CN115353527A - Boron-containing compound and application thereof - Google Patents
Boron-containing compound and application thereof Download PDFInfo
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- CN115353527A CN115353527A CN202210923557.7A CN202210923557A CN115353527A CN 115353527 A CN115353527 A CN 115353527A CN 202210923557 A CN202210923557 A CN 202210923557A CN 115353527 A CN115353527 A CN 115353527A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 152
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 41
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 239000003814 drug Substances 0.000 claims description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- 238000007112 amidation reaction Methods 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000001959 radiotherapy Methods 0.000 claims description 12
- 230000020477 pH reduction Effects 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 230000009435 amidation Effects 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 125000000732 arylene group Chemical group 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- -1 hexafluorophosphate Chemical compound 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 230000008685 targeting Effects 0.000 claims description 6
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 230000003439 radiotherapeutic effect Effects 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 27
- 231100000053 low toxicity Toxicity 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 61
- 239000000243 solution Substances 0.000 description 21
- 239000002245 particle Substances 0.000 description 12
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- 231100000135 cytotoxicity Toxicity 0.000 description 10
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- 239000002609 medium Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
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- 230000003833 cell viability Effects 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 5
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 230000003698 anagen phase Effects 0.000 description 5
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
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- 239000012224 working solution Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
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- 230000002147 killing effect Effects 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
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- 230000001146 hypoxic effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 230000035519 G0 Phase Effects 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 230000027311 M phase Effects 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- LBDSXVIYZYSRII-IGMARMGPSA-N alpha-particle Chemical compound [4He+2] LBDSXVIYZYSRII-IGMARMGPSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 239000002131 composite material Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 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 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000002665 ion therapy Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001678 irradiating effect Effects 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002324 minimally invasive surgery Methods 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035752 proliferative phase Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000191 radiation effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000000717 retained effect Effects 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
- A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a boron-containing compound and application thereof. The invention provides a compound shown as a formula I. The compound has low toxicity to tumor cells, and can be combined with boron neutron capture therapy for targeted cancer treatment.
Description
Technical Field
The invention relates to a boron-containing compound and application thereof.
Background
Boron Neutron Capture Therapy (BNCT) is a new technology for targeted cancer treatment by binary radiotherapy. The principle is that the peptide will have specific affinity with tumor 10 The B medicament is injected into a patient body, and the boron-containing medicament is specifically concentrated in the tumor. Then, irradiating with epithermal neutron beamThe tumor part is shot to the tumor part, 10 b atomic nucleus capturing thermal neutron to generate unstable composite nucleus 11 B， 11 B is then spontaneously split into an alpha particle with a kinetic energy of 1.78MeV and a particle with a kinetic energy of 1.01MeV 7 Li recoil nuclei (reaction cross section 6.3%); or one alpha particle with a kinetic energy of 1.47MeV and one with a kinetic energy of 0.84MeV 7 Li recoils the nucleus and emits one photon with an energy of 0.48MeV (reaction cross section 93.7%). Because the released particles have high energy and have the characteristics of high Linear Energy Transformation (LET) and low oxygen enhancement ratio, the effect of killing tumor cells with high selectivity and high strength can be achieved.
7 The range of Li recoil nucleus and alpha particle in biological tissue is about 5 μm and 9 μm, less than 10 μm of tumor cell diameter, so 7 Killing of Li and alpha particles is limited to uptake 10 B and its immediate neighbors. On the other hand, in the case of a liquid, 10 B(n，α) 7 the Li reaction cross section reaches 3840 target-en and is far larger than the reaction cross section of nuclides formed by neutrons, normal tissues of a human body and blood. Thus, neutron pairs are not ingested 10 The radiation damage effects of B normal tissue can be controlled at safe dose levels. Therefore, the treatment is known as cell-level radiotherapy, has the excellent characteristics of external radiotherapy and internal radiotherapy, and effectively avoids the side effects of conventional external radiotherapy and internal radiotherapy.
BNCT has particular advantages over other techniques for treating tumors:
1) Targeting of BNCT therapy
The boron-containing drug has targeting properties. The boron-containing medicine has high affinity with tumor cells, and is mainly absorbed by cancerous tissues and in tumor cells 10 The content of B is greater than that in normal cells 10 B content, and therefore the therapeutic dose of tumor cells is much greater than that of normal cells.
