB-02是M5与M3a按通用合成方法D制得，MS(ESI):1844(M+1)+。
实施例13 DB-03的合成：
DB-03是M11与M3a按通用合成方法E制得。MS(ESI)：1923(M+1)+。
实施例14 DB-04的合成：
化合物DB-04是按下列合成路线先由赖氨酸衍生物与M2a按合成方法E制得M15，TFA去除M15氮原子上的Boc保护后与DOTA衍生物按合成方法E制得M16，M16上Fmoc保护基取出后与M3d偶合，再经TFA去除DOTA上的Boc保护基，得到DB-04粗品，经制备液相纯化，冻干得到DB-04纯品。MS(ESI)：1909(M+1)+。
实施例15 DB-05的合成：
DB-05是M13与M3b偶合制得。MS(ESI)：2105(M+1)+。
实施例16 DB-06的合成：
DB-06是M14与M3c按通用合成方法F制得。MS(ESI):2173(M+1)+。
实施例17 DB-07的合成：
DB-07是M12与M3d偶合制得。MS(ESI)：2097(M+1)+。
实施例18 DB-08的合成：
DB-08是用合成DB-07的方法制备而成。MS(ESI)：2098(M+1)+。
实施例19 DB-09的合成：
DB-09是用与制备DB-08的方法合成：MS(ESI)：1703(M+1)+。
实施例20 DB-010的合成：
DB-10是用合成DB-04的方法制备。MS(ESI)：1949(M+1)+。
实施例21金属络合物177Lu-DB-01合成:
1)称取醋酸钠4.1g，加入45mL超纯水，完全溶解后，用冰醋酸调pH至4.0，再补超纯水至50mL，得1M的醋酸钠溶液。打开金属浴反应器，预热至95℃。
2)分别称量前体化合物DB-01(1mg)，分别加入1000μL的醋酸钠溶液，充分溶解后得1μg/μL的前体溶液。取前体溶液10μL(10μg)，再加入240μL的醋酸钠溶液稀释。然后分别加入250μCi的177LuCl3溶液，混匀后置于95℃的反应器上反应30min，使用C18Sep-Pak进行纯化。
3)称取EDTA钠盐0.5g，加入50mL生理盐水，充分溶解，得1％EDTA钠盐水溶液。取177LuCl3溶液2μL，点在瞬时薄层色谱层析硅胶板上距底部1cm处，吹干。取反应后的溶液2μL，点在瞬时薄层色谱层析硅胶板距上底部1cm处，吹干。以0.5mL的1％EDTA钠盐溶液为展开剂，将硅胶板底部置于玻璃试管的展开剂中，硅胶板底部伸入展开剂液面不超过5mm。盖上橡胶塞，待展开剂展开至9-10cm时取出硅胶板，吹干。γ扫描仪扫描硅胶板，对比177LuCl3溶液和反应后的溶液，通过峰面积计算放化纯度和标记率。
如表1所示，177LuCl3溶液在展开剂中展开至硅胶板顶部。
表1：区域:177Lu检测器:PMT

