CN115536608B - Oxazine compound and preparation method and application thereof - Google Patents
Oxazine compound and preparation method and application thereof Download PDFInfo
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- CN115536608B CN115536608B CN202211109688.8A CN202211109688A CN115536608B CN 115536608 B CN115536608 B CN 115536608B CN 202211109688 A CN202211109688 A CN 202211109688A CN 115536608 B CN115536608 B CN 115536608B
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- -1 Oxazine compound Chemical class 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052740 iodine Chemical group 0.000 claims description 5
- 239000011630 iodine Chemical group 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical group C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 125000004266 aziridin-1-yl group Chemical group [H]C1([H])N(*)C1([H])[H] 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 150000004893 oxazines Chemical class 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000005286 illumination Methods 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 244000052616 bacterial pathogen Species 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 241000894006 Bacteria Species 0.000 description 15
- 230000001580 bacterial effect Effects 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 8
- 239000007853 buffer solution Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- 229910052711 selenium Inorganic materials 0.000 description 5
- 239000011669 selenium Chemical group 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 229910052714 tellurium Chemical group 0.000 description 5
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical group [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000007747 plating Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- OLNMJIHADFYHAK-UHFFFAOYSA-N n,n-diethyl-4-nitrosoaniline Chemical compound CCN(CC)C1=CC=C(N=O)C=C1 OLNMJIHADFYHAK-UHFFFAOYSA-N 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000012221 photothermal agent Substances 0.000 description 2
- 238000007626 photothermal therapy Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003748 selenium group Chemical group *[Se]* 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 239000003575 carbonaceous material Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/36—[b, e]-condensed, at least one with a further condensed benzene ring
-
- 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
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems
Abstract
The invention relates to the field of photo-thermal reagents, in particular to an oxazine compound, a preparation method and application thereof. The oxazine compound provided by the invention has a structure shown as a formula (1). The oxazine compound provided by the invention has high molar absorptivity in a near infrared region, high photo-thermal conversion efficiency and excellent photo-thermal stability, and the oxazine compound has high photo-thermal conversion efficiency under near infrared illumination, and the generated heat can efficiently kill pathogenic bacteria or tumor cells.
Description
Technical Field
The invention relates to the field of photo-thermal reagents, in particular to an oxazine compound, a preparation method and application thereof.
Background
Photothermal therapy is a method of killing pathogens or tumor cells by converting light energy into heat energy through a photothermal agent, and has been attracting attention because of its non-invasiveness and good controllability. Compared with photodynamic therapy, photothermal therapy plays a therapeutic role by generating heat, is not limited by the anaerobic condition of the diseased micro-environment tissue, and therefore has better development prospect. Near infrared light (650-900 nm), on the other hand, has little tissue absorption and thus good penetration depth. In addition, near-infrared light has low phototoxicity to normal tissues, so development of photothermal agents with near-infrared light excitation is a research hotspot in recent years.
Inorganic nanomaterials typified by gold nanomaterials and carbon materials typified by carbon nanotubes are photothermal conversion materials which are currently being widely studied, but such materials are expensive to prepare, and are difficult to degrade in vivo and have an undefined toxicity to the human body, so that clinical conversion is difficult to be performed and large-scale application is difficult. The organic micromolecular photo-thermal reagent has the characteristics of clear structure and easy degradation and elimination in vivo, and has been approved for clinical application. For example, porphyrin compounds and indocyanine green-light thermal reagents, but the porphyrin compounds have the defects of weak near infrared absorption, low light-heat conversion efficiency and poor light stability of indocyanine green.
Disclosure of Invention
Therefore, the invention aims to solve the technical problems of low photo-thermal conversion efficiency and poor photo-stability of the existing organic photo-thermal reagent, thereby providing an oxazine compound and a preparation method and application thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
an oxazine compound having a structure represented by formula (1):
wherein n has a value of 0 or 1;
r1 is selected from C1-C5 alkyl substituted amino, C3-C6 nitrogen-containing heterocycle;
r2 is selected from halogen, m represents R 2 Number, selection ofAn integer from 1 to 6, for example 1,2,3,4, 5 or 6;
r3 is selected from optionally substituted alkyl or optionally substituted aryl;
x is selected from sulfur, selenium and tellurium.