2) High energy linear density (LET) characteristics
The traditional radiotherapy X-ray, gamma-ray and the like have low LET property, namely, the Relative Biological Effect (RBE) on the body is low, oxygen is required to enhance the biological radiation effect, but the fast invasion of malignant tumorsThe tumor tissue often has insufficient blood supply due to aggressive growth, so that local hypoxia is caused, and the treatment effect is relatively poor. Alpha particles and 7 the Li particles are high LET charged particles and can generate killing effect on oxygen-rich or oxygen-poor tumor cells. RBE of α particle, which is a BNCT nuclear reaction product, is the first to occur even with heavy ions such as protons and carbon ions.
3) The therapeutic effect is independent of the state of the cancer cells
Chemotherapy, X-knife, gamma-knife, and general radiotherapy generally work on tumor cells in the proliferative phase (G1, S, G2, and M phases) but are insensitive to resting (G0) tumor cells. The ability of tumor cells to grow in the G0 phase is the source of tumor recurrence. BNCT based on high LET, alpha particles and 7 the killing effect of the Li particles on the tumor cells is independent of the growth cycle of the cells, and the Li particles can also kill the tumor cells in a stationary phase. Hypoxic tumors become more resistant to conventional radiotherapy such as gamma rays, electron beams, etc. with low LET, and treatment based on BNCT does not cause errors as long as sufficient boron enters hypoxic cancer cells.
4) Fine therapeutic scale
Of the cancer therapies to date, the therapeutic effect range is as fine as micron level, and no other than neutron capture therapy is found. The most accurate minimally invasive surgery of surgery has the action scale limited to millimeter level, and the Bragg peak focusing dose depth in heavy ion therapy is about 2.5-3.0 cm. The finer the size of the treatment, the relatively smaller the side effects that are caused.
The ideal boron-containing targeted drug for BNCT treatment should meet the following requirements:
no toxicity to human body under clinical dosage;
10 the B medicament has high affinity to tumor tissues, and the concentration ratio of the tumor tissues to normal tissues can reach 4: l to 3: l;
per gram of tumor tissue 10 The concentration of the B medicament reaches 20-35 mug;
a therapeutic concentration can be maintained in the tumor tissue during the treatment.
Currently, BNCT is relatively slow in development, which is closely related to the relative lag in boron-containing drug development. Until now, the only boron-containing drugs entering clinical use were mercaptododecaborane disodium salt (BSH) and p-dicarboxboranophenylalanine (BPA), which was approved in japan in 2020 and was the first BNCT boron-containing drug approved for sale worldwide. As a key breakthrough link of BNCT technology, boron-containing drugs have the problems that BSH and BPA have far different effects from requirements, and the problems of insufficient tumor targeting specificity, insufficient affinity with tumor cells and the like exist. It has been found through intensive studies that the ratio of the boron concentration in tumor to normal tissue measured on human glioma samples with BSH, which is generally <1 (average 0.6), is considered to be a non-specific boron carrier. BPA, which typically produces boron concentrations no greater than 2.4, cannot penetrate into the internal components of tumor cells and is therefore only transiently retained within the cell. In addition, there are populations that do not take up BPA for some tumor cells. Clinically, BNCT is mainly used for treating cancers such as brain tumor, glioma and melanoma, and is also mainly limited by few types and limited indications of currently clinically available boron-containing drugs. Therefore, the development of boron targeted drugs with more indications, low toxicity and good targeting is imperative.
Fibroblast Activation Protein (FAP) is one of specific markers of Tumor-associated fibroblast (TAF), has special biological characteristics, and is expressed in Tumor stroma in a stable, rich and specific manner. The existing FAP inhibitors are mainly used for treating tumors. However, no FAP targeting drugs are currently available for use in boron neutron capture therapy.
Disclosure of Invention
The invention aims to solve the technical problem that the existing compound suitable for BNCT has a single structure, and therefore, the invention provides a boron-containing compound and application thereof. The compound has low toxicity to tumor cells, and can be combined with boron neutron capture therapy to treat cancer in a targeted manner.
The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
wherein R is 1 Is a single bond, C 1 ～C 10 Straight chain alkylene group, C 2 ～C 10 Branched alkylene group, C 5 ～C 8 Cycloalkylene radical, C 6 ～C 10 Arylene radical-C 1 ～C 4 Alkylene radical, C 1 ～C 4 alkylene-C 6 ～C 10 Arylene radical-C 1 ～C 4 An alkylene group,
Or C 6 ～C 10 An arylene group;
R 2 is hydroxy, C 1 ～C 5 Straight chain alkyl, C 3 ～C 6 Branched alkyl, C 5 ～C 8 Cycloalkyl radical, C 6 ～C 10 aryl-C 1 ～C 4 Alkyl radical, C 1 ～C 4 alkyl-C 6 ～C 10 aryl-C 1 ～C 4 An alkylene group,
Or C 6 ～C 10 An aryl group;
R 3 is hydroxy, C 1 ～C 5 Straight chain alkyl, C 3 ～C 6 Branched alkyl radical, C 5 ～C 8 Cycloalkyl radical, C 6 ～C 10 aryl-C 1 ～C 4 Alkyl radical, C 1 ～C 4 alkyl-C 6 ～C 10 aryl-C 1 ～C 4 Alkylene, or a mixture thereof,
Or C 6 ～C 10 An aryl group;
R 4 h, F or Cl;
R 5 h, F or Cl;
n is above 1 、n 2 And n 3 Independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
In one embodiment, the compound is represented by formula IIn the compounds of (1) or pharmaceutically acceptable salts thereof, some groups are defined below, and the remaining groups are defined as in any one of the other embodiments (hereinafter simply referred to as "in one embodiment"): r is as described 1 May be a single bond.