总面积:2401Counts
平均背景:0Counts
如表2所示，标记化合物177Lu-DB-01在展开剂中只能展开至硅胶板底部，其放化纯度为99.1％，标记率也是100％。
表2：区域:177Lu检测器:PMT
总面积:2498Counts
平均背景:0Counts
实施例22：DB-11的合成
DB-11采用以下通用合成方法制得：通过系列缩合反应，包括固相合成，得到中间体JH-04S10-01(MS：[M+H]+＝489.61)和DB-11-01(MS:[M+H]+＝788.50)，使用JH-04S10-01与DB-11-01缩合获得DB-11-02(MS:[M/2+H]+＝1015.43)，经脱保护得到DB-11-03(MS:[M/2+H]+＝852.81)，该中间体经与DOTA-NHS反应得到终产物化合物DB-11。HPLC：98.54％，RT:8.23；MS:[M/2+H]+＝1046.36。
实施例23：DB-12的合成
DB-12采用以下通用方法合成。由固相制得的DB-A1(MS:[M+H]+＝816.83)与DB-A2(MS:[M+H]+＝681.73)偶合得到DB-A3(MS:[M/2+H]+＝1139.49)，经过两次脱保护后，中间体DB-A5(MS:[M/2+H]+＝916.21)与DOTA-NHS反应得到DB-12。HPLC：95.58％，RT:10.963；MS:[M/2+H]+＝1109.90。
实施例24：DB-13的合成
DB-13参考DB-12的通用合成方法制得。HPLC：97.73％，RT：9.214；MS:[M/2+H]+＝1047.34。
实施例25：DB-14的合成
DB-14参考DB-12的通用合成方法制得。HPLC：95.8％,RT：9.52；MS:[M/2+H]+＝1047.34。
实施例26：DB-15的合成
DB-15参考通用方法D和E合成。HPLC：95.8％，RT:12.34；MS:[M/2+H]+＝1124.59。
实施例27：DB-16的合成
DB-16参考DB-11的通用方法合成。HPLC：96.62％，RT：9.543；MS:[M/2+H]+＝1012.36。
实施例28：DB-17的合成
DB-17参考通用方法D和E合成。HPLC：99.24％，RT：10.423；MS:[M/2+H]+＝937.27。
实施例29：DB-18的合成
DB-18参考通用方法D和E合成。HPLC：95.64％，RT:7.78；MS:[(M-1)/3-1]+＝626.37。
实施例30：DB-19的合成
DB-19参考通用方法D和E合成。HPLC：97.73％，RT:9.10；MS:[M/2+H]+＝1028.17。
实施例31：DB-20的合成
DB-20参考DB-11的通用方法合成。HPLC：98.95％，RT:11.294；MS:[M/2+H]+＝1074.49。
实施例32：DB-21的合成
DB-21参考通用方法D和E合成。HPLC：98.01％，RT:12.446；MS:[M/2+H]+＝1100.24。
以下效果实施例中使用的参比化合物结构如下：
效果实施例1靶向PSMA的候选分子的结合亲和力和解离常数测定
遵循制造商提供的仪器的说明书由Biacore 8K(GE Healthcare)确定解离常数。简而言之，将在PBS pH7.4,1mM TCEP,0.05％Tween20,2％DMSO缓冲液中稀释的PSMA-bio蛋白固定化在SA传感器芯片的流通池上。以PBS pH7.4,1mM TCEP,0.05％Tween20,2％DMSO为运行缓冲液，将具有五个系列稀释浓度的靶向PSMA的候选分子以30μL/min注射到流通池中，其中结合时间为90s。维持缓冲液流以解离1800s。使用Biacore 8K评价软件1.0和1:1结合的拟合模型评价候选小分子与PSMA蛋白相互作用的KD值。
结果显示在表3中。DB-01的结合亲和力比PSMA-617的结合亲和力略高。
表3通过Biacore8K测定的候选分子与PSMA蛋白结合动力学和亲和力
效果实施例2移植人前列腺癌细胞系22RV1的小鼠的Micro-SPECT/CT扫描成像实验
将人前列腺癌细胞系22RV1细胞皮下注射到裸鼠的腋下，以建立前列腺癌肿瘤模型。以约 3.7MBq(100μCi/200μL)静脉注射本发明的177Lu标记化合物[177Lu]DB-01，注射后第3小时、第5小时、第24小时、第72小时、第120小时和第168小时使用U-SPECT+/CT(MI Labs)采集SPECT/CT图像并对得到的SPECT/CT图像结果进行定量分析。
