CN118344391A - Novel boron-containing compound for boron neutron capture therapy - Google Patents
Novel boron-containing compound for boron neutron capture therapy Download PDFInfo
- Publication number
- CN118344391A CN118344391A CN202310208317.3A CN202310208317A CN118344391A CN 118344391 A CN118344391 A CN 118344391A CN 202310208317 A CN202310208317 A CN 202310208317A CN 118344391 A CN118344391 A CN 118344391A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- boron
- psma
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 122
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 82
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 65
- 230000008685 targeting Effects 0.000 claims abstract description 16
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims abstract description 15
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims abstract description 12
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims abstract 3
- 201000011510 cancer Diseases 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- -1 cyano, carbonyl Chemical group 0.000 claims description 15
- 210000004881 tumor cell Anatomy 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 10
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 229910006069 SO3H Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910018830 PO3H Inorganic materials 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 239000000539 dimer Substances 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000005647 linker group Chemical group 0.000 claims description 2
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 108700026220 vif Genes Proteins 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000006378 damage Effects 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 241000699670 Mus sp. Species 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical group C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000004992 fission Effects 0.000 description 2
- 230000005251 gamma ray Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 150000004032 porphyrins Chemical class 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical group C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JWDYCNIAQWPBHD-UHFFFAOYSA-N 1-(2-methylphenyl)glycerol Chemical compound CC1=CC=CC=C1OCC(O)CO JWDYCNIAQWPBHD-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- DBVFWZMQJQMJCB-UHFFFAOYSA-N 3-boronobenzoic acid Chemical compound OB(O)C1=CC=CC(C(O)=O)=C1 DBVFWZMQJQMJCB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OPVPGKGADVGKTG-BQBZGAKWSA-N Ac-Asp-Glu Chemical compound CC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OPVPGKGADVGKTG-BQBZGAKWSA-N 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010061825 Duodenal neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 101710183768 Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000005927 Myosarcoma Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 1
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 1
- KMNSVNDXMDMOCA-MCNHTDSKSA-N OC1(C[C@H](N)C(=O)O)CC=C(C=C1)O.[B] Chemical compound OC1(C[C@H](N)C(=O)O)CC=C(C=C1)O.[B] KMNSVNDXMDMOCA-MCNHTDSKSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 206010043515 Throat cancer Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- 108091005956 Type II transmembrane proteins Proteins 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- XWHTVJSRZQUVOT-UHFFFAOYSA-N aminosulfanyl-N-nitroiminophosphonamidic acid Chemical group NSP(=O)(N=N[N+](=O)[O-])O XWHTVJSRZQUVOT-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 201000000312 duodenum cancer Diseases 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Chemical group C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 102000006815 folate receptor Human genes 0.000 description 1
- 108020005243 folate receptor Proteins 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 201000011061 large intestine cancer Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- WHXSMMKQMYFTQS-IGMARMGPSA-N lithium-7 atom Chemical compound [7Li] WHXSMMKQMYFTQS-IGMARMGPSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000012804 lymphangiosarcoma Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000021332 multicellular organism growth Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000002077 muscle cancer Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical group OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000003868 tissue accumulation Effects 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Radiation-Therapy Devices (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of boron neutron capture therapy, and particularly provides a novel boron-containing compound for boron neutron capture therapy and a preparation method thereof, wherein the compound is composed of 10 B compound and a PSMA-targeted bracket structure, not only has the advantages of high targeting of PSMA directional therapy and space positioning provided by neutron beams, but also has extremely high enrichment concentration of boron in tumors, can reach 50ug/g, and can achieve good therapeutic effect without high-intensity neutron irradiation. This is also reflected from the sides, reducing the damage caused by neutron irradiation to normal healthy tissue, significantly improving the pharmacological effect of the boron-containing compounds, which is of great significance in the medical field for tumour therapy.
Description
Technical Field
The invention belongs to the field of Boron Neutron Capture Therapy (BNCT), and in particular relates to a compound containing 10 B compound and PSMA-targeted scaffold combination for boron neutron capture therapy, a preparation method thereof and a cancer therapy using the compound.
Background
Worldwide, cancer is the second leading cause of death next to coronary heart disease. Millions of people die each year from cancer, and about 1710 million new cancers exist in the 2018 world, wherein about 380 million malignant tumors in China occur, and the first disease incidence in the world is serious harm to life and health of people. Currently, means for treating cancer are mainly classified into surgical treatment, chemotherapy, targeted treatment, radiation treatment, and the like according to the kind and stage of cancer. Early and mid stage cancer patients are commonly high in survival rate after 5 years of prognosis by surgical excision assisted chemotherapy. However, for advanced cancers, systemic chemotherapy or radiation therapy is recommended because of the large tumor volume, tumor metastasis, or patient constitution, which are often not amenable to surgical treatment. Most of the chemotherapeutics and radiotherapy do not have tumor tissue targeting, and can cause killing effect on normal healthy tissues while inhibiting the growth of tumor cells, so that serious toxic and side effects are generated. Therefore, there is a need to develop new cancer treatments that improve the quality of life and extend survival of patients with advanced cancer.