In one embodiment, R is 2 May be a hydroxyl group.
In one embodiment, R is 3 May be a hydroxyl group.
In one embodiment, R is 4 And may be F or Cl.
In a certain scheme, R is 4 May be F.
In one embodiment, R is 5 And may be F or Cl.
In one embodiment, R is 5 May be F.
In one embodiment, the compound of formula I may be compound I-1:
the invention also provides a compound shown as a formula 2, a formula 3 or a formula 4:
wherein R is 31 Is C 1 ～C 4 An alkyl group;
in the compound represented by the formula 3, R 32 Is C 1 ～C 3 An alkyl group; r 33 Is C 1 ～C 3 An alkyl group; r 34 Is C 1 ～C 3 An alkyl group; r is 35 Is C 1 ～C 3 An alkyl group;
R 1 、R 2 and R 3 As defined above.
In one embodiment, the compound of formula 2 is compound 2-1:
in one embodiment, the compound of formula 3 is compound 3-1:
in one embodiment, the compound of formula 4 is compound 4-1:
the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: carrying out amidation reaction of the compound shown in the formula 4 and the compound shown in the formula a in a solvent in the presence of an amidation reagent to obtain the compound shown in the formula I,
in one embodiment, the amidation reaction may be carried out at atmospheric pressure.
In one embodiment, the amidation reaction may be carried out in the presence of oxygen.
In a certain embodiment, the amidation reagent may be a combination of N, N' -tetramethylchloroformamidine hexafluorophosphate (TCFH) and 1-methylimidazole.
Wherein the solvent is a solvent commonly used in such reactions in the art.
In a certain aspect, the solvent can be acetonitrile.
In a certain embodiment, the compound represented by formula 4 may be the above-mentioned compound 4-1.
In a certain embodiment, the molar volume ratio of the compound represented by formula 4 to the solvent may be 0.105mol/L.
In a certain embodiment, the molar ratio of the compound of formula 4 to N, N' -tetramethylchloroformamidine hexafluorophosphate (TCFH) in the amidation reagent may be 0.666.
In a certain embodiment, the molar volume ratio of the compound represented by formula 4 to 1-methylimidazole in the amidation reagent may be 1.575mol/L.
In a certain scheme, the reaction temperature may be 35 ℃.
In one embodiment, the reaction conditions may be a stirring reaction for 2 hours.
In a certain scheme, the preparation method further comprises the separation of a reaction product, and the separation can be acidification, extraction, washing, drying and column chromatography in sequence.
In one embodiment, the acidification may be acidification with trifluoroacetic acid. Acidification with 1% trifluoroacetic acid is preferred.
In one embodiment, the extraction may be ethyl acetate extraction. An equal volume of ethyl acetate extraction is preferred.
In one embodiment, the washing may be a sodium bicarbonate solution washing. An equal volume of sodium bicarbonate solution wash is preferred.
In one embodiment, the drying may be anhydrous sodium sulfate drying.
In one embodiment, the developing solvent used for column chromatography may be petroleum ether or ethyl acetate.
In one embodiment, the acidification may be acidification with 1% trifluoroacetic acid; the extraction can be equal volume of ethyl acetate for 3 times; the washing can be 2 times of washing with equal volume of sodium bicarbonate solution; the drying can be anhydrous sodium sulfate drying; the developing solvent used for column chromatography can be petroleum ether or ethyl acetate.
In one embodiment, the compound of formula I can be a compound of formula I-2:
the invention also provides a preparation method of the compound shown in the formula I-2, which comprises the following steps: (1) Reacting a compound represented by formula 1 with a compound represented by formula D in a solvent as shown below to obtain a compound represented by formula 2;
(2) Reacting a compound shown in a formula 2 with a compound shown in a formula C in a solvent as shown in the specification to obtain a compound shown in a formula 3;
(3) In a solvent, carrying out the following reaction on the compound shown in the formula 3 to obtain a compound shown in a formula 4-1;
(4) Carrying out amidation reaction of the compound shown in the formula 4-1 and the compound shown in the formula A in a solvent in the presence of an amidation reagent to obtain the compound shown in the formula I-2,
wherein the solvent is a solvent commonly used in such reactions in the art.