表4显示了[177Lu]DB-01注射后第3小时、第5小时、第24小时、第72小时、第120小时和第168小时，小鼠各器官的摄取量，即以定量％注射剂量(ID)/g表示的Micro-SPECT/CT定量分析结果。
由表4可知，[177Lu]DB-01在注射后初期很快通过肾脏和膀胱排泄。
在[177Lu]DB-01的情况下，其在肿瘤的摄取随时间增加，根据计算，在180分钟肿瘤的摄取为13.55±3.85％ID/g，肿瘤滞留时间明显延长，168小时的肿瘤摄取仍有7.85±1.16％ID/g。另外，[177Lu]DB-01化合物均从5hr开始肾脏摄取量的减少，并迅速排出体外。
表4[177Lu]DB-01随时间推移的小鼠各器官的摄取量(％ID/g)
由表4及附图1和附图2可以看到177Lu-DB-01在进入小鼠体内后迅速被分布到各个器官及靶点，其代谢的主要通路是通过排尿进行的，5小时后，在肿瘤内放射性药剂的浓度达到高点，随后逐步下降，24小时后，放射性药剂除了在肿瘤内的富集外，在其他器官的累计大大降低。7天后，在肿瘤内仍有相当量的放射性药剂存在，结果显示，本专利申请所披露的化合物与参照化合物PSMA-617相比，不仅具有更好的PSMA细胞亲和力，而且具有更优异的药代动力学，是更具有作为诊疗一体核药的潜力分子。
效果实施例3使用Biacore测试DB化合物对PSMA蛋白的亲和力
Biacore 8K(Cytiva)仪器用于检测PSMA蛋白(Sino biological)的配体结合。在SA芯片上捕获PSMA蛋白。在固定配体之前(流动路径1、2，流速为10μL/min)，用流动缓冲液在流动路径2上固定PSMA蛋白(10μg/ml，流速为5μL/min，注射时间为600s)，在50mM NaOH中连续注入三次1M NaCl，调节传感器表面。在每次配体注射后，包括在1M NaCl和50mM NaOH中使用异丙醇进行额外清洗(流动路径1、2，流速为10μL/min，注射时间为60s)。
所有化合物溶解在100％二甲基亚砜中并稀释至10mM，然后在分析缓冲液(PBS，pH 7.4，1mM TCEP(三-(2-羟乙基)膦)，0.05％P20，2％二甲基亚砜)中以适当的最高浓度稀释。使用以下条件运行分析物：15℃分析温度，分析步骤＝全部设置为LMW动力学；循环类型＝单循环(90s接触时间，1800s分离时间，30μL/min流速，流道1，2)；流道检测＝2-1)。使用Biacore Insight评估软件进行数据评估，数据适合1:1绑定模型。
Biacore结果见表5：pKD＝-LogKD,其中KD是Biacore测得的化合物对PSMA蛋白的结合 力。用KD(M)＝Kd(1/s)/Ka(1/Ms)来表达。A表示pKD>8；B表示8<pKD<7；C表示7<pKD<6；D表示pKD>6；
表5 Biacore测试结果
效果实施例4 177Lu标记及动物生物分布实验
PSMA阳性荷瘤小鼠组织分布：荷瘤动物(采购自上海阿拉莫医药科技有限公司)，将3x106的22rv1细胞(在50％基质胶中，康宁)皮下接种到6-9周左右的(Balb/c Nude)小鼠的动物右侧肩部。待肿瘤生长至适宜尺寸时，将177Lu放射性标记的DB化合物从小鼠的尾部静脉注入(约1.85MBq-3.7MBq/鼠，比活度为：22423.82KBq/μg)，动物给药后分别在24h使用二氧化碳吸入的方式对动物进行安乐死，安乐死后采集动物血液和脏器(血、肝、肾、肌肉、肿瘤)。
血液通过腹主动脉采血，采集后立即定量100μL到指定离心管中(称重)。脏器采集后使用去离子水清洗两次并擦干，放入事先称重的试管中，再次称重，计算样本重量，样本于采集当天进行测定。所有血液样本和组织样本使用伽马计数计测量放射性计数，结果如图3、图4、图5、图6、图7和表6所示。
经静脉给药后，177Lu标记的DB化合物快速分布到荷瘤小鼠的各个器官，在非靶向器官中摄取量始终较低且很快被代谢出体内，在血液中的清除速率较快，且主要是经肾脏代谢排出体外。在给药24小时后，Lu-177标记的化合物在肿瘤上的摄取仍维持较高水平，尤其是DB-12和DB-19在PSMA阳性的22RV1肿瘤细胞内具有异常高的摄取量。
表6 177Lu标记化合物的生物分布数据(n＝2)