Boron neutron capture therapy (Boron neutron capture therapy, BNCT) has become an attractive therapy in recent years in cancer treatment, particularly for the treatment of malignant tumors, which can selectively kill tumor cells using boron-containing drugs while retaining normal cells. Specifically, BNCT is a novel radiation therapy based on neutron capture and boron fission reactions. The treatment method consists of two separate steps (delivery of boron-containing reagent and neutron irradiation): firstly, boron-containing drugs are injected externally and are enriched in tumor cells, then, by neutron irradiation, the boron element captures neutrons and is subjected to nuclear fission to generate high-energy alpha ions and high-energy lithium 7, and then, the tumor cells in the gamma ray killing range (5-9 um) are released. BNCT has several advantages over traditional chemotherapy and radiation therapy: 1) The gamma ray range is small (5-9 um), only boron-containing cells are killed, and surrounding tissues are not damaged; 2) Absence of hypoxic cell radioresistance effects; 3) Avoiding the phenomenon of multi-drug resistance of chemotherapy and targeted drugs.
While the conceptual technique of BNCT is well known, the technical limitations associated with such treatments have delayed the development of this therapeutic approach, with the major impact barrier being the lack of ideal boron-containing agents. The ideal boron-containing reagent should possess the following characteristics: high intratumoral enrichment concentration, high selectivity (in vivo biodistribution tumor tissue/blood (T/B) concentration ratio > 3 and tumor tissue/normal tissue (T/N) concentration ratio > 3), low systemic toxicity, etc. From the current development history of boron-containing reagents, there are mainly three generations of boron reagents. The first generation of boron-containing agents were boric acid and its derivatives, which were first used in clinical trials in the 50 s and 60 s of the 20 th century, which were basic compounds but not identified to tumors, with low specificity. The second generation boron-containing reagent is developed, mainly comprising low molecular boron-containing compounds of undecahydrophobic disodium dodecaboride (BSH) and p-dihydroxyphenylalanine Boron (BPA), and although the performance is greatly improved compared with that of the first generation boron-containing reagent, and the BPA is approved to be marketed and the BSH is approved for clinical tests, the BNCT requirement cannot be met, the retention time in tumor cells is short, the selectivity is low (the concentration ratio of T/B and T/N can only reach > 1), and therefore, the effect of treating tumors is not ideal.
In recent years, research into third generation boron-containing agents has also been rapidly developed, mainly by linking boron-containing compounds with tumor targeting components to form novel boron-containing agents.
Various boronated porphyrin compounds are disclosed in US4959356A, CN1988848A, US5149801A, CN101605459a et al. Porphyrins are naturally occurring tetrapyrrole compounds which can remain in tumors for days to weeks and have affinity for various types of cancer, so that boronated porphyrins can increase their selectivity in tumor cells, further increasing the targeting of cancer treatment, but studies have shown that injection of such drugs can lead to high mortality in mice.
Different liposomes of boron-containing compounds are disclosed in CN1124921A, US5328678A, US20150238622A1 et al. Liposomes can entrap boron-containing compounds in their bilayer structure to increase the amount of 10 B they carry and/or to increase the tumor specificity of the liposome, thereby increasing the concentration of boron in tumor tissue and decreasing its concentration in blood. However, in the case of a liposome containing a hydrophilic boron-containing compound, when the boron-containing compound is encapsulated at a high concentration, the hydrophilic layer is ion-infiltrated to cause instability of the double membrane and collapse of plating, which results in leakage of the boron-containing compound, and thus, accumulation of boron in normal tissues and reduction of therapeutic effects are caused. In addition, a technique of binding a liposome and a hydrophobic boron-containing compound and encapsulating the boron compound in a phospholipid bilayer membrane has been developed, but this requires multistage and complicated synthesis, and therefore has many problems in terms of efficiency and cost.
In addition, there are many other novel boron-containing agents, such as a boronated folate receptor, a boronated Epidermal Growth Factor (EGF) or an Epidermal Growth Factor Receptor (EGFR) monoclonal antibody (monoclonal antibody), a boron-containing nanoparticle, etc., which, although they achieve a certain therapeutic effect, increase the concentration and selectivity of boron in tumor cells, have low killing efficiency of tumor cells, and thus, there is still a need to develop new boron-containing agents in order to achieve a sufficient therapeutic effect in BNCT.
Prostate cancer is a disease specific to men, with a second leading incidence of cancer in men around the world. Therefore, the method is particularly important for accurate treatment of the prostate cancer, and has the advantages of targeting tumor tissues, inhibiting the growth of tumor cells and preventing normal healthy tissues from being killed.
Prostate Specific Membrane Antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII) and folate hydrolase 1 (FOLH 1), is a type II transmembrane protein and zinc-dependent metallopeptidase that catalyzes the hydrolysis of N-acetyl-aspartic acid (NAAG) or other glutamate derivatives. It is limited to expression in a few normal tissues, such as the kidney, proximal small intestine and to a lesser extent the salivary glands, whereas expression in the epithelial cells of most prostate cancers and in the neovasculature of other solid tumors is enhanced 1000-fold, which properties make it considered the most popular target for therapeutic applications.