In a certain embodiment, in the step (1), the reaction may be performed under normal pressure; the reaction may be carried out in the presence of oxygen; the solvent may be methanol; the compound represented by formula D may be methanol; the reaction may be carried out in the presence of thionyl chloride; the reaction temperature may be 80 ℃; the reaction time may be 4 hours; the reaction may be quenched by the addition of water; the reaction may further comprise separation of the reaction product, which may be, in turn, adjustment of the pH of the reaction solution and filtration.
In a certain embodiment, in the step (1), the molar volume ratio of the compound represented by the formula 1 to the solvent may be 0.8mol/L; the molar volume ratio of the compound shown in the formula 1 to the compound shown in the formula D can be 0.8mol/L; the molar volume ratio of the compound shown in the formula 1 to the thionyl chloride can be 6.6mol/L; the pH of the reaction solution can be adjusted by sodium bicarbonate.
In a certain embodiment, in the step (2), the reaction may be performed under normal pressure; the reaction may be carried out under an inert atmosphere; the solvent may be 1, 4-dioxane; the compound shown in the formula 2 is the compound 2-1; the compound shown in the formula C can be pinacol borane; the reaction may be carried out in the presence of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and potassium acetate; the reaction temperature may be 80 ℃; the reaction time may be 12 hours; the reaction can also comprise the separation and purification of reaction products, and the separation and purification can be sequentially reaction liquid filtering, dilution, extraction, washing, drying, concentration and purification.
In a certain embodiment, in the step (2), the molar volume ratio of the compound represented by the formula 2 to the solvent may be 0.35mol/L; the molar ratio of the compound represented by formula 2 to the compound represented by formula C may be 0.67; the molar ratio of the compound represented by formula 2 to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride can be 20; the molar ratio of the compound shown in the formula 2 to potassium acetate can be 0.5; the extraction in the separation and purification is ethyl acetate extraction; the purification in the separation and purification is column chromatography purification.
In a certain embodiment, in the step (2), in the column chromatography purification in the separation and purification, the developing solvent is petroleum ether and ethyl acetate.
In a certain embodiment, in the step (3), the reaction may be performed under normal pressure; the reaction may be carried out in the presence of oxygen; the solvent may be 1, 4-dioxane; the compound shown in the formula 3 is the compound 3-1; the reaction may be carried out in the presence of hydrochloric acid; the reaction temperature may be 85 ℃; the reaction time may be 12 hours; the reaction can also comprise separation and purification of reaction products, and the separation and purification can be sequentially condensation of reaction liquid, pulping and filtration.
In a certain embodiment, in the step (3), the molar volume ratio of the compound represented by the formula 3 to the solvent may be 0.42mol/L; the concentration of the hydrochloric acid is 6mol/L; the molar volume ratio of the compound shown in the formula 3 to the hydrochloric acid can be 0.3mol/L; the pulping in the separation and purification is pulping by using petroleum ether and ethyl acetate.
In a certain embodiment, the reaction conditions in step (4) can refer to the reaction conditions in the preparation method of the compound represented by formula I.
The invention also provides a pharmaceutical composition, which comprises the substance X and pharmaceutic adjuvants; the substance X is the compound shown in the formula I or pharmaceutically acceptable salt thereof.
The invention also provides the application of the substance X in preparing the medicament; the substance X is the compound shown in the formula I or pharmaceutically acceptable salt thereof; the medicine is used for treating tumors.
In a certain scheme, the medicine for treating the tumor is a radiotherapy targeted medicine.
In a certain scheme, the radiotherapy targeted drug is a boron neutron capture therapy drug.
Unless otherwise defined, the terms used in the present invention have the following meanings:
the term "alkyl" refers to a group having the indicated number of carbon atoms (e.g., C) 1 ～C 4 ) Linear or branched alkyl. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and the like.
The term "alkylene" refers to a group having the indicated number of carbon atoms (e.g., C) 1 ～C 4 ) A divalent alkyl group that is linked to other groups through two sites. Alkylene groups include, but are not limited to
And the like.