Preferably, R 3 Selected from substituted or unsubstituted alkyl groups selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;
the number of the substituent groups in the substituted alkyl is 1-3, and the substituent groups are independently selected from phenyl, 4-hydroxymethyl phenyl, 4-carboxyphenyl, 3-sulfopropyl and 3-aminopropyl.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, and the kind and number of substituents may be arbitrary on the basis of realization unless otherwise specified.
In the present invention, the alkyl group may be a linear alkyl group or a branched alkyl group. Meanwhile, the alkyl group may be an unsubstituted alkyl group or a substituted alkyl group.
In the present invention, "unsubstituted alkyl" refers to an alkyl group that does not contain a heteroatom, including, but not limited to, the following examples: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. "unsubstituted alkyl" also includes branched isomers of straight chain alkyl groups, including, but not limited to, the following examples: -CH (CH) 3 ) 2 、-CH(CH 3 )(CH 2 CH 3 )、-CH(CH 2 CH 3 ) 2 、-C(CH3) 3 、-C(CH 2 CH 3 ) 3 、-CH 2 CH(CH 3 ) 2 or-CH 2 CH(CH 3 )(CH 2 CH 3 ) Etc.
"substituted alkyl" may be alkyl substituted with substituents including, but not limited to:
in the present invention, the aryl group may be an unsubstituted aryl group or a substituted aryl group.
"unsubstituted aryl" refers to an aryl group that does not contain heteroatoms, including, but not limited to: such as phenyl, biphenyl, or anthracenyl, and the like.
Preferably, the structure is as shown in formula (2):
wherein R1 is selected from C1-C5 alkyl substituted amino, C3-C6 nitrogen-containing heterocycle;
r2 is selected from halogen;
r3 is selected from optionally substituted alkyl or optionally substituted aryl;
x is selected from sulfur, selenium and tellurium.
Preferably, R1 is selected from the group consisting of azodimethylamino, azodiethylamino, aziridin-1-yl, azetidin-1-yl, pyrrol-1-yl, piperidin-1-yl;
r2 is selected from chlorine, bromine and iodine.
Preferably, R1 is selected from azomethine amino, azomethine amino;
r2 is selected from chlorine, bromine and iodine;
R 3 selected from the group consisting of
X is selected from sulfur.
Preferably, the oxazine compound has the following structure:
the oxazine compound provided by the invention has high molar absorptivity in a near infrared region, high photo-thermal conversion efficiency and excellent photo-thermal stability.
The invention also provides a preparation method of the oxazine compound, when X is selected from sulfur, the preparation method comprises the following steps:
dissolving a compound shown in a formula (3) and a compound shown in a formula (4) in a solvent, heating the obtained solution to reflux, adding a catalyst, and continuing the reflux reaction to obtain the oxazine compound;
when X is selected from selenium or tellurium, comprising the steps of:
dissolving a compound shown in a formula (3) and a compound shown in a formula (5) in a solvent, adding a catalyst, and heating and refluxing to react to obtain the oxazine compound;
wherein the compound of formula (3) has the following structure:
the compound represented by formula (4) has the following structure:
the compound represented by formula (5) has the following structure:
wherein n, m, R1, R2 and R3 are as defined above.
The oxazine compound with X being sulfur can be prepared by the method, and an exemplary reaction scheme is as follows:
the oxazine compound with X being selenium or tellurium can be prepared by the method, and an exemplary reaction flow is as follows:
preferably, when X is selected from sulfur, the solvent is methanol;
the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (4) is (2-2.01): 1, preferably 2:1;
the catalyst is silver carbonate, and the molar amount of the catalyst is 9-35% of the molar total amount of the compound shown in the formula (3) and the compound shown in the formula (4);
reflux reaction is continued for 1 to 1.5 hours;
preferably, the method further comprises the steps of filtering and purifying after the reflux reaction is finished. Preferably, the purification method is column chromatography, the solvent used in the column chromatography is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 10:1.