The high targeting of PSMA targeted therapeutic agents coupled with the high efficacy of BNCT suggests that boron-labeled PSMA targeted agents are likely to be effective BNCT agents, and this approach can be used to treat prostate cancer, potentially reducing non-targeted side effects including dry mouth and myelosuppression. There are currently relevant reports of PSMA-targeting boron-containing compounds, SINAN WANG et al, <<Synthesis and Initial Biological Evaluation of Boron-Containing Prostate-Specific Membrane Antigen Ligands for Treatment of Prostate Cancer Using Boron Neutron Capture Therapy>>,Molecular Pharmaceutics,vol.16,pages 3831-3841(2019), reporting eight PSMA-targeting boron-containing compounds, but these compounds have an intra-tumor concentration of boron of only about 4 μ g B/g, which is well below the 20ug B/g tumor threshold required in BNCT. Therefore, it is of great importance to find new boron-containing compounds for the treatment of prostate cancer with tumor tissue targeting, high intratumoral enrichment concentrations.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides a novel boron-containing compound which contains a PSMA-targeted bracket structure, so that the targeting and enrichment concentration of boron elements in tumor tissues are further improved, and the treatment effect of BNCT is enhanced.
It is another object of the present invention to provide a process for preparing the novel boron-containing compounds described above.
It is a further object of the present invention to provide the use of the novel boron-containing compounds described above for BNCT therapy.
According to the above object, the inventors of the present invention have repeatedly studied a novel boron-containing compound suitable for BNCT from the standpoint of improving the targeting and concentration of boron in tumor cells, being able to precisely inhibit the growth of tumor cells and not causing damage to normal healthy tissues, and finally completed the present invention.
The inventors have attempted to combine a boron 10 compound (10 B compound) with a PSMA-targeted scaffold moiety to form a new compound for use in boron neutron capture therapies. The inventors have surprisingly found that the compounds have very good targeting and enrichment concentrations in tumors.
To achieve the object of the present invention, the following embodiments are provided:
a novel compound comprising 10 B compound and PSMA targeting scaffold moiety has the structural formula shown in formula I:
Wherein [ 10 B ] is the moiety providing a 10 B atom source, L is a linkage, A is a scaffold moiety targeting PSMA.
Preferably, the structural formula of the PSMA-targeting scaffold moiety is shown in formula II:
Wherein R is CHR 1、O、S、NR1、CO、NR1CO、CONR1 or S (one of CH 2)p wherein p is 1,2 or 3, R 1 is H, C 1-C6 alkyl or one of aryl, m is 0,1, 2,3, 4,5 or 6;n is 0,1 or 2;Z each independently is at least one of CO 2R2、SO2H、SO3H、SO4H、PO2H、PO3 H or PO 4H2 wherein R 2 is hydrogen or a protecting group, wherein the protecting group is preferably one of S-t-Butyl-, methyl, ethyl, t-Butyl or benzyl, X is one of CH 2, NH or O, Q is carbonyl or absent, Y is NH or O or absent, W is one of CO2R2、SO2H、SO3H、SO4H、PO2H、PO3H、PO4H2、 tetrazolyl or NHCOR 3 wherein R 2 is as defined above and R 3 is a carboxyl-containing substituent or triazolyl.
Preferably, the structural formula of the PSMA-targeting scaffold moiety is further shown in formula III:
Wherein R, m, R 2, X, Y and W are as defined above, and X is further preferably one of NH or O, and Y is further preferably one of NH or O.
Preferably, the structural formula of the PSMA-targeting scaffold moiety is further shown in formula IV:
wherein R, m, R 2 and W are as defined above.
Preferably, the structural formula of the PSMA-targeting scaffold moiety is still further preferred:
Wherein R, R 2、R3, and m are as defined above.
Preferred structures are selected from those of the formula:
preferably, the linkage L is a carbon chain containing a peptide bond.
Preferably, the structural formula of the connection bond L is further shown as formula VII or VIII:
Wherein V 1,V2 is each independently a linear or branched C 1-C20 alkyl group, optionally substituted, or absent, wherein the position of the substituent is at least one of substituted on the linear chain or substituted on the branched chain, wherein substituted on the linear chain comprises at least one of substitution in the intermediate position or terminal position of the linear chain, and the substituent is at least one of alkenyl, alkynyl, halogen, aryl, nitro, cyano, carbonyl, ester, amino, amide linkage, or ether linkage; e is at least one of naphthyl, phenyl, biphenyl, indolyl (=2, 3-benzopyrrolyl) or benzothiazolyl, preferably naphthyl or phenyl; f is at least one of aryl, alkylaryl, cyclopentyl, cyclohexyl, cycloheptyl or C 1-C6 alkyl; i is 0,1 or 2, wherein when i is 2, the groups represented by E may be the same or different; j is 1,2,3 or 4, wherein when j is 2,3 or 4, the groups represented by F may be the same or different.
Preferred structures are selected from those of the formula:
Preferably, the [ 10 B ] is a carborane-containing gene, a dodecaborane-containing group, or a structure represented by the following formula IX:
Wherein R 4 and R 5 are each independently hydrogen, C 1-C6 alkyl or R 4 and R 5 are cyclized with the attached B and O atoms to form a 5-10 membered ring, preferably a ring synthesized as a 5-6 membered ring; r 6 is a linear or branched C 1-C20 alkyl, aryl, or cycloalkyl substituted or unsubstituted with a substituent, wherein the position of the substituent is at least one of linear or branched, wherein the linear substitution includes at least one of intermediate or terminal substitution in the linear chain, and the substituent is at least one of alkenyl, alkynyl, halogen, aryl, nitro, cyano, carbonyl, ester, amino, amide linkage, or ether linkage.
Preferred structures are selected from the structures shown below:
Preferably, the carborane-containing group is represented by formula XI below:
wherein R 6 is as defined above.