The term "cycloalkyl" refers to a group having the indicated number of carbon atoms (e.g., C) 5 ～C 8 ) A saturated monocyclic cyclic group consisting of only carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "aryl" refers to a group having the indicated number of carbon atoms (e.g., C) 6 ～C 10 ) Is a monocyclic or polycyclic ring radical consisting only of carbon atoms, andeach ring has aromaticity (according to the houcker rule). Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
The term "arylene" refers to a compound having the indicated number of carbon atoms (e.g., C) 6 ～C 10 ) A divalent cyclic group consisting of only carbon atoms, linked to other groups through two sites, which is monocyclic or polycyclic, and each ring has aromaticity (according to the houckel rule). Arylene includes, but is not limited to
And the like.
The term "pharmaceutically acceptable salt" refers to a salt of a compound obtained by reaction with a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base. When compounds contain relatively acidic functional groups, 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, potassium, calcium, aluminum, magnesium, bismuth, ammonium, and the like. When compounds contain relatively basic functional groups, 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, hydrochloride, sulfate, mesylate, and the like. See in particular the Handbook of Pharmaceutical Salts: properties, selection, and use (P.Heinrich Stahl, 2002).
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the compound has low toxicity to tumor cells, and can be combined with boron neutron capture therapy for targeted cancer treatment.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
A549 cells, hepG2 cells, U87MG cells, SCC9 cells, and A375 cells in the following examples were all derived from cell banks of the national academy of sciences of Shanghai;
the following examples
The manufacturer of the CCK-8 cell viability detection kit is Shanghai east atlantoan Biotech limited;
the manufacturer of PBS was shanghai bis 27955;
the manufacturer of DMEM high-glucose medium is shanghai eastern atlantoan biotechnology limited.
EXAMPLE 1 preparation of Compound I-1 of the present invention
1. Preparation of Compound I-1
The preparation route of I-1 is shown as follows:
the first step is as follows: compound 1 (50g, 198mmol) was dissolved in methanol (250 ml), thionyl chloride (30 ml) was slowly added thereto at room temperature, and the reaction solution was reacted at 80 ℃ for 4 hours. The reaction was quenched with water (50 ml), adjusted to pH 7 with sodium bicarbonate solution, filtered and the solid collected. The white compound 2-1 was obtained in 93% yield.
The identification data for compound 2-1 are as follows: LC-MS M (C) 11 H 8 BrNO 2 )＝266.09(m/z), [M+H] + 267.2
The second step is that: compound 2-1 (12.0 g,45.1 mmol), pinacol diboron ester (BDP) (17.2 g, 67.6 mmol) were dissolved in 1, 4-dioxane (130 ml), and then [1,1' -Bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl 2 ) (1.65g, 2.25mmol), potassium acetate (8.85g, 90.2mmol). The reaction solution was reacted at 80 ℃ for 12 hours under nitrogen protection. The reaction mixture was collected by filtration, diluted with water (50 ml), and extracted twice with ethyl acetate (100 ml/time). The organic phases were combined, washed twice with saturated brine (30 ml/time), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (developing solvent: petroleum ether, ethyl acetate). Product 3-1 was obtained as a yellow solid in 92% yield.
The identification data for compound 3-1 are as follows: LC-MS M (C) 17 H 20 BNO 4 )＝313.16(m/z), [M+H] + 314.1
The third step: compound 3-1 (13.0g, 41.5mmol) was dissolved in 1, 4-dioxane (100 ml), and hydrochloric acid (6 mol/L,138 ml) was slowly added. The reaction mixture was stirred at 85 ℃ for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was slurried with ethyl acetate/petroleum ether (1, 50ml) at room temperature for 30 minutes and filtered to give a yellow compound 4 in a yield of 95%.
The identification data for compound 4-1 are as follows: LC-MS M (C) 10 H 8 BNO 4 )＝216.99(m/z), [M+H] + 218
The fourth step: compound 4-1 (8g, 31.5mmol), compound a (20 g) were dissolved in acetonitrile (300 ml), and N, N, N ', N' -tetramethylchloroformamidinium hexafluorophosphate (TCFH) (13.3g, 47.3mmol), 1-methylimidazole (20 ml) were slowly added. The reaction mixture was stirred at 35 ℃ for 2 hours. The pH of the reaction solution was adjusted to 5 with 1% trifluoroacetic acid, and the reaction solution was extracted three times with ethyl acetate (500 ml/time). The organic phases were combined, washed twice with sodium bicarbonate solution (200 ml/time), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (developing solvent: petroleum ether, ethyl acetate). Product I-1 was obtained as an off-white solid in 48% yield.