Preferably, when X is selected from selenium or tellurium, the solvent is ethanol;
the molar ratio of the compound shown in the formula (3) to the compound shown in the formula (5) is 1 (3-3.05), preferably 1:3;
the catalyst is hydrochloric acid or acetic acid, and the molar amount of the catalyst is 0.2-12% of the molar total amount of the compound shown in the formula (3) and the compound shown in the formula (5);
heating and refluxing for 1-3 hours;
preferably, the method further comprises the steps of filtering and purifying after the reflux reaction is finished. Preferably, the purification method is column chromatography, the solvent used in the column chromatography is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 5:1.
The invention also provides application of the oxazine compound in preparation of an antibacterial or antitumor photothermal therapeutic agent.
The invention also provides application of the oxazine compound in bacterial infection sites or tumor imaging.
The beneficial effects are that:
the oxazine compound provided by the invention has a general structure shown in a formula (1), and has a high molar light absorption coefficient in a near infrared region and high photo-thermal conversion efficiency and excellent photo-thermal stability by being matched with substituent groups R1-R3 through a main ring structure.
Meanwhile, under near infrared illumination, the oxazine compound provided by the invention has high photo-thermal conversion efficiency, and the generated heat can kill pathogenic bacteria or tumor cells efficiently. In addition, under near infrared illumination, fluorescence can also image pathogen infection sites or tumor tissues, so that a diagnosis and treatment integrated system is constructed.
Further, when R1 is selected from nitrogen-nitrogen dimethylamino and nitrogen-nitrogen diethylamino; r2 is selected from chlorine, bromine and iodine; r is R 3 Selected from the group consisting ofWhen X is selected from sulfur, the oxazine compound has more excellent photo-thermal conversion efficiency and photo-thermal stability.
Furthermore, the preparation method of the oxazine compound provided by the invention selects proper raw materials, and synthesizes the oxazine compound through one-step reaction, so that the process is simple and feasible.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is an absorption spectrum of MtNBS in methanol and water in example 1 of the present invention;
FIG. 2 is a fluorescence emission spectrum of MtNBS in methanol in example 1 of the present invention;
FIG. 3 is a graph showing the temperature of the MtNBS solution according to the invention in example 1 with respect to time of illumination;
FIG. 4 is a graph showing the temperature rise and natural cooling of an aqueous MtNBS solution under laser irradiation in example 1 of the present invention;
FIG. 5 shows the photo-thermal efficiency of the aqueous MtNBS solution in example 1 of the present invention;
FIG. 6 is a graph showing the temperature change of MtNBS under repeated irradiation of external laser light in example 1 of the present invention;
FIG. 7 shows the photo-thermal inhibition of Pseudomonas aeruginosa by MtNBS in example 1 of the present invention;
FIG. 8 shows the photo-thermal inhibition of E.coli by MtNBS in example 1 of the present invention;
FIG. 9 shows the photo-thermal inhibition of Staphylococcus aureus by MtNBS in example 1 of the present invention;
FIG. 10 shows the photo-thermal inhibition of methicillin-resistant Staphylococcus aureus by MtNBS in example 1 of the present invention.
Detailed Description
The invention provides an oxazine compound with high-efficiency photo-thermal conversion efficiency in a near infrared region, a preparation method and application thereof in antibacterial and antitumor aspects, and the invention is further described in detail below for making the purposes, technical schemes and effects of the invention clearer and more definite. It should be understood that the examples described herein are for illustrative purposes only and are not intended to limit the present invention.