Preferably, the carborane is one of carborane containing at least two carbon atoms and at least three boron atoms, or containing at least one carbon atom and at least five boron atoms, and more preferably is a dimer of at least one or any of B 9H11C2R'、B10H11C2 R ' or B 11H10 CR ', wherein R ' is one of-H, -OH, -CH 2OH、-CH2F、-CH2Cl、-CH2 Br or-CH 2 I.
Preferred structures are selected from those of the formula:
Preferably, the carborane-containing group is selected from structures represented by the formula:
preferably, the dodecane containing group is of formula XII:
wherein R 6 is as defined above.
Preferably, the dodecane is BSH or B 12H12 2-, and the structural formula is shown as follows:
Preferably, the dodecane containing group is selected from structures of the formula:
Preferably, the novel compound comprising 10 B compound and PSMA-targeting scaffold moiety has a general structural formula shown in formula XIII or formula XIV:
wherein Z, X, Q, Y, W, m, n, R, V 1、E、i、F、j、V2 and [ 10 B ] are as defined above.
Preferably, the novel compound comprising 10 B compound and PSMA-targeting scaffold moiety has a general structural formula further shown in formula XV or formula XVI:
Wherein R 2、W、m、R、V1, E, i, F, j and [ 10 B ] are as defined above.
Preferably, as an example, the novel compound comprising 10 B compound and PSMA-targeting scaffold moiety has the structural formula:
Preferably, the method for preparing the novel compound comprising 10 B compound and PSMA-targeting scaffold moiety comprises synthesizing the 10 B compound-containing moiety, the linker moiety, and the PSMA-targeting scaffold moiety by existing amidation reactions.
Preferably, the use of the novel compound comprising 10 B compound and PSMA-targeting scaffold moiety for boron neutron capture therapy treatment of tumors, further including malignant tumors or metastatic tumors.
Preferably, the tumor is a prostate cancer or other solid tumor.
Further preferred is a method of treating a tumor comprising the steps of:
(1) Externally injecting a new compound comprising 10 B compound and a PSMA-targeting scaffold moiety into a patient;
(2) The compound in the step (1) is enriched in tumor cells, and then the compound has the effect of treating tumors when irradiated by thermalized neutrons.
The invention has the beneficial effects that:
Compared with the boron-containing compound disclosed by the prior art, the boron-containing compound obtained by the technical scheme has the advantages of high targeting property of PSMA directional treatment and space positioning provided by neutron beams, and has very high enrichment concentration of boron in tumors, which can reach 50ug/g, and can achieve good treatment effect without high-intensity neutron irradiation. The method can also be reflected from the side, reduces the damage of neutron irradiation to normal healthy tissues, obviously improves the pharmaceutical effect of the boron-containing compound, and has very important significance for tumor treatment in the medical field.
Drawings
Figures 1-9 show single intravenous infusion acute toxicity test weight change profiles for compounds PL0057, PL0221, PL0233, PL0249, PL0502, PL0519, PL0705, PL2061, respectively.
FIGS. 10-18 show tissue profiles of compounds PL0057, PL0221, PL0233, PL0249, PL0502, PL0519, PL0705, PL2061 and BPA, respectively.
Detailed Description
Terminology
In the present invention, "alkyl" means a saturated hydrocarbon group, which is a hydrocarbon group obtained by removing one hydrogen atom from an alkane molecule, and is preferably a linear or branched alkyl group substituted or unsubstituted with a substituent having 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, benzhydryl, benzyl, trichloroethyl, methylthioethyl, p-toluenesulfonylethyl, and the like, but is not limited thereto.
In the present specification, "aromatic group" means a group having aromatic properties including monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups such as benzene, naphthalene, anthracene, pyrene and the like, including heteroaryl groups which are 5-to 10-membered heteroaryl groups containing at least one heteroatom selected from N, O or S in the ring; but is not limited thereto. The aromatic ring may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, mercapto, imino, amido, phosphonate, phosphonite, carbonyl, carboxyl, silyl, aldehyde, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), oxy, and the like, but are not limited thereto. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings being "fused rings"), wherein at least one of the rings is an aromatic hydrocarbon and the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl, etc., but are not limited thereto.
In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In the present specification, "S-t-Butyl-" means a structure represented by the following formula,
In the present specification, "tumor" refers to an uncontrolled growth of a population of cells due to genetic mutation, including benign tumors and malignant tumors. In this specification, the term "malignancy" is used interchangeably with the term "cancer". The term "carcinoma" broadly includes carcinomas of the blood system such as carcinomas, sarcomas, and leukemias as of epithelial origin. Examples of cancers of epithelial origin include: stomach cancer, large intestine cancer, gall bladder cancer, bile duct cancer, pancreatic cancer, duodenal cancer, kidney cancer, prostate cancer, ovarian cancer, uterine cancer, breast cancer, skin cancer, hepatocellular carcinoma, tongue cancer, esophageal cancer, throat cancer, and the like, but are not limited thereto. Examples of sarcomas include: fibrosarcoma, malignant fibrous histiocytoma, dermal fibrosarcoma, liposarcoma, myosarcoma, angiosarcoma, kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, osteosarcoma, etc., but is not limited thereto. Examples of hematological malignancies include: leukemia, malignant lymphoma, multiple myeloma, and the like, but is not limited thereto. In the present specification, "tumor cells" means cells that form a tumor, and typically refer to cells that proliferate abnormally (so-called cancerous cells) regardless of surrounding normal tissues.