2. Structural identification
The LC-MS, NMR identification data for Compound I-1 are as follows:
LC-MS:M(C 17 H 15 BF 2 N 4 O 4 )＝388.14(m/z),[M+H] + 389.2。
1 H NMR:(400MHz,DMSO-d 6 )：δ9.09-9.06(m,1H),9.01(s,1H),8.64(s, 1H),8.28-8.27(m,2H),8.04(d,J＝7.2Hz,1H),8.01(d,J＝7.2Hz,1H),7.57(s, 1H),5.18(d,J＝9.6Hz,1H),4.36-4.16(m,4H),2.94-2.82(m,2H)。
F NMR:(400MHz,DMSO-d 6 )：δ-95.153,-103.648。
example 2: cytotoxicity of Compound I-1 on A549 cells
A549 cells in logarithmic growth phase were seeded onto 96-well plates at 1 × 10 per well 4 The cells were cultured overnight in DMEM high-sugar medium, the medium was aspirated, and the cells were washed 2 times with PBS (0.01 mol/L). Compound I-1 was added to fresh medium to prepare a series of concentration gradients of compound I-1 in solutions with concentrations of compound I-1 of 0, 100, 250, 500, 750. Mu.g/ml, respectively. Adding 100 mu L of the solution into a cell pore plate to be detected, sucking away a cell culture medium by using a pipette after the cells are treated by the drug for 48 hours, washing the cells for 2 times by using PBS (0.01 mol/L), adding 100uL of CCK8 working solution, and incubating the culture plate in an incubator for 2 hours; the absorbance at 450nm was measured with a microplate reader, and the effect of the drug on cell viability was calculated.
The test results are shown in table 1. The low cytotoxicity of the compound I-1 is an important index of BNCT, and can ensure that the boron concentration in tumor cells is maximized. The compound I-1 of the invention has lower toxicity to tumor cells and IC for A549 cells 50 320.2 mu g/ml, and meets the requirement of boron neutron capture treatment on low toxicity of boron-containing medicaments.
TABLE 1 inhibition of A549 cells by different concentrations of the compound
| Compound I-1 concentration (. Mu.g/ml) | Inhibition rate to A549 cells |
| 0 | 0.00％ |
| 100 | 30.78％ |
| 250 | 45.19％ |
| 500 | 70.73％ |
| 750 | 77.29％ |
Example 3: cytotoxicity of Compound I-1 on HepG2 cells
HepG2 cells in logarithmic growth phase were seeded on 96-well plates at 1 x 10 per well 4 The cells were cultured overnight in DMEM high-sugar medium, the medium was aspirated, and the cells were washed 2 times with PBS (0.01 mol/L). A series of concentration gradients of compound I-1-containing solutions were prepared by adding compound I-1 to fresh medium at concentrations of 0, 100, 250, 500, 750. Mu.g/ml for compound I-1. Adding 100 mu L of the solution into a cell pore plate to be detected, sucking away a cell culture medium by using a pipette after the cells are treated by the drug for 48 hours, washing the cells for 2 times by using PBS (0.01 mol/L), adding 100uL of CCK8 working solution, and incubating the culture plate in an incubator for 2 hours; the absorbance at 450nm was measured with a microplate reader, and the effect of the drug on cell viability was calculated.
The test results are shown in table 2. The low cytotoxicity of the compound I-1 is an important index of BNCT, and can ensure that the boron concentration in tumor cells is maximized. The compound I-1 of the invention has lower toxicity to tumor cells and IC for HepG2 cells 50 Is 421.4 mu g/ml, and meets the requirement of boron neutron capture treatment on low toxicity of boron-containing medicaments.
TABLE 2 inhibition of HepG2 cells by different concentrations of the compound
| Concentration of Compound I-1 (. Mu.g/ml) | Inhibition rate on HepG2 cells |
| 0 | 0.00％ |
| 100 | 15.50％ |
| 250 | 22.14％ |
| 500 | 56.64％ |
| 750 | 71.86％ |
Example 4: cytotoxicity of Compound I-1 on U87MG cells
U87MG cells in logarithmic growth phase were seeded onto 96-well plates at 1 × 10 per well 4 The individual cells were cultured overnight in DMEM high-sugar medium, the medium was aspirated off, and the cells were washed 2 times with PBS (0.01 mol/L). Compound I-1 was added to fresh medium to prepare a series of concentration gradients of compound I-1 in solutions with concentrations of compound I-1 of 0, 100, 250, 500, 750. Mu.g/ml, respectively. Adding 100 mu L of the solution into a cell pore plate to be detected, sucking away a cell culture medium by using a pipette after the cells are treated by the drug for 48 hours, cleaning the cells for 2 times by using PBS (0.01 mol/L), adding 100uL of CCK8 working solution, and incubating the culture plate in an incubator for 2 hours; measured at 450nm with microplate readerAnd calculating the influence of the drug on the cell viability.