Example 1
This example provides a method for preparing oxazine compound 4- (((1, 2,3, 4-tetrachloro-9- (dimethylamino) -5H-benzothiazin-5-ylidene) amino) methyl) benzyl alcohol (MtNBS, compound of formula C below) comprising the steps of:
20 mmol of 4- (((5, 6,7, 8-tetrachloronaphthalen-1-yl) amino) methyl) benzyl alcohol (formula (5)) [ formula A ] and 10 mmol of dimethyl amino substituted bunte (formula (B)) are added into a reactor, 30 ml of methanol is added for dissolution, heating reflux is carried out, then 3 mmol of silver carbonate is added, reflux reaction is continued for 1 hour, insoluble matters are filtered and the filtrate is collected for column chromatography (the solvent used by the column chromatography is dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 10:1), and the pure 4- (((1, 2,3, 4-tetrachloro-9- (dimethylamino) -5H-benzothiazine-5-subunit) amino) methyl) benzyl alcohol is obtained by purification, and the structural formula is shown as formula (C).
Example 2
The present example provides a method for preparing oxazine compound 4- (((1, 2,3, 4-tetrabromo-9- (diethylamino) -5H-benzophenoselenoxazin-5-ylidene) amino) methyl) benzoic acid (EtNBSe), comprising the steps of:
10 mmol of 3,3' -diselenediylbis (N, N-diethyl-4-nitrosoaniline) (formula (6)) and 30 mmol of 4- (((5, 6,7, 8-tetrabromonaphthalen-1-yl) amino) methyl) benzoic acid (formula (7)) are added into a reactor, 30 ml of ethanol is added for dissolution, then 0.1 mmol of hydrochloric acid is added, the reaction system is heated and refluxed for 2 hours, the filtrate obtained by suction filtration is subjected to column chromatography (the solvent used by the column chromatography is dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 5:1), and the pure 4- (((1, 2,3, 4-tetrabromo-9- (diethylamino) -5H-benzophenoselenazin-5-subunit) amino) methyl) benzoic acid is obtained by purification, and the structural formula is as shown in formula (8):
example 3
The embodiment provides a preparation method of oxazine compound 7- (benzyl imino) -9, 10, 11, 12-tetrabromo-N, N-diethyl-7H-naphtho [2,3] phenoselenoxazin-3-amine (BTNSe), which comprises the following steps:
10 millimoles of 3,3' -diselenediylbis (N, N-diethyl-4-nitrosoaniline) and 30 millimoles of N-benzyl-5, 6,7, 8-tetrabromoanthracene-1-amine (formula (9)) are added into a reactor, 30 milliliters of ethanol is added for dissolution, then 0.1 millimoles of acetic acid is added, heating reflux reaction is carried out for 2 hours, the filtrate obtained by suction filtration of the reaction system is subjected to column chromatography (the solvent used by the column chromatography is dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 5:1), and the pure 7- (benzyl imino) -9, 10, 11, 12-tetrabromo-N, N-diethyl-7H-naphtho [2,3] phenoselenoxazin-3-amine is purified by the following structural formula (10):
example 4
This example provides a process for the preparation of oxazine compounds 1,1' - ((((((5- (((3- (aziridin-1-yl) -8, 13-dibromo-9, 10, 11, 12-tetraiodo-7H-naphtho [2,3] phenoselenazin-7-ylidene) amino) methyl) -2- (2- (2- (2-guanidinoethoxy) ethoxy) -1, 3-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) biguanidino (ABIG), comprising the steps of:
20 mmole of 1,1'- ((((((5- (((9, 10-dibromo-5, 6,7, 8-tetraiodoanthracene-1-yl) amino) methyl) -2- (2- (2- (2-guanidinoethoxy) ethoxy) -1, 3-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) diguanidino (formula (11)) and 10 mmole of aziridin-1-yl substituted bunte (formula (12)) are added to a reactor, 30 ml of methanol are added for dissolution, reflux is heated, then 3 mmole of silver carbonate is added, reflux reaction is continued for 1 hour, insoluble matter is removed by filtration, column chromatography is carried out on the filtrate, the volume ratio of the solvent used for column chromatography is 10:1 of dichloromethane and methanol, and purification is carried out to obtain pure 1,1' ((((((5- (((3-1-bromo-1-8, 10-naphthyridine-1-yl) and 10- (-7-bromo-1-yl) is obtained, 3] phenoselenazin-7-ylidene) amino) methyl) -2- (2- (2- (2-guanidinoethoxy) ethoxy) -1, 3-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) biguanidino having the structural formula shown in formula (13):
example 5
The absorption spectrum of the oxazine compound MtNBS prepared in example 1 is tested, and the test result is shown in fig. 1, wherein 10 millimoles per liter of MtNBS dimethyl sulfoxide mother liquor is firstly prepared, then 30 millimoles per liter of MtNBS methanol solution is obtained by dilution with methanol, and an absorption curve is obtained by scanning in the range of 400-800 nanometers, and the maximum absorption peak is located at 660 nanometers. An aqueous solution of MtNBS was prepared at a concentration of 30 mol/liter, and the absorption spectrum was measured under the same conditions, and the absorption intensity was lower and the absorption peak was broader than that in methanol.