The boron-containing compounds of the present invention are meant to include all stereoisomers, geometric isomers, tautomers according to structural formula I, wherein each atom (excluding boron atoms) includes all isotopes. When one or more chiral centers are present in the molecule, the compounds of structural formula I may be in the form of a pharmaceutically acceptable racemate mixture or in the form of a single stereoisomer.
In order to better understand the technical solution of the present invention, the following description of the technical solution of the present invention is further provided with reference to specific examples, which are only for aiding in understanding the present invention and should not be taken as limiting the present invention in any way.
Example 1 the compounds of the present invention may be prepared by methods known in the art, exemplary schemes shown by the following formulas:
Or alternatively
Wherein R 2 is selected as protecting group, w, E, i, F, j is as defined above.
1) Synthesis of compounds of formula 1 or compounds of formula 4:
1.05eq of the compound of formula VII-1 or of the compound of formula VIII-1 and 1.2eq of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are taken in a reaction flask, dissolved in N, N-dimethylformamide (5V) and then 1.2eq of triethylamine are added, and 1.0eq of a solution of N, N-dimethylformamide (1V) of the compound of formula IV-1 is added dropwise under ice bath. Then reacted at room temperature for 12 hours. Removing the solvent under reduced pressure, adding ethyl acetate, washing twice with 0.5N diluted hydrochloric acid solution and saturated saline solution respectively, drying the organic phase with anhydrous magnesium sulfate, and filtering to remove the solvent to obtain the compound of formula 1 or the compound of formula 4;
2) Synthesis of compounds of formula 2 or 5:
Taking 1.0eq of a compound of formula 1 or a compound of formula 4, adding 3V of dichloromethane for dissolution, adding 3V of 3.0N HCl/EA solution, stirring for reaction for 6 hours, spin-drying the reaction solution, pulping by using methyl tertiary butyl ether, filtering and drying to obtain an intermediate compound, adding 5V of MeOH for dissolution, adding 10.0eq of NaOH aqueous solution (5V), reacting at room temperature for 12 hours, spin-drying the reaction solution, adding 5V of water, adding 6.0N hydrochloric acid solution for regulating pH to 1.0, extracting by using dichloromethane, combining organic phases for drying by using anhydrous magnesium sulfate, filtering and spin-drying to obtain the compound of formula 2 or the compound of formula 5.
3) Synthesis of compounds of formula 3 or 6:
Referring to the preparation method of the compound of formula 1 or the compound of formula 4 in the step 1), the compound of formula 3 or the compound of formula 6 is obtained through similar amidation reaction steps.
By way of example, the compounds shown in Table 1 below can be obtained by synthesis according to the synthetic method of the scheme described above:
taking a compound of the formula PL-0221 as an example, the specific synthetic steps are as follows:
1) Synthesis of compounds of formula 0221-c: 3.6g of the compound of formula 0221-a, 2.1g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1.3g N-hydroxysuccinimide were taken in a reaction flask, 50mL of N, N-dimethylformamide was added to dissolve, followed by 1.7mL of triethylamine, and 5.8g of an N, N-dimethylformamide (10 mL) solution of the compound of formula 0221-b was added dropwise under ice bath. Then reacted at room temperature for 12 hours. Removing the solvent under reduced pressure, adding ethyl acetate, washing twice with 0.5N diluted hydrochloric acid solution and saturated saline solution, drying the organic phase with anhydrous magnesium sulfate, and filtering to remove the solvent to obtain a compound of formula 0221-c;
2) Synthesis of Compounds of formulas 0221-d: 4.0g of the compound of formula 0221-c was taken in a reaction bottle, 15mL of methylene dichloride was added for dissolution, then 15mL of ethyl hydrogen chloride acetate solution was added for reaction at room temperature for 6h, the reaction solution was dried by spin, methyl tert-butyl ether was added for beating, and the light yellow solid was obtained by vacuum drying. Then 100mL of methanol was added to dissolve the solid, 30.0g of sodium hydroxide solid was added, 50mL of water was added, the reaction was carried out at room temperature for 12 hours, methanol was dried by spin-drying, then 6.0N hydrochloric acid solution was added to adjust pH to 1.0, extraction was carried out using methylene chloride, and the combined organic phases were dried over anhydrous magnesium sulfate and filtered to spin-dry to obtain the compound of formula 0221-d.
3) Synthesis of compounds of formula 0221-e: taking 1.6g of m-carboxyphenylboronic acid and 3.0g O- (N-succinimide) -1, 3-tetramethylurea tetrafluoroborate to a reaction bottle, adding 50mL of N, N-dimethylformamide to dissolve, reacting at room temperature for 12h, concentrating under reduced pressure to about 5mL, adding 200mL of ethyl acetate, precipitating a large amount of white solid, filtering and drying a filter cake to obtain a compound shown in a formula 0221-e.
4) Synthesis of Compound of formula PL-0221: 3.3g of the compound of formula 0221-d was taken in a reaction bottle, 10mL of N, N-dimethylformamide was added for dissolution, 0.8mL of triethylamine was added, followed by dropwise addition of 1.4g of N, N-dimethylformamide solution (5 mL) of the compound of formula 0221-e, and after reacting at room temperature for 12 hours, the reaction solution was dried by spinning. Ethyl acetate was added, and the mixture was washed twice with a 0.5N diluted hydrochloric acid solution and a saturated saline solution, and the organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by filtration to give a compound of formula PL-0221.