The test results are shown in table 3. The low cytotoxicity of the compound I-1 is an important index of BNCT, and can ensure that the boron concentration in tumor cells is maximized. The compound I-1 of the invention has lower toxicity to tumor cells and IC for U87MG cells 50 273.9 mu g/ml, and meets the requirement of boron neutron capture treatment on low toxicity of boron-containing medicaments.
TABLE 3 inhibition of U87MG cells by different concentrations of the compound
| Concentration of Compound I-1 (. Mu.g/ml) | Inhibition rate on U87MG cells |
| 0 | 0.00％ |
| 100 | 20.53％ |
| 250 | 43.50％ |
| 500 | 62.43％ |
| 750 | 71.63％ |
Example 5: cytotoxicity of Compound I-1 on SCC9 cells
SCC9 cells in logarithmic growth phase were seeded in 96-well plates at 1 × 10 per well 4 Individual cellDMEM high-sugar medium was incubated overnight, the medium was aspirated off, and the cells were washed 2 times with PBS (0.01 mol/L). A series of concentration gradients of solutions containing compound I-1 were prepared by adding compound I-1 to fresh medium at concentrations of 0, 100, 250, 500, 750. Mu.g/ml for compound I-1. Adding 100 mu L of the solution into a cell pore plate to be detected, sucking away a cell culture medium by using a pipette after the cells are treated by the drug for 48 hours, washing the cells for 2 times by using PBS (0.01 mol/L), adding 100uL of CCK8 working solution, and incubating the culture plate in an incubator for 2 hours; the absorbance at 450nm was measured with a microplate reader, and the effect of the drug on the cell viability was calculated.
The test results are shown in table 4. The low cytotoxicity of the compound I-1 is an important index of BNCT, and can ensure that the boron concentration in tumor cells is maximized. The compound I-1 of the invention has lower toxicity to tumor cells and IC for SCC9 cells 50 187.8 mu g/ml, and meets the requirement of boron neutron capture treatment on low toxicity of boron-containing medicaments.
TABLE 4 inhibition of SCC9 cells by compounds at different concentrations
Example 6: cytotoxicity of Compound I-1 on A375 cells
A375 cells in logarithmic growth phase were seeded onto 96-well plates at 1 × 10 per well 4 The cells were cultured overnight in DMEM high-sugar medium, the medium was aspirated, and the cells were washed 2 times with PBS (0.01 mol/L). A series of concentration gradients of solutions containing compound I-1 were prepared by adding compound I-1 to fresh medium at concentrations of 0, 100, 250, 500, 750. Mu.g/ml for compound I-1. Adding 100 μ L into cell well plate to be tested, sucking cell culture medium with pipette after treating cell for 48 hr, washing cell with PBS (0.01 mol/L) for 2 times, adding CCK8 working solution 100uL, and culturingIncubating the culture plate in an incubator for 2 hours; the absorbance at 450nm was measured with a microplate reader, and the effect of the drug on cell viability was calculated.
The test results are shown in table 5. The low cytotoxicity of the compound I-1 is an important index of BNCT, and can ensure that the boron concentration in tumor cells is maximized. The compound I-1 of the invention has lower toxicity to tumor cells and IC for A375 cells 50 Is 688.5 mu g/ml, and meets the requirement of boron neutron capture treatment on low toxicity of boron-containing medicaments.
TABLE 5 inhibition of A375 cells by various concentrations of the compound
| Concentration of Compound I-1 (. Mu.g/ml) | Inhibition rate on A375 cells |
| 0 | 0 |
| 100 | 23.49％ |
| 250 | 34.18％ |
| 500 | 41.81％ |
| 750 | 56.76％ |
Claims (13)
1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein:
wherein R is 1 Is a single bond, C 1 ～C 10 Straight chain alkylene group, C 2 ～C 10 Branched alkylene group, C 5 ～C 8 Cycloalkylene radical, C 6 ～C 10 Arylene radical-C 1 ～C 4 Alkylene radical, C 1 ～C 4 alkylene-C 6 ～C 10 Arylene radical-C 1 ～C 4 An alkylene group,
Or C 6 ～C 10 An arylene group;
R 2 is hydroxy, C 1 ～C 5 Straight chain alkyl, C 3 ～C 6 Branched alkyl radical, C 5 ～C 8 Cycloalkyl radical, C 6 ～C 10 aryl-C 1 ～C 4 Alkyl radical, C 1 ～C 4 alkyl-C 6 ～C 10 aryl-C 1 ～C 4 Alkylene, or a mixture thereof,
Or C 6 ～C 10 An aryl group;
R 3 is hydroxy, C 1 ～C 5 Straight chain alkyl, C 3 ～C 6 Branched alkyl radical, C 5 ～C 8 Cycloalkyl, C 6 ～C 10 aryl-C 1 ～C 4 Alkyl radical, C 1 ～C 4 alkyl-C 6 ～C 10 aryl-C 1 ～C 4 Alkylene, or a mixture thereof,
Or C 6 ～C 10 An aryl group;
R 4 h, F or Cl;
R 5 h, F or Cl;
n is said 1 、n 2 And n 3 Independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
2. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:
a) Said R 1 Is a single bond;
b) Said R 2 Is a hydroxyl group;
c) Said R 3 Is a hydroxyl group;
d) R is as described 4 Is F or Cl;
e) Said R 5 Is F or Cl.
3. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 2, wherein the compound of formula I is compound I-1:
4. a compound of formula 2, formula 3 or formula 4:
wherein R is 31 Is C 1 ～C 4 An alkyl group;
in the compound represented by the formula 3, R 32 Is C 1 ～C 3 An alkyl group; r 33 Is C 1 ～C 3 An alkyl group; r is 34 Is C 1 ～C 3 An alkyl group; r 35 Is C 1 ～C 3 An alkyl group;
R 1 、R 2 and R 3 As defined in claim 1-3 any of the above.
5. The compound of claim 4, wherein the compound satisfies one or more of the following conditions:
a) The compound shown in the formula 2 is a compound 2-1:
b) The compound represented by the formula 3 is a compound 3-1:
c) The compound represented by the formula 4 is a compound 4-1:
6. a process for the preparation of a compound of formula I as claimed in any one of claims 1 to 3, comprising the steps of: carrying out amidation reaction of the compound represented by formula 4 and the compound represented by formula a in a solvent in the presence of an amidation reagent to obtain the compound represented by formula I,
7. the method of claim 6, wherein the compound of formula I is prepared by a process that satisfies one or more of the following conditions:
a) The amidation reaction is carried out under normal pressure;
b) The amidation reaction is carried out in the presence of oxygen;
c) The amidation reagent is a combination of N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (TCFH) and 1-methylimidazole;
d) The solvent is acetonitrile;
e) The compound represented by the formula 4 is
f) The molar volume ratio of the compound shown in the formula 4 to the solvent is 0.105mol/L;
g) The reaction temperature is 35 ℃;
h) The reaction condition is stirring reaction for 2 hours;
i) The preparation method also comprises the separation of the reaction product, wherein the separation sequentially comprises acidification, extraction, washing, drying and column chromatography.
8. The method of claim 7, wherein the compound of formula I is prepared by a process that satisfies one or more of the following conditions:
a) The molar ratio of the compound represented by the formula 4 to N, N' -tetramethylformamidine hexafluorophosphate (TCFH) in the amidation reagent is 0.666;
b) The molar volume ratio of the compound shown in the formula 4 to the 1-methylimidazole in the amidation reagent is 1.575mol/L;
c) The acidification is acidification by trifluoroacetic acid;
d) The extraction is ethyl acetate extraction;
e) The washing is sodium bicarbonate solution washing;
f) The drying is anhydrous sodium sulfate drying;
g) The developing solvent used for column chromatography is petroleum ether and ethyl acetate.
9. The process according to claim 8 for the preparation of a compound of formula I, wherein the process for the preparation of a compound of formula I satisfies one or more of the following conditions:
a) The acidification is acidification by using 1% trifluoroacetic acid;
b) The extraction is equal-volume ethyl acetate extraction;
c) The washing is equal volume of sodium bicarbonate solution.
10. A pharmaceutical composition comprising a substance X and a pharmaceutical excipient, wherein the substance X is a compound of formula I as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
11. Use of a substance X for the manufacture of a medicament, wherein said substance X is a compound of formula I as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof; the medicine is used for treating tumors.
12. Use of substance X according to claim 11 for the preparation of a medicament for the treatment of tumors, wherein said medicament is a radiotherapeutic targeting medicament.
13. Use of substance X according to claim 12 for the preparation of a medicament, wherein the radiotherapy targeted drug is a boron neutron capture therapy drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210923557.7A CN115353527A (en) | 2022-08-02 | 2022-08-02 | Boron-containing compound and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210923557.7A CN115353527A (en) | 2022-08-02 | 2022-08-02 | Boron-containing compound and application thereof |
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| Publication Number | Publication Date |
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| CN115353527A true CN115353527A (en) | 2022-11-18 |
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| CN202210923557.7A Pending CN115353527A (en) | 2022-08-02 | 2022-08-02 | Boron-containing compound and application thereof |
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