The fluorescence emission spectrum of the oxazine compound MtNBS prepared in example 1 is tested, and the test result is shown in fig. 2, wherein 10 millimoles per liter of mother liquor of MtNBS is prepared first, then 10 millimoles per liter of methanol solution of MtNBS is obtained by dilution with methanol, 660 nm light excitation is used, and the emission spectrum of MtNBS is obtained, and the maximum emission peak is 690 nm.
Example 6
The photo-thermal performance of the oxazine compound MtNBS prepared in example 1 was tested, and the test result is shown in fig. 3, in which 10 millimoles per liter of mother liquor of MtNBS was prepared, diluted with water to obtain 30 millimoles per liter of aqueous solution of MtNBS, pure water was used as a reference, irradiation was performed with 660 nm laser, the laser power was set to 1 watt per square centimeter, the rise in the temperature of the solution was recorded, the rise in the temperature of the pure water of the reference was not significant, and the temperature of the sample solution was rapidly raised to 60 degrees celsius or higher in 180 seconds of irradiation time.
As shown in fig. 4, the laser irradiation was turned off after 180 seconds, and the change in temperature with time during natural cooling was recorded. As shown in fig. 5, the photothermal conversion efficiency of MtNBS was calculated as high as 89% by the cooling curve data processing.
As shown in fig. 6, mtNBS has good photo-thermal stability, and still maintains high photo-thermal conversion efficiency at least in five repeated heating and cooling cycles.
Example 7
Photo-thermal sterilization test for oxazine compound MtNBS prepared in example 1
As shown in FIG. 7, pseudomonas aeruginosa was cultured in broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with a buffer solution, the bacteria were diluted to a buffer solution so that the concentration of the bacteria was about 107 bacteria groups per ml, mtNBS was added so that the concentration was 30. Mu. Mol per liter, cultured for 1 hour, and then irradiated with 660 nm laser for 180 seconds, setting the laser power to 1W per square centimeter. Meanwhile, a control group (blank control) was set as described above, and the control group was different from the above method in that MtNBS was not added. After completion of irradiation, the plating was diluted with a control group to which MtNBS was not added and an experimental group to which MtNBS was added (with sample light), and bacterial growth was observed after 24 hours, and the bacterial survival rate of the experimental group to which MtNBS was added was almost 0, whereas the control group showed many bacteria.
As shown in FIG. 8, E.coli was cultured in a broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with a buffer solution, the bacteria were diluted to a buffer solution so that the concentration of the bacteria was about 107 bacteria group per ml, mtNBS was added so that the concentration thereof was 30. Mu. Mol per liter, cultured for 1 hour, and then irradiated with 660 nm laser for 180 seconds, and the laser power was set at 1W per square centimeter. Meanwhile, a control group (blank control) was set as described above, and the control group was different from the above method in that MtNBS was not added. After completion of irradiation, the plating was diluted with a control group to which MtNBS was not added and an experimental group to which MtNBS was added (with sample light), and bacterial growth was observed after 24 hours, and the bacterial survival rate of the experimental group to which MtNBS was added was almost 0, whereas the control group showed many bacteria.