EXAMPLE 2 Single intravenous infusion acute toxicity test
The experimental study employed 114 ICR mice, randomly divided into 19 groups. The administration was by intravenous infusion, 1 time on day 1 of the experiment, and the administration volumes were 10mL/kg. The sodium chloride injection was administered as vehicle control group, group 2 was administered with 5mg/kg of PL0057, group 3 was administered with 10mg/kg of PL0057, group 4 was administered with 5mg/kg of PL0221, group 5 was administered with 10mg/kg of PL0221, group 6 was administered with 5mg/kg of PL0233, group 7 was administered with 10mg/kg of PL0233, group 8 was administered with 5mg/kg of PL0249, group 9 was administered with 10mg/kg of PL0249, group 10 was administered with 5mg/kg of PL0502, group 11 was administered with 10mg/kg of PL0502, group 12 was administered with 5mg/kg of PL0519, group 13 was administered with 10mg/kg of PL0519, group 14 was administered with 5mg/kg of PL 5, group 15 was administered with 10mg/kg of PL 5, group 16 was administered with 5mg/kg of PL0502, group 11 was administered with 2062, group 10mg/kg of PL 19, group 1 was administered with 19 mg/kg of BPA. Group 19 animals were sacrificed and dissected on day 14. During the test, the clinical behavior observation, body weight and other items were examined. End of trial general anatomic observations were made on all animals.
Each group contained 3 female mice and 3 male mice, and weights of the mice were measured on days 1, 4, 7, 9, 12, and 14, respectively, and average weights of the female mice and the male mice were calculated according to gender, respectively, and the results are shown in table 3 below. ( And (3) injection: in the table, "(female)" means female mice, "(male)" means male mice )
TABLE 3 Table 3
As can be seen from the data results of table 3 above and the corresponding weight changes fig. 1-9, all the compounds used by injection (PL 0057, PL0221, PL0233, PL0249, PL0502, PL0519, PL0705, PL2061 and BPA) did not cause significant changes in the body weight of the mice, both similar to the body weight and growth trend of the control group, nor were there any significant abnormal clinical symptoms found after the first day of administration, both in female and in male mice. Therefore, in summary, in the administration dosage range of 5mg/kg to 10mg/kg of B, single intravenous compounds PL0057, PL0221, PL0233, PL0249, PL0502, PL0519, PL0705, PL2061 or BPA were administered to ICR mice with good safety and no significant toxicity.
Example 3 tissue distribution test
In the study, 108 Balb/c tumor-bearing mice (male) are adopted, the tumor-bearing cell strain is LNCaP (prostate cancer), the tumor volume reaches 150-200 mm 3, and the tumor cells are divided into 9 groups. Animals of groups 1-9 were given a single intravenous injection of B10 mg/kg of the corresponding drug (PL 0057, PL0221, PL0233, PL0249, PL0502, PL0519, PL0705, PL 2061) and the positive control BPA (4-boron 10-L-phenylalanine), and whole blood and tissue samples were collected at four time points 1, 4, 12 and 24 hours after administration, respectively. After collecting complete blood samples, 12 male mice in each group were again collected for heart, liver, spleen, lung, kidney, pancreas, brain, tumor, muscle, fat, stomach, large intestine, small intestine. And analyzing the total B concentration in the whole blood and the tissues by adopting an ICP-MS method, and finally calculating and calculating the boron concentration of the tumor, each tissue and the whole blood.
Four time points were taken for each group of 12 male mice, 3 male mice per time point, and the average of the boron concentrations of the tumor, tissues and whole blood of the mice per time point was calculated. The data averages for compounds PL0057, PL0221, PL0233, PL0249, PL0502, PL0519, PL0705, PL2061 and BPA are shown in tables 4-12 below, and the corresponding tissue profiles are shown in fig. 10-18.
TABLE 4 Table 4
TABLE 5
TABLE 6
TABLE 7
TABLE 8
TABLE 9
Table 10
TABLE 11
Table 12
From the data results shown in tables 4-12 above, and the corresponding tissue profiles 10-18, it can be seen that:
Boron was distributed mainly in the kidneys and tumors after administration of non-fasted male tumor-bearing mice PL0249, PL0221, PL0705, PL2061, PL0519 and PL0502 for a single intravenous injection, with almost no detectable in the fat, wherein tumor tissue reached peak concentrations (41049.35 ng/g, 39128.89ng/g, 49662.21ng/g, 45123.67ng/g, 21869.11ng/g and 19727.05ng/g, respectively) 1 hour after administration, and it was found by calculation that T/B values could reach 8.8, 7.1, 6.5, 6.4, 4.0 and 3.6, respectively. With the extension of time, boron is distributed and cleared in the tissue faster, and the problem of tissue accumulation is not caused.
However, when the non-fasted male tumor-bearing mouse compound PL0233 was given by single intravenous injection, boron was mainly distributed in the kidney and tumor, but was hardly detected in fat and brain tissue, but the distribution amount of boron in the tissue was small, and the peak concentration was reached after 1 hour of administration, with a peak concentration value of 7365.67ng/g, and a T/B value of 6.0 was calculated; boron was also distributed mainly in the kidneys and tumors and barely detectable in fat in the non-fasted male tumor-bearing mice following single intravenous administration of compound PL0057, but was distributed in the tissues in small amounts, reaching peak concentrations of 1153.93ng/g after 1 hour of administration, calculated to be T/B values of only 1.3. In addition, BPA was selected as a positive control, and single intravenous injection was administered to non-fasted male tumor-bearing mice, and as a result, boron was found to be widely distributed in various tissues, except for adipose tissue, which was not detected, and tissues with higher concentrations were concentrated in pancreas, tumor and kidney, wherein higher boron concentrations were still detected in brain tissue 4 hours after administration, indicating that the drug was able to permeate the blood brain barrier, and the T/B value was calculated to be 1.7.