效果实施例5竞争结合
(1)将对数生长期的22Rv1细胞，制成细胞悬液，细胞密度调整为1×104/mL接种1mL至24孔细胞培养板中。37℃孵箱中培养过夜。
(2)吸去细胞培养液，用PBS洗涤细胞1次，加入975μL无添加剂的培养基。
(3)每孔加入用放射性标记的固定浓度的PSMA-617配体(培养液中终浓度：2μCi/mL)25μL及不同浓度(培养液中终浓度：1000ng/ml，100ng/ml，10ng/ml，1ng/ml，0.1ng/ml，0.01ng/ml，0.001ng/ml,0ng/ml)的未标记的待测blocking化合物DB-18,DB-19,DB-13,E-3。
(4)冰上下孵育2小时。
(5)用冰冷的PBS洗涤细胞三次。
(6)用0.5mL1M氢氧化钠裂解细胞，用0.5mL PBS洗涤2次，收集氢氧化钠(0.5mL)和PBS(0.5mL×2)溶液，测定摄取计数。
实验结果见图8，结果显示化合物E-3,DB-13,DB-18和DB-19的IC50值分别是2.06nM,1.83nM,2.58nM和0.93nM。
效果实施例6细胞杀伤
A.将对数生长期的LNCaP细胞，制成细胞悬液，细胞密度调整为1×105/ml接种1ml至24孔细胞培养板中。37℃孵箱中培养24小时。
B.用含血清的培养基将177Lu标记化合物(177Lu-E-3)配制成放射性度浓度分别为5、15、45μCi/mL备用(未标记E-3用对应45μCi/mL的前体浓度)。
C.实验组分别加入上述177Lu标记化合物溶液1mL/孔，对照组加入含血清培养液1mL/孔。
D.置于培养箱中培养24h，全部更换新鲜培养基。
E.在第五天用增强型CCK8试剂盒检测各组细胞的增殖情况。
实验结果见图9，结果显示在所测试的剂量下，两个化合物与参比化合物均对细胞具有杀伤作用，而且成量效关系。在45μCi/mL的等同剂量下，DB-13具有更强的细胞杀伤作用，达到67％的细胞杀 伤率。
效果实施例7 cLogP的测定
取3个EP管，各加入0.1ml饱和正辛醇和80μl的超纯水，然后分别加入20μl(约1Mbq)的Lu-177标记的DB-13，DB-18和DB-19化合物溶液，振荡均匀后室温离心(2000r/min，5min，离心半径10cm)，各管从脂层和水层分别取100μl，测量两相的每分钟放射性计数，并计算LogP，结果取均值。
实验结果见图10，DB-13，DB-18，DB-19和E-3的实验logP分别为-1.96,-1.86,-1.79和-3.46，结果表明所测试的化合物均具有良好的水溶性。
效果实施例8 PPB的测试
取标记好的177Lu-E-3，177Lu-DB-13，177Lu-DB-18和177Lu-DB-19化合物(1μCi)，加入50μL的PBS，得20μCi/mL反应液。取50μL 20μCi/mL反应液加入到200μL血浆中，重复3管，混匀后室温孵育10min,后将样品加入到超滤管中，13000rpm离心45min，然后加入50μL生理盐水，继续离心15min，套管及滤过液分别计数。
PPB＝[(上层计数-本底计数)]/(下清计数+上层计数-2*本底计数)]*100％。
实验结果见图11，所合成的化合物与参比化合物相比，除DB-13具有更高的白蛋白结合率(DB-13：90.84％，E-3：86.61％)，DB-18和DB-19的白蛋白结合率均较参比化合物为低，分别为70.51％和59.07％。
效果实施例9治疗
将6-8周左右的(Balb/c Nude)小鼠用3x106细胞的22rv1(在50％基质胶中，康宁)在动物右侧肩胛骨皮下接种。待肿瘤生长至实验要求的尺寸时，将动物按肿瘤体积随机分配到11个实验组中，每组5只，对动物体重和肿瘤大小进行测量，分组当天按control组(生理盐水)，组1(177Lu-DB-130.15mCi/只)，组2(177Lu-DB-13 0.45mCi/只)，组3(177Lu-DB-13 0.05mCi/只)，组4(177Lu-B-11 0.05mCi/只)，组5(177Lu-DB-11 0.15mCi/只)，组6(177Lu-DB-11 0.45mCi/只)，组7(177Lu-PSMA-617 0.15mCi/只)，组8(177Lu-PSMA-617 0.45mCi/只)，组9(177Lu-DB-19 0.05mCi/只)，组10(177Lu-DB-19 0.15mCi/只)，组11(177Lu-DB-19 0.45mCi/只)开始给药，实验开始后每天进行一般健康和外观观察，在每个样品采样时间点前测量动物体重和肿瘤大小。在整个研究期间若发现任何异常观察结果都将需要被记录在原始数据中。
实验结果见图12、图13和表7，结果表明，较PSMA-617，DB-19在中，高两个不同剂量(0.15mCi和0.45mCi)上均表现出对肿瘤细胞优异的肿瘤生长抑制作用,DB-11在高剂量下(0.45mCi)在给药后具有一定的肿瘤生长抑制作用，但随着时间其抑制作用降低，不过仍较PSMA-617的抑制作用高。
表7

Claims (18)

  1. 一种如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    其中，X为
    R为含有放射性金属离子的基团或能够光学成像的基团；
    L1为化学键、
    L2为
    L3为
  2. 如权利要求1所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    X为 R为含有放射性金属离子的基团或能够光学成像的基团；
    L1为化学键、 L2为 L3为
  3. 如权利要求1或2所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述L1中羰基端与相连，所述L2羰基端与L1相连，所述L3羰基端与L2相连。
  4. 如权利要求1所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件中地一个或多个：
    (1)L1为化学键、 L2为 L3为 所述L1中的c端与相连，所述L2中的e端与L1相连，所述L3中的g端与L2相连；
    优选地，L1为化学键、 L2为 L3为 所述L1中的c端与相连，所述L2中的e端与L1相连，所述L3中的g端与L2相连；
    (2)X为 所述X的a端与R相连，所述X的两个b端与分别与两个L3相连；
    优选地，X为 所述X的a端与R相连，所述X的两个b端与分别与两个L3相连。
  5. 如权利要求1或2所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的含有放射性金属离子的基团由放射性金属离子与具有螯合金属离子功能的基团组成，所述的放射性金属离子与所述的具有螯合金属离子功能的基团螯合；例如所述的具有螯合金属离子功能的基团为 又例如所述的具有螯合金属离子功能的基团为 优选
  6. 如权利要求5所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足下述条件中的一个或多个：
    (1)所述的放射性金属离子具有下述作用中的一个或多个：1.PET成像；2.SPECT成像；3.放射性治疗；
    (2)所述的放射性金属离子具有下述作用中的一个或多个：1.示踪；2.递送；3.成像；4.治疗；
    (3)所述的放射性金属离子为68Ga、89Zr、64Cu、86Y、99mTc、111In、90Y、67Ga、177Lu、211At、153Sm、186Re、188Re、67Cu、212Pb、225Ac、213Bi、212Bi或212Pb，优选68Ga或177Lu；例如，所述的放射性金属离子为68Ga3+、89Zr4+、64Cu2+、86Y3+、99mTc4+、111In3+、90Y、67Ga3+、177Lu3+、211At、153Sm、186Re、188Re、67Cu2+、212Pb2+、225Ac3+、213Bi3+、212Bi或212Pb2+，优选68Ga3+或177Lu3+。
  7. 如权利要求1或2所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的含有放射性金属离子的基团为以下任一基团：
  8. 如权利要求1或2所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示的肽脲素衍生物具有如下结构：
    其中，M为放射性金属离子；所述放射性金属离子为3价的放射性金属离子，例如68Ga3+、86Y3+、111In3+、67Ga3+、177Lu3+、211At3+、153Sm3+、186Re3+、188Re3+、225Ac3+或213Bi3+，优选68Ga3+或177Lu3+。
  9. 如权利要求1所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示的肽脲素衍生物为化合物A与177Lu3+螯合形成的化合物，所述的化合物A的结构如下任一所示：





  10. 如权利要求1所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示的肽脲素衍生物为化合物A与68Ga3+螯合形成的化合物，所述的化合物A的结构如下任一所示：






  11. 一种如权利要求1～10中任一项所述的如式I所示的肽脲素衍生物的制备方法，其包括下述步骤：将放射性金属离子与如式II所示的化合物进行螯合，即可；
    所述的如式II所示的化合物中，R’为具有螯合金属离子功能的基团。
  12. 一种如式II所示的化合物；
    其中，R’为具有螯合金属离子功能的基团，X、L1、L2和L3的定义如权利要求1～10中任一项所述。
  13. 如权利要求12所述的如式II所示的化合物，所述的如式II所示的化合物中，所述的具有螯合金属离子功能的基团的定义如权利要求5所述。
  14. 如权利要求13所述的如式II所示的化合物，其特征在于，所述的如式II所示的化合物为






  15. 一种化合物，其特征在于，所述化合物为：

  16. 一种药物组合物，其包括物质X和药用辅料；所述的物质X为如权利要求1～10中任一项所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
  17. 一种物质X在制备药物中的应用；所述的物质X为如权利要求1～10中任一项所述的如式I所示的肽脲素衍生物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    所述的药物为治疗或诊断前列腺癌的药物，或者，所述的药物为使前列腺癌成像的药物。
  18. 如权利要求17所述的应用，所述的前列腺癌为去势抵抗的前列腺癌、转移性去势抵抗的前列腺癌或PSMA阳性前列腺癌。
PCT/CN2023/073860 2022-01-30 2023-01-30 一种肽脲素衍生物、含其的药物组合物及其应用 WO2023143612A1 (zh)

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