As shown in FIG. 9, staphylococcus aureus was cultured in broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with a buffer solution, the bacteria were diluted to a buffer solution so that the concentration of the bacteria was about 107 bacteria groups per ml, mtNBS was added so that the concentration thereof was 30. Mu. Mol per liter, cultured for 1 hour, and then irradiated with 660 nm laser for 180 seconds, and the laser power was set at 1W per square centimeter. Meanwhile, a control group (blank control) was set as described above, and the control group was different from the above method in that MtNBS was not added. After completion of irradiation, the plating was diluted with a control group to which MtNBS was not added and an experimental group to which MtNBS was added (with sample light), and bacterial growth was observed after 24 hours, and the bacterial survival rate of the experimental group to which MtNBS was added was almost 0, whereas the control group showed many bacteria.
As shown in fig. 10, methicillin-resistant staphylococcus aureus was placed in broth for cultivation for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with a buffer solution, the bacteria were diluted into the buffer solution to a concentration of about 107 bacteria per ml, mtNBS was added to a concentration of 30 micromoles per liter for cultivation for 1 hour, and then irradiated with 660 nm laser for 180 seconds, setting the laser power to 1 watt per square centimeter. Meanwhile, a control group (blank control) was set as described above, and the control group was different from the above method in that MtNBS was not added. After completion of irradiation, the plating was diluted with a control group to which MtNBS was not added and an experimental group to which MtNBS was added (with sample light), and bacterial growth was observed after 24 hours, and the bacterial survival rate of the experimental group to which MtNBS was added was almost 0, whereas the control group showed many bacteria.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (7)
1. An oxazine compound having a structure represented by the following formula (2):
wherein R1 is selected from C1-C5 alkyl substituted amino;
r2 is selected from halogen;
r3 is selected from
X is selected from sulfur.
2. The oxazine compound according to claim 1, wherein R1 is selected from the group consisting of azodimethylamino, azodiethylamino, aziridin-1-yl, azetidin-1-yl, pyrrol-1-yl, piperidin-1-yl;
r2 is selected from chlorine, bromine and iodine.
3. The oxazine compound according to claim 2, wherein R1 is selected from the group consisting of azomethine amino, azomethine amino;
r2 is selected from chlorine, bromine and iodine.
4. An oxazine compound according to any one of claims 1 to 3, having the structure:
5. a process for the preparation of oxazines according to any one of claims 1 to 4, wherein when X is chosen from sulphur, comprising the steps of:
dissolving a compound shown in a formula (3) and a compound shown in a formula (4) in a solvent, heating the obtained solution to reflux, adding a catalyst, and continuing the reflux reaction to obtain the oxazine compound;
wherein the compound of formula (3) has the following structure:
the compound represented by formula (4) has the following structure:
wherein R1, R2, R3 are as defined in claim 1, n=0, m=4.
6. The method according to claim 5, wherein when X is selected from sulfur, the solvent is methanol;
the molar ratio of the compound shown in the formula (3) to the compound shown in the formula (4) is (2-2.01): 1;
the catalyst is silver carbonate, and the molar amount of the catalyst is 9-35% of the molar total amount of the compound shown in the formula (3) and the compound shown in the formula (4);
reflux reaction is continued for 1 to 1.5 hours;
and the method also comprises the steps of filtering and purifying after the reflux reaction is finished.
7. Use of an oxazine compound according to any one of claims 1 to 4 for the preparation of an antibacterial or antitumor photothermal therapeutic agent.
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| US4962197A (en) * | 1988-02-12 | 1990-10-09 | Rowland Institute For Science | Photo-inactivation of cancer cells |
| CN103360385A (en) * | 2012-04-06 | 2013-10-23 | 上海交通大学医学院附属第三人民医院 | Compound and medicament for treating MRSA (Methicillin-resistant Staphylococcus Aureus) infection |
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