Thus, in summary, it can be seen that: compounds PL0249, PL0221, PL0705, PL2061, PL0519 and PL0502 had high boron enrichment and high targeting in tumor tissue, and T/B values were all greater than 3. In particular, the enrichment concentration of boron of the first four compounds can almost reach above 40000ng/g, and the T/B value can also reach above 6.0. However, when the positive controls BPA, compound PL0233 and PL0057 were used, the boron enrichment concentration in the tumor tissue was very low, the boron enrichment concentration of BPA was 8933.47ng/g, and the boron enrichment concentrations of compound PL0233 and compound PL0057 were 7365.67ng/g and 1153.93ng/g. In addition, the T/B values of BPA and compound PL0057 were less than 3, 1.7 and 1.3 respectively.
Claims (20)
1. A novel compound comprising 10 B compound and PSMA targeting scaffold moiety, characterized in that the structural formula is shown in formula (I),
Wherein, [ 10 B ] is the moiety providing a 10 B atom source, L is a linkage, A is a scaffold moiety targeting PSMA.
2. The compound of claim 1, wherein the PSMA-targeting scaffold moiety has the structural formula shown in formula (II):
Wherein R is CHR 1、O、S、NR1、CO、NR1CO、CONR1 or S (one of CH 2)p wherein p is 1,2 or 3, R 1 is H, C 1-C6 alkyl or one of aryl, m is 0,1, 2,3, 4,5 or 6;n is 0,1 or 2;Z each independently is at least one of CO 2R2、SO2H、SO3H、SO4H、PO2H、PO3 H or PO 4H2 wherein R 2 is hydrogen or a protecting group, wherein the protecting group is preferably one of S-t-Butyl-, methyl, ethyl, t-Butyl or benzyl, X is one of CH 2, NH or O, Q is carbonyl or absent, Y is NH or O or absent, W is one of CO2R2、SO2H、SO3H、SO4H、PO2H、PO3H、PO4H2、 tetrazolyl or NHCOR 3 wherein R 2 is as defined above and R 3 is a carboxyl-containing substituent or triazolyl.
3. The compound of claim 2, wherein the PSMA-targeting scaffold moiety has the structural formula shown in formula (III):
Wherein R, m, R 2, X, Y and W are as defined in claim 2, and X is further preferably one of NH or O, and Y is further preferably one of NH or O.
4. The compound of claim 3, wherein the PSMA-targeting scaffold moiety has a structure according to formula (IV):
wherein R, m, R 2 and W are as defined in claim 3.
5. The compound of claim 4, wherein the PSMA-targeting scaffold moiety has a structure according to formula (V) or (VI):
Wherein R, R 2、R3, and m are as defined in claim 4.
6. The compound of claim 5, wherein the PSMA-targeting scaffold moiety is selected from one of the structures of the formula:
7. the compound of claim 1, wherein the linkage L is a carbon chain containing a peptide bond.
8. The compound of claim 7, wherein the linkage L is of the structure shown in formula (VII) or formula (VIII):
Wherein V 1、V2 is each independently a linear or branched C 1-C20 alkyl group, optionally substituted, or absent, wherein the position of the substituent is at least one of substituted on the linear chain or substituted on the branched chain, wherein substituted on the linear chain comprises at least one of substitution in the intermediate position or terminal position of the linear chain, and the substituent is at least one of alkenyl, alkynyl, halogen, aryl, nitro, cyano, carbonyl, ester, amino, amide bond, or ether linkage; e is at least one of naphthyl, phenyl, biphenyl, indolyl (=2, 3-benzopyrrolyl) or benzothiazolyl, preferably naphthyl or phenyl; f is at least one of aryl, alkylaryl, cyclopentyl, cyclohexyl, cycloheptyl or C 1-C6 alkyl; i is 0, 1 or 2, wherein when i is 2, the groups represented by E may be the same or different; j is 1, 2,3 or 4, wherein when j is 2,3 or 4, the groups represented by F may be the same or different.
9. The compound of claim 8, wherein the linkage L is selected from one of the structures represented by the following formulas:
10. The compound of claim 1, wherein [ 10 B ] is one of a carborane-containing gene, a dodecaborane-containing group, or a structure of formula (IX):
Wherein R 4 and R 5 are each independently hydrogen, C 1-C6 alkyl or R 4 and R 5 are cyclized with the attached B and O atoms to form a 5-10 membered ring, preferably a ring synthesized as a 5-6 membered ring; r 6 is a linear or branched C 1-C20 alkyl, aryl, or cycloalkyl substituted or unsubstituted with a substituent, wherein the position of the substituent is at least one of substituted on the linear chain or substituted on the branched chain, wherein the substitution on the linear chain comprises at least one of substitution in an intermediate position or terminal position of the linear chain, the substituent being at least one of alkenyl, alkynyl, halogen, aryl, nitro, cyano, carbonyl, ester, amino, amide linkage, or ether linkage;
Preferably, the structure shown in the formula (IX) is selected from one of the structures shown in the following formulas:
11. the compound of claim 10, wherein the carborane-containing group is represented by formula (XI):
Wherein R 6 is as defined in claim 10; preferably, the carborane is one of carborane containing at least two carbon atoms and at least three boron atoms, or containing at least one carbon atom and at least five boron atoms, further preferably a dimer of at least one or any of B 9H11C2R'、B10H11C2 R ' or B 11H10 CR ', wherein R ' is one of-H, -OH, -CH 2OH、-CH2F、-CH2Cl、-CH2 Br or-CH 2 I; more preferably, the carborane is selected from one of the structures shown in the following formulas:
12. the compound of claim 11, wherein the carborane-containing group is selected from one of the structures of the following formulas:
13. The compound of claim 10, the dodecane containing group is of formula (XII):
Wherein R 6 is as defined in claim 10; preferably, the dodecane is BSH or B 12H12 2-, and the structural formula is shown as follows:
14. the compound of claim 13, wherein the dodecane containing group is selected from one of the structures of the formula:
15. A compound according to claim 1, having the formula (XIII) or (XIV):
Wherein Z, X, Q, Y, W, m, n, R, V 1、E、i、F、j、V2 and [ 10 B ] are as defined in claims 2, 8 and 10.
16. The compound of claim 15, wherein the structural formula is represented by formula (XV) or formula (XVI):
wherein R 2、W、m、R、V1, E, i, F, j and [ 10 B ] are as defined in claim 15.
17. The compound of claim 16, wherein the structural formula is selected from one of the structures shown in the formula:
18. A method of preparing the compound of claim 1, comprising synthetically preparing the compound from a moiety comprising 10 B compound, a linker moiety, and a PSMA-targeting scaffold moiety by an existing amidation reaction.
19. The use of a compound of claim 1 for the treatment of a tumor, including a malignant tumor or a metastatic tumor, by boron neutron capture therapy; preferably, the tumor is a prostate cancer or other solid tumor.
20. A method of treating a tumor comprising the steps of:
(1) Externally injecting the compound of claim 1 into a patient;
(2) The compound of the step (1) is enriched in tumor cells, and then irradiated by thermalized neutrons.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310208317.3A CN118344391A (en) | 2023-01-13 | 2023-01-13 | Novel boron-containing compound for boron neutron capture therapy |
| PCT/CN2024/070046 WO2024149105A1 (en) | 2023-01-13 | 2024-01-02 | New boron-containing compound for boron neutron capture therapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310208317.3A CN118344391A (en) | 2023-01-13 | 2023-01-13 | Novel boron-containing compound for boron neutron capture therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118344391A true CN118344391A (en) | 2024-07-16 |
Family
ID=91814670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310208317.3A Pending CN118344391A (en) | 2023-01-13 | 2023-01-13 | Novel boron-containing compound for boron neutron capture therapy |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN118344391A (en) |
| WO (1) | WO2024149105A1 (en) |
-
2023
- 2023-01-13 CN CN202310208317.3A patent/CN118344391A/en active Pending
-
2024
- 2024-01-02 WO PCT/CN2024/070046 patent/WO2024149105A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024149105A1 (en) | 2024-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101203501B1 (en) | Perturbed membrane-binding compounds and methods of using the same | |
| JP2005507857A (en) | Modified PSMA ligands and uses related thereto | |
| JP2002522443A (en) | Water-soluble prodrugs of hindered alcohol or phenol | |
| WO2016062370A1 (en) | 18f-tagged inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer | |
| WO2012078534A1 (en) | Psma-targeted dendrimers | |
| EP3946320A1 (en) | Hsp90-binding conjugates and formulations thereof | |
| JP2019534846A (en) | Chelated PSMA inhibitors | |
| EP3773670A1 (en) | Hsp90-targeting conjugates and formulations thereof | |
| CN116456967A (en) | Ionizable liposomes, their preparation and use in gene delivery | |
| EP2780041B1 (en) | Multimodal contrast and radiopharmaceutical agent for an imaging and a targeted therapy guided by imaging | |
| US10494341B2 (en) | Compound containing indoleacetic acid core structure and use thereof | |
| CN113230417A (en) | Preparation and application of glucose and triphenyl phosphonium modified brain tumor targeted liposome | |
| CN118344391A (en) | Novel boron-containing compound for boron neutron capture therapy | |
| CN106631957A (en) | Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof | |
| WO2023030509A1 (en) | Peptide-urea derivative, pharmaceutical composition containing same and application thereof | |
| WO2022242438A1 (en) | Texaphyrin-folate conjugate and preparation method therefor and application thereof | |
| WO2024149106A1 (en) | Novel boron-containing polymer for boron neutron capture therapy | |
| KR20220044496A (en) | Prostate specific membrane antigen (PSMA) ligands and uses thereof | |
| CN111943954A (en) | Dihydroporphin derivative and corresponding preparation method and application thereof | |
| KR20210012263A (en) | Synthesis of human EphA2-specific monobody conjugated with a novel radioactive compound for cancer diagnosis and therapy and use thereof | |
| US20070142336A1 (en) | Treatment of cancer | |
| CN104174024A (en) | Myristic acid-mediated brain-targeting polymer micelle drug-delivery system and its preparation method and use | |
| US20240100202A1 (en) | Psma-targeting conjugate and uses thereof | |
| CN117551008A (en) | Deferoxamine conjugate and preparation method and application thereof | |
| EP2900276A1 (en) | Bifunctional chelating agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |